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{"sheet":"MACE","index":0,"n_rows":523,"n_cols":6,"rows_kept":523,"merged":[[4,1,4,3],[5,0,8,0],[5,1,5,3],[5,5,6,5],[6,1,6,3],[7,1,7,3],[8,1,8,3],[9,0,16,0],[9,1,9,3],[9,5,10,5],[10,1,10,3],[11,1,11,3],[12,1,12,3],[13,1,13,3],[14,1,14,3],[15,1,15,3],[16,1,16,3],[17,0,21,0],[17,1,17,3],[18,1,18,3],[19,1,19,3],[19,5,20,5],[20,1,20,3],[21,1,21,3],[22,0,27,0],[22,1,22,3],[23,1,23,3],[24,1,24,3],[25,1,25,3],[25,5,26,5],[26,1,26,3],[27,1,27,3],[28,0,31,0],[28,1,28,3],[29,1,29,3],[30,1,30,3],[31,1,31,3],[32,1,32,3],[39,1,39,3],[40,0,43,0],[40,1,40,3],[40,5,41,5],[41,1,41,3],[42,1,42,3],[43,1,43,3],[44,0,51,0],[44,1,44,3],[44,5,45,5],[45,1,45,3],[46,1,46,3],[47,1,47,3],[48,1,48,3],[49,1,49,3],[50,1,50,3],[51,1,51,3],[52,0,56,0],[52,1,52,3],[53,1,53,3],[54,1,54,3],[54,5,55,5],[55,1,55,3],[56,1,56,3],[57,0,62,0],[57,1,57,3],[58,1,58,3],[59,1,59,3],[60,1,60,3],[60,5,61,5],[61,1,61,3],[62,1,62,3],[63,0,66,0],[63,1,63,3],[64,1,64,3],[65,1,65,3],[66,1,66,3],[67,1,67,3],[74,1,74,3],[75,0,78,0],[75,1,75,3],[75,5,76,5],[76,1,76,3],[77,1,77,3],[78,1,78,3],[79,0,86,0],[79,1,79,3],[79,5,80,5],[80,1,80,3],[81,1,81,3],[82,1,82,3],[83,1,83,3],[84,1,84,3],[85,1,85,3],[86,1,86,3],[87,0,91,0],[87,1,87,3],[88,1,88,3],[89,1,89,3],[89,5,90,5],[90,1,90,3],[91,1,91,3],[92,0,97,0],[92,1,92,3],[93,1,93,3],[94,1,94,3],[95,1,95,3],[95,5,96,5],[96,1,96,3],[97,1,97,3],[98,0,101,0],[98,1,98,3],[99,1,99,3],[100,1,100,3],[101,1,101,3],[102,1,102,3],[109,1,109,3],[110,0,113,0],[110,1,110,3],[110,5,111,5],[111,1,111,3],[112,1,112,3],[113,1,113,3],[114,0,121,0],[114,1,114,3],[114,5,115,5],[115,1,115,3],[116,1,116,3],[117,1,117,3],[118,1,118,3],[119,1,119,3],[120,1,120,3],[121,1,121,3],[122,0,126,0],[122,1,122,3],[123,1,123,3],[124,1,124,3],[124,5,125,5],[125,1,125,3],[126,1,126,3],[127,0,132,0],[127,1,127,3],[128,1,128,3],[129,1,129,3],[130,1,130,3],[130,5,131,5],[131,1,131,3],[132,1,132,3],[133,0,136,0],[133,1,133,3],[134,1,134,3],[135,1,135,3],[136,1,136,3],[137,1,137,3],[144,1,144,3],[145,0,148,0],[145,1,145,3],[145,5,146,5],[146,1,146,3],[147,1,147,3],[148,1,148,3],[149,0,156,0],[149,1,149,3],[149,5,150,5],[150,1,150,3],[151,1,151,3],[152,1,152,3],[153,1,153,3],[154,1,154,3],[155,1,155,3],[156,1,156,3],[157,0,161,0],[157,1,157,3],[158,1,158,3],[159,1,159,3],[159,5,160,5],[160,1,160,3],[161,1,161,3],[162,0,167,0],[162,1,162,3],[163,1,163,3],[164,1,164,3],[165,1,165,3],[165,5,166,5],[166,1,166,3],[167,1,167,3],[168,0,171,0],[168,1,168,3],[169,1,169,3],[170,1,170,3],[171,1,171,3],[172,1,172,3],[179,1,179,3],[180,0,183,0],[180,1,180,3],[180,5,181,5],[181,1,181,3],[182,1,182,3],[183,1,183,3],[184,0,191,0],[184,1,184,3],[184,5,185,5],[185,1,185,3],[186,1,186,3],[187,1,187,3],[188,1,188,3],[189,1,189,3],[190,1,190,3],[191,1,191,3],[192,0,196,0],[192,1,192,3],[193,1,193,3],[194,1,194,3],[194,5,195,5],[195,1,195,3],[196,1,196,3],[197,0,202,0],[197,1,197,3],[198,1,198,3],[199,1,199,3],[200,1,200,3],[200,5,201,5],[201,1,201,3],[202,1,202,3],[203,0,206,0],[203,1,203,3],[204,1,204,3],[205,1,205,3],[206,1,206,3],[207,1,207,3],[214,1,214,3],[215,0,218,0],[215,1,215,3],[215,5,216,5],[216,1,216,3],[217,1,217,3],[218,1,218,3],[219,0,226,0],[219,1,219,3],[219,5,220,5],[220,1,220,3],[221,1,221,3],[222,1,222,3],[223,1,223,3],[224,1,224,3],[225,1,225,3],[226,1,226,3],[227,0,231,0],[227,1,227,3],[228,1,228,3],[229,1,229,3],[229,5,230,5],[230,1,230,3],[231,1,231,3],[232,0,237,0],[232,1,232,3],[233,1,233,3],[234,1,234,3],[235,1,235,3],[235,5,236,5],[236,1,236,3],[237,1,237,3],[238,0,241,0],[238,1,238,3],[239,1,239,3],[240,1,240,3],[241,1,241,3],[242,1,242,3],[249,1,249,3],[250,0,253,0],[250,1,250,3],[250,5,251,5],[251,1,251,3],[252,1,252,3],[253,1,253,3],[254,0,261,0],[254,1,254,3],[254,5,255,5],[255,1,255,3],[256,1,256,3],[257,1,257,3],[258,1,258,3],[259,1,259,3],[260,1,260,3],[261,1,261,3],[262,0,266,0],[262,1,262,3],[263,1,263,3],[264,1,264,3],[264,5,265,5],[265,1,265,3],[266,1,266,3],[267,0,272,0],[267,1,267,3],[268,1,268,3],[269,1,269,3],[270,1,270,3],[270,5,271,5],[271,1,271,3],[272,1,272,3],[273,0,276,0],[273,1,273,3],[274,1,274,3],[275,1,275,3],[276,1,276,3],[277,1,277,3],[284,1,284,3],[285,0,288,0],[285,1,285,3],[285,5,286,5],[286,1,286,3],[287,1,287,3],[288,1,288,3],[289,0,296,0],[289,1,289,3],[289,5,290,5],[290,1,290,3],[291,1,291,3],[292,1,292,3],[293,1,293,3],[294,1,294,3],[295,1,295,3],[296,1,296,3],[297,0,301,0],[297,1,297,3],[298,1,298,3],[299,1,299,3],[299,5,300,5],[300,1,300,3],[301,1,301,3],[302,0,307,0],[302,1,302,3],[303,1,303,3],[304,1,304,3],[305,1,305,3],[305,5,306,5],[306,1,306,3],[307,1,307,3],[308,0,311,0],[308,1,308,3],[309,1,309,3],[310,1,310,3],[311,1,311,3],[312,1,312,3],[319,1,319,3],[320,0,323,0],[320,1,320,3],[320,5,321,5],[321,1,321,3],[322,1,322,3],[323,1,323,3],[324,0,331,0],[324,1,324,3],[324,5,325,5],[325,1,325,3],[326,1,326,3],[327,1,327,3],[328,1,328,3],[329,1,329,3],[330,1,330,3],[331,1,331,3],[332,0,336,0],[332,1,332,3],[333,1,333,3],[334,1,334,3],[334,5,335,5],[335,1,335,3],[336,1,336,3],[337,0,342,0],[337,1,337,3],[338,1,338,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["Unique ID","FIDELIO-DKD","Study ID","NCT02540993","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2020; 383:2219-2229","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Finerenone","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","MACE","Results","finerenone:228/2833,placebo:258/2841","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"PY","In protocol, Study drug must be permanently discontinued if any of the following occurs:the randomization code is broken by the investigator, or other responsible person, when knowledge of the subject’s treatment is required"]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"PY"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics and concomitant medications were balanced between the two groups "]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","The packaging and labeling will be designed to maintain the blinding of \r\nthe investigator’s team and the subjects. The study data will remain blinded until database lock and authorization of data release according to standard operating procedures.Appropriate measures will be taken to maintain blinding while bioanalysis is ongoing.\r\n"]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"PY"]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"PY","a total of 13,911 patients in 48 countries underwent screening, and 5734 patients underwent randomization,822 patients (29.0%) in the finerenone group and 801 patients (28.2%) in the placebo group had discontinued the trial regimen,The incidence of the primary composite outcome of kidney failure, a sustained decrease of at least 40% in the eGFR from baseline, or death from renal causes was significantly lower in the finerenone group than in the placebo group, occurring in 504 patients (17.8%) and 600 patients (21.1%)"]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","major adverse cardiovascular events,a composite of nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","A Clinical Event Committee (CEC), blinded to study treatment assignment, will adjudicate all events that could potentially fulfill the criteria for the primary, secondary or other endpoints during the study."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","The Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) trial was designed to test the hypothesis that finerenone slows CKD progression and reduces ardiovascular morbidity and mortality among patients with advanced CKD and type 2 diabetes."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","EMPA-REG OUTCOME","Study ID","NCT01131676","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2016; 375:323-334","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Empagliflozin","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","MACE","Results","HR 0.86","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Randomization was undertaken using a computer-generated random sequence and an interactive voice and web response system. "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","The baseline characteristics of the patients were generally similar in the two study groups"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","After randomisation at Visit 3, patients, Investigators and individuals involved with the trial conduct or analysis for the clinical trial report will remain blinded with regard to the randomised treatment assignments until after database lock. Drug supplies will be provided by the Department of Pharmaceutical Development of Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany. All study medication will be contained in medication boxes identified with the trial number and medication number. Each medication box will contain an appropriate amount of BI 10773 or placebo tablets, plus some reserve, for dosing until the next scheduled visit."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","We used a modified intention-to-treat approach to perform analyses in patients who had received at least one dose of a study drug. All analyses were performed at the nominal alpha level of 0.05 without correction for multiple hypothesis testing."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","A total of 7020 patients at 590 sites in 42 countries received at least one dose of a study drug.The primary outcome occurred in a significantly lower percentage of patients in the empagliflozin group (490 of 4687 [10.5%]) than in the placebo group (282 of 2333 [12.1%]) (hazard ratio in the empagliflozin group, 0.86; 95.02% confidence interval [CI], 0.74 to 0.99; P<0.001 for noninferiority and P=0.04 for superiority)  in the placebo group"]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","major adverse cardiovascular events,a composite of nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","Events will be prospectively adjudicated by an independent Clinical Events Committee.Accordingly, procedures, including restricted access to electronic systems, were put in place to ensure that the effect estimate remained blinded and data review by the regulators would not require premature disclosure of the effects of empagliflozin on  outcome. The data extraction, interim analysis and the following phase III  meta-analysis were performed by a group independent from the EMPA-REG OUTCOME™ trial team, so that the trial’s operational team and the academic Steering Committee remained blinded to the results."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","An assessment of renal outcomes was a prespecified objective of the trial, and outcomes were defined in a secondary statistical analysis plan."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","CANVAS Program","Study ID","NCT01032629","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2017; 377:644-657","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Canagliflozin","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","MACE","Results","Canagliflozin:126/994 Placebo:135/780","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y"," Randomization was performed centrally through an interactive Web-based response system with the use of a computer-generated randomization schedule with randomly permuted blocks that was prepared by the trial sponsor. "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics were balanced in the canagliflozin and placebo groups  and were similar across CANVAS and CANVAS-R "]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N"," Participants and all trial staff were unaware of the individual treatment assignments until completion of the trial. "]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","The primary hypothesis test was a test of noninferiority, with the use of a margin of 1.3 for the hazard ratio for the primary outcome with canagliflozin as compared with placebo in the full, integrated data set (i.e., all available follow-up data from all participants who underwent randomization) and with the intention-to-treat approach. "]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","The two trials involved a total of 10,142 participants, 4330 in CANVAS and 5812 in CANVAS-R. A total of 9734 participants (96.0%) completed the trial (i.e., were alive and were assessed for safety and efficacy outcomes during the final follow-up window or died before the final follow-up). Vital status was confirmed for 10,100 of the 10,142 participants"]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","major adverse cardiovascular events,a composite of nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","The independent Endpoint Adjudication Committee will apply the endpoint definitions contained in its charter and classify the outcome events while blinded to treatment assignment."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","Exploratory cardiovascular outcomes prespecified for evaluation were nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure,10 and the key prespecified exploratory renal outcomes were regression of albuminuria (using criteria comparable to those defined for category progression) and the renal composite comprising a 40% reduction in eGFR sustained for at least two consecutive measures, the need for renal-replacement therapy (dialysis or transplantation), or death from renal causes (defined as death with a proximate renal cause). Evaluation of total hospitalizations was also prespecified."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","DECLARE–TIMI 58","Study ID","NCT01730534. opens in new tab","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2019; 380:347-357","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Dapagliflozin","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","MACE","Results","Dapagliflozin:85/606 placebo:104/659","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"PY","The IVRS/IWRS will allocate the IP through the AZ prepared randomization scheme and provide the randomization number and the appropriate Kit IDs from IP available at the study center. Randomization numbers will be prepared by the global randomization administrator at AstraZeneca and made available for IVRS/IWRS use. "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics of the patients were balanced between the groups"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","The blinding is ensured by using double-blind, single-dummy technique. The active tablets and the respective placebo tablets will be identical in size, color, smell, and taste. The bottles with investigational products will be labeled with unique identification numbers allocated from the IVRS/IWRS. No member of the study delivery team at AZ, BMS, Hadassah, TIMI, or personnel at study centers or any clinical research organization (CRO) handling data will have access to the randomization scheme during the conduct of the study"]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","Analyses were performed according to the intention-to-treat principle with the use of adjudicated events. "]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"PY","A total of 3962 patients discontinued the trial regimen prematurely, at a rate of 5.7% per year, including 1811 of 8574 patients (21.1%) in the dapagliflozin group and 2151 of 8569 (25.1%) in the placebo group."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","major adverse cardiovascular events,a composite of nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","The complete, raw database was provided to the TIMI Study Group, which independently conducted all analyses reported in this article.Suspected CV outcome events in the study including the primary objective and secondary\r\nobjective will be centrally adjudicated by an independent clinical events committee. "]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","The primary safety outcome was MACE (defined as cardiovascular death, myocardial infarction, or ischemic stroke). The two primary efficacy outcomes were MACE and a composite of cardiovascular death or hospitalization for heart failure. Two secondary efficacy outcomes were prespecified. The first was a renal composite outcome, defined as a sustained decrease of 40% or more in estimated glomerular filtration rate (eGFR) — calculated by means of the Chronic Kidney Disease Epidemiology Collaboration equation22 — to less than 60 ml per minute per 1.73 m2 of body-surface area, new end-stage renal disease, or death from renal or cardiovascular causes. The other secondary outcome was death from any cause. A prespecified additional renal composite outcome included all the criteria described for the secondary renal outcome except for cardiovascular death. Serious adverse events and adverse events leading to discontinuation of dapagliflozin or placebo were collected comprehensively, as described in Section B in the Supplementary Appendix. "]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","CREDENCE","Study ID","NCT02065791","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2019; 380:2295-2306","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Canagliflozin","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","MACE","Results","Canagliflozin:217/2202 Placebo:269/2199","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Randomization and blinding will be used to minimize bias in the assignment of subjects to treatment groups, to increase the likelihood that known and unknown subject attributes (eg, demographic and baseline characteristics) are evenly balanced across treatment groups. "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","The baseline characteristics of the patients were similar in the two groups "]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","All study drug after randomization will be provided in a double-blind manner.Randomization and blinding will be used to minimize bias in the assignment of subjects to treatment groups, to increase the likelihood that known and unknown subject attributes (eg, demographic and baseline characteristics) are evenly balanced across treatment groups. "]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","In the intention-to-treat population, we used a stratified Cox proportional-hazards model to analyze the primary and secondary outcomes, according to the category of estimated GFR at screening. "]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"PY","At the trial conclusion at a median follow-up of 2.62 years (range, 0.02 to 4.53), 1201 patients (27.3%) in the two groups had discontinued therapy (Table S3 and Figs. S1 and S2 in the Supplementary Appendix); the rate of adherence to the trial regimen was 84% during follow-up. A total of 4361 patients (99.1%) were either alive with follow-up at the end of the trial or had died before the final follow-up visit. Consent was withdrawn by 16 patients (0.4%), and vital status was ascertained for all but 6 patients (4395 [99.9%])."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","major adverse cardiovascular events,a composite of nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","The IEAC will be responsible for adjudicating all renal and CV events that are components in the primary and secondary composite endpoints in this study. The IEAC is composed of external specialists, blinded to treatment assignment. The operations, processes, and endpoint definitions to be employed by the committee are defined in its charter."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","The key measure of the efficacy is the reduction in the primary composite endpoint of ESKD, doubling of serum creatinine, renal or CV death. The secondary measures of efficacy are the reduction in the composite endpoint of CV death and hospitalized congestive heart failure; the composite endpoint of CV death, non-fatal MI, and non-fatal stroke (ie, 3-point MACE);hospitalized congestive heart failure; the renal composite endpoint of ESKD, doubling of serum creatinine, and renal death; CV death; all-cause death; and the CV composite endpoint of CV death, nonfatal MI, nonfatal stroke, hospitalized congestive heart failure, and hospitalized unstable angina. Additional exploratory measures of efficacy include reduction in a composite endpoint of ESKD and renal or CV death and reductions in each individual component of the composite endpoints including ESKD, doubling of serum creatinine, renal death, CV death, nonfatal MI, nonfatal stroke, hospitalized congestive heart failure, hospitalized unstable angina, as well as the changes in eGFR and albuminuria over time. \r\n"]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","VERTIS CV ","Study ID","NCT01986881","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2020; 383:1425-1435","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Ertugliflozin","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","MACE","Results","Ertugliflozin:188/1198 Placebo:87/607","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y"," Randomization was performed at a central location with the use of an interactive voice-response system and was based on a computer-generated schedule with randomly permuted blocks, stratified according to geographic region."]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","The baseline characteristics of the patients were well balanced between the ertugliflozin group and the placebo group "]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","Tablets will be packaged into bottles or blister cards.Pfizer will provide investigator sites with sufficient amounts of blinded investigational product to accommodate expected recruitment. Investigational product will be assigned to subjects via IVRS or equivalent.The trial will be subject-, investigator- and sponsor- blinded."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","The primary analysis will be an intention-to-treat (ITT) analysis, which will include all randomized subjects who have taken at least one dose of investigational product across the Phase 2 and 3 development program. STests of superiority with respect to the outcomes（a composite of death from cardiovascular causes or hospitalization for heart failure; death from cardiovascular causes; and a composite of death from renal causes, renal replacement therapy, or doubling of the serum creatinine level） were performed on an intention-to-treat basis in all patients who had undergone randomization, with no limit on the time window for the ascertainment of outcomes."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","The trial regimen was permanently discontinued before trial completion — for reasons other than death — by 23.5% of the patients in the ertugliflozin group and by 27.9% of the patients in the placebo group (Table S4). Final vital status was known for 99.3% of the patients."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","major adverse cardiovascular events,a composite of nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","All the primary and secondary outcome events were centrally adjudicated by a cardiovascular adjudication committee in a blinded manner. All potential cardiovascular endpoints across the ertugliflozin Phase 2 and Phase 3 \r\ndevelopment program are to be adjudicated by members of an independent Endpoint Adjudication Committee (EAC) who will be blinded to the treatment assignment. Endpoint definitions will be included in the Endpoint Adjudication Manual used by the EAC. "]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","The data from the two ertugliflozin dose groups were prespecified to be pooled for the assessment of cardiovascular and renal outcomes."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","DAPA-CKD ","Study ID","NCT03036150","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2020; 383:1436-1446","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Dapagliflozin","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","MACE","Results","Dapagliflozin:113/1455 placebo:118/1451","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Investigators used an interactive voice-response or Web-response system to determine trial-group assignments.Participants and all trial personnel (except the members of the independent data monitoring committee) were unaware of the trial-group assignments. "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","The baseline characteristics, including medications for type 2 diabetes and kidney disease, were balanced between the dapagliflozin and placebo groups"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","Dapagliflozin and placebo were packaged identically, with uniform tablet appearance, labeling, and administration schedules.Participants and all trial personnel (except the members of the independent data monitoring committee) were unaware of the trial-group assignments. "]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","The primary efficacy analysis was based on the intention-to-treat population, which included all the participants who had undergone randomization. A Cox proportional-hazards regression model that was stratified according to the factors used at randomization (type 2 diabetes and urinary albumin-to-creatinine ratio) and that was adjusted for the baseline estimated GFR was used to estimate the hazard ratio and 95% confidence intervals for dapagliflozin as compared with placebo for the primary and secondary outcomes. "]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","Dapagliflozin was discontinued for reasons other than death in 274 participants, and placebo was discontinued in 309 participants (12.7% and 14.4%, respectively). In all, 4289 participants (99.7%) completed the trial"]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","major adverse cardiovascular events,a composite of nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","The analyses that were conducted by the sponsor were replicated by an independent academic group at the University Medical Center Groningen. "]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","The analytical approach and power calculations have been published previously, and the complete prespecified statistical analysis plan is available with the protocol at NEJM.org. There was non different in analysis plan between protocol and the results."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","SCORED ","Study ID","NCT03315143","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2021; 384:129-139","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Sotagliflozin","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","MACE","Results","Sotagliflozin:343/5292 placebo:442/5292","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","The Randomization and the treatment allocation will be performed centrally by an IRT. The study biostatistician provides the Randomization scheme to the IRT. Then, the IRT generates the patient Randomization list from which it allocates treatment to the patients."]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics were similar in the two groups "]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","During the double-blind Treatment period each treatment package will be labeled with a number, which is generated by a computer program from Sanofi. Investigators will not have access to the Randomization (treatment) code except under circumstances described in Section 8.3.2. The Randomization and the treatment allocation will be performed centrally by an IRT. The study biostatistician provides the Randomization scheme to the IRT. Then, the IRT generates the patient Randomization list from which it allocates treatment to the patients. The CEC will review and adjudicate events in a blinded manner. "]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","All efficacy analyses followed the intention-to-treat principle."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","Vital status was available for 99.4% of the patients; 142 (1.3%) did not complete final trial visits, of whom 67 had unknown end-of-trial vital status. "]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","major adverse cardiovascular events,a composite of nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","An independent Clinical Endpoint Committee (CEC) will review and adjudicate all events of \r\ndeath, MACE (CV death, non-fatal MI or non-fatal stroke), selected CV and renal events, diabetic \r\nketoacidosis (DKA) and bone fractures in a treatment-blinded manner.An expert committee will review all potential cases of drug-induced liver injuries (DILIs) in a \r\ntreatment blinded manner to evaluate causality.The CEC will review and adjudicate events in a blinded manner. "]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","Primary end-point events according to stratification factors and in selected prespecified subgroups are shown in Figure S3.Prespecified and post hoc evaluations of composite end points as a function of normo-, micro-, and macroalbuminuria are presented in Tables S6 and S7.In protocol,As explained in Section 4, the first primary endpoint of 3-point MACE is in concordance with appropriate FDA guidance (2008 FDA Guidance for Industry: Diabetes Mellitus- Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes; 35). The second primary endpoint is of interest to prospectively evaluate the potential benefit of sotagliflozin on HF and CV death, 2 important clinical events in patients with T2D that have been shown previously to be influenced by SGLT2 inhibition (20). If NI of sotagliflozin is met on 3-point MACE, superiority will also be assessed. "]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","Cherney","Study ID","NCT03242018","Assessor","Zhang and Jiang"]
["Ref or Label","Diabetes Obes Metab. 2021 Dec;23(12):2632-2642.","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Sotagliflozin","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","MACE","Results","Sotagliflozin:7/184 placebo:12/93","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"PY"," Patients will continue to receive the blinded medication (sotagliflozin 400 mg, 200 mg, or placebo) to which they were randomized on Day 1. Patients who received rescue medication during the initial 26-week Treatment Period will continue on the same rescue medication during the double-blind \r\nExtension PeriodBias will be minimized by randomizing the patients to treatment groups, blinding the patients, the Investigators, and the Sponsor to the treatment allocations, and by adjudicating endpoints in a blinded fashion. "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"PY"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics were balanced between treatment groups"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","During the double-blind Treatment Period, each treatment package will be labeled with a number, which is generated by a computer program from the Sanofi. Investigators will not have access to the randomization (treatment) code except under circumstances described in Section 8.3.2. The randomization and the treatment allocation will be performed centrally by an IRT. The study biostatistician provides the randomization scheme to the IRT. Then, the IRT generates the patient randomization list from which it allocates treatment arms to the patients. Treatment kit containing 2 wallets of 38 tablets each (identical to sotagliflozin 200 mg in appearance) will be dispensed as needed for the duration of the treatment period in a double-blind manner"]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","The primary analysis of the primary efficacy endpoint was performed on the intent-to-treat population with an analysis of covariance (ANCOVA) model"]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","In this study, 277 patients enrolled and randomized. In 26 weeks, 230 patients completed the study.In 52 weeks, 200 patients completed the study.  KFP: Sotagliflozin:24/184 placebo:10/93"]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","major adverse cardiovascular events,a composite of nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","The Clinical Endpoint Committees (CECs) is/are comprised of experts in cardiology and nephrology (and other appropriate medical specialties such as neurology and endocrinology as needed) who are independen of the Sponsor and the contract research organization (CRO). The CEC(s) will review and adjudicate all deaths, major adverse cardiac events (MACE), selected CV events (MI, stroke, unstable angina leading to hospitalization, and heart failure leading to hospitalization), selected renal events, bone fracture, and DKA.The two committees will review the cases in a treatment-blinded manner and will present their assessments to the DMC. "]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","There was non different in analysis plan between protocol and the results."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","HARMONY ","Study ID","NCT02465515","Assessor","Zhang and Jiang"]
["Ref or Label","Lancet. 2018 Oct 27;392(10157):1519-1529","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Albiglutide","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","MACE","Results","Albiglutide:116/1098 placebo:128/1124","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Patients were assigned in a 1:1 ratio to receive subcutaneous injections of albiglutide or placebo (with matched administration device, diluent, and volume injected) once a week, according to a sequestered, fixed, \r\ncomputer-generated randomisation code that used balanced permuted blocks of treatment group allocations, without stratification. Investigators used an interactive voice or web response system to obtain treatment assignment. All investigators and patients involved in the trial were masked to treatment group"]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","The demographic and clinical characteristics of the patients were similar between the two groups "]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","Patients were assigned in a 1:1 ratio to receive subcutaneous injections of albiglutide or placebo (with matched administration device, diluent, and volume injected) once a week, according to a sequestered, fixed, \r\ncomputer-generated randomisation code that used balanced permuted blocks of treatment group allocations, without stratification. Investigators used an interactive voice or web response system to obtain treatment assignment. All investigators and patients involved in the trial were masked to treatment group"]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","The primary outcome was the first occurrence of any component of the composite outcome, which comprised death from cardiovascular causes, myocardial infarction, and stroke, in an intention-to-treat population. "]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"PY","Vital status was not known for 61 (0·6%) of 9463 participants, which included 30 patients from the albiglutide group and 31 patients from the placebo group (figure 1). 1140 (24%) of 4731 patients assigned to receive albiglutide and 1297 (27%) of 4732 patients assigned to receive placebo discontinued study medication prematurely for reasons other than death. "]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","major adverse cardiovascular events,a composite of nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N"," An independent clinical events classi\u0002fication committee, whose members were unaware of the trial group assignments, assessed all the components of the primary composite outcome, secondary cardio\u0002vascular outcomes, and death; these events are defined in the clinical event definitions "]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","The statistical analyses were done by a contract research organisation on behalf of the sponsor, according to a prespecified plan.Of all three components of the primary outcome, which were prespecified secondary outcomes, only myocardial infarction showed a significant point estimate that indicated beneficial effect. "]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","EXSCEL","Study ID","NCT01144338","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2017; 377:1228-1239","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Exenatide","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","MACE","Results","Exenatide:280/1557 placebo:282/1620","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","An interactive voice-response system assigned patients on the basis of computer-generated block randomization within each site, with stratification according to history of cardiovascular disease. "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","The demographic, disease, and clinical characteristics of the patients did not differ significantly between the groups"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N"," Sufficient study medication will be provided to the study site for enrollment of all subjects. Study medication kits will be labeled with unique package numbers (this is not the subject randomization number). At Visit 1 (Day 0), study site personnel must contact the interactive voice response system (IVRS) to randomly assign subjects. The study-site personnel must call the IVRS at all subsequent visits (except Study Termination) to record the visit and confirm the kit assignment. The calls to the IVRS will ensure the resupply of additional kits required for upcoming visits. If medication is allocated to a subject incorrectly, the sponsor must be notified. At Study Termination or Early Termination, the site must call the IVRS to record study termination. TThe sponsor, the study-site personnel, and the subjects will be blinded to \r\ntreatment allocation. "]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","The time-to-event analyses were performed with the use of a Cox proportional-hazards model for primary, secondary, and exploratory outcomes in the intention-to-treat population, stratified according to history of cardiovascular disease, with trial regimen as an explanatory variable. The intention-to-treat population included all patients who underwent randomization. "]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","A total of 14,187 patients (96.2%) completed the trial, and vital status was obtained for 98.8% of the patients. "]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","major adverse cardiovascular events,a composite of nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","An independent clinical events classification committee whose members were unaware of the trial-group assignments adjudicated all the components of the primary composite outcome, secondary outcomes, ventricular arrhythmias that led to intervention, neoplasms, and pancreatitis; these events are defined in the Clinical Event Definitions section in the Supplementary Appendix."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","The statistical analysis plan prespecified the use of hierarchical testing in the following order: noninferiority for the primary composite outcome, superiority for the primary composite outcome, superiority for all-cause mortality, superiority for each component of the cardiovascular composite (tested with the use of the Hochberg procedure), and finally, if all three components were superior, superiority for hospitalization for acute coronary syndrome and for hospitalization for heart failure (tested with the use of the Hochberg procedure)."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","PIONEER-6","Study ID","NCT02692716","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2019; 381:841-851","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Semaglutide","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","MACE","Results","Semaglutide:20/434 placebo:25/422","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","At visit 2, subjects are randomised into one of the two treatment arms. The randomisation session must be performed in IV/WRS and will include allocation of dispensing unit numbers (DUNs) to be dispensed to the subject.A trial-specific IV/WRS will be set up which can be accessed at any time via the internet or telephone. Access to the IV/WRS must be restricted to and controlled by authorised persons. IV/WRS user manuals will be provided to each trial site. IV/WRS is used for: Screening,Screening failure, Randomisation"]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics were similar in the two groups."]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","All tablets containing oral semaglutide or placebo are identical with regards to visual appearance to maintain the blinding of the trial"]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y"," Full analysis set (FAS): includes all randomised subjects. The statistical evaluation of the FAS will follow the intention-to-treat (ITT) principle and subjects will contribute to the evaluation “as randomised”."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y"," In total, 3172 patients (99.7%) completed the trial; 1347 (84.7%) completed the trial regimen with oral semaglutide and 1435 (90.1%) with placebo"]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","major adverse cardiovascular events,a composite of nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","The events are reviewed by the EAC in a blinded manner. The EAC will have no authorisation to impact trial conduct, trial protocol or amendments."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","There was non different in analysis plan between protocol and the results."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","SUSTAIN-6","Study ID","NCT01720446","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2016; 375:1834-1844","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Semaglutide","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","MACE","Results","Semaglutide:45/469 placebo:53/470","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","A randomisation session will be carried out by using the IV/WRS.A trial-specific IV/WRS will be set up which can be accessed at any time via the internet and/or telephone. Access to the IV/WRS must be restricted to and controlled by authorised persons."]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Demographic and clinical characteristics of the patients at baseline were similar across treatment groups"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","Patients were randomized in a 1:1:1:1 ratio to receive either 0.5 mg or 1.0 mg of once-weekly subcutaneous semaglutide or volume-matched placebo, which maintained blinding within dose. \r\n"]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","All results were analyzed on an intention-to-treat basis that included the full analysis set"]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","3297 underwent randomization; of these patients, 3232 (98.0%) attended the last follow-up visit at an investigator site, were contacted by telephone, or died during the trial. The date of the last patient visit was March 15, 2016. Vital status was known for 99.6% of the patients by the end of the trial"]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","major adverse cardiovascular events,a composite of nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","An external independent EAC is established for the trial to perform adjudication, standardisation and assessment of events for randomised subjects in an independent and blinded manner.The components of the primary endpoint and other key safety outcomes will be subject to blinded external adjudication"]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","The prespecified analysis for the primary outcome was a Cox proportional-hazards model, with pooled treatment (semaglutide vs. placebo) as a fixed factor, and categorized according to all possible combinations of stratification factors used for randomization. "]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","LEADER","Study ID","NCT01179048","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2017; 377:839-848   N Engl J Med 2016; 375:311-322      Am Heart J","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Liraglutide","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","MACE","Results","Liraglutide:172/1116 placebo:233/1042","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Patients demonstrating ≥50% adherence to the regimen and willingness to continue with the injection protocol throughout the trial then underwent randomization, which was carried out for all subjects using the interactive voice/web response system. "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","The characteristics of the patients at baseline were generally balanced between the trial groups"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","Liraglutide will be available at a concentration of 6.0 mg/mL and supplied in a 3 mL disposable pen-injector. Placebo is supplied in an identical disposable pen-injector. After randomisation, treatment with liraglutide or placebo will be double-blind throughout the trial. "]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","The full analysis set includes all randomized subjects with evaluation by intention-to-treat, and subjects will be evaluated as randomized."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y"," The vital status was known in 99.7% of the patients. A total of 96.8% of the patients completed a final visit, died, or had a primary outcome."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","major adverse cardiovascular events,a composite of nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","All components of the cardiovascular and microvascular endpoints will be adjudicated by an independent Adjudication Committee in a blinded manner. "]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","Therefore, we report here the results of a prespecified analysis of the effects of liraglutide on renal outcomes.The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal (including silent) myocardial infarction, or nonfatal stroke. Prespecified exploratory outcomes included an expanded composite cardiovascular outcome (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina pectoris or heart failure), death from any cause, a composite renal and retinal microvascular outcome (nephropathy [defined as the new onset of macroalbuminuria or a doubling of the serum creatinine level and an eGFR of ≤45 ml per minute per 1.73 m2, the need for continuous renal-replacement therapy, or death from renal disease] and retinopathy [defined as the need for retinal photocoagulation or treatment with intravitreal agents, vitreous hemorrhage, or the onset of diabetes-related blindness]), neoplasms, and pancreatitis — all of which were adjudicated in a blinded fashion by an external, independent event-adjudication committee. "]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","FIGARO-DKD","Study ID","NCT02545049","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2021; 385:2252-2263     Am J Nephrol. 2019 Nov; 50(5): 345–356.","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Finerenone","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","MACE(included HHF)","Results","finerenone:458/3686 placebo:519/3666","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Eligible patients were randomized 1:1 via an interactive telephone/web-based system to receive once-daily treatment with either finerenone or placebo. Treatment assignment was determined by computer-generated random sequence with stratification by ­region (North America, Latin America, Europe, Asia, Other), eGFR category at screening (25 to <45, 45 to <60, and ≥60 mL/min/1.73 m2), category of albuminuria at screening (high or very high albuminuria), and history of CVD (present or absent). "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics were balanced between treatment groups"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","Finerenone IR tablets (10 mg and 20 mg) and placebo tablets will be identical in appearance (size, shape, color). The packaging and labeling will be designed to maintain the blinding of the investigator’s team and the subjects. The study data will remain blinded until database lock and authorization of data release according to standard operating procedures.\r\n"]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","The statistical analyses will follow the intention-to-treat principle and will be based primarily on the full analysis set consisting of all randomized patients considered valid for analysis. "]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"PY"]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","a composite of nonfatal MI, nonfatal stroke, death from cardiovascular causes, or HHF"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","A Clinical Event Committee (CEC), blinded to study treatment assignment, will adjudicate all events that could potentially fulfill the criteria for the primary, secondary or other endpoints during the study.All potential outcome events are independently reviewed and adjudicated by a Clinical Event Committee, which consists of 3 subcommittees (cardiac, renal, and neuro). All potential outcome events are randomly distributed to 2 members of the appropriate subcommittee. If there is disagreement between the 2 initial reviewers, the event will be distributed to a third reviewer. If the third reviewer does not agree with either of the first 2 reviewers, the event will be reviewed at a panel meeting in order to reach a decision"]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","The main prespecified primary endpoint is a composite of nonfatal MI, nonfatal stroke, death from cardiovascular causes, or HHF"]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]

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["Unique ID","EMPA-REG OUTCOME","Study ID","NCT01131676","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2016; 375:323-334","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Empagliflozin","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","kidney function progression","Results","HR 0.58","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Randomization was undertaken using a computer-generated random sequence and an interactive voice and web response system. "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","The baseline characteristics of the patients were generally similar in the two study groups"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","After randomisation at Visit 3, patients, Investigators and individuals involved with the trial conduct or analysis for the clinical trial report will remain blinded with regard to the randomised treatment assignments until after database lock. Drug supplies will be provided by the Department of Pharmaceutical Development of Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany. All study medication will be contained in medication boxes identified with the trial number and medication number. Each medication box will contain an appropriate amount of BI 10773 or placebo tablets, plus some reserve, for dosing until the next scheduled visit."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","We used a modified intention-to-treat approach to perform analyses in patients who had received at least one dose of a study drug. All analyses were performed at the nominal alpha level of 0.05 without correction for multiple hypothesis testing."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","A total of 7020 patients at 590 sites in 42 countries received at least one dose of a study drug.Incident or worsening nephropathy occurred in 525 of 4124 patients (12.7%) in the empagliflozin group and in 388 of 2061 patients (18.8%) in the placebo group"]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","A composite of progression to macroalbuminuria (urinary albuminto-creatinine ratio, >300 mg of albumin per gram of creatinine); a doubling of the serum creatinine level, accompanied by an eGFR of <=45 ml per minute per 1.73 m2, as calculated by the MDRD formula; the initiation of renal-replacement therapy; or death from renal disease."]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","Events will be prospectively adjudicated by an independent Clinical Events Committee.Accordingly, procedures, including restricted access to electronic systems, were put in place to ensure that the effect estimate remained blinded and data review by the regulators would not require premature disclosure of the effects of empagliflozin on  outcome. The data extraction, interim analysis and the following phase III  meta-analysis were performed by a group independent from the EMPA-REG OUTCOME™ trial team, so that the trial’s operational team and the academic Steering Committee remained blinded to the results."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","An assessment of renal outcomes was a prespecified objective of the trial, and outcomes were defined in a secondary statistical analysis plan."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","CANVAS Program","Study ID","NCT01032629","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2017; 377:644-657","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Canagliflozin","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","kidney function progression","Results","Canagliflozin:41/994 Placebo:42/780","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y"," Randomization was performed centrally through an interactive Web-based response system with the use of a computer-generated randomization schedule with randomly permuted blocks that was prepared by the trial sponsor. "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics were balanced in the canagliflozin and placebo groups  and were similar across CANVAS and CANVAS-R "]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N"," Participants and all trial staff were unaware of the individual treatment assignments until completion of the trial. "]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","The primary hypothesis test was a test of noninferiority, with the use of a margin of 1.3 for the hazard ratio for the primary outcome with canagliflozin as compared with placebo in the full, integrated data set (i.e., all available follow-up data from all participants who underwent randomization) and with the intention-to-treat approach. "]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","The two trials involved a total of 10,142 participants, 4330 in CANVAS and 5812 in CANVAS-R. A total of 9734 participants (96.0%) completed the trial (i.e., were alive and were assessed for safety and efficacy outcomes during the final follow-up window or died before the final follow-up). Vital status was confirmed for 10,100 of the 10,142 participants"]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","A composite of end-stage kidney disease, renal death, or either 40% decrease in eGFR or doubling of serum creatinine."]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","The independent Endpoint Adjudication Committee will apply the endpoint definitions contained in its charter and classify the outcome events while blinded to treatment assignment."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","Exploratory cardiovascular outcomes prespecified for evaluation were nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure,10 and the key prespecified exploratory renal outcomes were regression of albuminuria (using criteria comparable to those defined for category progression) and the renal composite comprising a 40% reduction in eGFR sustained for at least two consecutive measures, the need for renal-replacement therapy (dialysis or transplantation), or death from renal causes (defined as death with a proximate renal cause). Evaluation of total hospitalizations was also prespecified."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","DECLARE–TIMI 58","Study ID","NCT01730534. opens in new tab","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2019; 380:347-357","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Dapagliflozin","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","kidney function progression","Results","Dapagliflozin:21/606 placebo:38/659","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"PY","The IVRS/IWRS will allocate the IP through the AZ prepared randomization scheme and provide the randomization number and the appropriate Kit IDs from IP available at the study center. Randomization numbers will be prepared by the global randomization administrator at AstraZeneca and made available for IVRS/IWRS use. "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics of the patients were balanced between the groups"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","The blinding is ensured by using double-blind, single-dummy technique. The active tablets and the respective placebo tablets will be identical in size, color, smell, and taste. The bottles with investigational products will be labeled with unique identification numbers allocated from the IVRS/IWRS. No member of the study delivery team at AZ, BMS, Hadassah, TIMI, or personnel at study centers or any clinical research organization (CRO) handling data will have access to the randomization scheme during the conduct of the study"]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","Analyses were performed according to the intention-to-treat principle with the use of adjudicated events. "]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"PY","A total of 3962 patients discontinued the trial regimen prematurely, at a rate of 5.7% per year, including 1811 of 8574 patients (21.1%) in the dapagliflozin group and 2151 of 8569 (25.1%) in the placebo group."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","A composite of a sustained decrease of at least 40% in the estimated glomerular filtration rate (eGFR) from baseline, end-stage renal disease, or renal death"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","The complete, raw database was provided to the TIMI Study Group, which independently conducted all analyses reported in this article.Suspected CV outcome events in the study including the primary objective and secondary\r\nobjective will be centrally adjudicated by an independent clinical events committee. "]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","The primary safety outcome was MACE (defined as cardiovascular death, myocardial infarction, or ischemic stroke). The two primary efficacy outcomes were MACE and a composite of cardiovascular death or hospitalization for heart failure. Two secondary efficacy outcomes were prespecified. The first was a renal composite outcome, defined as a sustained decrease of 40% or more in estimated glomerular filtration rate (eGFR) — calculated by means of the Chronic Kidney Disease Epidemiology Collaboration equation22 — to less than 60 ml per minute per 1.73 m2 of body-surface area, new end-stage renal disease, or death from renal or cardiovascular causes. The other secondary outcome was death from any cause. A prespecified additional renal composite outcome included all the criteria described for the secondary renal outcome except for cardiovascular death. Serious adverse events and adverse events leading to discontinuation of dapagliflozin or placebo were collected comprehensively, as described in Section B in the Supplementary Appendix. "]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","CREDENCE","Study ID","NCT02065791","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2019; 380:2295-2306","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Canagliflozin","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","kidney function progression","Results","Canagliflozin:153/2202 Placebo:224/2199","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Randomization and blinding will be used to minimize bias in the assignment of subjects to treatment groups, to increase the likelihood that known and unknown subject attributes (eg, demographic and baseline characteristics) are evenly balanced across treatment groups. "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","The baseline characteristics of the patients were similar in the two groups "]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","All study drug after randomization will be provided in a double-blind manner.Randomization and blinding will be used to minimize bias in the assignment of subjects to treatment groups, to increase the likelihood that known and unknown subject attributes (eg, demographic and baseline characteristics) are evenly balanced across treatment groups. "]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","In the intention-to-treat population, we used a stratified Cox proportional-hazards model to analyze the primary and secondary outcomes, according to the category of estimated GFR at screening. "]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"PY","At the trial conclusion at a median follow-up of 2.62 years (range, 0.02 to 4.53), 1201 patients (27.3%) in the two groups had discontinued therapy (Table S3 and Figs. S1 and S2 in the Supplementary Appendix); the rate of adherence to the trial regimen was 84% during follow-up. A total of 4361 patients (99.1%) were either alive with follow-up at the end of the trial or had died before the final follow-up visit. Consent was withdrawn by 16 patients (0.4%), and vital status was ascertained for all but 6 patients (4395 [99.9%])."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","A composite of end-stage kidney disease, doubling of serum creatinine level, or renal death"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","The IEAC will be responsible for adjudicating all renal and CV events that are components in the primary and secondary composite endpoints in this study. The IEAC is composed of external specialists, blinded to treatment assignment. The operations, processes, and endpoint definitions to be employed by the committee are defined in its charter."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","The key measure of the efficacy is the reduction in the primary composite endpoint of ESKD, doubling of serum creatinine, renal or CV death. The secondary measures of efficacy are the reduction in the composite endpoint of CV death and hospitalized congestive heart failure; the composite endpoint of CV death, non-fatal MI, and non-fatal stroke (ie, 3-point MACE);hospitalized congestive heart failure; the renal composite endpoint of ESKD, doubling of serum creatinine, and renal death; CV death; all-cause death; and the CV composite endpoint of CV death, nonfatal MI, nonfatal stroke, hospitalized congestive heart failure, and hospitalized unstable angina. Additional exploratory measures of efficacy include reduction in a composite endpoint of ESKD and renal or CV death and reductions in each individual component of the composite endpoints including ESKD, doubling of serum creatinine, renal death, CV death, nonfatal MI, nonfatal stroke, hospitalized congestive heart failure, hospitalized unstable angina, as well as the changes in eGFR and albuminuria over time. \r\n"]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","DAPA-CKD ","Study ID","NCT03036150","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2020; 383:1436-1446","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Dapagliflozin","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","kidney function progression","Results","Dapagliflozin:103/1455 placebo:173/1451","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Investigators used an interactive voice-response or Web-response system to determine trial-group assignments.Participants and all trial personnel (except the members of the independent data monitoring committee) were unaware of the trial-group assignments. "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","The baseline characteristics, including medications for type 2 diabetes and kidney disease, were balanced between the dapagliflozin and placebo groups"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","Dapagliflozin and placebo were packaged identically, with uniform tablet appearance, labeling, and administration schedules.Participants and all trial personnel (except the members of the independent data monitoring committee) were unaware of the trial-group assignments. "]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","The primary efficacy analysis was based on the intention-to-treat population, which included all the participants who had undergone randomization. A Cox proportional-hazards regression model that was stratified according to the factors used at randomization (type 2 diabetes and urinary albumin-to-creatinine ratio) and that was adjusted for the baseline estimated GFR was used to estimate the hazard ratio and 95% confidence intervals for dapagliflozin as compared with placebo for the primary and secondary outcomes. "]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","Dapagliflozin was discontinued for reasons other than death in 274 participants, and placebo was discontinued in 309 participants (12.7% and 14.4%, respectively). In all, 4289 participants (99.7%) completed the trial"]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","A composite of a sustained decline of 50% or more in eGFR (confirmed by a second serum creatinine after at least 28 days), onset of end-stage kidney disease (defined as maintenance dialysis for more than 28 days, kidney transplantation, or eGFR <15 mL/min per 1.73 m² confirmed by a second measurement after at least 28 days), or death from kidney causes."]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","The analyses that were conducted by the sponsor were replicated by an independent academic group at the University Medical Center Groningen. "]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","The analytical approach and power calculations have been published previously, and the complete prespecified statistical analysis plan is available with the protocol at NEJM.org. There was non different in analysis plan between protocol and the results."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","SCORED ","Study ID","NCT03315143","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2021; 384:129-139","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Sotagliflozin","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","kidney function progression","Results","Sotagliflozin:37/5292 placebo:52/5292","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","The Randomization and the treatment allocation will be performed centrally by an IRT. The study biostatistician provides the Randomization scheme to the IRT. Then, the IRT generates the patient Randomization list from which it allocates treatment to the patients."]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics were similar in the two groups "]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","During the double-blind Treatment period each treatment package will be labeled with a number, which is generated by a computer program from Sanofi. Investigators will not have access to the Randomization (treatment) code except under circumstances described in Section 8.3.2. The Randomization and the treatment allocation will be performed centrally by an IRT. The study biostatistician provides the Randomization scheme to the IRT. Then, the IRT generates the patient Randomization list from which it allocates treatment to the patients. The CEC will review and adjudicate events in a blinded manner. "]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","All efficacy analyses followed the intention-to-treat principle."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","Vital status was available for 99.4% of the patients; 142 (1.3%) did not complete final trial visits, of whom 67 had unknown end-of-trial vital status. "]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","A composite of first occurrence of a sustained decrease of ≥50% in the eGFR from baseline for ≥30 days, long-term dialysis, renal transplantation, or sustained eGFR of <15 ml/min/1.73 m2 for ≥30 days"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","An independent Clinical Endpoint Committee (CEC) will review and adjudicate all events of \r\ndeath, MACE (CV death, non-fatal MI or non-fatal stroke), selected CV and renal events, diabetic \r\nketoacidosis (DKA) and bone fractures in a treatment-blinded manner.An expert committee will review all potential cases of drug-induced liver injuries (DILIs) in a \r\ntreatment blinded manner to evaluate causality.The CEC will review and adjudicate events in a blinded manner. "]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","Primary end-point events according to stratification factors and in selected prespecified subgroups are shown in Figure S3.Prespecified and post hoc evaluations of composite end points as a function of normo-, micro-, and macroalbuminuria are presented in Tables S6 and S7.In protocol,As explained in Section 4, the first primary endpoint of 3-point MACE is in concordance with appropriate FDA guidance (2008 FDA Guidance for Industry: Diabetes Mellitus- Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes; 35). The second primary endpoint is of interest to prospectively evaluate the potential benefit of sotagliflozin on HF and CV death, 2 important clinical events in patients with T2D that have been shown previously to be influenced by SGLT2 inhibition (20). If NI of sotagliflozin is met on 3-point MACE, superiority will also be assessed. "]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","Cherney","Study ID","NCT03242018","Assessor","Zhang and Jiang"]
["Ref or Label","Diabetes Obes Metab. 2021 Dec;23(12):2632-2642.","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Sotagliflozin","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","kidney function progression","Results","Sotagliflozin:24/184 placebo:10/93","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"PY"," Patients will continue to receive the blinded medication (sotagliflozin 400 mg, 200 mg, or placebo) to which they were randomized on Day 1. Patients who received rescue medication during the initial 26-week Treatment Period will continue on the same rescue medication during the double-blind \r\nExtension PeriodBias will be minimized by randomizing the patients to treatment groups, blinding the patients, the Investigators, and the Sponsor to the treatment allocations, and by adjudicating endpoints in a blinded fashion. "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"PY"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics were balanced between treatment groups"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","During the double-blind Treatment Period, each treatment package will be labeled with a number, which is generated by a computer program from the Sanofi. Investigators will not have access to the randomization (treatment) code except under circumstances described in Section 8.3.2. The randomization and the treatment allocation will be performed centrally by an IRT. The study biostatistician provides the randomization scheme to the IRT. Then, the IRT generates the patient randomization list from which it allocates treatment arms to the patients. Treatment kit containing 2 wallets of 38 tablets each (identical to sotagliflozin 200 mg in appearance) will be dispensed as needed for the duration of the treatment period in a double-blind manner"]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","The primary analysis of the primary efficacy endpoint was performed on the intent-to-treat population with an analysis of covariance (ANCOVA) model"]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","In this study, 277 patients enrolled and randomized. In 26 weeks, 230 patients completed the study.In 52 weeks, 200 patients completed the study.  KFP: Sotagliflozin:24/184 placebo:10/93"]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","A composite of Sustained ≥50 decrease in eGFR，Sustained eGFR <15 mL/min/1.73m2，Chronic dialysis，Renal transplant，Renal death"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","The Clinical Endpoint Committees (CECs) is/are comprised of experts in cardiology and nephrology (and other appropriate medical specialties such as neurology and endocrinology as needed) who are independen of the Sponsor and the contract research organization (CRO). The CEC(s) will review and adjudicate all deaths, major adverse cardiac events (MACE), selected CV events (MI, stroke, unstable angina leading to hospitalization, and heart failure leading to hospitalization), selected renal events, bone fracture, and DKA.The two committees will review the cases in a treatment-blinded manner and will present their assessments to the DMC. "]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","There was non different in analysis plan between protocol and the results."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","ARTS-DN","Study ID","NCT1874431","Assessor","Zhang and Jiang"]
["Ref or Label","JAMA. 2015;314(9):884-894.","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Finerenone","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","kidney function progression","Results","finerenone:7/715 placebo:2/93","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Randomization was done centrally by an interactive voice/web response system using computer-generated randomization lists, and participants, investigators, and the sponsor’s clinical team were blinded to treatment allocation."]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","The baseline characteristics of the patients were similar in treatment groups "]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","Randomization was done centrally by an interactive voice/web response system using computer-generated randomization lists, and participants, investigators, and the sponsor’s clinical team were blinded to treatment allocation.The packaging and labeling will be designed to maintain the blinding of the investigator’s team and to the subjects. The study data will remain blinded for each treatment group, until database lock and authorization of data release according to standard operating procedures.Appropriate measures will be taken to maintain blinding while bioanalysis is ongoing"]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y"," It was planned to have approximately 75 patients valid for the full analysis set (modified intention to treat) in each treatment group, with a possible increase to 90 patients per treatment group to increase the amount of safety data for patients with very high albuminuria."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","823 patients were randomized (Figure 1 and eTable 1 in Supplement 2); 764 patients (93%) completed treatment."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","A decrease in eGFR of 40% or more at any time postbaseline"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"PY","The protocol did not specify the use of an independent outcome evaluation center or blinded outcome evaluators."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"N","The outcome indicators were objective and could not be influenced by the statistician's ideas."]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","For the primary analysis, dose dependency was assessed by fitting an analysis-of-covariance model to the log-transformed ratios of UACR at day 90 to UACR at baseline (eAppendix in Supplement 2), including the factors treatment group, region, and type of albuminuria and the log-transformed baseline UACR as a covariate nested within type of albuminuria, and testing a prespecified linear contrast at a 1-sided significance level of .05.The prespecified secondary end point of the placebo\u0002corrected ratio of UACR at baseline vs at day 30, day 60, and day 90"]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","FIGARO-DKD","Study ID","NCT02545049","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2021; 385:2252-2263     Am J Nephrol. 2019 Nov; 50(5): 345–356.","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Finerenone","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","kidney function progression","Results","finerenone:350/3686 placebo:395/3666","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Eligible patients were randomized 1:1 via an interactive telephone/web-based system to receive once-daily treatment with either finerenone or placebo. Treatment assignment was determined by computer-generated random sequence with stratification by ­region (North America, Latin America, Europe, Asia, Other), eGFR category at screening (25 to <45, 45 to <60, and ≥60 mL/min/1.73 m2), category of albuminuria at screening (high or very high albuminuria), and history of CVD (present or absent). "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics were balanced between treatment groups"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","Finerenone IR tablets (10 mg and 20 mg) and placebo tablets will be identical in appearance (size, shape, color). The packaging and labeling will be designed to maintain the blinding of the investigator’s team and the subjects. The study data will remain blinded until database lock and authorization of data release according to standard operating procedures.\r\n"]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","The statistical analyses will follow the intention-to-treat principle and will be based primarily on the full analysis set consisting of all randomized patients considered valid for analysis. "]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"PY"]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","a composite of kidney failure, a sustained decrease of at least 40% in the eGFR from baseline, or death from renal causes"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","A Clinical Event Committee (CEC), blinded to study treatment assignment, will adjudicate all events that could potentially fulfill the criteria for the primary, secondary or other endpoints during the study.All potential outcome events are independently reviewed and adjudicated by a Clinical Event Committee, which consists of 3 subcommittees (cardiac, renal, and neuro). All potential outcome events are randomly distributed to 2 members of the appropriate subcommittee. If there is disagreement between the 2 initial reviewers, the event will be distributed to a third reviewer. If the third reviewer does not agree with either of the first 2 reviewers, the event will be reviewed at a panel meeting in order to reach a decision"]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","The main prespecified secondary endpoint is a composite of time to first occurrence of kidney failure, a sustained decrease of eGFR ≥40% from baseline over at least 4 weeks, or renal death."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","REWIND","Study ID","NCT01394952","Assessor","Zhang and Jiang"]
["Ref or Label","Lancet. 2019 Jul 13;394(10193):121-130.","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Dulaglutide","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","kidney function progression","Results","Dulaglutide:219/1081 placebo:251/1118","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Randomisation was done by a computer-generated random code with an interactive web response system with stratification by site. All investigators and participants were masked to treatment allocation. The independent data monitoring committee and the statisticians supporting the com\u0002mittee’s activities were the only people with access to unblinded data."]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics were similar in the two groups "]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","All investigators and participants were masked to treatment allocation. "]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","All efficacy and safety analyses were done according to an intention-to-treat approach that included all ran\u0002domly assigned participants irrespective of adherence, as described in the protocol and prespecified statistical analysis plan"]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","During a median follow-up of 5·4 years (IQR 5·1–5·9) comprising 51 820 person-years, the primary composite outcome status was known in 9610 (97·1%) participants"]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","The composite renal outcome was defined as the development of macroalbuminuria (development of UACR >33·9 mg/mmol in people with a lower baseline \nconcentration), a sustained 30% or greater decline in eGFR (ie, based on two consecutive eGFR concentrations), or new chronic renal replacement therapy comprising dialysis or renal transplantation."]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","Potential cardiovascular outcomes, all deaths, and pancreatic and thyroid safety outcomes were adjudicated by an independent clinical endpoint committee that was masked to treatment assignment. "]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","All efficacy and safety analyses were done according to an intention-to-treat approach that included all ran\u0002domly assigned participants irrespective of adherence, as described in the protocol and prespecified statistical analysis plan"]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","EXSCEL","Study ID","NCT01144338","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2017; 377:1228-1239","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Exenatide","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","kidney function progression","Results","Exenatide:63/1557 placebo:67/1620","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","An interactive voice-response system assigned patients on the basis of computer-generated block randomization within each site, with stratification according to history of cardiovascular disease. "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","The demographic, disease, and clinical characteristics of the patients did not differ significantly between the groups"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N"," Sufficient study medication will be provided to the study site for enrollment of all subjects. Study medication kits will be labeled with unique package numbers (this is not the subject randomization number). At Visit 1 (Day 0), study site personnel must contact the interactive voice response system (IVRS) to randomly assign subjects. The study-site personnel must call the IVRS at all subsequent visits (except Study Termination) to record the visit and confirm the kit assignment. The calls to the IVRS will ensure the resupply of additional kits required for upcoming visits. If medication is allocated to a subject incorrectly, the sponsor must be notified. At Study Termination or Early Termination, the site must call the IVRS to record study termination. TThe sponsor, the study-site personnel, and the subjects will be blinded to \r\ntreatment allocation. "]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","The time-to-event analyses were performed with the use of a Cox proportional-hazards model for primary, secondary, and exploratory outcomes in the intention-to-treat population, stratified according to history of cardiovascular disease, with trial regimen as an explanatory variable. The intention-to-treat population included all patients who underwent randomization. "]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","A total of 14,187 patients (96.2%) completed the trial, and vital status was obtained for 98.8% of the patients. "]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","renal composite 1 (time to first event of a 40% decline in eGFR [11], renal replacement, or renal death)"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","An independent clinical events classification committee whose members were unaware of the trial-group assignments adjudicated all the components of the primary composite outcome, secondary outcomes, ventricular arrhythmias that led to intervention, neoplasms, and pancreatitis; these events are defined in the Clinical Event Definitions section in the Supplementary Appendix."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","The statistical analysis plan prespecified the use of hierarchical testing in the following order: noninferiority for the primary composite outcome, superiority for the primary composite outcome, superiority for all-cause mortality, superiority for each component of the cardiovascular composite (tested with the use of the Hochberg procedure), and finally, if all three components were superior, superiority for hospitalization for acute coronary syndrome and for hospitalization for heart failure (tested with the use of the Hochberg procedure)."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","LEADER","Study ID","NCT01179048","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2017; 377:839-848   N Engl J Med 2016; 375:311-322      Am Heart J","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Liraglutide","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","kidney function progression","Results","Liraglutide:146/1116 placebo:156/1042","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Patients demonstrating ≥50% adherence to the regimen and willingness to continue with the injection protocol throughout the trial then underwent randomization, which was carried out for all subjects using the interactive voice/web response system. "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","The characteristics of the patients at baseline were generally balanced between the trial groups"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","Liraglutide will be available at a concentration of 6.0 mg/mL and supplied in a 3 mL disposable pen-injector. Placebo is supplied in an identical disposable pen-injector. After randomisation, treatment with liraglutide or placebo will be double-blind throughout the trial. "]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","The full analysis set includes all randomized subjects with evaluation by intention-to-treat, and subjects will be evaluated as randomized."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y"," The vital status was known in 99.7% of the patients. A total of 96.8% of the patients completed a final visit, died, or had a primary outcome."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","The composite renal outcome consisted of new-onset persistent macroalbuminuria, persistent doubling of the serum creatinine level and an estimated GFR of 45 ml or less per minute per 1.73 m2 of body-surface area (hereafter referred to as persistent doubling of the serum creatinine level), the need for continuous renal-replacement therapy (end-stage renal disease) with no reversible cause of the renal disease, or death from renal disease."]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","All components of the cardiovascular and microvascular endpoints will be adjudicated by an independent Adjudication Committee in a blinded manner. "]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","Therefore, we report here the results of a prespecified analysis of the effects of liraglutide on renal outcomes.The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal (including silent) myocardial infarction, or nonfatal stroke. Prespecified exploratory outcomes included an expanded composite cardiovascular outcome (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina pectoris or heart failure), death from any cause, a composite renal and retinal microvascular outcome (nephropathy [defined as the new onset of macroalbuminuria or a doubling of the serum creatinine level and an eGFR of ≤45 ml per minute per 1.73 m2, the need for continuous renal-replacement therapy, or death from renal disease] and retinopathy [defined as the need for retinal photocoagulation or treatment with intravitreal agents, vitreous hemorrhage, or the onset of diabetes-related blindness]), neoplasms, and pancreatitis — all of which were adjudicated in a blinded fashion by an external, independent event-adjudication committee. "]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]

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["Unique ID","FIDELIO-DKD","Study ID","NCT02540993","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2020; 383:2219-2229","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Finerenone","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","Hospitalization for heart failure","Results","HR 0.86","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"PY","In protocol, Study drug must be permanently discontinued if any of the following occurs:the randomization code is broken by the investigator, or other responsible person, when knowledge of the subject’s treatment is required"]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"PY"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics and concomitant medications were balanced between the two groups "]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","The packaging and labeling will be designed to maintain the blinding of \r\nthe investigator’s team and the subjects. The study data will remain blinded until database lock and authorization of data release according to standard operating procedures.Appropriate measures will be taken to maintain blinding while bioanalysis is ongoing.\r\n"]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"PY"]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"PY","a total of 13,911 patients in 48 countries underwent screening, and 5734 patients underwent randomization,822 patients (29.0%) in the finerenone group and 801 patients (28.2%) in the placebo group had discontinued the trial regimen,The incidence of the primary composite outcome of kidney failure, a sustained decrease of at least 40% in the eGFR from baseline, or death from renal causes was significantly lower in the finerenone group than in the placebo group, occurring in 504 patients (17.8%) and 600 patients (21.1%)"]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","hospitalization for heart failure"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","A Clinical Event Committee (CEC), blinded to study treatment assignment, will adjudicate all events that could potentially fulfill the criteria for the primary, secondary or other endpoints during the study."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","The Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) trial was designed to test the hypothesis that finerenone slows CKD progression and reduces ardiovascular morbidity and mortality among patients with advanced CKD and type 2 diabetes."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","EMPA-REG OUTCOME","Study ID","NCT01131676","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2016; 375:323-334","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Empagliflozin","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","Hospitalization for heart failure","Results","HR 0.65","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Randomization was undertaken using a computer-generated random sequence and an interactive voice and web response system. "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","The baseline characteristics of the patients were generally similar in the two study groups"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","After randomisation at Visit 3, patients, Investigators and individuals involved with the trial conduct or analysis for the clinical trial report will remain blinded with regard to the randomised treatment assignments until after database lock. Drug supplies will be provided by the Department of Pharmaceutical Development of Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany. All study medication will be contained in medication boxes identified with the trial number and medication number. Each medication box will contain an appropriate amount of BI 10773 or placebo tablets, plus some reserve, for dosing until the next scheduled visit."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","We used a modified intention-to-treat approach to perform analyses in patients who had received at least one dose of a study drug. All analyses were performed at the nominal alpha level of 0.05 without correction for multiple hypothesis testing."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","Overall, 97.0% of patients completed the study, with 25.4% of patients prematurely discontinuing a study drug. Final vital status was available for 99.2% of patients."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","hospitalization for heart failure"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","Events will be prospectively adjudicated by an independent Clinical Events Committee.Accordingly, procedures, including restricted access to electronic systems, were put in place to ensure that the effect estimate remained blinded and data review by the regulators would not require premature disclosure of the effects of empagliflozin on  outcome. The data extraction, interim analysis and the following phase III  meta-analysis were performed by a group independent from the EMPA-REG OUTCOME™ trial team, so that the trial’s operational team and the academic Steering Committee remained blinded to the results."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","An assessment of renal outcomes was a prespecified objective of the trial, and outcomes were defined in a secondary statistical analysis plan."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","CANVAS Program","Study ID","NCT01032629","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2017; 377:644-657","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Canagliflozin","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","Hospitalization for heart failure","Results","Canagliflozin:40/994 Placebo:58/780","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y"," Randomization was performed centrally through an interactive Web-based response system with the use of a computer-generated randomization schedule with randomly permuted blocks that was prepared by the trial sponsor. "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics were balanced in the canagliflozin and placebo groups  and were similar across CANVAS and CANVAS-R "]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N"," Participants and all trial staff were unaware of the individual treatment assignments until completion of the trial. "]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","The primary hypothesis test was a test of noninferiority, with the use of a margin of 1.3 for the hazard ratio for the primary outcome with canagliflozin as compared with placebo in the full, integrated data set (i.e., all available follow-up data from all participants who underwent randomization) and with the intention-to-treat approach. "]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","The two trials involved a total of 10,142 participants, 4330 in CANVAS and 5812 in CANVAS-R. A total of 9734 participants (96.0%) completed the trial (i.e., were alive and were assessed for safety and efficacy outcomes during the final follow-up window or died before the final follow-up). Vital status was confirmed for 10,100 of the 10,142 participants"]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","hospitalization for heart failure"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","The independent Endpoint Adjudication Committee will apply the endpoint definitions contained in its charter and classify the outcome events while blinded to treatment assignment."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","Exploratory cardiovascular outcomes prespecified for evaluation were nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure,10 and the key prespecified exploratory renal outcomes were regression of albuminuria (using criteria comparable to those defined for category progression) and the renal composite comprising a 40% reduction in eGFR sustained for at least two consecutive measures, the need for renal-replacement therapy (dialysis or transplantation), or death from renal causes (defined as death with a proximate renal cause). Evaluation of total hospitalizations was also prespecified."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","DECLARE–TIMI 58","Study ID","NCT01730534. opens in new tab","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2019; 380:347-357","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Dapagliflozin","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","Hospitalization for heart failure","Results","Dapagliflozin:29/606 placebo:48/659","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"PY","The IVRS/IWRS will allocate the IP through the AZ prepared randomization scheme and provide the randomization number and the appropriate Kit IDs from IP available at the study center. Randomization numbers will be prepared by the global randomization administrator at AstraZeneca and made available for IVRS/IWRS use. "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics of the patients were balanced between the groups"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","The blinding is ensured by using double-blind, single-dummy technique. The active tablets and the respective placebo tablets will be identical in size, color, smell, and taste. The bottles with investigational products will be labeled with unique identification numbers allocated from the IVRS/IWRS. No member of the study delivery team at AZ, BMS, Hadassah, TIMI, or personnel at study centers or any clinical research organization (CRO) handling data will have access to the randomization scheme during the conduct of the study"]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","Analyses were performed according to the intention-to-treat principle with the use of adjudicated events. "]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"PY","A total of 3962 patients discontinued the trial regimen prematurely, at a rate of 5.7% per year, including 1811 of 8574 patients (21.1%) in the dapagliflozin group and 2151 of 8569 (25.1%) in the placebo group."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","hospitalization for heart failure"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","The complete, raw database was provided to the TIMI Study Group, which independently conducted all analyses reported in this article.Suspected CV outcome events in the study including the primary objective and secondary\r\nobjective will be centrally adjudicated by an independent clinical events committee. "]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","The primary safety outcome was MACE (defined as cardiovascular death, myocardial infarction, or ischemic stroke). The two primary efficacy outcomes were MACE and a composite of cardiovascular death or hospitalization for heart failure. Two secondary efficacy outcomes were prespecified. The first was a renal composite outcome, defined as a sustained decrease of 40% or more in estimated glomerular filtration rate (eGFR) — calculated by means of the Chronic Kidney Disease Epidemiology Collaboration equation22 — to less than 60 ml per minute per 1.73 m2 of body-surface area, new end-stage renal disease, or death from renal or cardiovascular causes. The other secondary outcome was death from any cause. A prespecified additional renal composite outcome included all the criteria described for the secondary renal outcome except for cardiovascular death. Serious adverse events and adverse events leading to discontinuation of dapagliflozin or placebo were collected comprehensively, as described in Section B in the Supplementary Appendix. "]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","CREDENCE","Study ID","NCT02065791","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2019; 380:2295-2306","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Canagliflozin","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","Hospitalization for heart failure","Results","Canagliflozin:89/2202 Placebo:141/2199","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Randomization and blinding will be used to minimize bias in the assignment of subjects to treatment groups, to increase the likelihood that known and unknown subject attributes (eg, demographic and baseline characteristics) are evenly balanced across treatment groups. "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","The baseline characteristics of the patients were similar in the two groups "]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","All study drug after randomization will be provided in a double-blind manner.Randomization and blinding will be used to minimize bias in the assignment of subjects to treatment groups, to increase the likelihood that known and unknown subject attributes (eg, demographic and baseline characteristics) are evenly balanced across treatment groups. "]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","In the intention-to-treat population, we used a stratified Cox proportional-hazards model to analyze the primary and secondary outcomes, according to the category of estimated GFR at screening. "]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"PY","At the trial conclusion at a median follow-up of 2.62 years (range, 0.02 to 4.53), 1201 patients (27.3%) in the two groups had discontinued therapy (Table S3 and Figs. S1 and S2 in the Supplementary Appendix); the rate of adherence to the trial regimen was 84% during follow-up. A total of 4361 patients (99.1%) were either alive with follow-up at the end of the trial or had died before the final follow-up visit. Consent was withdrawn by 16 patients (0.4%), and vital status was ascertained for all but 6 patients (4395 [99.9%])."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","hospitalization for heart failure"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","The IEAC will be responsible for adjudicating all renal and CV events that are components in the primary and secondary composite endpoints in this study. The IEAC is composed of external specialists, blinded to treatment assignment. The operations, processes, and endpoint definitions to be employed by the committee are defined in its charter."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","The key measure of the efficacy is the reduction in the primary composite endpoint of ESKD, doubling of serum creatinine, renal or CV death. The secondary measures of efficacy are the reduction in the composite endpoint of CV death and hospitalized congestive heart failure; the composite endpoint of CV death, non-fatal MI, and non-fatal stroke (ie, 3-point MACE);hospitalized congestive heart failure; the renal composite endpoint of ESKD, doubling of serum creatinine, and renal death; CV death; all-cause death; and the CV composite endpoint of CV death, nonfatal MI, nonfatal stroke, hospitalized congestive heart failure, and hospitalized unstable angina. Additional exploratory measures of efficacy include reduction in a composite endpoint of ESKD and renal or CV death and reductions in each individual component of the composite endpoints including ESKD, doubling of serum creatinine, renal death, CV death, nonfatal MI, nonfatal stroke, hospitalized congestive heart failure, hospitalized unstable angina, as well as the changes in eGFR and albuminuria over time. \r\n"]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","VERTIS CV ","Study ID","NCT01986881","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2020; 383:1425-1435","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Ertugliflozin","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","Hospitalization for heart failure","Results","Ertugliflozin:45/1199 Placebo:45/608","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y"," Randomization was performed at a central location with the use of an interactive voice-response system and was based on a computer-generated schedule with randomly permuted blocks, stratified according to geographic region."]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","The baseline characteristics of the patients were well balanced between the ertugliflozin group and the placebo group "]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","Tablets will be packaged into bottles or blister cards.Pfizer will provide investigator sites with sufficient amounts of blinded investigational product to accommodate expected recruitment. Investigational product will be assigned to subjects via IVRS or equivalent.The trial will be subject-, investigator- and sponsor- blinded."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","The primary analysis will be an intention-to-treat (ITT) analysis, which will include all randomized subjects who have taken at least one dose of investigational product across the Phase 2 and 3 development program. STests of superiority with respect to the outcomes（a composite of death from cardiovascular causes or hospitalization for heart failure; death from cardiovascular causes; and a composite of death from renal causes, renal replacement therapy, or doubling of the serum creatinine level） were performed on an intention-to-treat basis in all patients who had undergone randomization, with no limit on the time window for the ascertainment of outcomes."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","The trial regimen was permanently discontinued before trial completion — for reasons other than death — by 23.5% of the patients in the ertugliflozin group and by 27.9% of the patients in the placebo group (Table S4). Final vital status was known for 99.3% of the patients."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","Hospitalization for heart failure"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","All the primary and secondary outcome events were centrally adjudicated by a cardiovascular adjudication committee in a blinded manner. All potential cardiovascular endpoints across the ertugliflozin Phase 2 and Phase 3 \r\ndevelopment program are to be adjudicated by members of an independent Endpoint Adjudication Committee (EAC) who will be blinded to the treatment assignment. Endpoint definitions will be included in the Endpoint Adjudication Manual used by the EAC. "]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","The data from the two ertugliflozin dose groups were prespecified to be pooled for the assessment of cardiovascular and renal outcomes."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","DAPA-CKD ","Study ID","NCT03036150","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2020; 383:1436-1446","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Dapagliflozin","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","Hospitalization for heart failure","Results","Dapagliflozin:31/1455 placebo:64/1451","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Investigators used an interactive voice-response or Web-response system to determine trial-group assignments.Participants and all trial personnel (except the members of the independent data monitoring committee) were unaware of the trial-group assignments. "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","The baseline characteristics, including medications for type 2 diabetes and kidney disease, were balanced between the dapagliflozin and placebo groups"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","Dapagliflozin and placebo were packaged identically, with uniform tablet appearance, labeling, and administration schedules.Participants and all trial personnel (except the members of the independent data monitoring committee) were unaware of the trial-group assignments. "]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","The primary efficacy analysis was based on the intention-to-treat population, which included all the participants who had undergone randomization. A Cox proportional-hazards regression model that was stratified according to the factors used at randomization (type 2 diabetes and urinary albumin-to-creatinine ratio) and that was adjusted for the baseline estimated GFR was used to estimate the hazard ratio and 95% confidence intervals for dapagliflozin as compared with placebo for the primary and secondary outcomes. "]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","Dapagliflozin was discontinued for reasons other than death in 274 participants, and placebo was discontinued in 309 participants (12.7% and 14.4%, respectively). In all, 4289 participants (99.7%) completed the trial"]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","Hospitalization for heart failure"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","The analyses that were conducted by the sponsor were replicated by an independent academic group at the University Medical Center Groningen. "]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","The analytical approach and power calculations have been published previously, and the complete prespecified statistical analysis plan is available with the protocol at NEJM.org. There was non different in analysis plan between protocol and the results."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","SCORED ","Study ID","NCT03315143","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2021; 384:129-139","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Sotagliflozin","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","Hospitalization for heart failure","Results","Sotagliflozin:106/5292 placebo:159/5292","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","The Randomization and the treatment allocation will be performed centrally by an IRT. The study biostatistician provides the Randomization scheme to the IRT. Then, the IRT generates the patient Randomization list from which it allocates treatment to the patients."]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics were similar in the two groups "]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","During the double-blind Treatment period each treatment package will be labeled with a number, which is generated by a computer program from Sanofi. Investigators will not have access to the Randomization (treatment) code except under circumstances described in Section 8.3.2. The Randomization and the treatment allocation will be performed centrally by an IRT. The study biostatistician provides the Randomization scheme to the IRT. Then, the IRT generates the patient Randomization list from which it allocates treatment to the patients. The CEC will review and adjudicate events in a blinded manner. "]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","All efficacy analyses followed the intention-to-treat principle."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","Vital status was available for 99.4% of the patients; 142 (1.3%) did not complete final trial visits, of whom 67 had unknown end-of-trial vital status. "]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","Hospitalization for heart failure"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","An independent Clinical Endpoint Committee (CEC) will review and adjudicate all events of \r\ndeath, MACE (CV death, non-fatal MI or non-fatal stroke), selected CV and renal events, diabetic \r\nketoacidosis (DKA) and bone fractures in a treatment-blinded manner.An expert committee will review all potential cases of drug-induced liver injuries (DILIs) in a \r\ntreatment blinded manner to evaluate causality.The CEC will review and adjudicate events in a blinded manner. "]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","Primary end-point events according to stratification factors and in selected prespecified subgroups are shown in Figure S3.Prespecified and post hoc evaluations of composite end points as a function of normo-, micro-, and macroalbuminuria are presented in Tables S6 and S7.In protocol,As explained in Section 4, the first primary endpoint of 3-point MACE is in concordance with appropriate FDA guidance (2008 FDA Guidance for Industry: Diabetes Mellitus- Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes; 35). The second primary endpoint is of interest to prospectively evaluate the potential benefit of sotagliflozin on HF and CV death, 2 important clinical events in patients with T2D that have been shown previously to be influenced by SGLT2 inhibition (20). If NI of sotagliflozin is met on 3-point MACE, superiority will also be assessed. "]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","Cherney","Study ID","NCT03242018","Assessor","Zhang and Jiang"]
["Ref or Label","Diabetes Obes Metab. 2021 Dec;23(12):2632-2642.","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Sotagliflozin","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","Hospitalization for heart failure","Results","Sotagliflozin:4/184 placebo:3/93","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"PY"," Patients will continue to receive the blinded medication (sotagliflozin 400 mg, 200 mg, or placebo) to which they were randomized on Day 1. Patients who received rescue medication during the initial 26-week Treatment Period will continue on the same rescue medication during the double-blind \r\nExtension PeriodBias will be minimized by randomizing the patients to treatment groups, blinding the patients, the Investigators, and the Sponsor to the treatment allocations, and by adjudicating endpoints in a blinded fashion. "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"PY"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics were balanced between treatment groups"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","During the double-blind Treatment Period, each treatment package will be labeled with a number, which is generated by a computer program from the Sanofi. Investigators will not have access to the randomization (treatment) code except under circumstances described in Section 8.3.2. The randomization and the treatment allocation will be performed centrally by an IRT. The study biostatistician provides the randomization scheme to the IRT. Then, the IRT generates the patient randomization list from which it allocates treatment arms to the patients. Treatment kit containing 2 wallets of 38 tablets each (identical to sotagliflozin 200 mg in appearance) will be dispensed as needed for the duration of the treatment period in a double-blind manner"]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","The primary analysis of the primary efficacy endpoint was performed on the intent-to-treat population with an analysis of covariance (ANCOVA) model"]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","In this study, 277 patients enrolled and randomized. In 26 weeks, 230 patients completed the study.In 52 weeks, 200 patients completed the study.  KFP: Sotagliflozin:24/184 placebo:10/93"]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","Hospitalization for heart failure"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","The Clinical Endpoint Committees (CECs) is/are comprised of experts in cardiology and nephrology (and other appropriate medical specialties such as neurology and endocrinology as needed) who are independen of the Sponsor and the contract research organization (CRO). The CEC(s) will review and adjudicate all deaths, major adverse cardiac events (MACE), selected CV events (MI, stroke, unstable angina leading to hospitalization, and heart failure leading to hospitalization), selected renal events, bone fracture, and DKA.The two committees will review the cases in a treatment-blinded manner and will present their assessments to the DMC. "]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","There was non different in analysis plan between protocol and the results."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","FIGARO-DKD","Study ID","NCT02545049","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2021; 385:2252-2263     Am J Nephrol. 2019 Nov; 50(5): 345–356.","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Finerenone","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","Hospitalization for heart failure","Results","finerenone:117/3686 placebo:163/3666","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Eligible patients were randomized 1:1 via an interactive telephone/web-based system to receive once-daily treatment with either finerenone or placebo. Treatment assignment was determined by computer-generated random sequence with stratification by ­region (North America, Latin America, Europe, Asia, Other), eGFR category at screening (25 to <45, 45 to <60, and ≥60 mL/min/1.73 m2), category of albuminuria at screening (high or very high albuminuria), and history of CVD (present or absent). "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics were balanced between treatment groups"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","Finerenone IR tablets (10 mg and 20 mg) and placebo tablets will be identical in appearance (size, shape, color). The packaging and labeling will be designed to maintain the blinding of the investigator’s team and the subjects. The study data will remain blinded until database lock and authorization of data release according to standard operating procedures.\r\n"]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","The statistical analyses will follow the intention-to-treat principle and will be based primarily on the full analysis set consisting of all randomized patients considered valid for analysis. "]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"PY"]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","Hospitalization for heart failure"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","A Clinical Event Committee (CEC), blinded to study treatment assignment, will adjudicate all events that could potentially fulfill the criteria for the primary, secondary or other endpoints during the study.All potential outcome events are independently reviewed and adjudicated by a Clinical Event Committee, which consists of 3 subcommittees (cardiac, renal, and neuro). All potential outcome events are randomly distributed to 2 members of the appropriate subcommittee. If there is disagreement between the 2 initial reviewers, the event will be distributed to a third reviewer. If the third reviewer does not agree with either of the first 2 reviewers, the event will be reviewed at a panel meeting in order to reach a decision"]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","The main prespecified secondary endpoint is a composite of time to first occurrence of kidney failure, a sustained decrease of eGFR ≥40% from baseline over at least 4 weeks, or renal death."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","EXSCEL","Study ID","NCT01144338","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2017; 377:1228-1239","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Exenatide","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","Hospitalization for heart failure","Results","Exenatide:93/1557 placebo:88/1620","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","An interactive voice-response system assigned patients on the basis of computer-generated block randomization within each site, with stratification according to history of cardiovascular disease. "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","The demographic, disease, and clinical characteristics of the patients did not differ significantly between the groups"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N"," Sufficient study medication will be provided to the study site for enrollment of all subjects. Study medication kits will be labeled with unique package numbers (this is not the subject randomization number). At Visit 1 (Day 0), study site personnel must contact the interactive voice response system (IVRS) to randomly assign subjects. The study-site personnel must call the IVRS at all subsequent visits (except Study Termination) to record the visit and confirm the kit assignment. The calls to the IVRS will ensure the resupply of additional kits required for upcoming visits. If medication is allocated to a subject incorrectly, the sponsor must be notified. At Study Termination or Early Termination, the site must call the IVRS to record study termination. TThe sponsor, the study-site personnel, and the subjects will be blinded to \r\ntreatment allocation. "]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","The time-to-event analyses were performed with the use of a Cox proportional-hazards model for primary, secondary, and exploratory outcomes in the intention-to-treat population, stratified according to history of cardiovascular disease, with trial regimen as an explanatory variable. The intention-to-treat population included all patients who underwent randomization. "]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","A total of 14,187 patients (96.2%) completed the trial, and vital status was obtained for 98.8% of the patients. "]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","Hospitalization for heart failure"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","An independent clinical events classification committee whose members were unaware of the trial-group assignments adjudicated all the components of the primary composite outcome, secondary outcomes, ventricular arrhythmias that led to intervention, neoplasms, and pancreatitis; these events are defined in the Clinical Event Definitions section in the Supplementary Appendix."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","The statistical analysis plan prespecified the use of hierarchical testing in the following order: noninferiority for the primary composite outcome, superiority for the primary composite outcome, superiority for all-cause mortality, superiority for each component of the cardiovascular composite (tested with the use of the Hochberg procedure), and finally, if all three components were superior, superiority for hospitalization for acute coronary syndrome and for hospitalization for heart failure (tested with the use of the Hochberg procedure)."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","LEADER","Study ID","NCT01179048","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2017; 377:839-848   N Engl J Med 2016; 375:311-322      Am Heart J","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Liraglutide","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","Hospitalization for heart failure","Results","Liraglutide:81/1116 placebo:103/1042","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Patients demonstrating ≥50% adherence to the regimen and willingness to continue with the injection protocol throughout the trial then underwent randomization, which was carried out for all subjects using the interactive voice/web response system. "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","The characteristics of the patients at baseline were generally balanced between the trial groups"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","Liraglutide will be available at a concentration of 6.0 mg/mL and supplied in a 3 mL disposable pen-injector. Placebo is supplied in an identical disposable pen-injector. After randomisation, treatment with liraglutide or placebo will be double-blind throughout the trial. "]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","The full analysis set includes all randomized subjects with evaluation by intention-to-treat, and subjects will be evaluated as randomized."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y"," The vital status was known in 99.7% of the patients. A total of 96.8% of the patients completed a final visit, died, or had a primary outcome."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","Hospitalization for heart failure"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","All components of the cardiovascular and microvascular endpoints will be adjudicated by an independent Adjudication Committee in a blinded manner. "]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","Therefore, we report here the results of a prespecified analysis of the effects of liraglutide on renal outcomes.The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal (including silent) myocardial infarction, or nonfatal stroke. Prespecified exploratory outcomes included an expanded composite cardiovascular outcome (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina pectoris or heart failure), death from any cause, a composite renal and retinal microvascular outcome (nephropathy [defined as the new onset of macroalbuminuria or a doubling of the serum creatinine level and an eGFR of ≤45 ml per minute per 1.73 m2, the need for continuous renal-replacement therapy, or death from renal disease] and retinopathy [defined as the need for retinal photocoagulation or treatment with intravitreal agents, vitreous hemorrhage, or the onset of diabetes-related blindness]), neoplasms, and pancreatitis — all of which were adjudicated in a blinded fashion by an external, independent event-adjudication committee. "]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]

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["Unique ID","FIDELIO-DKD","Study ID","NCT02540993","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2020; 383:2219-2229","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Finerenone","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","death from any cause","Results","HR 0.90","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"PY","In protocol, Study drug must be permanently discontinued if any of the following occurs:the randomization code is broken by the investigator, or other responsible person, when knowledge of the subject’s treatment is required"]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"PY"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics and concomitant medications were balanced between the two groups "]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","The packaging and labeling will be designed to maintain the blinding of \r\nthe investigator’s team and the subjects. The study data will remain blinded until database lock and authorization of data release according to standard operating procedures.Appropriate measures will be taken to maintain blinding while bioanalysis is ongoing.\r\n"]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"PY"]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"PY","a total of 13,911 patients in 48 countries underwent screening, and 5734 patients underwent randomization,822 patients (29.0%) in the finerenone group and 801 patients (28.2%) in the placebo group had discontinued the trial regimen,The incidence of the primary composite outcome of kidney failure, a sustained decrease of at least 40% in the eGFR from baseline, or death from renal causes was significantly lower in the finerenone group than in the placebo group, occurring in 504 patients (17.8%) and 600 patients (21.1%)"]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","death from any cause"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","A Clinical Event Committee (CEC), blinded to study treatment assignment, will adjudicate all events that could potentially fulfill the criteria for the primary, secondary or other endpoints during the study."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","The Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) trial was designed to test the hypothesis that finerenone slows CKD progression and reduces ardiovascular morbidity and mortality among patients with advanced CKD and type 2 diabetes."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","EMPA-REG OUTCOME","Study ID","NCT01131676","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2016; 375:323-334","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Empagliflozin","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","death from any cause","Results","Empagliflozin:68/1212,placebo:40/607","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Randomization was undertaken using a computer-generated random sequence and an interactive voice and web response system. "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","The baseline characteristics of the patients were generally similar in the two study groups"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","After randomisation at Visit 3, patients, Investigators and individuals involved with the trial conduct or analysis for the clinical trial report will remain blinded with regard to the randomised treatment assignments until after database lock. Drug supplies will be provided by the Department of Pharmaceutical Development of Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany. All study medication will be contained in medication boxes identified with the trial number and medication number. Each medication box will contain an appropriate amount of BI 10773 or placebo tablets, plus some reserve, for dosing until the next scheduled visit."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","We used a modified intention-to-treat approach to perform analyses in patients who had received at least one dose of a study drug. All analyses were performed at the nominal alpha level of 0.05 without correction for multiple hypothesis testing."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","A total of 7020 patients at 590 sites in 42 countries received at least one dose of a study drug.The primary outcome occurred in a significantly lower percentage of patients in the empagliflozin group (490 of 4687 [10.5%]) than in the placebo group (282 of 2333 [12.1%]) (hazard ratio in the empagliflozin group, 0.86; 95.02% confidence interval [CI], 0.74 to 0.99; P<0.001 for noninferiority and P=0.04 for superiority)  in the placebo group"]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","death from any cause"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","Events will be prospectively adjudicated by an independent Clinical Events Committee.Accordingly, procedures, including restricted access to electronic systems, were put in place to ensure that the effect estimate remained blinded and data review by the regulators would not require premature disclosure of the effects of empagliflozin on  outcome. The data extraction, interim analysis and the following phase III  meta-analysis were performed by a group independent from the EMPA-REG OUTCOME™ trial team, so that the trial’s operational team and the academic Steering Committee remained blinded to the results."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","An assessment of renal outcomes was a prespecified objective of the trial, and outcomes were defined in a secondary statistical analysis plan."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","DECLARE–TIMI 58","Study ID","NCT01730534. opens in new tab","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2019; 380:347-357","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Dapagliflozin","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","death from any cause","Results","Dapagliflozin:71/606 placebo:87/659","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"PY","The IVRS/IWRS will allocate the IP through the AZ prepared randomization scheme and provide the randomization number and the appropriate Kit IDs from IP available at the study center. Randomization numbers will be prepared by the global randomization administrator at AstraZeneca and made available for IVRS/IWRS use. "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics of the patients were balanced between the groups"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","The blinding is ensured by using double-blind, single-dummy technique. The active tablets and the respective placebo tablets will be identical in size, color, smell, and taste. The bottles with investigational products will be labeled with unique identification numbers allocated from the IVRS/IWRS. No member of the study delivery team at AZ, BMS, Hadassah, TIMI, or personnel at study centers or any clinical research organization (CRO) handling data will have access to the randomization scheme during the conduct of the study"]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","Analyses were performed according to the intention-to-treat principle with the use of adjudicated events. "]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"PY","A total of 3962 patients discontinued the trial regimen prematurely, at a rate of 5.7% per year, including 1811 of 8574 patients (21.1%) in the dapagliflozin group and 2151 of 8569 (25.1%) in the placebo group."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","death from any cause"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","The complete, raw database was provided to the TIMI Study Group, which independently conducted all analyses reported in this article.Suspected CV outcome events in the study including the primary objective and secondary\r\nobjective will be centrally adjudicated by an independent clinical events committee. "]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","The primary safety outcome was MACE (defined as cardiovascular death, myocardial infarction, or ischemic stroke). The two primary efficacy outcomes were MACE and a composite of cardiovascular death or hospitalization for heart failure. Two secondary efficacy outcomes were prespecified. The first was a renal composite outcome, defined as a sustained decrease of 40% or more in estimated glomerular filtration rate (eGFR) — calculated by means of the Chronic Kidney Disease Epidemiology Collaboration equation22 — to less than 60 ml per minute per 1.73 m2 of body-surface area, new end-stage renal disease, or death from renal or cardiovascular causes. The other secondary outcome was death from any cause. A prespecified additional renal composite outcome included all the criteria described for the secondary renal outcome except for cardiovascular death. Serious adverse events and adverse events leading to discontinuation of dapagliflozin or placebo were collected comprehensively, as described in Section B in the Supplementary Appendix. "]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","CREDENCE","Study ID","NCT02065791","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2019; 380:2295-2306","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Canagliflozin","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","death from any cause","Results","Canagliflozin:168/2202 Placebo:201/2199","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Randomization and blinding will be used to minimize bias in the assignment of subjects to treatment groups, to increase the likelihood that known and unknown subject attributes (eg, demographic and baseline characteristics) are evenly balanced across treatment groups. "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","The baseline characteristics of the patients were similar in the two groups "]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","All study drug after randomization will be provided in a double-blind manner.Randomization and blinding will be used to minimize bias in the assignment of subjects to treatment groups, to increase the likelihood that known and unknown subject attributes (eg, demographic and baseline characteristics) are evenly balanced across treatment groups. "]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","In the intention-to-treat population, we used a stratified Cox proportional-hazards model to analyze the primary and secondary outcomes, according to the category of estimated GFR at screening. "]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"PY","At the trial conclusion at a median follow-up of 2.62 years (range, 0.02 to 4.53), 1201 patients (27.3%) in the two groups had discontinued therapy (Table S3 and Figs. S1 and S2 in the Supplementary Appendix); the rate of adherence to the trial regimen was 84% during follow-up. A total of 4361 patients (99.1%) were either alive with follow-up at the end of the trial or had died before the final follow-up visit. Consent was withdrawn by 16 patients (0.4%), and vital status was ascertained for all but 6 patients (4395 [99.9%])."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","death from any cause"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","The IEAC will be responsible for adjudicating all renal and CV events that are components in the primary and secondary composite endpoints in this study. The IEAC is composed of external specialists, blinded to treatment assignment. The operations, processes, and endpoint definitions to be employed by the committee are defined in its charter."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","The key measure of the efficacy is the reduction in the primary composite endpoint of ESKD, doubling of serum creatinine, renal or CV death. The secondary measures of efficacy are the reduction in the composite endpoint of CV death and hospitalized congestive heart failure; the composite endpoint of CV death, non-fatal MI, and non-fatal stroke (ie, 3-point MACE);hospitalized congestive heart failure; the renal composite endpoint of ESKD, doubling of serum creatinine, and renal death; CV death; all-cause death; and the CV composite endpoint of CV death, nonfatal MI, nonfatal stroke, hospitalized congestive heart failure, and hospitalized unstable angina. Additional exploratory measures of efficacy include reduction in a composite endpoint of ESKD and renal or CV death and reductions in each individual component of the composite endpoints including ESKD, doubling of serum creatinine, renal death, CV death, nonfatal MI, nonfatal stroke, hospitalized congestive heart failure, hospitalized unstable angina, as well as the changes in eGFR and albuminuria over time. \r\n"]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","VERTIS CV ","Study ID","NCT01986881","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2020; 383:1425-1435","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Ertugliflozin","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","death from any cause","Results","Ertugliflozin:64/1177  Placebo:28/597","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y"," Randomization was performed at a central location with the use of an interactive voice-response system and was based on a computer-generated schedule with randomly permuted blocks, stratified according to geographic region."]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","The baseline characteristics of the patients were well balanced between the ertugliflozin group and the placebo group "]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","Tablets will be packaged into bottles or blister cards.Pfizer will provide investigator sites with sufficient amounts of blinded investigational product to accommodate expected recruitment. Investigational product will be assigned to subjects via IVRS or equivalent.The trial will be subject-, investigator- and sponsor- blinded."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","The primary analysis will be an intention-to-treat (ITT) analysis, which will include all randomized subjects who have taken at least one dose of investigational product across the Phase 2 and 3 development program. STests of superiority with respect to the outcomes（a composite of death from cardiovascular causes or hospitalization for heart failure; death from cardiovascular causes; and a composite of death from renal causes, renal replacement therapy, or doubling of the serum creatinine level） were performed on an intention-to-treat basis in all patients who had undergone randomization, with no limit on the time window for the ascertainment of outcomes."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","The trial regimen was permanently discontinued before trial completion — for reasons other than death — by 23.5% of the patients in the ertugliflozin group and by 27.9% of the patients in the placebo group (Table S4). Final vital status was known for 99.3% of the patients."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","death from any cause"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","All the primary and secondary outcome events were centrally adjudicated by a cardiovascular adjudication committee in a blinded manner. All potential cardiovascular endpoints across the ertugliflozin Phase 2 and Phase 3 \r\ndevelopment program are to be adjudicated by members of an independent Endpoint Adjudication Committee (EAC) who will be blinded to the treatment assignment. Endpoint definitions will be included in the Endpoint Adjudication Manual used by the EAC. "]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","The data from the two ertugliflozin dose groups were prespecified to be pooled for the assessment of cardiovascular and renal outcomes."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","DAPA-CKD ","Study ID","NCT03036150","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2020; 383:1436-1446","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Dapagliflozin","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","death from any cause","Results","Dapagliflozin:84/1455 placebo:113/1451","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Investigators used an interactive voice-response or Web-response system to determine trial-group assignments.Participants and all trial personnel (except the members of the independent data monitoring committee) were unaware of the trial-group assignments. "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","The baseline characteristics, including medications for type 2 diabetes and kidney disease, were balanced between the dapagliflozin and placebo groups"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","Dapagliflozin and placebo were packaged identically, with uniform tablet appearance, labeling, and administration schedules.Participants and all trial personnel (except the members of the independent data monitoring committee) were unaware of the trial-group assignments. "]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","The primary efficacy analysis was based on the intention-to-treat population, which included all the participants who had undergone randomization. A Cox proportional-hazards regression model that was stratified according to the factors used at randomization (type 2 diabetes and urinary albumin-to-creatinine ratio) and that was adjusted for the baseline estimated GFR was used to estimate the hazard ratio and 95% confidence intervals for dapagliflozin as compared with placebo for the primary and secondary outcomes. "]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","Dapagliflozin was discontinued for reasons other than death in 274 participants, and placebo was discontinued in 309 participants (12.7% and 14.4%, respectively). In all, 4289 participants (99.7%) completed the trial"]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","death from any cause"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","The analyses that were conducted by the sponsor were replicated by an independent academic group at the University Medical Center Groningen. "]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","The analytical approach and power calculations have been published previously, and the complete prespecified statistical analysis plan is available with the protocol at NEJM.org. There was non different in analysis plan between protocol and the results."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","SCORED ","Study ID","NCT03315143","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2021; 384:129-139","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Sotagliflozin","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","death from any cause","Results","Sotagliflozin:246/5292 placebo:246/5292","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","The Randomization and the treatment allocation will be performed centrally by an IRT. The study biostatistician provides the Randomization scheme to the IRT. Then, the IRT generates the patient Randomization list from which it allocates treatment to the patients."]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics were similar in the two groups "]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","During the double-blind Treatment period each treatment package will be labeled with a number, which is generated by a computer program from Sanofi. Investigators will not have access to the Randomization (treatment) code except under circumstances described in Section 8.3.2. The Randomization and the treatment allocation will be performed centrally by an IRT. The study biostatistician provides the Randomization scheme to the IRT. Then, the IRT generates the patient Randomization list from which it allocates treatment to the patients. The CEC will review and adjudicate events in a blinded manner. "]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","All efficacy analyses followed the intention-to-treat principle."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","Vital status was available for 99.4% of the patients; 142 (1.3%) did not complete final trial visits, of whom 67 had unknown end-of-trial vital status. "]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","death from any cause"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","An independent Clinical Endpoint Committee (CEC) will review and adjudicate all events of \r\ndeath, MACE (CV death, non-fatal MI or non-fatal stroke), selected CV and renal events, diabetic \r\nketoacidosis (DKA) and bone fractures in a treatment-blinded manner.An expert committee will review all potential cases of drug-induced liver injuries (DILIs) in a \r\ntreatment blinded manner to evaluate causality.The CEC will review and adjudicate events in a blinded manner. "]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","Primary end-point events according to stratification factors and in selected prespecified subgroups are shown in Figure S3.Prespecified and post hoc evaluations of composite end points as a function of normo-, micro-, and macroalbuminuria are presented in Tables S6 and S7.In protocol,As explained in Section 4, the first primary endpoint of 3-point MACE is in concordance with appropriate FDA guidance (2008 FDA Guidance for Industry: Diabetes Mellitus- Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes; 35). The second primary endpoint is of interest to prospectively evaluate the potential benefit of sotagliflozin on HF and CV death, 2 important clinical events in patients with T2D that have been shown previously to be influenced by SGLT2 inhibition (20). If NI of sotagliflozin is met on 3-point MACE, superiority will also be assessed. "]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","Cherney","Study ID","NCT03242018","Assessor","Zhang and Jiang"]
["Ref or Label","Diabetes Obes Metab. 2021 Dec;23(12):2632-2642.","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Sotagliflozin","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","death from any cause","Results","Sotagliflozin:5/184 placebo:5/93","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"PY"," Patients will continue to receive the blinded medication (sotagliflozin 400 mg, 200 mg, or placebo) to which they were randomized on Day 1. Patients who received rescue medication during the initial 26-week Treatment Period will continue on the same rescue medication during the double-blind \r\nExtension PeriodBias will be minimized by randomizing the patients to treatment groups, blinding the patients, the Investigators, and the Sponsor to the treatment allocations, and by adjudicating endpoints in a blinded fashion. "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"PY"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics were balanced between treatment groups"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","During the double-blind Treatment Period, each treatment package will be labeled with a number, which is generated by a computer program from the Sanofi. Investigators will not have access to the randomization (treatment) code except under circumstances described in Section 8.3.2. The randomization and the treatment allocation will be performed centrally by an IRT. The study biostatistician provides the randomization scheme to the IRT. Then, the IRT generates the patient randomization list from which it allocates treatment arms to the patients. Treatment kit containing 2 wallets of 38 tablets each (identical to sotagliflozin 200 mg in appearance) will be dispensed as needed for the duration of the treatment period in a double-blind manner"]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","The primary analysis of the primary efficacy endpoint was performed on the intent-to-treat population with an analysis of covariance (ANCOVA) model"]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","In this study, 277 patients enrolled and randomized. In 26 weeks, 230 patients completed the study.In 52 weeks, 200 patients completed the study.  KFP: Sotagliflozin:24/184 placebo:10/93"]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","death from any cause"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","The Clinical Endpoint Committees (CECs) is/are comprised of experts in cardiology and nephrology (and other appropriate medical specialties such as neurology and endocrinology as needed) who are independen of the Sponsor and the contract research organization (CRO). The CEC(s) will review and adjudicate all deaths, major adverse cardiac events (MACE), selected CV events (MI, stroke, unstable angina leading to hospitalization, and heart failure leading to hospitalization), selected renal events, bone fracture, and DKA.The two committees will review the cases in a treatment-blinded manner and will present their assessments to the DMC. "]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","There was non different in analysis plan between protocol and the results."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","FIGARO-DKD","Study ID","NCT02545049","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2021; 385:2252-2263     Am J Nephrol. 2019 Nov; 50(5): 345–356.","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Finerenone","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","death from any cause","Results","finerenone:333/3686 placebo:370/3666","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Eligible patients were randomized 1:1 via an interactive telephone/web-based system to receive once-daily treatment with either finerenone or placebo. Treatment assignment was determined by computer-generated random sequence with stratification by ­region (North America, Latin America, Europe, Asia, Other), eGFR category at screening (25 to <45, 45 to <60, and ≥60 mL/min/1.73 m2), category of albuminuria at screening (high or very high albuminuria), and history of CVD (present or absent). "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics were balanced between treatment groups"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","Finerenone IR tablets (10 mg and 20 mg) and placebo tablets will be identical in appearance (size, shape, color). The packaging and labeling will be designed to maintain the blinding of the investigator’s team and the subjects. The study data will remain blinded until database lock and authorization of data release according to standard operating procedures.\r\n"]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","The statistical analyses will follow the intention-to-treat principle and will be based primarily on the full analysis set consisting of all randomized patients considered valid for analysis. "]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"PY"]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","death from any cause"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","A Clinical Event Committee (CEC), blinded to study treatment assignment, will adjudicate all events that could potentially fulfill the criteria for the primary, secondary or other endpoints during the study.All potential outcome events are independently reviewed and adjudicated by a Clinical Event Committee, which consists of 3 subcommittees (cardiac, renal, and neuro). All potential outcome events are randomly distributed to 2 members of the appropriate subcommittee. If there is disagreement between the 2 initial reviewers, the event will be distributed to a third reviewer. If the third reviewer does not agree with either of the first 2 reviewers, the event will be reviewed at a panel meeting in order to reach a decision"]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","The main prespecified secondary endpoint is a composite of time to first occurrence of kidney failure, a sustained decrease of eGFR ≥40% from baseline over at least 4 weeks, or renal death."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","EXSCEL","Study ID","NCT01144338","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2017; 377:1228-1239","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Exenatide","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","death from any cause","Results","Exenatide:195/1557 placebo:200/1620","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","An interactive voice-response system assigned patients on the basis of computer-generated block randomization within each site, with stratification according to history of cardiovascular disease. "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","The demographic, disease, and clinical characteristics of the patients did not differ significantly between the groups"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N"," Sufficient study medication will be provided to the study site for enrollment of all subjects. Study medication kits will be labeled with unique package numbers (this is not the subject randomization number). At Visit 1 (Day 0), study site personnel must contact the interactive voice response system (IVRS) to randomly assign subjects. The study-site personnel must call the IVRS at all subsequent visits (except Study Termination) to record the visit and confirm the kit assignment. The calls to the IVRS will ensure the resupply of additional kits required for upcoming visits. If medication is allocated to a subject incorrectly, the sponsor must be notified. At Study Termination or Early Termination, the site must call the IVRS to record study termination. TThe sponsor, the study-site personnel, and the subjects will be blinded to \r\ntreatment allocation. "]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","The time-to-event analyses were performed with the use of a Cox proportional-hazards model for primary, secondary, and exploratory outcomes in the intention-to-treat population, stratified according to history of cardiovascular disease, with trial regimen as an explanatory variable. The intention-to-treat population included all patients who underwent randomization. "]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","A total of 14,187 patients (96.2%) completed the trial, and vital status was obtained for 98.8% of the patients. "]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","death from any cause"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","An independent clinical events classification committee whose members were unaware of the trial-group assignments adjudicated all the components of the primary composite outcome, secondary outcomes, ventricular arrhythmias that led to intervention, neoplasms, and pancreatitis; these events are defined in the Clinical Event Definitions section in the Supplementary Appendix."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","The statistical analysis plan prespecified the use of hierarchical testing in the following order: noninferiority for the primary composite outcome, superiority for the primary composite outcome, superiority for all-cause mortality, superiority for each component of the cardiovascular composite (tested with the use of the Hochberg procedure), and finally, if all three components were superior, superiority for hospitalization for acute coronary syndrome and for hospitalization for heart failure (tested with the use of the Hochberg procedure)."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","LEADER","Study ID","NCT01179048","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2017; 377:839-848   N Engl J Med 2016; 375:311-322      Am Heart J","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Liraglutide","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","death from any cause","Results","Liraglutide:144/1116 placebo:178/1042","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Patients demonstrating ≥50% adherence to the regimen and willingness to continue with the injection protocol throughout the trial then underwent randomization, which was carried out for all subjects using the interactive voice/web response system. "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","The characteristics of the patients at baseline were generally balanced between the trial groups"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","Liraglutide will be available at a concentration of 6.0 mg/mL and supplied in a 3 mL disposable pen-injector. Placebo is supplied in an identical disposable pen-injector. After randomisation, treatment with liraglutide or placebo will be double-blind throughout the trial. "]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","The full analysis set includes all randomized subjects with evaluation by intention-to-treat, and subjects will be evaluated as randomized."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y"," The vital status was known in 99.7% of the patients. A total of 96.8% of the patients completed a final visit, died, or had a primary outcome."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","death from any cause"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","All components of the cardiovascular and microvascular endpoints will be adjudicated by an independent Adjudication Committee in a blinded manner. "]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","Therefore, we report here the results of a prespecified analysis of the effects of liraglutide on renal outcomes.The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal (including silent) myocardial infarction, or nonfatal stroke. Prespecified exploratory outcomes included an expanded composite cardiovascular outcome (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina pectoris or heart failure), death from any cause, a composite renal and retinal microvascular outcome (nephropathy [defined as the new onset of macroalbuminuria or a doubling of the serum creatinine level and an eGFR of ≤45 ml per minute per 1.73 m2, the need for continuous renal-replacement therapy, or death from renal disease] and retinopathy [defined as the need for retinal photocoagulation or treatment with intravitreal agents, vitreous hemorrhage, or the onset of diabetes-related blindness]), neoplasms, and pancreatitis — all of which were adjudicated in a blinded fashion by an external, independent event-adjudication committee. "]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]

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["Unique ID","FIDELIO-DKD","Study ID","NCT02540993","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2020; 383:2219-2229","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Finerenone","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","death from cardiovascular causes","Results","HR 0.86","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"PY","In protocol, Study drug must be permanently discontinued if any of the following occurs:the randomization code is broken by the investigator, or other responsible person, when knowledge of the subject’s treatment is required"]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"PY"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics and concomitant medications were balanced between the two groups "]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","The packaging and labeling will be designed to maintain the blinding of \r\nthe investigator’s team and the subjects. The study data will remain blinded until database lock and authorization of data release according to standard operating procedures.Appropriate measures will be taken to maintain blinding while bioanalysis is ongoing.\r\n"]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"PY"]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"PY","a total of 13,911 patients in 48 countries underwent screening, and 5734 patients underwent randomization,822 patients (29.0%) in the finerenone group and 801 patients (28.2%) in the placebo group had discontinued the trial regimen,The incidence of the primary composite outcome of kidney failure, a sustained decrease of at least 40% in the eGFR from baseline, or death from renal causes was significantly lower in the finerenone group than in the placebo group, occurring in 504 patients (17.8%) and 600 patients (21.1%)"]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","death from cardiovascular causes"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","A Clinical Event Committee (CEC), blinded to study treatment assignment, will adjudicate all events that could potentially fulfill the criteria for the primary, secondary or other endpoints during the study."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","The Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) trial was designed to test the hypothesis that finerenone slows CKD progression and reduces ardiovascular morbidity and mortality among patients with advanced CKD and type 2 diabetes."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","EMPA-REG OUTCOME","Study ID","NCT01131676","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2016; 375:323-334","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Empagliflozin","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","death from cardiovascular causes","Results","Empagliflozin:75/1212,placebo:48/607","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Randomization was undertaken using a computer-generated random sequence and an interactive voice and web response system. "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","The baseline characteristics of the patients were generally similar in the two study groups"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","After randomisation at Visit 3, patients, Investigators and individuals involved with the trial conduct or analysis for the clinical trial report will remain blinded with regard to the randomised treatment assignments until after database lock. Drug supplies will be provided by the Department of Pharmaceutical Development of Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany. All study medication will be contained in medication boxes identified with the trial number and medication number. Each medication box will contain an appropriate amount of BI 10773 or placebo tablets, plus some reserve, for dosing until the next scheduled visit."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","We used a modified intention-to-treat approach to perform analyses in patients who had received at least one dose of a study drug. All analyses were performed at the nominal alpha level of 0.05 without correction for multiple hypothesis testing."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","A total of 7020 patients at 590 sites in 42 countries received at least one dose of a study drug.The primary outcome occurred in a significantly lower percentage of patients in the empagliflozin group (490 of 4687 [10.5%]) than in the placebo group (282 of 2333 [12.1%]) (hazard ratio in the empagliflozin group, 0.86; 95.02% confidence interval [CI], 0.74 to 0.99; P<0.001 for noninferiority and P=0.04 for superiority)  in the placebo group"]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","death from cardiovascular causes"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","Events will be prospectively adjudicated by an independent Clinical Events Committee.Accordingly, procedures, including restricted access to electronic systems, were put in place to ensure that the effect estimate remained blinded and data review by the regulators would not require premature disclosure of the effects of empagliflozin on  outcome. The data extraction, interim analysis and the following phase III  meta-analysis were performed by a group independent from the EMPA-REG OUTCOME™ trial team, so that the trial’s operational team and the academic Steering Committee remained blinded to the results."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","An assessment of renal outcomes was a prespecified objective of the trial, and outcomes were defined in a secondary statistical analysis plan."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","CANVAS Program","Study ID","NCT01032629","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2017; 377:644-657","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Canagliflozin","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","death from cardiovascular causes","Results","Canagliflozin:83/994 Placebo:64/780","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y"," Randomization was performed centrally through an interactive Web-based response system with the use of a computer-generated randomization schedule with randomly permuted blocks that was prepared by the trial sponsor. "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics were balanced in the canagliflozin and placebo groups  and were similar across CANVAS and CANVAS-R "]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N"," Participants and all trial staff were unaware of the individual treatment assignments until completion of the trial. "]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","The primary hypothesis test was a test of noninferiority, with the use of a margin of 1.3 for the hazard ratio for the primary outcome with canagliflozin as compared with placebo in the full, integrated data set (i.e., all available follow-up data from all participants who underwent randomization) and with the intention-to-treat approach. "]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","The two trials involved a total of 10,142 participants, 4330 in CANVAS and 5812 in CANVAS-R. A total of 9734 participants (96.0%) completed the trial (i.e., were alive and were assessed for safety and efficacy outcomes during the final follow-up window or died before the final follow-up). Vital status was confirmed for 10,100 of the 10,142 participants"]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","death from cardiovascular causes"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","The independent Endpoint Adjudication Committee will apply the endpoint definitions contained in its charter and classify the outcome events while blinded to treatment assignment."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","Exploratory cardiovascular outcomes prespecified for evaluation were nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure,10 and the key prespecified exploratory renal outcomes were regression of albuminuria (using criteria comparable to those defined for category progression) and the renal composite comprising a 40% reduction in eGFR sustained for at least two consecutive measures, the need for renal-replacement therapy (dialysis or transplantation), or death from renal causes (defined as death with a proximate renal cause). Evaluation of total hospitalizations was also prespecified."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","DECLARE–TIMI 58","Study ID","NCT01730534. opens in new tab","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2019; 380:347-357","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Dapagliflozin","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","death from cardiovascular causes","Results","Dapagliflozin:32606 placebo:40/659","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"PY","The IVRS/IWRS will allocate the IP through the AZ prepared randomization scheme and provide the randomization number and the appropriate Kit IDs from IP available at the study center. Randomization numbers will be prepared by the global randomization administrator at AstraZeneca and made available for IVRS/IWRS use. "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics of the patients were balanced between the groups"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","The blinding is ensured by using double-blind, single-dummy technique. The active tablets and the respective placebo tablets will be identical in size, color, smell, and taste. The bottles with investigational products will be labeled with unique identification numbers allocated from the IVRS/IWRS. No member of the study delivery team at AZ, BMS, Hadassah, TIMI, or personnel at study centers or any clinical research organization (CRO) handling data will have access to the randomization scheme during the conduct of the study"]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","Analyses were performed according to the intention-to-treat principle with the use of adjudicated events. "]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"PY","A total of 3962 patients discontinued the trial regimen prematurely, at a rate of 5.7% per year, including 1811 of 8574 patients (21.1%) in the dapagliflozin group and 2151 of 8569 (25.1%) in the placebo group."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","death from cardiovascular causes"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","The complete, raw database was provided to the TIMI Study Group, which independently conducted all analyses reported in this article.Suspected CV outcome events in the study including the primary objective and secondary\r\nobjective will be centrally adjudicated by an independent clinical events committee. "]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","The primary safety outcome was MACE (defined as cardiovascular death, myocardial infarction, or ischemic stroke). The two primary efficacy outcomes were MACE and a composite of cardiovascular death or hospitalization for heart failure. Two secondary efficacy outcomes were prespecified. The first was a renal composite outcome, defined as a sustained decrease of 40% or more in estimated glomerular filtration rate (eGFR) — calculated by means of the Chronic Kidney Disease Epidemiology Collaboration equation22 — to less than 60 ml per minute per 1.73 m2 of body-surface area, new end-stage renal disease, or death from renal or cardiovascular causes. The other secondary outcome was death from any cause. A prespecified additional renal composite outcome included all the criteria described for the secondary renal outcome except for cardiovascular death. Serious adverse events and adverse events leading to discontinuation of dapagliflozin or placebo were collected comprehensively, as described in Section B in the Supplementary Appendix. "]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","CREDENCE","Study ID","NCT02065791","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2019; 380:2295-2306","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Canagliflozin","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","death from cardiovascular causes","Results","Canagliflozin:110/2202 Placebo:140/2199","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Randomization and blinding will be used to minimize bias in the assignment of subjects to treatment groups, to increase the likelihood that known and unknown subject attributes (eg, demographic and baseline characteristics) are evenly balanced across treatment groups. "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","The baseline characteristics of the patients were similar in the two groups "]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","All study drug after randomization will be provided in a double-blind manner.Randomization and blinding will be used to minimize bias in the assignment of subjects to treatment groups, to increase the likelihood that known and unknown subject attributes (eg, demographic and baseline characteristics) are evenly balanced across treatment groups. "]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","In the intention-to-treat population, we used a stratified Cox proportional-hazards model to analyze the primary and secondary outcomes, according to the category of estimated GFR at screening. "]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"PY","At the trial conclusion at a median follow-up of 2.62 years (range, 0.02 to 4.53), 1201 patients (27.3%) in the two groups had discontinued therapy (Table S3 and Figs. S1 and S2 in the Supplementary Appendix); the rate of adherence to the trial regimen was 84% during follow-up. A total of 4361 patients (99.1%) were either alive with follow-up at the end of the trial or had died before the final follow-up visit. Consent was withdrawn by 16 patients (0.4%), and vital status was ascertained for all but 6 patients (4395 [99.9%])."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","death from cardiovascular causes"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","The IEAC will be responsible for adjudicating all renal and CV events that are components in the primary and secondary composite endpoints in this study. The IEAC is composed of external specialists, blinded to treatment assignment. The operations, processes, and endpoint definitions to be employed by the committee are defined in its charter."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","The key measure of the efficacy is the reduction in the primary composite endpoint of ESKD, doubling of serum creatinine, renal or CV death. The secondary measures of efficacy are the reduction in the composite endpoint of CV death and hospitalized congestive heart failure; the composite endpoint of CV death, non-fatal MI, and non-fatal stroke (ie, 3-point MACE);hospitalized congestive heart failure; the renal composite endpoint of ESKD, doubling of serum creatinine, and renal death; CV death; all-cause death; and the CV composite endpoint of CV death, nonfatal MI, nonfatal stroke, hospitalized congestive heart failure, and hospitalized unstable angina. Additional exploratory measures of efficacy include reduction in a composite endpoint of ESKD and renal or CV death and reductions in each individual component of the composite endpoints including ESKD, doubling of serum creatinine, renal death, CV death, nonfatal MI, nonfatal stroke, hospitalized congestive heart failure, hospitalized unstable angina, as well as the changes in eGFR and albuminuria over time. \r\n"]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","VERTIS CV ","Study ID","NCT01986881","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2020; 383:1425-1435","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Ertugliflozin","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","death from cardiovascular causes","Results","Ertugliflozin:111/1198 Placebo:64/607","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y"," Randomization was performed at a central location with the use of an interactive voice-response system and was based on a computer-generated schedule with randomly permuted blocks, stratified according to geographic region."]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","The baseline characteristics of the patients were well balanced between the ertugliflozin group and the placebo group "]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","Tablets will be packaged into bottles or blister cards.Pfizer will provide investigator sites with sufficient amounts of blinded investigational product to accommodate expected recruitment. Investigational product will be assigned to subjects via IVRS or equivalent.The trial will be subject-, investigator- and sponsor- blinded."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","The primary analysis will be an intention-to-treat (ITT) analysis, which will include all randomized subjects who have taken at least one dose of investigational product across the Phase 2 and 3 development program. STests of superiority with respect to the outcomes（a composite of death from cardiovascular causes or hospitalization for heart failure; death from cardiovascular causes; and a composite of death from renal causes, renal replacement therapy, or doubling of the serum creatinine level） were performed on an intention-to-treat basis in all patients who had undergone randomization, with no limit on the time window for the ascertainment of outcomes."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","The trial regimen was permanently discontinued before trial completion — for reasons other than death — by 23.5% of the patients in the ertugliflozin group and by 27.9% of the patients in the placebo group (Table S4). Final vital status was known for 99.3% of the patients."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","death from cardiovascular causes"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","All the primary and secondary outcome events were centrally adjudicated by a cardiovascular adjudication committee in a blinded manner. All potential cardiovascular endpoints across the ertugliflozin Phase 2 and Phase 3 \r\ndevelopment program are to be adjudicated by members of an independent Endpoint Adjudication Committee (EAC) who will be blinded to the treatment assignment. Endpoint definitions will be included in the Endpoint Adjudication Manual used by the EAC. "]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","The data from the two ertugliflozin dose groups were prespecified to be pooled for the assessment of cardiovascular and renal outcomes."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","DAPA-CKD ","Study ID","NCT03036150","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2020; 383:1436-1446","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Dapagliflozin","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","death from cardiovascular causes","Results","Dapagliflozin:56/1455 placebo:66/1451","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Investigators used an interactive voice-response or Web-response system to determine trial-group assignments.Participants and all trial personnel (except the members of the independent data monitoring committee) were unaware of the trial-group assignments. "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","The baseline characteristics, including medications for type 2 diabetes and kidney disease, were balanced between the dapagliflozin and placebo groups"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","Dapagliflozin and placebo were packaged identically, with uniform tablet appearance, labeling, and administration schedules.Participants and all trial personnel (except the members of the independent data monitoring committee) were unaware of the trial-group assignments. "]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","The primary efficacy analysis was based on the intention-to-treat population, which included all the participants who had undergone randomization. A Cox proportional-hazards regression model that was stratified according to the factors used at randomization (type 2 diabetes and urinary albumin-to-creatinine ratio) and that was adjusted for the baseline estimated GFR was used to estimate the hazard ratio and 95% confidence intervals for dapagliflozin as compared with placebo for the primary and secondary outcomes. "]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","Dapagliflozin was discontinued for reasons other than death in 274 participants, and placebo was discontinued in 309 participants (12.7% and 14.4%, respectively). In all, 4289 participants (99.7%) completed the trial"]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","death from cardiovascular causes"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","The analyses that were conducted by the sponsor were replicated by an independent academic group at the University Medical Center Groningen. "]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","The analytical approach and power calculations have been published previously, and the complete prespecified statistical analysis plan is available with the protocol at NEJM.org. There was non different in analysis plan between protocol and the results."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","SCORED ","Study ID","NCT03315143","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2021; 384:129-139","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Sotagliflozin","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","death from cardiovascular causes","Results","Sotagliflozin:155/5292 placebo:170/5292","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","The Randomization and the treatment allocation will be performed centrally by an IRT. The study biostatistician provides the Randomization scheme to the IRT. Then, the IRT generates the patient Randomization list from which it allocates treatment to the patients."]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics were similar in the two groups "]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","During the double-blind Treatment period each treatment package will be labeled with a number, which is generated by a computer program from Sanofi. Investigators will not have access to the Randomization (treatment) code except under circumstances described in Section 8.3.2. The Randomization and the treatment allocation will be performed centrally by an IRT. The study biostatistician provides the Randomization scheme to the IRT. Then, the IRT generates the patient Randomization list from which it allocates treatment to the patients. The CEC will review and adjudicate events in a blinded manner. "]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","All efficacy analyses followed the intention-to-treat principle."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","Vital status was available for 99.4% of the patients; 142 (1.3%) did not complete final trial visits, of whom 67 had unknown end-of-trial vital status. "]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","death from cardiovascular causes"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","An independent Clinical Endpoint Committee (CEC) will review and adjudicate all events of \r\ndeath, MACE (CV death, non-fatal MI or non-fatal stroke), selected CV and renal events, diabetic \r\nketoacidosis (DKA) and bone fractures in a treatment-blinded manner.An expert committee will review all potential cases of drug-induced liver injuries (DILIs) in a \r\ntreatment blinded manner to evaluate causality.The CEC will review and adjudicate events in a blinded manner. "]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","Primary end-point events according to stratification factors and in selected prespecified subgroups are shown in Figure S3.Prespecified and post hoc evaluations of composite end points as a function of normo-, micro-, and macroalbuminuria are presented in Tables S6 and S7.In protocol,As explained in Section 4, the first primary endpoint of 3-point MACE is in concordance with appropriate FDA guidance (2008 FDA Guidance for Industry: Diabetes Mellitus- Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes; 35). The second primary endpoint is of interest to prospectively evaluate the potential benefit of sotagliflozin on HF and CV death, 2 important clinical events in patients with T2D that have been shown previously to be influenced by SGLT2 inhibition (20). If NI of sotagliflozin is met on 3-point MACE, superiority will also be assessed. "]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","Cherney","Study ID","NCT03242018","Assessor","Zhang and Jiang"]
["Ref or Label","Diabetes Obes Metab. 2021 Dec;23(12):2632-2642.","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Sotagliflozin","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","death from cardiovascular causes","Results","Sotagliflozin:1/184 placebo:5/93","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"PY"," Patients will continue to receive the blinded medication (sotagliflozin 400 mg, 200 mg, or placebo) to which they were randomized on Day 1. Patients who received rescue medication during the initial 26-week Treatment Period will continue on the same rescue medication during the double-blind \r\nExtension PeriodBias will be minimized by randomizing the patients to treatment groups, blinding the patients, the Investigators, and the Sponsor to the treatment allocations, and by adjudicating endpoints in a blinded fashion. "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"PY"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics were balanced between treatment groups"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","During the double-blind Treatment Period, each treatment package will be labeled with a number, which is generated by a computer program from the Sanofi. Investigators will not have access to the randomization (treatment) code except under circumstances described in Section 8.3.2. The randomization and the treatment allocation will be performed centrally by an IRT. The study biostatistician provides the randomization scheme to the IRT. Then, the IRT generates the patient randomization list from which it allocates treatment arms to the patients. Treatment kit containing 2 wallets of 38 tablets each (identical to sotagliflozin 200 mg in appearance) will be dispensed as needed for the duration of the treatment period in a double-blind manner"]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","The primary analysis of the primary efficacy endpoint was performed on the intent-to-treat population with an analysis of covariance (ANCOVA) model"]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","In this study, 277 patients enrolled and randomized. In 26 weeks, 230 patients completed the study.In 52 weeks, 200 patients completed the study.  KFP: Sotagliflozin:24/184 placebo:10/93"]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","death from cardiovascular causes"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","The Clinical Endpoint Committees (CECs) is/are comprised of experts in cardiology and nephrology (and other appropriate medical specialties such as neurology and endocrinology as needed) who are independen of the Sponsor and the contract research organization (CRO). The CEC(s) will review and adjudicate all deaths, major adverse cardiac events (MACE), selected CV events (MI, stroke, unstable angina leading to hospitalization, and heart failure leading to hospitalization), selected renal events, bone fracture, and DKA.The two committees will review the cases in a treatment-blinded manner and will present their assessments to the DMC. "]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","There was non different in analysis plan between protocol and the results."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","FIGARO-DKD","Study ID","NCT02545049","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2021; 385:2252-2263     Am J Nephrol. 2019 Nov; 50(5): 345–356.","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Finerenone","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","death from cardiovascular causes","Results","finerenone:194/3686 placebo:214/3666","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Eligible patients were randomized 1:1 via an interactive telephone/web-based system to receive once-daily treatment with either finerenone or placebo. Treatment assignment was determined by computer-generated random sequence with stratification by ­region (North America, Latin America, Europe, Asia, Other), eGFR category at screening (25 to <45, 45 to <60, and ≥60 mL/min/1.73 m2), category of albuminuria at screening (high or very high albuminuria), and history of CVD (present or absent). "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics were balanced between treatment groups"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","Finerenone IR tablets (10 mg and 20 mg) and placebo tablets will be identical in appearance (size, shape, color). The packaging and labeling will be designed to maintain the blinding of the investigator’s team and the subjects. The study data will remain blinded until database lock and authorization of data release according to standard operating procedures.\r\n"]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","The statistical analyses will follow the intention-to-treat principle and will be based primarily on the full analysis set consisting of all randomized patients considered valid for analysis. "]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"PY"]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","death from cardiovascular causes"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","A Clinical Event Committee (CEC), blinded to study treatment assignment, will adjudicate all events that could potentially fulfill the criteria for the primary, secondary or other endpoints during the study.All potential outcome events are independently reviewed and adjudicated by a Clinical Event Committee, which consists of 3 subcommittees (cardiac, renal, and neuro). All potential outcome events are randomly distributed to 2 members of the appropriate subcommittee. If there is disagreement between the 2 initial reviewers, the event will be distributed to a third reviewer. If the third reviewer does not agree with either of the first 2 reviewers, the event will be reviewed at a panel meeting in order to reach a decision"]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","The main prespecified secondary endpoint is a composite of time to first occurrence of kidney failure, a sustained decrease of eGFR ≥40% from baseline over at least 4 weeks, or renal death."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","EXSCEL","Study ID","NCT01144338","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2017; 377:1228-1239","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Exenatide","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","death from cardiovascular causes","Results","Exenatide:133/1557 placebo:126/1620","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","An interactive voice-response system assigned patients on the basis of computer-generated block randomization within each site, with stratification according to history of cardiovascular disease. "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","The demographic, disease, and clinical characteristics of the patients did not differ significantly between the groups"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N"," Sufficient study medication will be provided to the study site for enrollment of all subjects. Study medication kits will be labeled with unique package numbers (this is not the subject randomization number). At Visit 1 (Day 0), study site personnel must contact the interactive voice response system (IVRS) to randomly assign subjects. The study-site personnel must call the IVRS at all subsequent visits (except Study Termination) to record the visit and confirm the kit assignment. The calls to the IVRS will ensure the resupply of additional kits required for upcoming visits. If medication is allocated to a subject incorrectly, the sponsor must be notified. At Study Termination or Early Termination, the site must call the IVRS to record study termination. TThe sponsor, the study-site personnel, and the subjects will be blinded to \r\ntreatment allocation. "]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","The time-to-event analyses were performed with the use of a Cox proportional-hazards model for primary, secondary, and exploratory outcomes in the intention-to-treat population, stratified according to history of cardiovascular disease, with trial regimen as an explanatory variable. The intention-to-treat population included all patients who underwent randomization. "]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","A total of 14,187 patients (96.2%) completed the trial, and vital status was obtained for 98.8% of the patients. "]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","death from cardiovascular causes"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","An independent clinical events classification committee whose members were unaware of the trial-group assignments adjudicated all the components of the primary composite outcome, secondary outcomes, ventricular arrhythmias that led to intervention, neoplasms, and pancreatitis; these events are defined in the Clinical Event Definitions section in the Supplementary Appendix."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","The statistical analysis plan prespecified the use of hierarchical testing in the following order: noninferiority for the primary composite outcome, superiority for the primary composite outcome, superiority for all-cause mortality, superiority for each component of the cardiovascular composite (tested with the use of the Hochberg procedure), and finally, if all three components were superior, superiority for hospitalization for acute coronary syndrome and for hospitalization for heart failure (tested with the use of the Hochberg procedure)."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]
[]
[]
["Unique ID","LEADER","Study ID","NCT01179048","Assessor","Zhang and Jiang"]
["Ref or Label","N Engl J Med 2017; 377:839-848   N Engl J Med 2016; 375:311-322      Am Heart J","Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Liraglutide","Comparator","placebo","Source"," Journal article(s); Trial protocol"]
["Outcome","death from cardiovascular causes","Results","Liraglutide:380/1116 placebo:109/1042","Weight",1]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Patients demonstrating ≥50% adherence to the regimen and willingness to continue with the injection protocol throughout the trial then underwent randomization, which was carried out for all subjects using the interactive voice/web response system. "]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","The characteristics of the patients at baseline were generally balanced between the trial groups"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"N","Liraglutide will be available at a concentration of 6.0 mg/mL and supplied in a 3 mL disposable pen-injector. Placebo is supplied in an identical disposable pen-injector. After randomisation, treatment with liraglutide or placebo will be double-blind throughout the trial. "]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"N"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"NA"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","The full analysis set includes all randomized subjects with evaluation by intention-to-treat, and subjects will be evaluated as randomized."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y"," The vital status was known in 99.7% of the patients. A total of 96.8% of the patients completed a final visit, died, or had a primary outcome."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","death from cardiovascular causes"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","There was no different between intervention groups in the measuremeant of the outcome"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"N","All components of the cardiovascular and microvascular endpoints will be adjudicated by an independent Adjudication Committee in a blinded manner. "]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"NA"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","Therefore, we report here the results of a prespecified analysis of the effects of liraglutide on renal outcomes.The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal (including silent) myocardial infarction, or nonfatal stroke. Prespecified exploratory outcomes included an expanded composite cardiovascular outcome (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina pectoris or heart failure), death from any cause, a composite renal and retinal microvascular outcome (nephropathy [defined as the new onset of macroalbuminuria or a doubling of the serum creatinine level and an eGFR of ≤45 ml per minute per 1.73 m2, the need for continuous renal-replacement therapy, or death from renal disease] and retinopathy [defined as the need for retinal photocoagulation or treatment with intravitreal agents, vitreous hemorrhage, or the onset of diabetes-related blindness]), neoplasms, and pancreatitis — all of which were adjudicated in a blinded fashion by an external, independent event-adjudication committee. "]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","there is only one possible way in which the outcome domian can be measured"]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N"]
[null,"Risk of bias judgement",null,null,"Low"]
["Overall bias","Risk of bias judgement",null,null,"Low"]