Impact of Device-aided Therapies on Quality of Life in Patients with Parkinson´s Disease. A Comparative Multicenter Observational Study.
DiegoSantos-García1,2,3
ÁngelaSolleiro2
GuillermoGonzález-Ortega4
PabloMir5,6,7
NuriaLópez-Ariztegui8
InésLegarda9
MariaEstherRojas-Pérez10
AlejandroPeral-Quirós11
IriaCabo12
RocíoGarcía-Ramos13
PilarSánchez-Alonso14
JorgeHernández-Vara15
MartaBlázquez-Estrada16
ÁlvaroSánchez-Ferro6,17
DATs-PDGETM1
SpanishRegistryGroup1
Dr.
DiegoSantosGarcía18✉Phone+34 646173341Emaildiegosangar@yahoo.es1
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CHUAC, Complejo Hospitalario Universitario de A Coruña, A CoruñaSpain2Grupo de Investigación en Enfermedad de Parkinson y otros Trastornos del MovimientoINIBIC (Instituto de Investigación Biomédica de A Coruña), A CoruñaSpain
3Hospital San RafaelA Coruña. 4 Fundación Degen, A CoruñaSpain
4Hospital Universitario de MóstolesMadridSpain
5Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de SevillaUnidad de Trastornos del Movimiento, Hospital Universitario Virgen del Rocío, CSIC/Universidad de SevillaSevilleSpain
6CIBERNED (Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas)Spain
7Departamento de Medicina, Facultad de MedicinaUniversidad de SevillaSevillaSpain
8Hospital Universitario de ToledoToledoSpain
9Hospital Universitario Son EspasesPalma de MallorcaSpain
10Hospital Universitario de la Candelaria, Santa Cruz de TenerifeSpain
11Consorci Sanitari Integral, Hospital Moisés Broggi, Sant Joan DespíBarcelonaSpain
12Complejo Hospitalario Universitario de Pontevedra (CHOP)PontevedraSpain
13Hospital Universitario Clínico San CarlosMadridSpain
14Hospital Universitario Puerta de HierroMadridSpain
15Hospital Vall d´hebronBarcelonaSpain
16Hospital Universitario Central de Asturias (HUCA)OviedoSpain
17Hospital 12 de OctubreMadridSpain
18Department of NeurologyHospital Universitario de A Coruña (HUAC), Complejo Hospitalario Universitario de A Coruña (CHUAC)C/ As Xubias 8415006A CoruñaSpain
Diego Santos-García1,2,3,4, Ángela Solleiro2, Guillermo González-Ortega5, Pablo Mir6,7,8, Nuria López-Ariztegui9, Inés Legarda10, Maria Esther Rojas-Pérez11, Alejandro Peral-Quirós12, Iria Cabo13, Rocío García-Ramos14, Pilar Sánchez-Alonso15, Jorge Hernández-Vara16, Marta Blázquez-Estrada17, Álvaro Sánchez-Ferro7,18; DATs-PD GETM Spanish Registry Group (Appendix 1).
1CHUAC, Complejo Hospitalario Universitario de A Coruña, A Coruña, Spain. 2Grupo de Investigación en Enfermedad de Parkinson y otros Trastornos del Movimiento, INIBIC (Instituto de Investigación Biomédica de A Coruña), A Coruña, Spain. 3Hospital San Rafael, A Coruña. 4Fundación Degen, A Coruña, Spain. 5Hospital Universitario de Móstoles, Madrid, Spain. 6Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain. 7CIBERNED (Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas), Spain. 8Departamento de Medicina, Facultad de Medicina, Universidad de Sevilla, Sevilla, Spain. 9Hospital Universitario de Toledo, Toledo, Spain. 10Hospital Universitario Son Espases, Palma de Mallorca, Spain. 11Hospital Universitario de la Candelaria, Santa Cruz de Tenerife, Spain. 12Consorci Sanitari Integral, Hospital Moisés Broggi, Sant Joan Despí, Barcelona, Spain. 13Complejo Hospitalario Universitario de Pontevedra (CHOP), Pontevedra, Spain. 14Hospital Universitario Clínico San Carlos, Madrid, Spain. 15Hospital Universitario Puerta de Hierro, Madrid, Spain. 16Hospital Vall d´hebron, Barcelona, Spain. 17Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain. 18Hospital 12 de Octubre, Madrid, Spain.
Word count: abstract, 247; text, 4,430 (without references). Tables: 5. Figures: 4.
Supplementary Material
None.
Running title
Effect of DATs on Quality of Life in Parkinson´s Disease.
Keywords:
Device-aided therapies
Deep Brain stimulation
Infusion
Parkinson´s disease
Quality of life
Subcutaneous
*Corresponding author:
Dr. Diego Santos García, Department of Neurology, Hospital Universitario de A Coruña (HUAC), Complejo Hospitalario Universitario de A Coruña (CHUAC), C/ As Xubias 84, 15006, A Coruña, Spain; e-mail: diegosangar@yahoo.es; Tel: + 34 646173341.
Abbreviations:
ADLS
Schwab and England Activities of Daily Living Scale
CSAI
continuous subcutaneous apomorphine infusion
DAT
device-aided therapy
DBS
deep brain stimulation
EUROHIS-QOL8
European Health Interview Survey-Quality of Life 8-item index
fLD/fCD
foslevodopa-foscarbidopa
FOG
freezing of gait
H&Y
Hoehn & Yahr
LCIG
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levodopa-carbidopa intestinal gel infusionLECIG
levodopa-entacapone-carbidopa intestinal gel infusion
LEED
levodopa equivalent daily dose
MSs
Motor Symptoms score
NMS
non-motor symptoms
NMSs
Non-Motor Symptoms score
PD
Parkinson´s disease
PDQ-39SI
39-item Parkinson’s Disease Quality of Life Questionnaire
PwP
people with Parkinson´s disease
QoL
quality of life
PIGD
postural instability gait difficulty
UPDRS
Unified Parkinson´s Disease Rating Scale.
ABSTRACT
Background and objective:
Device aided-therapies (DATs) improve health-related quality of life (HRQoL) in patients with Parkinson´s disease (PwP). However, no studies comparing all DATs have been conducted to date. Our aim was to compare the effect of different DATs on HRQoL and other disease-related variables in PwP.
Patients and Methods:
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Data from baseline (V1) and the 6-month follow-up visit (V3.6M) were collected from a descriptive, observational, prospective, multicenter, clinical registry conducted in Spain entitled DATs-PD GETM Spanish Registry. The primary endpoint was the change from V1 to V3.6M in the 39-item Parkinson's Disease Questionnaire (PDQ-39) total score. Relative change (RC) and Cohen´s d (d) effect were applied. The effect over many other variables was also analyzed.Results
HRQoL improved significantly in the entire cohort (N = 137) with a moderate decrease of 13.4% in the PDQ-39 total score (from 58.9 ± 22.9 at V1 to 51.0 ± 26.8 at V3.6M; d = 0.51; p < 0.0001). No differences in the change of the PDQ-39 total score were detected between both subcutaneous therapies (i.e., foslevodopa/foscarbidopa [fLD/fCD] and continuous subcutaneous apomorphine infusion [CSAI]; p = 0.666) and between subcutaneous and enteral therapies (p = 0.721). Although a greater improvement in HRQoL was observed in PwP treated with deep brain stimulation (DBS) (N = 30; RC=-26.3%; d = 0.83; p = 0.002) compared to those who received a pump system (N = 107; RC=-10.2%; d = 0.41; p = 0.003) (p = 0.009), the effect was not significant after adjustment to age, sex, and disease duration (p = 0.161). Off time, dyskinesia, motor symptoms, and non-motor symptoms improved significantly in the entire cohort.
Conclusion
HRQoL improved in PwP after being treated with a DAT.
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INTRODUCTION
There is currently no curative treatment for patients with Parkinson´s disease (PwP), and research is underway into various molecules that could potentially slow disease progression. From a practical perspective, and in the context of a neurodegenerative disease such as Parkinson´s disease (PD), management is currently symptomatic, with the goal of improving some of the patient's symptoms, which may help them perceive a better quality of life (QoL) and greater autonomy for activities of daily living (ADL) [1]. Symptomatic treatment includes dopaminergic therapy but also therapies that act at the level of other neurotransmitters. First-line medication (i.e., oral medication and rotigotine patch) and on-demand therapies (i.e., inhaled levodopa, sublingual and subcutaneous apomorphine pen) may be sufficient to optimize patients' response initially [2]. However, device aided-therapy (DAT) may be indicated in PwP who develop clinical fluctuations with a good response to levodopa but who alternate with disabling OFF episodes [3]. Deep brain stimulation (DBS), continuous subcutaneous apomorphine infusion (CSAI), and levodopa-carbidopa intestinal gel infusion (LCIG) have been used in many countries for many years [4]. But new DATs have recently emerged, such as levodopa-entacapone-carbidopa intestinal gel infusion (LECIG) and subcutaneous infusion of foslevodopa-foscarbidopa (fLD/fCD) [5, 6]. In this new scenario where there are different options, it is of utmost interest to compare the effectiveness as well as the safety and tolerability between the different DATs under daily clinical practice conditions. Particularly considering the symptomatic nature of these therapies, improving QoL and autonomy for ADL can be considered a primary objective to be achieved, and comparing differences between them is particularly relevant. There are very few studies comparing the differences in effect between DBS, CSAI, and LCIG, but no data with the new therapies, LECIG and fLD/fCD [7–9]. To our knowledge, the only study published to date in which all DATs were included is a Spanish cohort study that analyzed in detail the profile of PwP treated with each of these therapies during the year 2024 (N = 313), with approximately half of the DATs prescribed being f/LD/fCD and less than 11% being enteral therapies [10].
The aim of this study was to compare the effect that different DATs cause in PwP on the QoL and autonomy for ADL. Changes in motor and non-motor symptoms (NMS), as well as tolerability and safety, were also analyzed.
METHODS/DESIGN
Data for the analysis conducted in this study were obtained from the Device-Aided Therapies in Parkinson´s Disease GETM Spanish Registry (DATs-PD GETM Spanish Registry) [11]. This is a descriptive, observational, prospective, multicenter, open study proposed as a clinical registry with progressive inclusion of PwP treated with a DAT in daily clinical practice conditions. The methodology of the DATs-PD GETM Spanish Registry has recently been published and can be consulted [11]. Regarding this specific proposal, the study was designed as an open-label, prospective, observational, 6-month, multicenter comparative study.
Eligibility criteria
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More than 30 centers from Spain with neurology teams with experience in the management of PD (Appendix 1) are participating in the DATs-PD GETM Spanish Registry. PwP treated with a DAT should be sequentially included according to the DATs-PD GETM Spanish Registry protocol: DBS, fLD/fCD, CSAI, LCIG, and LECIG. Specifically, the eligibility criteria are [11]: 1) diagnosis of PD according to the MDS criteria [12]; 2) start of treatment with a DAT from January 1, 2024; 3) the patient's desire to participate on a completely voluntary basis; 4) signing of an informed consent.Visits
The registry includes 3 types of visits: 1) baseline visit (V1), which is when the DAT is indicated by the neurologist; 2) start visit (V2), which is when the DAT is initiated by the patient; 3) follow-up visit (V3), with the patient already receiving the DAT. The first follow-up visit is at 6 months +/- 3 months (V3.6M) and then annually for at least 5 years. For the present study in particular, a follow-up time of 6 ± 3 months was considered; that is, data from visits V1, V2, and V3.6M were taken into account.
Assessments
Data collected from visits V1, V2, and V3.6M [11] were considered for the analysis. Two types of analysis were conducted: “effectiveness analysis” and “safety analysis”. For the effectiveness analysis, only PwP who completed visit 3.6M on a date no later than May 30, 2025, were included. For the safety analysis (a brief analysis as it was not the real objective of this study), all PwP treated with a DAT until 30/MAY/2025 were included. In addition to sociodemographic and non-PD and PD-related data, the following assessments were applied at each site when evaluated in clinic: Unified Parkinson´s Disease Rating Scale (UPDRS-III) [13]; Hoehn & Yahr (H&Y) [14]; the 39-item Parkinson's Disease Questionnaire (PDQ-39) [15]; European Health Interview Survey-Quality of Life 8-item index (EUROHIS-QOL8) [16]; and Schwab and England Activities of Daily Living Scale (ADLS) [17].
Moreover, information about 16 motor symptoms was collected: percentage of the awaking day during the OFF state (0%; 1–25%; 26–50%; 51–75%; 76–100%); OFF time (hours) per day; percentage of the awaking day with dyskinesia (0%; 1–25%; 26–50%; 51–75%; 76–100%); dyskinesia severity; painful dyskinesia; nocturnal akinesia; morning akinesia; morning dystonia; freezing of gait (FOG) during the OFF state; FOG during the ON state; falls; posture; tremor during the OFF state; tremor during the ON state; hypomimia; speech problems. A score for 15 out of 16 symptoms (OFF time per day was excluded) from 0 to 4 (0, no symptom; 1, slight; 2, moderate; 3, severe; 4, very severe; or according to the percentage if applicable) and a total Motor Symptoms score (MSs) from 0 (15 x 0; minimum) to 60 (15 x 4; maximum) was calculated. Specifically, a Dyskinesia score was calculated using the items “percentage of the awaking day with dyskinesia”, “dyskinesia severity”, and “painful dyskinesia”, ranging from 0 (3 x 0; minimum) to 12 (3 x 4; maximum). Regarding NMS, information about 20 different aspects was collected: visual hallucinations; psychosis; impulse control disorder; depression; anxiety; apathy; REM behavior disorder; restless legs; falling asleep insomnia; maintenance insomnia; diurnal somnolence; nicturia; other urinary symptoms; symptomatic orthostatic hypotension; constipation; sialorrhea; dysphagia; fatigue; PD-related pain; sweating. Similarly, as with the motor symptoms, the same methodology was applied with NMS, and a score for each item from 0 to 4 and a total Non-Motor Symptoms score (NMSs) from 0 (20 x 0; minimum) to 80 (20 x 4; maximum) was calculated. Moreover, 4 NMS domains scores were defined: Psychiatric/mood score was calculated using the items “visual hallucinations”, “psychosis”, “impulse control disorder”, “depression”, “anxiety”, and “apathy”, ranging from 0 (6 x 0; minimum) to 24 (6 x 4; maximum); Sleep/fatigue score was calculated using the items “REM behavior disorder”, “restless legs”, “falling asleep insomnia”, “maintenance insomnia”, “diurnal somnolence”, and “fatigue”, ranging from 0 (6 x 0; minimum) to 24 (6 x 4; maximum); Dysautonomia score was calculated using the items “other urinary symptoms”, “symptomatic orthostatic hypotension”, “constipation”, and “sweating”, ranging from 0 (4 x 0; minimum) to 16 (4 x 4; maximum); Pain score according to the item “PD-related pain” (from 0 to 4). Conversion of doses of medicines to L-dopa equivalent daily dose (LEDD) was carried out following Nyholm & Jost [18].
Data collection and statistical analysis
Data were collected using REDCap (https://project-redcap.org/). This is a web application for managing online surveys and databases. REDCap has been used to date in more than 160 countries by more than 3,700,000 users. It offers a free, easy-to-use, and secure method of flexible yet robust data collection. Data collected were transferred to a statistical package for subsequent analysis (SPSS 20.0 for Windows). Remote monitoring of the data was carried out (A.S.). Because the data were obtained from the registry, the sample size was considered according to the data available for each of the analysis variables.
Different variables were expressed as quantitative and/or qualitative variables. After checking of normality for continuous variables (Shapiro-Wilk's test), comparisons were carried out intra- and intergroup, applying parametric (Student's t test for paired or unpaired data) or nonparametric tests (Wilcoxon's/Mann-Whitney's tests). Proportions were compared by chi-squared test. For evaluating the magnitude of the change, in addition to the difference between V1 and V3.6M, the relative change [RC = mean (TestV3.6M – TestV1) × 100/mean TestV1)] [19] and Cohen's d effect size [ES = mean (TestV3.6M – TestV1)/SD TestV1] [20] were calculated. Cohen’s d effect size was considered to be: absent, < 0.2; small, 0.2 – <0.5; moderate, 0.5 – <0.8; large, 0.8–1.3; or very large, ≥ 1.3. P values were computed using general linear models (GLM) repeated measures without and after adjustment to covariates (age, sex, and disease duration).
The primary endpoint was the change from V1 to V3.6M in the PDQ-39 total score (health-related QoL). The PDQ-39 includes 39 items grouped into 8 domains: (1) Mobility (items 1 to 10); (2) Activities of daily living (ADL) (items 11 to 16); (3) Emotional well-being (items 17 to 22); (4) Stigma (items 23 to 26); (5) Social support (items 27 to 29); (6) Cognition (items 30 to 33); (7) Communication (items 34 to 36); (8) Pain and discomfort (items 37 to 39). For each item, the score may range from 0 (never) to 4 (always). The symptoms refer to the 4 weeks prior to assessment. Domain total scores were expressed as a percentage of the corresponding maximum possible score, and a summary index is obtained as the average of the domain scores. Analysis addressed the following other points: 1) change from V1 to V3.6M in the EUROHIS-QOL8 total score (global QoL); 2) change from V1 to V3.6M in ADLS total score; 3) change from V1 to V3.6M in the OFF time per day; 4) change from V1 to V3.6M in the MSs; 5) change from V1 to V3.6M in the NMSs; 6) adverse effects (AEs) and frequency of discontinuation of the therapy and reasons.
Standard protocol approvals, registrations, and patient consents
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The project is being conducted in accordance with the ICH Good Clinical Practice version 6 Revision 2 standard, the fundamental ethical principles established in the Declaration of Helsinki and the Oviedo Convention, as well as the Spanish legal requirements for biomedical research (Biomedical Research Law 14/2007). The Project has been approved on 02/APR/2024 by the IRB “Comité de Ética de la Investigación Clínica de Galicia from Spain” with code number 2024/109. A
Written informed consents from all participants in this study were obtained.Data availability
The protocol, statistical analysis plan and unidentified participant data will be available on request.
RESULTS
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A total of 232 PwP (66.5 ± 9.3 years old at V2; 63.5% males) were treated with a DAT and included in the analysis. The most frequent was fLD/fCD (42.2%), followed by DBS (26.3%), CSAI (18.5%), LECIG (9.9%), and LCIG (3%). Subcutaneous therapies accounted for 60.8%, while enteral therapies accounted for 12.9%. PwP treated with DBS were younger than those treated with a pump system (60.6 ± 6.8 vs 68.6 ± 9.2; p < 0.0001) and had a primary caregiver less frequently (30% vs 62.9%; p < 0.0001) (Table 1). Regarding PD-related variables, differences between groups were observed in disease duration (p = 0.024), previous psychosis (p = 0.043), time with fluctuations (p = 0.002), daily OFF time (p < 0.0001), H&Y-OFF (p = 0.010), UPDRS-III-OFF (p = 0.010), UPDRS-III-ON (p < 0.0001), NMSs (p = 0.001), ADLS-OFF (p < 0.0001), and ADLS-ON (p = 0.001) (Table 2). Specifically, PwP treated with DBS had a less severe overall condition compared to those treated with a pump, with a lower burden of NMS (NMSs 8.3 ± 5.7 vs 12.8 ± 7.3; p < 0.0001), a lower UPDRS-III score in OFF (33.9 ± 9.5 vs 39.4 ± 12.3; p = 0.003) and ON (14.3 ± 8.1 vs 21.5 ± 11.0; p < 0.0001) states, and a better health-related QoL (PDQ-39, 49.1 ± 23.0 vs 60.8 ± 23.4; p = 0.004) and greater autonomy in OFF (74.0 ± 17.4 vs 55.1 ± 22.7; p < 0.0001) and ON (89.1 ± 12.6 vs 79.1 ± 17.4; p < 0.0001) states (Table 2). Regarding PD treatment, 41.3% of PwP had received an on-demand therapy before starting with the DAT and up to 26.1% a previous DAT, being more frequent in those who were treated with enteral therapy (46.7%) and less in those treated with CSAI (7%) (Table 2).DBS N = 61 | fLD/fCD N = 98 | CSAI N = 43 | LCIG N = 7 | LECIG N = 23 | LCIG/LECIG N = 30 | DATs-pump N = 171 | All cohort N = 232 | pa | pb | pc | pd | |
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Age at initiation of DAT Gender (males) (%) Principal caregiver (%): Civil status (%): -Married -Single -Widowed -Other Living style (%): -With the partner -Alone -With a son/daughter -Institutionalized -Other Comorbidities (%): - Arterial hypertension - Diabetes mellitus - Dyslipemia - AF/arrhythmia - Ischemic cardiopathy - Lung disease - Renal disease - Polyneuropathy Treatments (%): - Antihypertensive - Antidiabetics - Hypolipidemic agents - Antidepressant - Benzodiazepine - Antipsychotic - Anti-dementia | 60.6 ± 6.8 72.1 30 70.5 18 0 11.5 75.4 13.1 4.9 1.6 4.9 24.6 10 23 4.9 0 4.9 0 0 25 8.2 16.4 26.2 29.5 4.9 0 | 68.5 ± 8.7 60.8 65.3 72.4 14.4 6.1 7.1 73.5 12.2 3.1 2 9.2 42.9 14.4 28.6 7.1 3.1 9.2 4.2 2.1 39.8 14.3 23.7 34.7 40.2 14.3 12.2 | 67.9 ± 8.9 57.1 57.1 81.4 9.3 7 2.3 81.4 9.3 7 0 2.3 46.5 25.6 34.9 7 4.7 4.7 4.7 0 41.9 20.9 30.2 27.9 39.4 7 0 | 62.4 ± 16.5 85.7 100 71.4 14.3 14.3 0 71.4 14.3 0 0 14.3 14.3 14.3 28.6 0 14.3 0 0 0 14.3 14.3 14.3 0 14.3 0 0 | 71.9 ± 8.2 56.5 52.2 82.6 0 8.7 8.7 82.6 13 4.4 0 0 52.2 21.7 39.1 0 4.3 4.3 8.7 4.3 47.8 21.7 43.5 52.2 60.9 21.7 17.4 | 69.7 ± 11.2 63.3 63.3 80 3.3 10 6.7 80 13.4 3.3 0 3.3 43.3 20 36.7 0 6.7 3.3 6.7 3.3 40 20 36.7 40 50 16.7 13.3 | 68.6 ± 9.2 60.4 62.9 76 11.1 7 5.9 76.6 11.7 4.1 1.2 6.4 43.9 18.2 31.6 5.8 4.1 7 4.7 1.8 40.4 17 27.6 33.9 40.6 12.9 9.4 | 66.5 ± 9.3 63.5 54.3 74.6 12.9 5.2 7.3 76.6 11.7 4.1 1.2 6.4 38.8 16.1 29.3 5.6 3 6.5 3.5 1.3 36.4 14.7 24.7 31.9 37.7 10.8 6.9 | < 0.0001 0.291 < 0.0001 0.287 0.932 0.034 0.260 0.569 0.658 0.243 0.676 0.328 0.467 0.126 0.364 0.099 0.056 0.060 0.099 0.002 | 0.718 0.412 0.233 0.541 0.353 0.348 0.430 0.738 0.520 0.541 0.749 0.603 0.608 0.481 0.228 0.270 0.278 0.343 0.173 0.010 | 0.444 0.439 0.588 0.661 0.885 0.557 0.479 0.324 0.137 0.355 0.341 0.431 0.444 0.567 0.398 0.160 0.284 0.170 0.335 0.300 | < 0.0001 0.068 < 0.0001 0.045 0.982 0.006 0.096 0.133 0.540 0.114 0.410 0.081 0.397 0.023 0.069 0.055 0.172 0.083 0.063 0.006 |
| The results represent percentages, mean ± SD or median [p25, p75]; pa, comparison between all DATs; pb, comparison between both subcutaneous therapies, fLD/fCD and CSAI; pc, comparison between subcutaneous (fLD/fCD + SCAI) and enteral therapies (LCGI + LECIG); pd, comparison between DBS and DATs using a pump (DATs-pump). Chi-square, ANOVA, t-Student and/or Mann-Whitney-Wilcoxon tests were applied according to the type of analysis and distribution of the variables. P values < 0.05 are shown in bold. | ||||||||||||
| AF, atrial fibrillation; CSAI, continuous subcutaneous apomorphine infusion; DAT, device-aided therapy; DBS, deep brain stimulation; fLD/fCD, foslevodopa-foscarbidopa; LCIG, levodopa-carbidopa intestinal gel infusion; LECIG, levodopa-entacapone-carbidopa intestinal gel infusion; PwP, patients with Parkinson´s disease. | ||||||||||||
DBS N = 61 | fLD/fCD N = 98 | CSAI N = 43 | LCIG N = 7 | LECIG N = 23 | LCIG/LECIG N = 30 | DATs-pump N = 171 | All cohort N = 232 | pa | pb | pc | pd | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
Disease duration (y) Motor phenotype (%): - Tremor dominant - Indeterminate - PIGD Treatment for PD (%): - MAO-B inhibitor - Dopamine agonist - COMT inhibitor - Amantadine Previous ODT Previous DAT LEDD (mg) Previous psychosis (%) Cognitive impairment (%): - MCI (%) - Dementia (%) Time with fluctuations (y) H&Y – OFF H&Y – ON UPDRS – III – OFF UPDRS – III – ON Daily OFF time (h) MSs Dyskinesia score NMSs PDQ-39 EUROHIS-QOL8 ADLS – OFF ADLS – ON | 11.4 ± 4.9 29.4 37.3 33.3 71.7 70.0 63.3 31.7 36.7 26.7 1352.7 ± 526.6 3.3 19.7 0 4.4 ± 2.4 3 [2, 3] 2 [1, 2] 33.9 ± 9.5 14.3 ± 8.1 4.5 ± 2.1 9.9 ± 4.4 2.9 ± 2.3 8.3 ± 5.7 49.1 ± 23.0 24.7 ± 4.1 74.0 ± 17.4 89.1 ± 12.6 | 14.5 ± 10.3 22.6 38.7 38.7 72.4 46.9 57.1 27.6 39.2 27.8 1385.9 ± 576.2 17.3 29.9 3.1 5.9 ± 3.5 3 [2, 4] 2 [2, 2] 37.8 ± 11.6 19.6 ± 10.9 4.6 ± 2.4 9.3 ± 4.7 2.8 ± 2.3 13.0 ± 7.4 60.4 ± 21.7 24.1 ± 4.9 56.1 ± 22.9 80.5 ± 15.3 | 10.7 ± 3.9 28.9 23.7 47.4 88.4 69.8 58.1 20.9 60.5 7.0 1238.5 ± 446.0 4.7 20.9 0 4.2 ± 2.3 3 [2, 3] 2 [2, 2] 38.2 ± 10.8 23.5 ± 10.2 4.9 ± 2.9 9.4 ± 4.3 2.2 ± 1.9 11.4 ± 7.9 60.8 ± 28.6 22.6 ± 5.6 58.1 ± 22.7 88.8 ± 18.2 | 9.9 ± 2.9 50.0 16.7 33.3 42.9 28.6 42.9 0 28.6 42.9 1561.5 ± 1061.8 14.3 42.9 0 4.6 ± 2.4 3 [2, 4] 2 [2, 2] 46.0 ± 14.3 25.8 ± 12.6 6.1 ± 2.7 8.7 ± 2.9 1.6 ± 1.1 14.6 ± 6.2 60.5 ± 12.1 22.2 ± 2.8 50.0 ± 21.6 70.0 ± 20.0 | 12.4 ± 3.3 42.9 33.3 23.8 56.5 43.5 43.5 17.4 30.4 47.8 1552.5 ± 818.2 13 30.4 8.7 6.2 ± 2.5 3 [3, 4] 2 [2,2.8] 45.6 ± 14.5 24.6 ± 11.4 7.2 ± 3.8 9.9 ± 2.8 2.3 ± 1.8 13.9 ± 6.0 63.3 ± 22.7 22.8 ± 3.5 46.8 ± 21.4 74.2 ± 21.4 | 11.8 ± 3.3 44.4 29.6 25.9 53.5 40.0 43.3 13.3 30.0 46.7 1555.2 ± 868.7 13.3 33.3 6.7 5.9 ± 2.5 3 [3, 4] 2 [2,2.5] 45.6 ± 14.2 24.9 ± 11.4 6.9 ± 3.6 9.7 ± 2.8 2.1 ± 1.7 14.0 ± 5.9 62.7 ± 20.7 22.7 ± 3.2 47.7 ± 21.0 73.1 ± 20.7 | 13.1 ± 8.3 27.8 33.5 38.6 73.1 51.5 55.0 23.4 42.9 25.9 1372.9 ± 606.1 13.5 28.2 2.9 5.4 ± 3.2 3 [2, 4] 2 [2, 2] 39.4 ± 12.3 21.5 ± 11.0 5.1 ± 2.9 9.4 ± 4.3 2.6 ± 2.1 12.8 ± 7.3 60.8 ± 23.4 23.5 ± 4.9 55.1 ± 22.7 79.1 ± 17.4 | 12.6 ± 7.6 28.3 34.4 37.3 72.7 56.3 57.1 25.5 41.3 26.1 1367.8 ± 585.9 10.8 26 2.2 5.2 ± 3.0 3 [2, 4] 2 [2, 2] 37.9 ± 11.8 19.5 ± 10.8 4.9 ± 2.7 9.5 ± 4.3 2.7 ± 2.1 11.6 ± 7.2 57.9 ± 23.8 23.7 ± 4.7 60.3 ± 22.9 81.9 ± 16.7 | 0.024 0.389 0.021 0.005 0.510 0.279 0.066 0.005 0.460 0.043 0.150 0.002 0.010 0.557 0.001 < 0.0001 < 0.0001 0.909 0.213 0.001 0.083 0.365 < 0.0001 0.001 | 0.021 0.258 0.028 0.010 0.531 0.271 0.016 0.003 0.184 0.032 0.360 0.006 0.227 0.870 0.868 0.068 0.446 0.923 0.141 0.235 0.931 0.195 0.668 0.937 | 0.370 0.094 0.009 0.119 0.014 0.113 0.046 0.006 0.146 0.624 0.244 0.380 0.104 0.833 0.002 0.088 < 0.0001 0.740 0.244 0.220 0.700 0.453 0.065 0.045 | 0.146 0.789 0.477 0.009 0.165 0.138 0.396 0.515 0.841 0.028 0.143 0.022 0.003 0.044 0.003 < 0.0001 0.122 0.502 0.192 < 0.0001 0.004 0.198 < 0.0001 < 0.0001 |
| The results represent percentages, mean ± SD or median [p25, p75]; pa, comparison between all DATs; pb, comparison between both subcutaneous therapies, fLD/fCD and CSAI; pc, comparison between subcutaneous (fLD/fCD + SCAI) and enteral therapies (LCGI + LECIG); pd, comparison between DBS and DATs using a pump (DATs-pump). Chi-square, ANOVA, t-Student and/or Mann-Whitney-Wilcoxon tests were applied according to the type of analysis and distribution of the variables. P values < 0.05 are shown in bold. The information was not collected for all patients. The lowest sample size was N = 139 for EUROHIS-QOL8 (59.9%), N = 175 for PDQ-39 (75.4%), N = 190 (81.9%) for ADLS – OFF, and N = 192 (82.8%) for ADLS – OFF; the sample was > 90% for the rest of variables. | ||||||||||||
| ADL, Schwab and England Activities of Daily Living Scale; BMI, body mass index; COMT, catechol-O-methyltransferase; CSAI, continuous subcutaneous apomorphine infusion; DAT, device-aided therapy; DBS, deep brain stimulation; EUROHIS-QOL8, European Health Interview Survey-Quality of Life 8-item index; fLD/fCD, foslevodopa-foscarbidopa; H&Y, Hoehn & Yahr; LCIG, levodopa-carbidopa intestinal gel infusion; LECIG, levodopa-entacapone-carbidopa intestinal gel infusion; LEED, levodopa equivalent daily dose; MAO-B, type-B monoamine oxidase; MCI, mild cognitive impairment; MSs, motor symptoms score; NMSs, non-motor symptoms score; ODT, on-demand therapy (i.e., inhaled levodopa or apomorphine); PDQ-39SI, 39-item Parkinson’s Disease Quality of Life Questionnaire; PIGD, postural instability gait difficulty; UPDRS, Unified Parkinson´s Disease Rating Scale; y, years. | ||||||||||||
The mean follow-up time (days) was 190.3 ± 71.1: LCIG 230.6 ± 32.9; DBS 217.5 ± 111.4; LECIG 191.2 ± 46.0; CSAI 182.4 ± 45.3; fLD/fCD 173.1 ± 46.5. Health-related QoL improved significantly in the entire cohort with a moderate decrease of 13.4% in the PDQ-39 total score (N = 137; from 58.9 ± 22.9 at V1 to 51.0 ± 26.8 at V3.6M; Cohen’s d = 0.51; p < 0.0001). Of all DATs, the PDQ-39 total score decreased from V1 to V3.6M significantly only in PwP treated with DBS (RC = -26.3%; Cohen’s d = 0.83; p = 0.002) and with fLD/fCD (RC = -12.6%; Cohen’s d = 0.46; p = 0.009) (Fig. 1A and Table 3). No differences in the change of the PDQ-39 total score were detected between both subcutaneous therapies (i.e., fLD/fCD and CSAI; p = 0.666) and between subcutaneous and enteral therapies (p = 0.721) (Table 3). Although a greater improvement in health-related QoL was observed in PwP treated with DBS compared to those who received a pump system (RC = -10.2%; Cohen’s d = 0.41; p = 0.003) (p = 0.009), the effect was not significant after adjustment to age, sex, and disease duration (p = 0.161) (Table 3). By domains, significant improvement was observed in the entire cohort in “Mobility” (p < 0.0001), “Daily activities” (p < 0.0001), “Emotional state” (p = 0.014), “Communication” (p = 0.042), and “Bodily discomfort” (p = 0.004), with the greatest improvement in “Daily activities” (RC = -17.5%) and “Mobility” (RC = -15.9%) (Table 3). Of all DATs, PwP treated with DBS had the greatest improvement in “Mobility” (p = 0.002), “Daily activities” (p = 0.036), and Stigma (p = 0.029), but again without statistical significance after adjustment to covariates (Table 3 and Fig. 2A). Only PwP treated with DBS had a significantly greater decrease than those who received a pump system in the Mobility domain score (p = 0.029) independently of age, sex, and disease duration. No differences were found between subcutaneous therapies in the change from V1 to V3.6M in any of the PDQ-39 domains (Table 3 and Fig. 2B). “Stigma” impaired in PwP treated with an enteral therapy compared to those who received a subcutaneous therapy (p = 0.016), but cognition improved significantly more in PwP who received an enteral therapy compared to those treated with a subcutaneous therapy (p = 0.038) even after adjustment to covariates (Table 3 and Fig. 2C). With respect to global QoL (EUROHIS-QOL8 total score), no significant change was detected from V1 to V3.6M in either the entire cohort or any specific DAT group (Table 4 and Fig. 1B). However, by domains, improvement was observed in “Overall QoL” (p = 0.004), “General health” (p < 0.0001), and “Activity” (p = 0.034), with a significantly greater improvement in “General health” in PwP treated with DBS (RC = + 30.4%; Cohen’s d = 1.00; p = 0.002) compared to the rest of DATs (RC = + 14.3; Cohen´s d = 0.45; p = 0.006) even after adjustment to age, sex, and disease duration (p = 0.015, all DATs; p = 0.037, DBS vs DATs-pump).
Fig. 1
Change from V1 to V3.6M in the mean PDQ-39 total score (A) and EUROHIS-QOL8 total score (B) of PwP treated with a different DAT. *, p < 0.005. Data are presented as box plots, with the box representing the median and the two middle quartiles (25–75%). Mild outliers (O) are data points that are more extreme than Q1–1.5. CSAI, continuous subcutaneous apomorphine infusion; DBS, deep brain stimulation; DAT, device-aided therapy; EUROHIS-QOL8, European Health Interview Survey-Quality of Life 8-item index; fLD/fCD, foslevodopa/foscarbidopa; LCIG, levodopa-carbidopa intestinal gel infusion; LECIG, levodopa-entacapone-carbidopa intestinal gel infusion; PDQ-39SI, 39-item Parkinson’s Disease Quality of Life Questionnaire; PwP, patients with Parkinson´s disease.
DBS N = 30 | fLD/fCD N = 64 | CSAI N = 28 | LCIG N = 4 | LECIG N = 11 | LCIG/LECIG N = 15 | DATs-pump N = 107 | All cohort N = 137 | pa | pb | pc | pd | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
PDQ-39 total score V1 V3.6M Relative change % Cohen´s effect size p value (change) | 52.5 ± 21.6 38.7 ± 24.0 -26.3 0.83 0.002 | 61.1 ± 21.9 53.4 ± 25.2 -12.6 0.46 0.009 | 61.1 ± 26.7 57.9 ± 32.3 -5.3 0.25 0.342 | 60.5 ± 12.1 56.3 ± 9.9 -6.9 1.22 0.144 | 58.0 ± 24.5 51.4 ± 24.9 -11.4 0.46 0.374 | 58.7 ± 21.6 52.7 ± 21.7 -10.2 0.49 0.256 | 60.7 ± 23.1 54.5 ± 26.7 -10.2 0.41 0.003 | 58.9 ± 22.9 51.0 ± 26.8 -13.4 0.51 < 0.0001 | 0.128 0.586 | 0.666 0.721 | 0.721 0.666 | 0.009 0.161 |
Mobility V1 V3.6M Relative change % Cohen´s effect size p value (change) | 42.9 ± 19.4 26.2 ± 20.2 -38.2 1.11 < 0.0001 | 56.9 ± 23.9 49.6 ± 28.3 -12.8 0.38 0.034 | 53.1 ± 27.2 47.3 ± 29.5 -10.9 0.40 0.130 | 67.5 ± 18.7 65.0 ± 15.1 -3.7 0.48 0.465 | 62.3 ± 33.0 57.8 ± 35.1 -7.2 0.24 0.635 | 63.7 ± 29.0 59.8 ± 30.3 -6.1 0.25 0.600 | 56.8 ± 25.5 50.4 ± 28.6 -11.3 0.37 0.007 | 53.6 ± 24.8 45.1 ± 28.7 -15.9 0.51 < 0.0001 | 0.002 0.056 | 0.575 0.429 | 0.183 0.128 | < 0.0001 0.029 |
Daily activities V1 V3.6M Relative change % Cohen´s effect size p value (change) | 41.5 ± 23.6 21.7 ± 14.4 -47.8 1.10 < 0.0001 | 49.0 ± 26.8 44.4 ± 26.3 -9.4 0.29 0.026 | 47.6 ± 20.9 41.5 ± 27.7 -12.8 0.39 0.184 | 58.3 ± 15.2 54.2 ± 13.6 -7.3 0.49 0.705 | 45.8 ± 30.3 38.3 ± 32.5 -16.3 0.47 0.283 | 49.2 ± 27.1 42.5 ± 29.1 -13.6 0.47 0.207 | 48.5 ± 25.3 43.2 ± 26.8 -10.9 0.35 0.005 | 46.9 ± 25.0 38.7 ± 26.2 -17.5 0.51 < 0.0001 | 0.036 0.346 | 0.716 0.648 | 0.983 0.802 | 0.003 0.127 |
Emotional state V1 V3.6M Relative change % Cohen´s effect size p value (change) | 35.1 ± 23.4 33.2 ± 24.8 -5.4 0.11 0.695 | 38.0 ± 24.1 31.0 ± 21.1 -18.4 0.36 0.077 | 44.6 ± 25.4 41.5 ± 27.9 -6.9 0.28 0.239 | 19.4 ± 13.4 20.8 ± 14.4 + 7.2 0.71 0.317 | 49.6 ± 32.9 35.6 ± 24.5 -28.2 0.98 0.042 | 43.1 ± 32.0 32.4 ± 23.1 -24.8 0.77 0.050 | 40.5 ± 25.4 34.2 ± 23.6 -15.6 0.39 0.010 | 39.1 ± 24.9 33.7 ± 23.7 -13.8 0.33 0.014 | 0.198 0.245 | 0.080 0.112 | 0.933 0.857 | 0.480 0.489 |
Stigma V1 V3.6M Relative change % Cohen´s effect size p value (change) | 26.4 ± 21.2 17.5 ± 21.3 -33.7 0.54 0.053 | 17.1 ± 22.9 16.6 ± 21.3 -2.9 0.03 0.805 | 22.6 ± 25.7 21.5 ± 25 -4.9 0.09 0.835 | 4.2 ± 3.6 2.1 ± 3.6 -50 0.71 0.317 | 2.8 ± 5.8 3.9 ± 6.4 + 39.2 0.64 0.157 | 3.1 ± 5.3 3.6 ± 5.9 + 16.1 0.21 0.564 | 16.8 ± 22.9 16.2 ± 21.6 -3.6 0.04 0.829 | 18.9 ± 22.8 16.4 ± 21.4 -13.2 0.16 0.237 | 0.029 0.078 | 0.269 0.199 | 0.007 0.016 | 0.168 0.617 |
Social support V1 V3.6M Relative change % Cohen´s effect size p value (change) | 12.1 ± 21.1 14.1 ± 20.4 + 16.5 0.16 0.670 | 13.4 ± 15.1 13.8 ± 19.2 + 2.9 0.04 0.819 | 12.0 ± 21.6 19.4 ± 27.2 + 61.7 0.48 0.039 | 16.7 ± 28.1 16.7 ± 28.1 0 0.00 1.000 | 9.4 ± 15.1 9.4 ± 15.1 0 0.00 1.000 | 11.8 ± 19.3 11.8 ± 19.3 0 0.00 1.000 | 12.7 ± 17.3 14.9 ± 21.5 + 17.3 0.17 0.424 | 12.6 ± 18.1 14.7 ± 21.2 + 16.7 0.17 0.350 | 0.913 0.868 | 0.589 0.444 | 0.652 0.646 | 0.816 0.942 |
Cognition V1 V3.6M Relative change % Cohen´s effect size p value (change) | 25.4 ± 17.6 22.1 ± 17.0 -12.9 0.36 0.181 | 30.4 ± 20.9 29.0 ± 19.4 -4.6 0.12 0.519 | 29.7 ± 25.2 31.7 ± 22.6 + 6.7 0.16 0.471 | 20.3 ± 20.0 21.8 ± 25.8 + 7.3 0.28 0.655 | 21.9 ± 26.1 14.4 ± 19.3 -34.2 0.57 0.306 | 21.4 ± 23.7 16.5 ± 20.5 -22.3 0.42 0.472 | 29.0 ± 22.4 28.1 ± 20.1 -3.1 0.08 0.653 | 28.2 ± 21.4 26.6 ± 20.1 -5.7 0.13 0.347 | 0.241 0.259 | 0.822 0.935 | 0.053 0.038 | 0.242 0.691 |
Communication V1 V3.6M Relative change % Cohen´s effect size p value (change) | 21.7 ± 19.5 26.1 ± 22.4 + 20.3 0.29 0.249 | 31.2 ± 21.5 24.3 ± 18.9 -22.1 0.48 0.003 | 24.4 ± 23.9 25.9 ± 21.4 + 6.1 0.10 0.942 | 25.0 ± 16.7 18.8 ± 10.5 -24.8 1.1 0.180 | 20.8 ± 16.3 15.0 ± 21.1 -27.9 0.81 0.083 | 22.0 ± 15.9 16.1 ± 18.3 -16.1 0.91 0.031 | 28.1 ± 21.7 23.6 ± 19.6 -16 0.34 0.001 | 26.5 ± 21.4 24.5 ± 20.4 -7.5 0.18 0.042 | 0.560 0.497 | 0.550 0.800 | 0.138 0.227 | 0.607 0.217 |
Bodily discomfort V1 V3.6M Relative change % Cohen´s effect size p value (change) | 36.8 ± 24.8 30.7 ± 22.1 -16.5 0.35 0.142 | 42.3 ± 25.2 32.9 ± 23.1 -22.2 0.53 0.003 | 47.0 ± 29.7 45.2 ± 25.2 -3.8 0.11 0.495 | 35.4 ± 38.7 25.0 ± 31.9 -29.4 1.85 0.102 | 32.6 ± 31.3 37.1 ± 29.9 + 13.8 0.24 0.398 | 33.3 ± 31.9 33.9 ± 29.8 + 1.8 0.03 0.823 | 42.3 ± 27.5 36.3 ± 25.0 -14.2 0.35 0.007 | 41.1 ± 26.9 34.9 ± 24.6 -15.1 0.35 0.004 | 0.260 0.459 | 0.094 0.135 | 0.311 0.205 | 0.247 0.841 |
| The results represent mean ± SD at V1 and at V3.6M, relative change (%), and Cohen´s effect size. PDQ-39 total score ranges from 0 to 156. Each domain is expressed as a percentage (0-100). The Wilcoxon test was applied to calculate p-value change (from V1 to V3.6M). pa, comparison between all DATs; pb, comparison between both subcutaneous therapies, fLD/fCD and CSAI; pc, comparison between subcutaneous (fLD/fCD + SCAI) and enteral therapies (LCGI + LECIG); pd, comparison between DBS and DATs using a pump (DATs-pump). P values were computed using general linear models (GLM) repeated measures. First, the unadjusted p-value for covariates is shown, and below, the p-value after adjustment for covariates (age, sex, and disease duration). P values < 0.05 are shown in bold. | ||||||||||||
| CSAI, continuous subcutaneous apomorphine infusion; DAT, device-aided therapy; DBS, deep brain stimulation; fLD/fCD, foslevodopa-foscarbidopa; LCIG, levodopa-carbidopa intestinal gel infusion; LECIG, levodopa-entacapone-carbidopa intestinal gel infusion; PDQ-39SI, 39-item Parkinson’s Disease Quality of Life Questionnaire. | ||||||||||||
Fig. 2
A. Mean value of each domain of the PDQ-39 at V1 and at V3.6M in patients who were treated with DBS (in green) and those treated with a pump system (DATs-pump) (in red). B. Mean value of each domain of the PDQ-39 at V1 and at V3.6M in patients who were treated with fLD/fCD (in blue) and those treated with CSAI (in orange). C. Mean value of each domain of the PDQ-39 at V1 and at V3.6M in patients who were treated with enteral infusion (in grey) and those treated with subcutaneous infusion (in violet). *, a significant difference (p < 0.05) using GLM repeated measures between both therapies from V1 to V3.6M was observed without adjustment; **, a significant difference (p < 0.05) using GLM repeated measures between both therapies from V1 to V3.6M was observed after adjustment to covariates (age, sex, and disease duration). CSAI, continuous subcutaneous apomorphine infusion; DAT, device-aided therapy; DBS, deep brain stimulation; fLD/fCD, foslevodopa/foscarbidopa; GLM, general linear models; LCIG, levodopa-carbidopa intestinal gel infusion; LECIG, levodopa-entacapone-carbidopa intestinal gel infusion; PDQ-39SI, 39-item Parkinson’s Disease Quality of Life Questionnaire; PwP, patients with Parkinson´s disease.
DBS N = 27 | fLD/fCD N = 49 | CSAI N = 23 | LCIG N = 4 | LECIG N = 7 | LCIG/LECIG N = 11 | DATs-pump N = 83 | All cohort N = 110 | pa | pb | pc | pd | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
EUROHIS-QOL8 V1 V3.6M Relative change % Cohen´s effect size p value (change) | 24.2 ± 4.2 25.1 ± 4.7 + 3.7 0.22 0.423 | 23.5 ± 5.1 24.7 ± 5.4 -3.4 0.27 0.183 | 22.6 ± 5.3 23.2 ± 6.1 + 2.7 0.14 0.474 | 23.0 ± 2.5 24.8 ± 1.3 + 7.8 0.71 0.285 | 23.7 ± 3.7 24.9 ± 6.5 + 5.1 0.18 0.612 | 23.5 ± 3.2 24.8 ± 5.1 + 5.5 0.31 0.358 | 23.2 ± 4.9 24.3 ± 5.6 + 4.7 0.24 0.093 | 23.5 ± 4.7 24.5 ± 5.3 + 4.3 0.23 0.070 | 0.650 0.583 | 0.273 0.258 | 0.757 0.790 | 0.331 0.298 |
Overall QoL V1 V3.6M Relative change % Cohen´s effect size p value (change) | 2.7 ± 0.7 3.2 ± 1.0 + 18.5 0.67 0.021 | 2.7 ± 0.9 2.9 ± 1.1 + 7.4 0.41 0.054 | 2.6 ± 0.9 2.7 ± 1.0 + 3.8 0.06 0.854 | 2.5 ± 0.6 2.5 ± 0.6 0 0 1.000 | 2.7 ± 0.9 3.1 ± 0.7 + 14.8 0.53 0.317 | 2.6 ± 0.8 2.9 ± 0.7 + 11.5 0.38 0.366 | 2.6 ± 0.9 2.9 ± 1.0 + 11.5 0.32 0.054 | 2.6 ± 0.9 3.0 ± 1.0 + 15.4 0.41 0.004 | 0.587 0.671 | 0.378 0.475 | 0.952 0.697 | 0.338 0.297 |
General health V1 V3.6M Relative change % Cohen´s effect size p value (change) | 2.3 ± 0.7 3.0 ± 0.8 + 30.4 1.00 0.002 | 2.2 ± 0.7 2.4 ± 1.1 + 9.1 0.31 0.151 | 1.8 ± 0.8 2.2 ± 0.9 + 22.2 0.61 0.049 | 1.8 ± 0.5 2.0 ± 0.0 + 11.1 0.71 0.317 | 2.4 ± 0.8 3.1 ± 0.9 + 29.2 1.05 0.102 | 2.2 ± 0.7 2.7 ± 0.9 + 22.7 0.94 0.063 | 2.1 ± 0.8 2.4 ± 1.0 + 14.3 0.45 0.006 | 2.1 ± 0.8 2.5 ± 1.0 + 19.0 0.58 < 0.0001 | 0.005 0.015 | 0.120 0.142 | 0.289 0.294 | 0.010 0.037 |
Energy V1 V3.6M Relative change % Cohen´s effect size p value (change) | 3.0 ± 0.8 2.9 ± 0.9 -3.3 0.06 0.806 | 2.7 ± 0.9 2.8 ± 1.1 + 3.7 0.15 0.387 | 2.8 ± 0.9 2.7 ± 1.1 -3.5 0.05 0.788 | 2.0 ± 0.8 2.5 ± 0.6 + 25 0.71 0.317 | 2.3 ± 0.5 3.4 ± 0.5 + 47.8 2.34 0.023 | 2.2 ± 0.6 3.1 ± 0.7 + 40.9 1.54 0.015 | 2.6 ± 0.8 2.8 ± 1.0 + 7.7 22.2 0.148 | 2.7 ± 0.9 2.9 ± 0.9 + 7.4 0.16 0.225 | 0.375 0.494 | 0.896 0.914 | 0.665 0.654 | 0.126 0.336 |
Activity V1 V3.6M Relative change % Cohen´s effect size p value (change) | 2.7 ± 0.9 3.0 ± 0.9 + 11.1 0.38 0.189 | 2.3 ± 0.9 2.5 ± 1.0 + 8.7 0.16 0.292 | 2.3 ± 1.2 2.7 ± 1.2 + 17.4 0.40 0.166 | 2.3 ± 0.5 2.3 ± 0.9 0 0 1.000 | 2.4 ± 0.5 2.8 ± 1.1 + 16.7 0.43 0.480 | 2.4 ± 0.5 2.6 ± 1.0 + 8.3 0.32 0.527 | 2.3 ± 0.9 2.6 ± 1.1 + 13.0 0.25 0.089 | 2.4 ± 0.9 2.7 ± 1.0 + 12.5 0.28 0.034 | 0.138 0.236 | 0.794 0.869 | 0.813 0.826 | 0.013 0.031 |
Esteem V1 V3.6M Relative change % Cohen´s effect size p value (change) | 3.1 ± 1.0 2.9 ± 1.1 -6.4 0.17 0.520 | 2.9 ± 1.0 3.0 ± 1.2 + 3.4 0.10 0.620 | 2.7 ± 1.1 3.0 ± 1.1 + 11.1 0.32 0.233 | 3.3 ± 0.5 3.3 ± 0.0 0 0 1.000 | 3.1 ± 0.9 2.8 ± 1.1 -9.7 0.27 0.593 | 3.2 ± 0.7 3.0 ± 1.0 -6.3 0.22 0.593 | 2.8 ± 1.0 2.9 ± 1.1 + 3.6 0.11 0.409 | 2.9 ± 1.0 2.9 ± 1.1 0.0 0.04 0.673 | 0.860 0.903 | 0.644 0.603 | 0.482 0.506 | 0.541 0.661 |
Relationships V1 V3.6M Relative change % Cohen´s effect size p value (change) | 3.5 ± 0.9 3.5 ± 0.9 0 0 0.961 | 3.5 ± 1.0 3.6 ± 1.1 + 2.9 0.11 0.588 | 3.2 ± 1.1 3.3 ± 1.1 + 3.1 0.09 0.700 | 4.0 ± 0.0 4.0 ± 0.0 0 0 1.000 | 3.3 ± 0.8 3.0 ± 1.0 -9.1 0.36 0.480 | 3.5 ± 0.7 3.4 ± 0.9 -2.8 0.29 0.480 | 3.4 ± 1.0 3.5 ± 1.1 + 2.9 0.07 0.645 | 3.4 ± 0.9 3.5 ± 1.0 + 2.9 0.05 0.662 | 0.956 0.218 | 0.157 0.105 | 0.968 0.904 | 0.921 0.418 |
Finances V1 V3.6M Relative change % Cohen´s effect size p value (change) | 3.4 ± 0.9 3.2 ± 0.8 -5.9 0.37 0.141 | 3.5 ± 1.0 3.6 ± 0.9 + 2.9 0.14 0.419 | 3.2 ± 1.1 3.1 ± 0.9 -3.1 0.100 0.573 | 3.3 ± 0.9 3.8 ± 1.3 + 15.2 0.71 0.317 | 3.4 ± 1.2 3.0 ± 1.5 -11.8 0.53 0.276 | 3.4 ± 1.2 3.3 ± 1.4 -2.9 0.11 0.705 | 3.5 ± 1.0 3.4 ± 1.0 + 2.9 0.03 0.897 | 3.4 ± 0.9 3.4 ± 1.0 0.0 0.06 0.562 | 0.260 0.256 | 0.038 0.037 | 0.709 0.672 | 0.471 0.851 |
Home V1 V3.6M Relative change % Cohen´s effect size p value (change) | 3.6 ± 0.8 3.3 ± 0.9 -8.3 0.31 0.298 | 3.8 ± 0.9 3.8 ± 0.9 0 0.02 0.969 | 4.0 ± 3.1 3.6 ± 1.3 -11.1 0.46 0.099 | 4.0 ± 0.8 4.5 ± 0.6 + 12.5 0.71 0.317 | 4.0 ± 0.8 3.4 ± 1.3 -15.0 0.49 0.414 | 4.0 ± 0.8 3.8 ± 1.2 -5.0 0.17n 0.854 | 3.9 ± 0.9 3.7 ± 1.1 -5.1 0.16 0.327 | 3.8 ± 0.9 3.6 ± 1.1 -5.2 0.19 0.178 | 0.233 0.452 | 0.931 0.992 | 0.660 0.676 | 0.039 0.111 |
| The results represent mean ± SD at V1 and at V3.6M, relative change (%), and Cohen´s effect size. EUROHIS-QOL8 total score ranges from 8 to 40. Each domain is expressed as a percentage (0-100). The Wilcoxon test was applied to calculate p-value change (from V1 to V3.6M). pa, comparison between all DATs; pb, comparison between both subcutaneous therapies, fLD/fCD and CSAI; pc, comparison between subcutaneous (fLD/fCD + SCAI) and enteral therapies (LCGI + LECIG); pd, comparison between DBS and DATs using a pump (DATs-pump). P values were computed using general linear models (GLM) repeated measures. First, the unadjusted p-value for covariates is shown, and below, the p-value after adjustment for covariates (age, sex, and disease duration). P values < 0.05 are shown in bold. | ||||||||||||
| CSAI, continuous subcutaneous apomorphine infusion; DAT, device-aided therapy; DBS, deep brain stimulation; EUROHIS-QOL8, European Health Interview Survey-Quality of Life 8-item index; fLD/fCD, foslevodopa-foscarbidopa; LCIG, levodopa-carbidopa intestinal gel infusion; LECIG, levodopa-entacapone-carbidopa intestinal gel infusion. | ||||||||||||
PwP improved from V1 to V3.6M in daily OFF time (RC = -62%; Cohen’s d = 1.62; p < 0.0001), dyskinesias (Dyskinesia score; RC = -42.9%; Cohen’s d = 0.67; p < 0.0001), motor symptoms (MSs; RC = -39.4%; Cohen’s d = 1.08; p < 0.0001), NMS (NMSs; RC = -27.1%; Cohen’s d = 0.66; p < 0.0001), and autonomy for activities of daily living (ADL) during the ON state (ADLS; RC = + 2%; Cohen’s d = 0.15; p = 0.030). By groups according to DAT received, daily OFF time decreased significantly in all of them, with a mean range reduction from 2.8 ± 2.3 hours per day with CSAI to 5.1 ± 4.5 hours per day with LECIG (Table 5 and Fig. 3A). PwP who received LECIG were at baseline a greater percentage of the day during the OFF state (p = 0.006) (Fig. 3B), but at the end of follow-up no differences between groups were detected (p = 0.055), with only 5 patients out of 186 (2.7%) with OFF time during > 50% of the day (Fig. 3C). On the other side, only those PwP treated with DBS (RC = -64.5%; Cohen’s d = 1.08; p < 0.0001) and fLD/fCD (RC = -51.7%; Cohen’s d = 0.89; p < 0.0001) improved in dyskinesias (Dyskinesia score) (Table 5), with no differences observed between groups at baseline in the percentage of the day with dyskinesias (p = 0.766) (Fig. 4A), but with a higher percentage of patients without dyskinesias in those treated with DBS (61.8%) and fLD/fCD (48.4%) at the final visit (p = 0.007) (Fig. 4B). Among all DATs, the greatest improvement in NMS burden (p = 0.005 after adjustment to covariates) was observed with fLD/fCD (NMSs; RC = -32.6%; Cohen’s d = 0.85; p < 0.0001) followed by CSAI (NMSs; RC = -26.9%; Cohen’s d = 0.58; p = 0.017), with a lower effect of DBS compared with DATs using a pump system (p = 0.001) (Table 5). In contrast, no differences were detected between all DATs in their effect over motor-symptoms burden (p = 0.217) (Table 5). In relation to NMS scores, significant differences in the change from V1 to V3.6M were detected between PwP treated with DBS vs. pump in “Psychiatric/mood”, “Sleep/fatigue”, and “Dysautonomia” (Table 5).
DBS | fLD/fCD | CSAI | LCIG | LECIG | LCIG/LECIG | DATs-pump | All cohort | pa | pb | pc | pd | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
Daily OFF time (h) N V1 V3.6M OFF time reduction Relative change % Cohen´s effect size p value (change) | 49 4.5 ± 2.0 1.5 ± 2.2 3 ± 2.6 -66.7 1.63 < 0.0001 | 81 4.7 ± 2.4 1.9 ± 1.9 2.8 ± 2.3 -59.6 1.67 < 0.0001 | 34 4.9 ± 2.9 1.8 ± 1.8 3.1 ± 2.3 -63.3 1.93 < 0.0001 | 6 6.3 ± 2.9 2.5 ± 2.4 3.8 ± 2.6 -60.3 2.05 0.043 | 16 7.5 ± 4.1 2.4 ± 1.8 5.1 ± 4.5 -68 1.62 0.001 | 22 7.2 ± 3.8 2.4 ± 1.9 4.8 ± 4.0 -66.7 1.67 < 0.0001 | 137 5.2 ± 2.9 1.9 ± 1.9 3.2 ± 2.7 -63.5 1.64 < 0.0001 | 186 5.0 ± 2.8 1.9 ± 2.3 3.1 ± 2.7 -62 1.62 < 0.0001 | 0.008 0.009 | 0.031 0.091 | 0.001 0.002 | 0.112 0.161 |
Dyskinesia score N V1 V3.6M Relative change % Cohen´s effect size p value (change) | 55 3.1 ± 2.3 1.1 ± 1.6 -64.5 1.08 < 0.0001 | 91 2.9 ± 2.3 1.4 ± 1.6 -51.7 0.89 < 0.0001 | 37 2.4 ± 1.9 2.3 ± 1.8 -4.1 0.04 0.975 | 7 1.6 ± 1.1 2.6 ± 2.1 + 62.5 0.78 0.167 | 19 2.4 ± 1.9 2.2 ± 2.2 -8.3 0.09 0.635 | 26 2.2 ± 1.8 2.3 ± 2.1 + 4.5 0.09 0.741 | 154 2.7 ± 2.2 1.8 ± 1.8 -33.3 0.53 < 0.0001 | 209 2.8 ± 2.2 1.6 ± 1.8 -42.9 0.67 < 0.0001 | 0.879 0.666 | 0.306 0.390 | 0.903 0.703 | 0.571 0.336 |
MSs N V1 V3.6M Relative change % Cohen´s effect size p value (change) | 54 10.1 ± 4.4 5.8 ± 3.9 -42.6 1.14 < 0.0001 | 89 9.6 ± 4.7 5.3 ± 4.2 -44.8 1.14 < 0.0001 | 37 10.1 ± 4.0 7.1 ± 3.8 -29.7 0.23 0.001 | 7 8.7 ± 2.9 7.1 ± 4.1 -18.4 0.67 0.246 | 19 10.1 ± 3.0 7.1 ± 4.1 -29.7 1.23 0.005 | 26 9.7 ± 2.9 7.1 ± 4.1 -26.8 1.09 0.002 | 152 9.7 ± 4.2 6.1 ± 4.1 -37.1 1.05 < 0.0001 | 206 9.9 ± 4.4 6.0 ± 4.2 -39.4 1.08 < 0.0001 | 0.426 0.217 | 0.094 0.034 | 0.423 0.365 | 0.916 0.751 |
NMSs N V1 V3.6M Relative change % Cohen´s effect size p value (change) | 51 8.2 ± 5.8 6.6 ± 6.6 -19.5 0.36 0.043 | 84 13.5 ± 7.5 9.1 ± 6.4 -32.6 0.85 < 0.0001 | 36 11.9 ± 7.9 8.7 ± 5.6 -26.9 0.58 0.017 | 7 14.6 ± 6.3 13.3 ± 6.4 -8.9 0.82 0.168 | 18 13.4 ± 5.9 10.6 ± 4.4 -20.9 0.76 0.035 | 25 13.8 ± 5.9 11.3 ± 5.1 -18.1 0.73 0.013 | 145 13.1 ± 7.4 9.4 ± 6.0 -28.2 0.76 < 0.0001 | 196 11.8 ± 7.3 8.6 ± 6.3 -27.1 0.66 < 0.0001 | 0.001 0.005 | 0.395 0.394 | 0.221 0.257 | < 0.0001 0.001 |
Psychiatric/mood N V1 V3.6M Relative change % Cohen´s effect size p value (change) | 51 2.0 ± 2.1 1.4 ± 1.9 -30.0 0.43 0.025 | 85 3.3 ± 2.6 2.2 ± 2.1 -33.3 0.55 0.0001 | 37 3.2 ± 3.1 1.9 ± 2.1 -40.6 0.68 0.006 | 7 5.1 ± 2.6 3.1 ± 1.5 -39.2 1.31 0.061 | 18 4.5 ± 2.7 3.1 ± 1.8 -31.1 0.64 0.077 | 25 4.7 ± 2.7 3.1 ± 1.7 -34.0 0.76 0.014 | 147 3.5 ± 2.8 2.3 ± 2.1 -34.3 0.63 < 0.0001 | 197 3.1 ± 2.7 2.1 ± 2.1 -32.3 0.59 < 0.0001 | < 0.0001 0.001 | 0.619 0.687 | 0.007 0.005 | < 0.0001 0.001 |
Sleep/fatigue N V1 V3.6M Relative change % Cohen´s effect size p value (change) | 51 2.9 ± 2.4 2.4 ± 2.7 -17.2 0.21 0.258 | 86 4.5 ± 3.3 2.6 ± 2.4 -42.2 0.81 < 0.0001 | 37 3.2 ± 2.6 2.9 ± 2.3 -12.5 0.15 0.528 | 7 3.1 ± 2.2 4.7 ± 2.4 + 51.6 0.82 0.172 | 18 4.6 ± 2.5 3.6 ± 2.8 -21.8 0.73 0.048 | 25 4.2 ± 2.4 3.9 ± 2.7 -7.2 0.16 0.510 | 147 4.1 ± 3.0 2.9 ± 2.4 -29.3 0.56 < 0.0001 | 199 3.8 ± 2.9 2.8 ± 2.5 -26.3 0.47 < 0.0001 | 0.085 0.143 | 0.304 0.279 | 0.174 0.221 | 0.022 0.045 |
Dysautonomia N V1 V3.6M Relative change % Cohen´s effect size p value (change) | 51 1.9 ± 1.6 1.5 ± 1.8 -21.1 0.37 0.071 | 85 3.1 ± 2.4 2.5 ± 2.1 -19.3 0.34 0.013 | 37 2.9 ± 2.1 2.1 ± 2.1 -27.6 0.46 0.038 | 7 3.1 ± 2.0 3.0 ± 2.4 -3.2 0.19 0.705 | 18 2.6 ± 1.3 2.5 ± 1.3 -3.8 0.09 0.749 | 25 2.8 ± 1.5 2.6 ± 1.7 -7.2 0.11 0.624 | 148 3.0 ± 2.2 2.4 ± 2.0 -20.0 0.35 0.001 | 198 2.7 ± 2.1 2.2 ± 1.9 -18.5 0.35 < 0.0001 | 0.006 0.060 | 0.399 0.424 | 0.940 0.829 | < 0.0001 0.010 |
Pain N V1 V3.6M Relative change % Cohen´s effect size p value (change) | 57 0.5 ± 0.9 0.4 ± 0.8 -20.0 0.14 0.557 | 98 0.6 ± 1.0 0.4 ± 0.8 -33.3 0.21 0.151 | 42 0.8 ± 1.2 0.3 ± 0.8 -62.5 0.69 0.008 | 7 0.3 ± 0.8 0.1 ± 0.4 -66.6 0.42 0.414 | 22 0.5 ± 0.9 0.2 ± 0.6 -60 0.67 0.063 | 29 0.5 ± 0.8 0.2 ± 0.6 -60.0 0.59 0.046 | 169 0.6 ± 1.0 0.4 ± 0.8 -33.3 0.35 0.002 | 226 0.6 ± 1.0 0.4 ± 0.8 -33.3 0.31 0.003 | 0.723 0.729 | 0.877 0.337 | 0.213 0.197 | 0.897 1.000 |
ADLS – OFF N V1 V3.6M Relative change % Cohen´s effect size p value (change) | 43 73.0 ± 18.0 76.0 ± 18.4 + 4.1 0.20 0.237 | 61 54.9 ± 23.5 54.7 ± 23.9 -0.3 0.01 0.876 | 32 56.5 ± 21.6 62.5 ± 19.8 + 10.6 0.43 0.103 | 7 50.0 ± 21.6 52.9 ± 16.0 + 5.8 0.53 0.317 | 17 45.3 ± 21.8 47.6 ± 19.1 + 5.1 0.24 0.618 | 24 46.7 ± 21.4 49.2 ± 18.2 + 5.1 0.29 0.417 | 117 52.7 ± 22.7 55.7 ± 22.1 + 5.7 0.15 0.211 | 160 58.9 ± 23.1 61.2 ± 23.0 + 3.9 0.17 0.095 | < 0.0001 < 0.0001 | 0.256 0.404 | 0.106 0.146 | < 0.0001 < 0.0001 |
ADLS - ON N V1 V3.6M Relative change % Cohen´s effect size p value (change) | 45 88.7 ± 12.5 91.8 ± 13.9 + 3.5 0.29 0.069 | 68 80.4 ± 15.6 80.7 ± 16.2 + 0.3 0.02 0.412 | 34 79.7 ± 18.8 83.8 ± 15.2 + 5.1 0.47 0.056 | 7 70.0 ± 20.0 71.4 ± 18.6 + 2 0.31 0.564 | 17 73.5 ± 22.6 71.2 ± 21.2 -3.1 0.28 0.458 | 24 72.5 ± 21.5 71.3 ± 20.1 -1.7 0.31 0.632 | 126 78.7 ± 18.7 79.8 ± 17.2 + 1.4 0.10 0.180 | 171 81.2 ± 17.1 82.9 ± 17.2 + 2.1 0.15 0.030 | < 0.0001 0.002 | 0.699 0.708 | 0.087 0.047 | < 0.0001 0.003 |
| The results represent mean ± SD at V1 and at V3.6M, relative change (%), and Cohen´s effect size. The Wilcoxon test was applied to calculate p-value change (from V1 to V3.6M). pa, comparison between all DATs; pb, comparison between both subcutaneous therapies, fLD/fCD and CSAI; pc, comparison between subcutaneous (fLD/fCD + SCAI) and enteral therapies (LCIG + LECIG); pd, comparison between DBS and DATs using a pump (DATs-pump). P values were computed using general linear models (GLM) repeated measures. First, the unadjusted p-value for covariates is shown, and below, the p-value after adjustment for covariates (age, sex, and disease duration). P values < 0.05 are shown in bold. | ||||||||||||
| ADLS, Schwab and England Activities of Daily Living Scale; CSAI, continuous subcutaneous apomorphine infusion; DAT, device-aided therapy; DBS, deep brain stimulation; fLD/fCD, foslevodopa-foscarbidopa; h, hours; LCIG, levodopa-carbidopa intestinal gel infusion; LECIG, levodopa-entacapone-carbidopa intestinal gel infusion; LEED, levodopa equivalent daily dose; MNs, motor symptoms score; NMSs, non-motor symptoms score. | ||||||||||||
Fig. 3
A. Change from V1 to V3.6M in the mean daily OFF time (hours) of PwP treated with a different DAT. *, p < 0.005. Data are presented as box plots, with the box representing the median and the two middle quartiles (25–75%). Mild outliers (O) are data points that are more extreme than Q1–1.5. Frequency of patients with different percentage of the day in OFF time (0% vs. 1–25% vs. 26–50% vs. 51–75% vs. 76–100%) at V1 (B) and at V3.6M (C) in different DAT groups. CSAI, continuous subcutaneous apomorphine infusion; DAT, device-aided therapy; DBS, deep brain stimulation; fLD/fCD, foslevodopa/foscarbidopa; LCIG, levodopa-carbidopa intestinal gel infusion; LECIG, levodopa-entacapone-carbidopa intestinal gel infusion; PwP, patients with Parkinson´s disease.
Fig. 4
Frequency of PwP with different percentage of the day with dyskinesia (0% vs. 1–25% vs. 26–50% vs. 51–75% vs. 76–100%) at V1 (A) and at V3.6M (B) in different DAT groups. CSAI, continuous subcutaneous apomorphine infusion; DAT, device-aided therapy; DBS, deep brain stimulation; fLD/fCD, foslevodopa/foscarbidopa; LCIG, levodopa-carbidopa intestinal gel infusion; LECIG, levodopa-entacapone-carbidopa intestinal gel infusion; PwP, patients with Parkinson´s disease.
According to the data of the entire DATs-PD GETM Spanish Registry cohort until 30/MAY/2025, 60 out of 481 (12.5%) PwP discontinued with the therapy: 3/13 (23.1%) LCIG, 14/89 (15.7%) CSAI, 36/246 (14.6%) fLD/fCD, 6/50 (12%) LECGI, and 1/83 (1.2%) DBS (p = 0.005). After excluding DBS, the rate of discontinuation of the DATs-pump group was 59/398 (14.8%). A total of 14 patients switched to a second DAT after being treated with a first DAT: 4 from fLD/fCD to LECGI; 3 from CSAI to fLD/fCD; 2 from LECGI to LCGI; and 1 from DBS to fLD/fCD, fLD/fCD to DBS, fLD/fCD to LCIG, CSAI to DBS, and CSAI to LECIG. The reasons for discontinuation of DAT were any complication related to the therapy (N = 26; 5.4%), a direct decision of the patient and/or principal caregiver (N = 13; 2.7%), and another reason (N = 21; 4.4%). A total of 370 adverse events (41.1% slight; 36.7% moderate; 22.2% severe) were reported: 270 in PwP treated with a subcutaneous DAT (i.e., fLD/fCD and CSAI; N = 335), 58 in PwP treated with DBS (N = 89), and 42 in those PwP treated with an enteral therapy (i.e., LCIG and LECIG; N = 63). More than 80% of complications were resolved without sequelae. Nodules and other skin complications were reported in 77 (22.3%) and 23 (6.9%), respectively, of the PwP who were treated with a subcutaneous DAT. Two patients died due to causes not related to DAT (urinary sepsis and myocardial infarct).
DISCUSION
The present real-world data study observed an improvement in PwP who were treated with a DAT on their health-related QoL as well as on their motor symptoms and NMS, with a significant OFF time reduction after a 6-month follow-up, with a good safety profile. It was observed that PwP treated with DBS were the youngest and less affected and improved their QoL more than the rest of the patients. A greater OFF time reduction was found in PwP treated with an enteral therapy, whereas DBS and fLD/fCD demonstrated a better effect over dyskinesia, and fLD/fCD showed the most effectiveness over NMS. Importantly, these findings should be interpreted with caution given the small sample size of some of the groups (i.e., enteral therapies) and the short follow-up time, making it necessary to observe a larger number of patients followed for a longer period.
An important aspect of this study is that it includes the recently introduced DATs fLD/fCD and LECIG [21] and that all DATs (DBS, fLD/fCD, CSAI, LCIG, LECIG) were compared. Although the comparative effectiveness of some DATs in PwP has been reported [7–9, 22, 23] and some recent publications suggest algorithms for the indication of a DAT, including already the more recently approved DATs (i.e., fLD/fCD and LECIG) [24], this is the first study to show comparative data about real-world evidence effectiveness among all DATs. The data show, as already observed in a recent publication with patients from the same cohort [10], a difference in the profile of PwP selected for DBS compared to the rest of the patients, with younger patients with a lower NMS burden and better motor status during the OFF and ON states, as well as greater autonomy for ADL and a better overall health-related QoL in the group of PwP selected for DBS. In contrast, the profile of patients who received fLD/fCD was quite similar to those who were treated with CSAI and an enteral therapy and comparable to 53 PD patients treated with fLD/fCD in a recently published single-center retrospective cross-sectional study conducted in Germany [25]. In this aspect, more studies about the profile of PwP treated with new DATs in real clinical conditions are required.
A
Our study demonstrates, in line with previous publications [26–29], that DATs improve the health-related QoL of PwP. In the entire cohort, a reduction in the mean PDQ-39 score (range from 0 to 156) of almost 8 points was observed in 137 PwP after a mean follow-up of 190 days, above the 7.36 (4.72 for the PDQ-39SI) defined as clinically meaningful improvement [30]. Specifically, a significant improvement was found in mobility, ADL, emotional state, communication, and bodily discomfort, something previously reported [29]. The fact that PwP treated with DBS had a less advanced profile compared to PwP who were treated with a pump system could explain the differences in terms of greater improvement in health-related QoL, given that having an already better QoL before being treated and with a more optimal ON status and greater autonomy during the ON state could facilitate achieving greater improvement in QoL after starting with the DAT. This idea has been demonstrated at least with early exercise implemented in PwP [31]. In fact, DBS allows for greater autonomy with a lower necessity of a principal caregiver, and this probably helps reduce stigma in PwP compared to wearing a pump that is crucial to response [32], as we observed. Moreover, differences between subcutaneous therapies (i.e., fLD/fCD vs. CSAI) and between subcutaneous and enteral therapies were not found. On the contrary, PwP didn't have a significant increase in the EUROHIS-QoL8 total score, although they did improve aspects more related to their PD, such as overall QoL, general health, and activity, and again with a greater benefit observed in overall QoL in those treated with DBS. Taken together, our findings support the idea that DATs improve QoL [33] and raise the interesting question of whether introducing a pump therapy earlier in PwP with a less advanced profile, as in those patients treated with DBS, may result in greater improvements in QoL. Related to this, a study to assess the real-life effectiveness of fLD/fCD in adult German participants at initial stages of advanced PD with time since beginning of motor fluctuations ≤ 3 years (EARLY-FOS; NCT06916507) is ongoing.The reduction of about 60% in OFF time for all DATs agrees with the literature [29, 34]. Specifically, the reduction in OFF time was greater than 2.5 hours in all groups, being greater than 1 hour per day, which is considered the minimum relevant change [35]. However, since PwP treated with enteral therapies had more hours during the OFF state before starting with the DAT, the number of hours of OFF time reduction was greater in this group (ranging from 2.8 for CSAI to 5.1 hours for LECGI). These findings are consistent with the ceiling effect suggested of continuous dopaminergic delivery in the OFF time reduction, with many suggested determinant factors involved [36]. Of particular interest is the improvement achieved with fLD/fCD in dyskinesias (52%), motor symptoms (45%), and NMS burden (32.6%). As a factor influencing the QoL of PwP [37], improving dyskinesias is an important goal [38]. In this context, our findings align with data from a post-hoc analysis of the phase 3, open-label trial (NCT03781167) that showed that continuous delivery of LDp/CDp was associated with significant improvements in dyskinesia and QoL in patients with relevant/significant troublesome dyskinesia at baseline [39]. LCIG has already been shown to improve dyskinesias in PwP [40], so it is necessary and very interesting to obtain evidence of whether fLD/fCD could be (or not) more effective and whether 24-hour infusion could influence this response [41]. Regarding NMS, previous studies have already shown the beneficial effect of levodopa infusion on NMS burden [8, 9, 42], and because fLD/fCD metabolizes to levodopa/carbidopa [43], fLD/fCD could have a good profile to improve NMS in PwP as well [44, 45]. Specifically, fLD/fCd produced the greatest benefit with a 42% improvement in sleep/fatigue, as reported in clinical trials [5, 45, 46]. On the other hand, the observed benefit of SCAI on mood and pain is also known and worth taking into account [8, 47, 48]. Finally, the rate of discontinuation of different DATs and adverse events reported were according to what was described in other studies [5–9, 21–25, 49, 50]. The fact that the follow-up time was short would explain, in part, the low dropout rate observed (13%), making a detailed analysis not contemplated here of management, complications, dropouts, and DATs switching in the medium to long term necessary. In summary, more data collected from more patients for longer time follow-up are required to define the better profile for each DAT, including effectiveness, safety, and costs as well [51].
As it has been previously commented, our findings must be interpreted very cautiously due to the various limitations that exist. Firstly, although the overall sample size is relatively large for a study with this type of treatment (i.e., DATs), it varies between groups, resulting in a small sample size for enteral therapies. Secondly, the follow-up period is short, making it necessary to observe medium- to long-term outcomes. Thirdly, although some validated scales and/or questionnaires were used (H&Y, UPDRS, ADLS, PDQ-39, etc.), some scores defined to measure other symptoms lack validation. Fourthly, there are all the limitations inherent to the methodology used, which is the extraction of data from a registry, such as not completing all variables in all cases. Fifthly, despite the indication of consecutive inclusion of patients treated with DAT in the hospitals participating from Spain, this was not fulfilled, and there is an inclusion bias. Sixthly, the reporting of adverse events compared to a specifically targeted study could be underestimated. Finally, this is not a study specifically designed to assess changes in QoL but rather data from everyday clinical practice. However, having information on the response under daily clinical practice conditions is of great value since it reflects patients' daily response to DATs. Moreover, this is the first study in which all currently available DATs have been compared in a total population of more than 200 PwP.
In conclusion, the present study observed improvement in PwP after treatment with a DAT in terms of OFF time, motor symptoms, NMS, and QoL. Among the DATs, fLD/fCD was the most used, while enteral therapies were the least used. Patients treated with DBS had a less advanced disease state at baseline with a better health-related QoL and improved their QoL more than those treated with a pump. Studies with more patients and longer follow-up time are needed.
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Author Contribution
1) Research project: A. Conception, B. Organization, C. Execution; 2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3) Manuscript: A. Writing of the first draft, B. Review and Critique. Diego Santos-García: 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B, 3C. Ángela Solleiro: 1C, 3B, 3C. Guillermo González-Ortega: 1B, 1C, 3B, 3C. Pablo Mir: 1C, 3B, 3C. Nuria López-Ariztegui: 1C, 3B, 3C. Inés Legarda: 1C, 3B, 3C. María Esther Rojas-Pérez: 1C, 3B, 3C. Alejandro Peral-Quirós: 1C, 3B, 3C. Iria Cabo: 1C, 3B, 3C. Rocío García-Ramos: 1C, 3B, 3C. Pilar Sánchez-Alonso: 1C, 3B, 3C. Jorge Hernández-Vara: 1C, 3B, 3C. Marta Blázquez-Estrada: 1C, 3B, 3C. Álvaro Sánchez-Ferro: 1B, 1C, 3B, 3C.
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Data Availability
The protocol, statistical analysis plan and unidentified participant data will be available on request.
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Legend of Figures
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Acknowledgement
We would like to thank all patients who collaborated in this study. Many thanks also to Fundación Española de Ayuda a la Investigación en Enfermedades Neurodegenerativas y/o de Origen Genético (https://fundaciondegen.org/), Grupo de Estudio de Trastornos del Movimiento (GETM), Sociedad Española de Neurología (SEN) and Fundación Profesor Novoa Santos.
Authors’ Roles
1) Research project: A. Conception, B. Organization, C. Execution; 2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3) Manuscript: A. Writing of the first draft, B. Review and Critique. Diego Santos-García: 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B, 3C. Ángela Solleiro: 1C, 3B, 3C. Guillermo González-Ortega: 1B, 1C, 3B, 3C. Pablo Mir: 1C, 3B, 3C. Nuria López-Ariztegui: 1C, 3B, 3C. Inés Legarda: 1C, 3B, 3C. María Esther Rojas-Pérez: 1C, 3B, 3C. Alejandro Peral-Quirós: 1C, 3B, 3C. Iria Cabo: 1C, 3B, 3C. Rocío García-Ramos: 1C, 3B, 3C. Pilar Sánchez-Alonso: 1C, 3B, 3C. Jorge Hernández-Vara: 1C, 3B, 3C. Marta Blázquez-Estrada: 1C, 3B, 3C. Álvaro Sánchez-Ferro: 1B, 1C, 3B, 3C.
Financial Disclosures for the previous 12 months
Diego Santos-García has received honoraria for educational presentations and advice service by Abbvie, UCB Pharma, Lundbeck, KRKA, Zambon, Bial, Italfarmaco, Teva, Archímedes, Esteve, Stada, financial compensation for INIBIC / Fundación Professor Novoa Santos in relation to activity as a PI in phase 2 to phase 4 clinical trials for Parkinson's disease and other movement disorders, and grants from the “Fundación Professor Novoa Santos” as a result of the “CONVOCATORIA DE AYUDAS PARA LA REALIZACIÓN DE PROYECTOS DE INVESTIGACIÓN PARA GRUPOS EMERGENTES Y ASOCIADOS DEL INIBIC (2023/2024)”. Ángella Solleiro has nothing to report. GGO has received honoraria for educational purposes from ABBIE, Zambon, Bial, Esteve and Italfarmaco.
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Pablo Mir has received financial support from the Spanish Ministry of Science and Innovation (RTC2019-007150-1), the Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional (ISCIII-FEDER) (PI16/01575, PI18/01898, PI19/01576, PI20/00613, PI21/01875, PI22/01704, PI23/00512), the Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía (CVI-02526, CTS-7685), the Consejería de Salud y Bienestar Social de la Junta de Andalucía (PI-0471-2013, PE-0210-2018, PI-0459-2018, PE-0186-2019), the Consejería de Transformación Económica, Industria, Conocimiento y Universidades de la Junta de Andalucía (PY20_00896), and support for attending meetings and/or travel or honorarium for lecturing from Abbott, Allergan, Abbvie, Bial, Britannia, Italfarmaco, Merz, UCB, Teva and Zambon. Nuría López-Ariztegui has received honoraria for educational presentations and advice service or travel grants by Abbvie, Italfarmaco, Stada, Lundbeck, UCB, Esteve, Abbott, Zambon, and Bial. Inés Legarda has received honoraria for educational presentations and advice service by Abbvie, UCB Pharma, Zambon, Bial, and Teva. Maria Esther Rojas-Pérez has nothing to report. Alejandro Peral Quirós has nothing to report. Iria Cabo has received honoraria for educational presentations and advice service by Abbvie, Zambon, Bial, Orion, Italfarmaco and Esteve. Rocío García-Ramos has received honoraria and grants for lecturing, advisory services from Abbvie, Zambón, Bial, Merk, Stada. Pilar Sánchez-Alonso has received honoraria for educational presentations and advice service by Abbvie, UCB Pharma, Lundbeck, KRKA, Zambon, Bial, and Teva. Jorge Hernández-Vara has received travel bursaries and educational grants from Abbvie and has received honoraria for educational presentations from Abbvie, Teva, Bial, Zambon, Italfarmaco, and Sanofi-Genzyme. Marta Blázquez-Estrada has received honoraria for educational presentations by Dysport, Esteve, Bial, Italfármaco, Boston Sc. and Stada and for advice service by Esteve, Bial, Suazio. Álvaro Sánchez-Ferro has received grants or contracts from ERA-NET Horizon 2020 program JPCOFUND2 (reference number HESOCARE-329-073), MDS (eDiary project) and Instituto de Salud Carlos III (reference number P122/01177), consulting fees from Abbvie, Esteve, Orion Pharma, and Prim, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Abbvie, Bayer, Esteve, MDS Society, EAN, Novartis, Monitor, Organon, Roche, SEN, Stada, Teva, and Zambon.A
Funding Sources
and Conflict of Interest
The authors declare that there are no funding sources or conflicts of interest relevant to this work. We received grants from the “Fundación Professor Novoa Santos” as a result of the "CONVOCATORIA DE AYUDAS PARA LA REALIZACIÓN DE PROYECTOS DE INVESTIGACIÓN PARA GRUPOS EMERGENTES Y ASOCIADOS DEL INIBIC (2023/2024)".
Ethical Compliance Statement
The project is being conducted in accordance with the ICH Good Clinical Practice version 6 Revision 2 standard, the fundamental ethical principles established in the Declaration of Helsinki and the Oviedo Convention, as well as the Spanish legal requirements for biomedical research (Biomedical Research Law 14/2007). The Project has been approved on 02/APR/2024 by the IRB “Comité de Ética de la Investigación Clínica de Galicia from Spain” with code number 2024/109. Written informed consents from all participants in this study were obtained.
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We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The protocol, statistical analysis plan and unidentified participant data will be available on request.Appendix 1.
DATs-PD GETM Spanish Registry STUDY GROUP (only members who participated with available data for this analysis are here included)
Adarmes Gómez AD, Aldaz A, Alonso-Modino D, Álvarez Sauco M, Ávila Rivera A, Belmonte S, Blázquez-Estrada M, Caballero Sánchez L, Caballol Pons N, Cabo I, Campo Caballero D, Cantarero Duque S, Carrillo García F, Casas Peña E, Castaño García B, Castellano Guerrero AM, Castrillo Sanz A, Cerdán Santacruz DM, Cores Bartolomé C, Cots Foraster A, Cubo Delgado E, Delgado Ballestero T, Escalante Arroyo S, Escamilla Sevilla F, Fanjul Arbos S, Feliz Feliz C, Fernández-Pajarín G, Fernández Revuelta A, Fernández Valle T, Freire Álvarez E, Gamo González E, García Fernández C, García Herruzo A, García-Ramos R, García Ruíz Espiga P, Garrote Espina L, Gil Villar MP, Gómez Esteban JC, Gómez López de San Román C, Gómez Rapela C, González MV, González Ardura J, González-Ortega G, González Rojas N, Hernández Javier C, Hernández-Vara J, Jesús Maestre S, Legarda Ramírez I, López-Ariztegui N, López Blanco R, López Dominguez D, López Manzanares L, López Valdés E, Lorenzo Barreto P, Lorenzo Brito JM, Lozano D, Macías García D, Madrid Navarro CJ, Martí Martínez S, Martín García R, Martínez Castrillo JC, Mata Álvarez Santullano M, Méndez Guerrero A, Mendoza Rodríguez A, Mir Rivera P, Mondragón Rezola E, Monterde Ortega A, Morales Casado MI, Muñoz Delgado L, Muro I, Novo Ponte S, Ojeda Lepe E, Pardina Vilella L, Pareés Moreno I, Paz González JM, Peral Quirós A, Pérez Calvo C, Pérez Rangel D, Perona Moratalla A, Planas-Ballvé A, Prendes Fernández P, Quibus Requena L, Rábano Suárez P, Ramírez J, Rivero de Aguilar Pensado A, Rojas-Pérez María E, Ribacoba Díaz C, Romero Fábrega JC, Ruiz López M, Ruíz Martínez J, Samaniego Vinueza LB, San Eufrasio Martínez M, Sánchez Alonso P, Sánchez-Ferro A, Sánchez Rodríguez A, Sancho Saldana A, Santos-García D, Solano Vila B, Solleiro Vidal A, Suárez San Martín E, Tabar Comellas G, Tijero Merino B, Valero García MF, Vela L, Vinagre Aragón A, Vivas Villacampa L, Vives Pastor B.
First Name | Last Name | Centre |
|---|---|---|
Diego | Santos García | Complejo Hospitalario Universitario de A Coruña |
Jose Manuel | Paz González | Complejo Hospitalario Universitario de A Coruña |
Carlos | Cores Bartolomé | Complejo Hospitalario Universitario de A Coruña |
Lucia Belen | Samaniego Vinueza | Complejo Hospitalario Universitario de A Coruña |
Ángela | Solleiro Vidal*** | Complejo Hospitalario Universitario de A Coruña |
María | Álvarez Sauco | Hospital General Universitario de Elche |
Eric | Freire Álvarez | Hospital General Universitario de Elche |
Juan Carlos | Martínez Castrillo | Hospital Universitario Ramón y Cajal |
Isabel | Pareés Moreno | Hospital Universitario Ramón y Cajal |
Samira | Fanjul Arbos | Hospital Universitario Ramón y Cajal |
Ana Belén | Perona Moratalla | Complejo Hospitalario Universitario de Albacete |
Inés | Legarda Ramírez | Hospital Universitario Son Espases |
Bàrbara | Vives Pastor | Hospital Universitario Son Espases |
María Fuensanta | Valero García | Hospital Universitario Son Espases |
Esther | Cubo Delgado | Hospital Universitario de Burgos |
Nuria | López-Ariztegui | Hospital Universitario de Toledo |
Maria Isabel | Morales Casado | Hospital Universitario de Toledo |
Guillermo | Tabar Comellas | Hospital Universitario de Toledo |
Déborah | Alonso-Modino | Hospital Universitario de la Candelaria |
Jesús Norelis | Lorenzo Brito | Hospital Universitario de la Candelaria |
María Esther | Rojas-Pérez | Hospital Universitario de la Candelaria |
Carolina | Hernández Javier | Hospital Universitario de la Candelaria |
Iria | Cabo | Complejo Hospitalario Universitario de Pontevedra |
Alejandro | Rivero de Aguilar Pensado | Complejo Hospitalario Universitario de Pontevedra |
Jorge | Hernández Vara | Hospital Universitario Vall d´Hebron |
Maria Victoria | González | Hospital Universitario Vall d´Hebron |
Sara | Belmonte** | Hospital Universitario Vall d´Hebron |
Juan Carlos | Romero Fábrega | Hospital Universitario Virgen de las Nieves |
Francisco | Escamilla Sevilla | Hospital Universitario Virgen de las Nieves |
Lucía | Triguero Cueva | Hospital Universitario Virgen de las Nieves |
Carlos Javier | Madrid Navarro | Hospital Universitario Virgen de las Nieves |
Asunción | Ávila Rivera | Complex Hospitalari Moisès Broggi |
Núria | Caballol Pons | Complex Hospitalari Moisès Broggi |
Anna | Planas-Ballvé | Complex Hospitalari Moisès Broggi |
Alejandro | Peral Quirós | Complex Hospitalari Moisès Broggi |
Dolors | Lozano | Complex Hospitalari Moisès Broggi |
Álvaro | Sánchez-Ferro | Hospital 12 de Octubre |
Pablo | Rábano Suárez | Hospital 12 de Octubre |
Antonio | Méndez Guerrero | Hospital 12 de Octubre |
Daniel | Pérez Rangel | Hospital 12 de Octubre |
Jesús | Ramírez | Hospital 12 de Octubre |
Rocío | García-Ramos | Hospital Clínico Universitario San Carlos |
Ana | Fernández Revuelta | Hospital Clínico Universitario San Carlos |
Eva | López Valdés | Hospital Clínico Universitario San Carlos |
Carmen | Ribacoba Díaz | Hospital Clínico Universitario San Carlos |
Ana | Aldaz | Hospital Clínico Universitario San Carlos |
Pilar | Sánchez-Alonso | Hospital Puerta de Hierro |
Sabela | Novo Ponte | Hospital Puerta de Hierro |
Elisa | Gamo González | Hospital Puerta de Hierro |
Raquel | Martín García | Hospital Puerta de Hierro |
Pablo | Mir Rivera | Hospital Universitario Virgen del Rocío |
Laura | Muñoz Delgado | Hospital Universitario Virgen del Rocío |
Astrid Daniela | Adarmes Gómez | Hospital Universitario Virgen del Rocío |
Elena | Ojeda Lepe | Hospital Universitario Virgen del Rocío |
Silvia | Jesús Maestre | Hospital Universitario Virgen del Rocío |
Daniel | Macías García | Hospital Universitario Virgen del Rocío |
Fátima | Carrillo García | Hospital Universitario Virgen del Rocío |
Ana María | Castellano Guerrero*** | Hospital Universitario Virgen del Rocío |
Manuela | San Eufrasio Martínez*** | Hospital Universitario Virgen del Rocío |
Cristina | Pérez Calvo*** | Hospital Universitario Virgen del Rocío |
Andrés | García Herruzo | Hospital Universitario Virgen del Rocío |
Cristina | Gómez Rapela***** | Hospital Universitario Virgen del Rocío |
Lorena | Garrote Espina***** | Hospital Universitario Virgen del Rocío |
Natalia | González Rojas***** | Hospital Universitario Virgen del Rocío |
Marta | Blázquez-Estrada | Hospital Universitario Central de Asturias |
Esther | Suárez San Martín | Hospital Universitario Central de Asturias |
Ciara | García Fernández | Hospital Universitario Central de Asturias |
Patricia | Prendes Fernández**** | Hospital Universitario Central de Asturias |
Pilar | Tartiere***** | Hospital Universitario Central de Asturias |
Pedro | García Ruíz Espiga | Hospital Fundación Jiménez Díaz |
Cici | Feliz Feliz | Hospital Fundación Jiménez Díaz |
Marina | Mata Álvarez-Santullano | Hospital Universitario Infanta Sofía |
Juan Carlos | Gómez Esteban | Hospital de Cruces |
Tamara | Fernández Valle | Hospital de Cruces |
Marta | Ruiz López | Hospital de Cruces |
Beatriz | Tijero Merino | Hospital de Cruces |
Lydia | López Manzanares | Hospital Universitario La Princesa |
Inés | Muro | Hospital Universitario La Princesa |
Elena | Casas Peña | Hospital Universitario La Princesa |
Pablo | Lorenzo Barreto | Hospital Universitario La Princesa |
Maria Pilar | Gil Villar | Hospital Universitari Arnau de Vilanova |
Agustín | Sancho Saldana | Hospital Universitari Arnau de Vilanova |
Laura | Quibus Requena | Hospital Universitari Arnau de Vilanova |
Berta | Solano Vila | Hospital Josep Trueta de Girona y Hospital Santa Caterina de Salt |
Anna | Cots Foraster | Hospital Josep Trueta de Girona y Hospital Santa Caterina de Salt |
Daniel | López Dominguez | Hospital Josep Trueta de Girona y Hospital Santa Caterina de Salt |
Lilian | Vivas Villacampa | Hospital Josep Trueta de Girona y Hospital Santa Caterina de Salt |
Jessica | González Ardura | Hospital de Cabueñes |
Belén | Castaño García | Hospital de Cabueñes |
Antonio | Sánchez Rodríguez | Hospital de Cabueñes |
Sonia | Escalante Arroyo | Hospital Virgen de la Cinta |
Tania | Delgado Ballestero | Parc Taulí |
Débora María | Cerdán Santacruz | Hospital General de Segovia |
Amelia | Mendoza Rodríguez | Hospital General de Segovia |
Ana | Castrillo Sanz | Hospital General de Segovia |
Lorena | Caballero Sánchez | Hospital General de Segovia |
Claudia | Gómez López de San Román | Hospital General de Segovia |
Gustavo | Fernández-Pajarín | Complejo Hospitalario Universitario de Santiago de Compostela |
Ángela | Monterde Ortega | Hospital Universitario Joan XXIII |
Susana | Cantarero Duque | Hospital Universitario de Móstoles |
Guillermo | González-Ortega | Hospital Universitario de Móstoles |
Silvia | Martí Martínez | Hospital General Universitario Alicante |
Lydia | Vela | Hospital Fundación de Alcorcón |
Javier | Ruíz Martínez | Hospital Universitario Donostia |
Elisabet | Mondragón Rezola | Hospital Universitario Donostia |
Ana | Vinagre Aragón | Hospital Universitario Donostia |
Lara | Pardina Vilella | Hospital Universitario Donostia |
David | Campo Caballero | Hospital Universitario Donostia |
Roberto | López Blanco | Hospital Universitario Severo Ochoa, Leganés, Madrid |
The researchers are listed by center in chronological order according to the date they confirmed their participation in the project.
* This investigator works at 2 different centers.
All investigators are neurologists except those ones with the symbol: ** SN (specialized nurse); ***graduate in Biology (she will be responsible for remote data monitoring); ****neuropsychologist; *****, study coordinator