Section/topic	No	SPIRIT 2025 checklist item description	Manuscript page #s
Administrative information
Title and structured summary	1a	Title stating the trial design, population, and interventions, with identification as a protocol	Title page
1b	Structured summary of trial design and methods, including items from the World Health Organization Trial Registration Data Set	1
Protocol version	2	Version date and identifier	Title page
Roles and responsibilities	3a	Names, affiliations, and roles of protocol contributors	Title page
3b	Name and contact information for the trial sponsor	32
3c	Role of trial sponsor and funders in design, conduct, analysis, and reporting of trial; including any authority over these activities	32
3d	Composition, roles, and responsibilities of the coordinating site, steering committee, endpoint adjudication committee, data management team, and other individuals or groups overseeing the trial, if applicable	Not applicable
Open science
Trial registration	4	Name of trial registry, identifying number (with URL), and date of registration. If not yet registered, name of intended registry	1
Protocol and statistical analysis plan	5	Where the trial protocol and statistical analysis plan can be accessed	24-25
Data sharing	6	Where and how the individual de-identified participant data (including data dictionary), statistical code, and any other materials will be accessible	32
Funding and conflicts of interest	7a	Sources of funding and other support (for example, supply of drugs)	32
7b	Financial and other conflicts of interest for principal investigators and steering committee members	32
Dissemination policy	8	Plans to communicate trial results to participants, healthcare professionals, the public, and other relevant groups (for example, reporting in trial registry, plain language summary, publication)	25
Introduction
Background and rationale	9a	Scientific background and rationale, including summary of relevant studies (published and unpublished) examining benefits and harms for each intervention	2-4
9b	Explanation for choice of comparator	3-4
Objectives	10	Specific objectives related to benefits and harms	4-5
Methods: Patient and public involvement, trial design
Patient and public involvement	11	Details of, or plans for, patient or public involvement in the design, conduct, and reporting of the trial	6
Trial design	12	Description of trial design including type of trial (for example, parallel group, crossover), allocation ratio, and framework (for example, superiority, equivalence, non-inferiority, exploratory)	4-10
Methods: Participants, interventions, and outcomes
Trial setting	13	Settings (for example, community, hospital) and locations (for example, countries, sites) where the trial will be conducted	7-8
Eligibility criteria	14a	Eligibility criteria for participants	8-9
14b	If applicable, eligibility criteria for sites and for individuals who will deliver the interventions (for example, surgeons, physiotherapists)	16-17
Intervention and comparator	15a	Intervention and comparator with sufficient details to allow replication including how, when, and by whom they will be administered. If relevant, where additional materials describing the intervention and comparator (for example, intervention manual) can be accessed	15-18
15b	Criteria for discontinuing or modifying allocated intervention/comparator for a trial participant (for example, drug dose change in response to harms, participant request, or improving/worsening disease)	18
15c	Strategies to improve adherence to intervention/comparator protocols, if applicable, and any procedures for monitoring adherence (for example, drug tablet return, sessions attended)	12-15
15d	Concomitant care that is permitted or prohibited during the trial	8
Outcomes	16	Primary and secondary outcomes, including the specific measurement variable (for example, systolic blood pressure), analysis metric (for example, change from baseline, final value, time to event), method of aggregation (for example, median, proportion), and time point for each outcome	18-19
Harms	17	How harms are defined and will be assessed (for example, systematically, non-systematically)	5-6
Participant timeline	18	Time schedule of enrollment, interventions (including any run-ins and washouts), assessments, and visits for participants. A schematic diagram is highly recommended (see Table 2)	4
Sample size	19	How sample size was determined, including all assumptions supporting the sample size calculation	6-8
Recruitment	20	Strategies for achieving adequate participant enrollment to reach target sample size	9-10
Methods: Assignment of interventions
Randomization:	10-11
Sequence generation	21a	Who will generate the random allocation sequence and the method used	10
21b	Type of randomization (simple or restricted) and details of any factors for stratification. To reduce predictability of a random sequence, other details of any planned restriction (for example, blocking) should be provided in a separate document that is unavailable to those who enroll participants or assign interventions	10-11
Allocation concealment mechanism	22	Mechanism used to implement the random allocation sequence (for example, central computer/telephone; sequentially numbered, opaque, sealed containers), describing any steps to conceal the sequence until interventions are assigned	10-11
Implementation	23	Whether the personnel who will enroll and those who will assign participants to the interventions will have access to the random allocation sequence	10-11
Blinding	24a	Who will be blinded after assignment to interventions (for example, participants, care providers, outcome assessors, data analysts)	10-11
24b	If blinded, how blinding will be achieved and description of the similarity of interventions	Not applicable
24c	If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant’s allocated intervention during the trial	Not applicable
Methods: Data collection, management, and analysis
Data collection methods	25a	Plans for assessment and collection of trial data, including any related processes to promote data quality (for example, duplicate measurements, training of assessors) and a description of trial instruments (for example, questionnaires, laboratory tests) along with their reliability and validity, if known. Reference to where data collection forms can be accessed, if not in the protocol	19-23
25b	Plans to promote participant retention and complete follow-up, including list of any outcome data to be collected for participants who discontinue or deviate from intervention protocols	12-14, 18
Data management	26	Plans for data entry, coding, security, and storage, including any related processes to promote data quality (for example, double data entry; range checks for data values). Reference to where details of data management procedures can be accessed, if not in the protocol	23-24
Statistical methods	27a	Statistical methods used to compare groups for primary and secondary outcomes, including harms	23-25
27b	Definition of who will be included in each analysis (for example, all randomized participants), and in which group	23-25
27c	How missing data will be handled in the analysis	23-25
27d	Methods for any additional analyses (for example, subgroup and sensitivity analyses)	23-25
Methods: Monitoring
Data monitoring committee	28a	Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of whether it is independent from the sponsor and funder; conflicts of interest and reference to where further details about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not needed	23
28b	Explanation of any interim analyses and stopping guidelines, including who will have access to these interim results and make the final decision to terminate the trial	23
Trial monitoring	29	Frequency and procedures for monitoring trial conduct. If there is no monitoring, give explanation	14-15
Ethics
Research ethics approval	30	Plans for seeking research ethics committee/institutional review board approval	5-6
Protocol amendments	31	Plans for communicating important protocol modifications to relevant parties	5
Consent or assent	32a	Who will obtain informed consent or assent from potential trial participants or authorized proxies, and how	5
32b	Additional consent provisions for collection and use of participant data and biological specimens in ancillary studies, if applicable	Not applicable
Confidentiality	33	How personal information about potential and enrolled participants will be collected, shared, and maintained in order to protect confidentiality before, during, and after the trial	23-24
Ancillary and post-trial care	34	Provisions, if any, for ancillary and post-trial care, and for compensation to those who suffer harm from trial participation	5-6