Influence of Therapeutic Failure on the Psychosocial Experience of Patients With Relapsing-remitting Multiple Sclerosis
Conditions: Multiple Sclerosis
Sponsor: University Hospital, Caen

 
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1 
 
Protocol acronym: INPSYSEP 
RCB ID: 2025-A01541-48 
CHU NUMBER: 25-0187 
 
NON-INTERVENTIONAL RESEARCH (NIR) 
TITLE: INFLUENCE OF THERAPEUTIC FAILURE ON THE PSYCHOSOCIAL EXPERIENCE OF 
PATIENTS WITH RELAPSING-REMITTING MULTIPLE SCLEROSIS (INPSYSEP) 
STUDY SPONSOR: 
 
Avenue de la Côte de Nacre, 14033 
CAEN CEDEX - Tel: 02 31 06 57 81 
 
COORDINATING INVESTIGATOR 
 Dr Pierre Branger   
CRC-SEP Neurology Department 
CHU CAEN NORMANDIE  
Tel: 02 31 06 46 17 
Fax: 02 31 06 46 27 
Email: branger-p@chu-caen.fr 
 
HEAD OF SCIENCE UNIT  
Prof Gilles Defer  
CRC-SEP Neurology Department 
CHU CAEN NORMANDIE  
Tel: 02 31 06 46 17 
Fax: 02 31 06 46 27 
Email: defer-gi@chu-caen.fr 
& 
Dr Delphine Grynberg 
 Université de Lille 
Rue du barreau 
BP 60149 
59653 Villeneuve d’Ascq Cedex 
Tel: 03 20 96 52 39 
Email: delphine.grynberg@univ-lille.fr  
 

 
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This protocol contains confidential information and must only be used for the conduct of the study. The protocol 
must not be passed on to persons not involved in this study, nor used for any other purpose, without prior written 
agreement of the coordinating investigator. 
 
Version tracking 
☒ 
Initial version 
V01 
Date of version V01: 
25/08/2025 
☐ 
Amended version 
V… 
Date of version V …: 
../../.... 
 
If amended, purpose of significant change: 
........................................................................................................... 
☐ 
Favourable opinion from the CPP 
Authorisation date: 
../../.... 
 
 
 
 
History of protocol updates 
Version 
Date 
Reason for update 
01 
25/08/2025 
Applying for a promotion at CHU CAEN NORMANDIE 
XX 
../../.... 
Responses sent to the CPP (admissibility) 
01 
25/08/2025 
Approved by the CPP on 05/12/2025 
 
 
 

 
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CONTENTS - TABLE OF CONTENTS 
 
1. 
GENERAL INFORMATION ................................................................. Erreur ! Signet non défini. 
 
2. 
SYNOPSIS .......................................................................................... Erreur ! Signet non défini.  
3. 
RESUME ............................................................................................ Erreur ! Signet non défini. 
4.  
SCIENTIFIC JUSTIFICATION FOR STUDY AND GENERAL DESCRIPTION OF RESEARCH .... Erreur ! 
Signet non défini. 
5. 
RESEARCH OBJECTIVES  .................................................................... Erreur ! Signet non défini. 
6. 
EVALUATION CRITERIA  .................................................................... Erreur ! Signet non défini. 
7. 
RESEARCH METHODOLOGY ............................................................. Erreur ! Signet non défini. 
8. 
SELECTION AND EXCLUSION OF RESEARCH PARTICIPANTS ............. Erreur ! Signet non défini. 
9. 
PRACTICAL CONDUCT OF THE STUDY  ............................................. Erreur ! Signet non défini. 
10. 
DESCRIPTION OF THE DATA TO BE COLLECTED  .............................. Erreur ! Signet non défini. 
11. 
STATISTICAL METHODOLOGY  ......................................................... Erreur ! Signet non défini. 
12. 
VIGILANCE ........................................................................................ Erreur ! Signet non défini. 
13. 
PARTICIPATION IN THE STUDY ......................................................... Erreur ! Signet non défini. 
14. 
RIGHTS OF ACCESS TO DATA AND SOURCE DOCUMENTS ............... Erreur ! Signet non défini. 
15. 
DATA PROCESSING AND STORAGE OF DOCUMENTS AND RESEARCH DATA Erreur ! 
Signet 
non défini. 
16. 
REGULATORY CONSIDERATIONS AND INVESTIGATOR OBLIGATIONSErreur ! 
Signet 
non 
défini. 
17. 
LEGAL AND ETHICAL CONSIDERATIONS  .......................................... Erreur ! Signet non défini. 
18. 
PUBLICATION RULES ........................................................................ Erreur ! Signet non défini. 
19. 
BIBLIOGRAPHIE ................................................................................ Erreur ! Signet non défini. 
 
 
 
 

 
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GENERAL INFORMATION 
 
Regulatory information: 
 
ACRONYM 
 
Title 
INFLUENCE 
OF 
THERAPEUTIC 
FAILURE 
ON 
THE 
PSYCHOSOCIAL EXPERIENCE OF PATIENTS WITH RELAPSING-
REMITTING MULTIPLE SCLEROSIS (INPSYSEP) 
RCB ID number 
2025-A01541-48 
CHU number 
25-0187 
Number and date of version of 
approved protocol 
V01 du 25/08/2025 
 
Signature of protocol 
 
CHU CAEN NORMANDIE 
NOM 
DATE 
SIGNATURE 
Directeur Général ou son 
représentant 
Mme Aurélie VILLERS 
27/08/2025 
Fabien Chaillot  
P/o responsable des 
affaires réglementaires 
 
 
Investigateur coordonnateur 
 
Dr Pierre Branger   
27/08/2025 
 
 
 
 

 
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Participating investigators: 
 
Main 
investigator 
Centre 
Service 
Mailing 
address 
Professional email, Telephone, 
Fax 
Dr Pierre 
Branger 
CRC-SEP 
Neurology 
Department 
CHU 
CAEN 
NORMANDIE  
Avenue 
Côte 
de Nacre 
14033 
CAEN 
Cedex 
Email: branger-p@chu-caen.fr 
Tél: 02 31 06 46 17 
Fax: 02 31 06 46 27 
Dr Bertrand 
Bourre 
CHU de 
Rouen 
Normandie 
Neurology 
Department 
37 boulevard 
Gambetta 
76000 Rouen  
Email: bertrand.bourre@chu-
rouen.fr 
Tél: 02 32 88 33 99 
Fax: 02 32 88 09 68 
Dr Al Khedr 
Abdullatif 
CHU 
d’Amiens 
Neurology 
Department 
1 Rond point 
professeur 
Christian 
Cabrol 80054 
AMIENS  
Email: AlKhedr.Abdullatif@chu-
amiens.fr 
Tel: 03 22 66 78 65 
Fax: 03 22 66 82 44 
Prof Hélène 
Zéphir 
CHRU  
de Lille 
Neurology 
Department 
Hôpital 
Salengro 
Email: helene.zephir@chru-lille.fr 
Tél: 03 20 44 57 65 
Fax: 03 20 44 44 84 
Prof Arnaud 
Kwiatkowski 
Groupement 
des Hôpitaux 
de l’Institut 
Catholique de 
Lille (GHICL) 
Neurology 
Department 
Hôpital Saint 
Vincent 
de 
Paul 
Email : 
Kwiatkowski.Arnaud@ghicl.net 
Tél: 03 20 87 49 01 
Associate 
investigator 
Centre 
Service 
Mailing 
address 
Professional email, Telephone, 
Fax 
Dr Charlotte 
Arnaud 
CRC-SEP 
Neurology 
Department 
CHU 
CAEN 
NORMANDIE  
Avenue 
Côte 
de Nacre 
14033 
CAEN 
Cedex 
Email: arnaud-ch@chu-caen.fr 
Tél: 02 31 06 46 17 
Fax: 02 31 06 46 27 
Dr Nathalie 
Derache 
CRC-SEP 
Neurology 
Department 
CHU 
CAEN 
NORMANDIE  
Avenue 
Côte 
de Nacre 
14033 
CAEN 
Cedex 
Email: derache-n@chu-caen.fr 
Tel: 02 31 06 52 73 
Fax: 02 31 06 46 27 

 
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6 
 
 
▲ Remember to collect the CVs, dated, signed and bearing the registration number with the Order of 
Physicians or RPPS, as well as BPC training date, to make a submission to the CPP 
 
Scientific team: 
 
Last name - 
first name 
Establishment 
Mailing 
address 
Professional email, 
Telephone, Fax 
Prof Gilles 
Defer 
CRC-SEP  
CHU 
CAEN 
NORMANDIE  
Avenue 
Côte 
de 
Nacre 
14033 CAEN Cedex  
Email: defer-gi@chu-caen.fr 
Tel: 02 31 06 46 17 
Fax: 02 31 06 46 27 
Dr Delphine 
Grynberg 
Université de 
Lille 
Rue 
du 
barreau 
BP 60149 
59653 
Villeneuve 
d’Ascq Cedex 
Email: 
delphine.grynberg@univ-lille.fr 
Tél: 03 20 96 52 39 
Prof Sophie 
Lelorain 
Université de 
Lausanne 
Université 
de 
Lausanne, 
Switzerland 
Email: sophie.lelorain@unil.ch 
Tel: 0041 79 277 15 42 
Dr Olivier 
Dejardin 
INSERM U1086 
ANTICIPE 
CHU 
CAEN 
NORMANDIE  
Avenue Côte de 
Nacre 
14033 
CAEN 
Cedex 
Email: 
olivier.dejardin@unicaen.fr 
Tél: 02 31 06 31 06 
Research, Prevention and Public Health Division: 
 
Biostatistics and Clinical Research Unit, CHU CAEN NORMANDIE 
Sponsoring Methodologist 
 
Dr Remy MORELLO 
Biostatistics and Clinical Research Unit 
CHU CAEN NORMANDIE 
 
14033 CAEN Cedex 
Tel: 02 31 06 24 71 
Email: morello-r@chu-caen.fr 
Ms Audrey SULTAN  
Research engineer  
CHU CAEN NORMANDIE 
14033 CAEN Cedex  
Tel: 02 31 06 33 58 
Email: sultan-a@chu-caen.fr 
 

 
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Research, Innovation and Sponsorship Department 
 
Mr Fabien CHAILLOT 
Head of Regulatory Affairs 
CHU CAEN NORMANDIE  
14033 CAEN Cedex 
Tel: 02 31 06 57 74 
Email: chaillot-f@chu-caen.fr 
 
Ms Clémence TOMADESSO 
Project Manager 
CHU CAEN NORMANDIE  
14033 CAEN Cedex 
Tel: 02 31 06 53 86 
Email: tomadesso-c@chu-caen.fr  
 
 
 
 
 
 
 
 
 

 
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Abbreviations: 
Abbreviation 
Meaning 
BMI 
Body Mass Index 
CRA 
Clinical Research Associate 
CRC-SEP 
Centre de Ressources et de Compétences Sclérose En Plaques (French MS 
expert centre)  
CHU 
Centre Hospitalier Universitaire (University Hospital) 
CPP 
Comité de Protection des Personnes (French Independent Ethics Committee) 
DMT 
Disease Modifying Treatment 
e-CRF 
electronic Case Report Form 
EDI 
European Deprivation Index  
EDMUS 
European Database for Multiple Sclerosis 
EDSS 
Expanded Disability Status Scale 
GDPR 
General Data Protection Regulation 
HADS 
Hospital Anxiety and Depression Scale 
ICECAP-A 
ICEpop CAPability measure for Adults 
iPCQ 
iMTA Productivity Cost Questionnaire 
MCID 
Minimal Clinically Important Difference 
MR 
Méthodologie de Référence (Reference Methodology) 
MS 
Multiple Sclerosis 
NIR 
Non-Interventional Research 
OFSEP 
Observatoire Français de la Sclérose en Plaques (French Multiple Sclerosis 
Observatory) 
PREM 
Patient Reported Experience Measurement 
PROM 
Patient Reported Outcome Measurement 
QoL 
Quality of Life 
RRMS 
Relapsing-Remitting Multiple Sclerosis 
SES 
Socioeconomic Status 
Th-F 
Therapeutic Failure 

 
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SYNOPSIS 
 
Title of study 
INFLUENCE OF THERAPEUTIC FAILURE ON THE PSYCHOSOCIAL 
EXPERIENCE OF PATIENTS WITH RELAPSING-REMITTING MULTIPLE 
SCLEROSIS  
Protocol  
INPSYSEP 
Sponsor 
CHU CAEN NORMANDIE 
RCB ID NUMBER 2025-A01541-48 
Type of research 
Non-Interventional Research (NIR) 
Coordinating 
investigator 
Dr Pierre Branger   
CRC-SEP Neurology Department 
CHU CAEN NORMANDIE  
Tel: 02 31 06 46 17 
Fax: 02 31 06 46 27 
Email: branger-p@chu-caen.fr 
 
Head of science 
unit 
Prof Gilles Defer  
CRC-SEP Neurology Department 
CHU CAEN NORMANDIE  
Tel: 02 31 06 46 17 
Fax: 02 31 06 46 27 
Email: defer-gi@chu-caen.fr 
& 
Prof Delphine Grynberg 
Université de Lille 
Rue du barreau 
BP 60149 
59653 Villeneuve d’Ascq Cedex 
Tél: 03 20 96 52 39 
Email: delphine.grynberg@univ-lille.fr 
  
Population 
concerned  
Patients with MS 
Objectives of the 
study  
Main objective: 
• 
To compare changes in QoL at 2 years in RRMS patients treated for at 
least 6 months and less than 3 years, according to the occurrence or 
non-occurrence of Th-F. 
 
Secondary objective(s): 
• 
To compare, according to the occurrence or non-occurrence of a Th-F, 
the 2-year change in the QoL, in well-being, in distress and activity 
levels (PROM), of RRMS patients treated for at least 6 months and less 
than 3 years, in accordance with the care experience (PREM) and SES. 
• 
To assess the impact of Th-F at the time of the event (TE) between 
inclusion T0 and T1 (2-year follow-up) on PROMs and PREMs, 
compared with values at T0 (group of patients with Th-F only). 
• 
To assess the impact of PROMs and PREMs at inclusion (T0) and their 
relation to SSE at the risk of developing Th-F. 
 
 

 
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Inclusion criteria 
• Patient aged 18 or over. 
• Patient with RRMS according to McDonald 2024 criteria. 
• Uninterrupted use of a moderately effective treatment, or highly 
effective treatment only if it is the first DMT, for at least 6 months. 
• Collection of non-objection. 
• Patient affiliated to the social security system. 
 
Exclusion criteria 
• Patient with progressive MS.  
• Patient treated continuously with the same DMT for 3 years or more.  
• Patient who received a second line DMT or an immunosuppressant 
before taking a first line DMT. 
• Patients who have received mitoxantrone as the first treatment 
• Pregnant or breast-feeding woman at the time of inclusion.  
• Severe cognitive and/or psychological disorders which, according to the 
investigator (with or without a neuropsychological assessment), prevent 
the participant from completing the self-questionnaires independently 
and accurately. 
 
Assessment 
criteria  
Primary: 
• 
To compare changes in health-related quality of life (MusiQoL scale) at 
2 years (T1) in regard to whether or not Th-F had occurred. 
 
Secondary: 
• 
To compare changes in health-related quality of life (QoL) at 2 years 
(T1) in regard to whether or not Th-F had occurred, and in interaction 
with patients’ experience, quality of care (PREM) and socioeconomic 
status.  
We hypothesise that the deterioration in QoL between inclusion (T0) 
and the end of the observation period (T1 = T0 +2 years) will be greater 
in patients suffering from Th-F than in patients without Th-F (who 
constitute the control group, between-subjects model), especially as 
patients have reported a poor quality of care (PREM) and a low 
socioeconomic level at T0. 
• 
To compare changes at 2 years (T1) in other PROM measures: 
symptoms of anxiety and depression (HADS scale), well-being (ICAP 
scale) and level of activity (iPCQ scale) as a function of the occurrence 
or non-occurrence of Th-F, and in interaction with patients’ experience, 
quality of care (PREM-MusiCare scale) and SES. 
• 
To assess the impact of Th-F at the time of the event (TE) on PROMs 
and PREMs, compared with the values at T0 (for the group of patients 
with Th-F). 
 
Act(s) or visit(s) 
added by search  
At inclusion (T0), TE and T1: Completion of 5 questionnaires (MusiQoL, HADS, 
ICECAP-A, iPCQ, MusiCare).  
The questionnaires will be completed either as an online survey (a link to the 
survey on the LimeSurvey platform will be available via an invitation sent to the 
patient by email) or on a paper copy handed over during a routine visit or sent 
by post to participants’ homes. Questionnaires take an estimated 1h to 
complete. 
Number of 
patients  
Based on published works and our experience, we have set a participation rate 
of 50% to 70% and a 2-year Th-F rate of 15% to 20%. For a total number of 
patients that could be included of around 300, we hope to recruit between 150 

 
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and 210 patients in the study, including 23 to 30 patients with a Th-F at 2 years 
of around 15% and 32 to 42 patients with a Th-F at 2 years of 20%. With these 
numbers, considering a power of 80% and a type 1 error of 5% (two-tailed 
Student t-test), it will be possible to highlight an effect size (standardised 
difference) of around 0.6, corresponding to an effect size value between 
moderate and high, corresponding to a threshold generally accepted as the 
minimal clinically important difference for quality of life. 
 
Number of centres  
5 centres:  
• 
CRC-SEP 
• 
CHU Rouen Normandie 
• 
CHU Amiens 
• 
Groupement des Hôpitaux de l’Institut Catholique de Lille 
• 
CHU de Lille 
 
Provisional 
agenda 
 
- 
Duration of inclusion: 12 months  
 
- 
Duration of monitoring period: 30 months maximum 
 
 

 
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SCIENTIFIC JUSTIFICATION FOR STUDY AND GENERAL DESCRIPTION OF RESEARCH 
 
Rationale (context and assumptions) 
Multiple sclerosis (MS), an inflammatory, neurodegenerative disease of the central nervous system, 
affects around 120,000 patients in France and is the leading cause of non-traumatic disability in 
young adults. It affects patients’ health-related quality of life (QoL) and has a significant economic 
impact on patients and society as a whole. Early initiation of disease-modifying therapy (DMT) is 
recommended in relapsing-remitting MS (RRMS)1. Nevertheless, according to a recent French 
cohort, 30% of patients initially treated with a first-line FT will switch to a highly effective compound 
within 5 years2 due to its ineffectiveness. Therapeutic failure (Th-F) is therefore a frequent 
occurrence, but its psychological, social and economic consequences are poorly understood. These 
elements are generally the subject of measurements reported by patients, and several studies have 
highlighted the importance of taking them into account in the management of these patients3. 
Here, we will study two categories of these measures in a Th-F situation. On the one hand, we will 
examine patient-reported outcome measurements (PROMs). Patients’ psychological distress and 
their QoL are two important examples of psychosocial impacts in patients with MS, compared to the 
general population. The impact on activity levels is also well known4, but the specific effect of Th-F 
has not yet been studied. On the other hand, we will also study patients’ experiences of their care 
pathway and their opinion on the quality of care (patient-reported experience measurement [PREM]). 
Some PREMs refer to care coordination, satisfaction with the relationship with carers or doctors’ 
empathy levels. To date, data on the experience of MS patients regarding their care pathway remains 
limited and non-existent during Th-F5.  
Finally, the influence of socioeconomic status (SES) on PROMs and PREMs is worth considering. 
In the general population, we know that patients’ experience of care can be influenced by their 
socioeconomic status6. Compared with research on other diseases (notably cardiovascular diseases 
and cancers), there is relatively little work on the association between socioeconomic status and 
MS7 and none has focused on the topic of Th-F. 
We therefore hypothesise that a quality of care perceived favourably by MS patients may moderate 
the negative impact of Th-F on their QoL, anxiety/depression and activity levels (as recently 
described in oncology8), and a more recent measure of abilities assessing well-being defined in a 
broad sense, as a function of their SES.  
Inter-regional context - the FHU PRECISE specifies the following: Few studies have explored 
the links between PREMs, PROMs and Th-F in MS. In an original and innovative way, these 
questions are at the heart of the inter-regional hospital-university federation, FHU PRECISE 
(PREcision health in Complex Immune-mediated inflammatory diseases), accredited by Aviesan 
(Alliance nationale pour les sciences de la vie et de la santé) on January 1st, 2021. Its aim is to 
improve support for patients suffering from complex immunodeficiency diseases by bringing them 
the latest innovations in care, research and teaching. Our project is part of Work Package 4 (leaders: 
Gilles Defer - Delphine Grynberg), which has taken an innovative transdisciplinary approach to 
understanding the impact of psycho-socioeconomic factors on the development and experiences of 
patients with complex dysimmune diseases, through collaboration between medical researchers, 
MS specialists in this case and researchers in epidemiology and human and social sciences. It is 
fully in line with current recommendations for investigating PROMs in clinical trials9. At the same 
time, the evaluation of the quality of care (PREM) and of the SES is an innovative complementary 
approach. 
 
 
Key words: Patient-reported-outcome, Patient-reported-experience, quality of life, socioeconomic 
status, therapeutic failure, multiple sclerosis. 
 
 
 
 

 
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13 
 
RESEARCH OBJECTIVES 
 
1. Primary objective: 
  
To compare changes in QoL at 2 years in RRMS patients treated for at least 6 months and less than 
3 years, according to the occurrence or non-occurrence of Th-F. 
 
 
Secondary objectives: 
 
a) To compare, according to the occurrence or non-occurrence of a Th-F, the 2-year change in 
the QoL, in well-being, in distress and activity levels (PREM), of RRMS patients treated for 
at least 6 months and less than 3 years, relating to the care experience (PREM) and SES. 
 
b) To assess the impact of Th-F at the time of the event (TE) between inclusion T0 and T1 (2-
year follow-up) on PROMs and PREMs, compared with values at T0 (group of patients with 
Th-F only). 
 
c) To assess the impact of PROMs and PREMs at inclusion (T0) and their relation to SES at 
the risk of developing Th-F.  
 
EVALUATION CRITERIA 
 
1. Main assessment criterion: 
 
We hypothesise that the deterioration in quality of life (MusiQoL scale) between inclusion (T0) and 
the end of the observation period (T1) will be greater in patients with Th-F than in patients without 
Th-F (who constitute the control group, between-subjects model). 
The criterion will be a comparison of changes in health-related quality of life (QoL)10 at 2 years (T1) 
depending on the occurrence or non-occurrence of Th-F.  
 
Secondary assessment criteria: 
 
- To compare changes in health-related quality of life (QoL)10 at 2 years (T1) depending on the 
occurrence or non-occurrence of Th-F, and in interaction with patients’ experience and quality of 
care (PREM) and socioeconomic status. The difference is likely to be greater the more patients 
report poor quality of care (PREM) and low socioeconomic status. 
- To compare changes at 2 years (T1) in other PROMs: symptoms of anxiety and depression (HADS 
scale11), well-being (ICAP scale12) and level of activity (IPCQ scale13) as a function of the 
occurrence or non-occurrence of Th-F, and in interaction with patients’ experience and quality of 
care (PREM musical scale14), and their SSE15. 
- To assess the impact of Th-F at the time of the event (TE) on PROMs and PREMs, compared with 
the values at T0 (for the group of patients with Th-F only). 
 
 
 
 

 
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RESEARCH METHODOLOGY 
 
Experimental design: 
 
This is a prospective multicentre study involving the MS expert centres of the CHUs of Caen, Rouen, 
Amiens and Lille, as well as the Neurology Department of the Groupement des Hôpitaux de l’Institut 
Catholique de Lille (GHICL). The Normandie and Hauts-de-France MS networks (Normandie-SEP 
and PARC-SEP) will provide support for patients’ follow-up. Université de Lille will be involved in 
centralising the response to the questionnaires. Université de Lausanne will be involved in 
interpreting the results. 
 
 
 
 
SELECTION AND EXCLUSION OF RESEARCH PARTICIPANTS 
 
1. Criteria for inclusion of research participants: 
• 
1) Patient aged 18 or over.  
• 
2) Patient with RRMS according to McDonald 2024 criteria. 
• 
3) Uninterrupted use of a moderately effective treatment, or highly effective treatment only if 
it is the first DMT, for at least 6 months.  
• 
4) Collection of non-objection. 
• 
5) Patient affiliated to the social security system. 
 
Criteria for non-inclusion of research participants: 
• 
1) Patient with progressive MS.  
• 
2) Patient treated continuously with the same DMT for 3 years or more.  
• 
3) Patient who received a second line DMT or an immunosuppressant before taking a first 
line DMT (see Appendix 1). 
• 
4)Patients who have received mitoxantrone as the first treatment 
• 
5) Pregnant or breast-feeding woman at the time of inclusion.  
• 
6) Severe cognitive and/or psychological disorders which, according to the investigator (with 
or without a neuropsychological assessment), prevent the participant from completing the 
self-questionnaires independently and accurately. 
 
 
 

 
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15 
 
PRACTICAL CONDUCT OF THE STUDY 
 
1- Selection of participants  
Patients will be identified on the basis of regional clinico-radiological cohorts (EDMUS software) and 
local database in the investigating centres, all of which participate in the Observatoire Français de 
la Sclérose en Plaques (OFSEP). EDMUS (European Database for Multiple Sclerosis) is a specific 
software package with a standardised language, which has been fully integrated into the daily 
practice of MS expert centres for many years. 
 
Once the patients have been pre-selected from the regional and local cohorts (EDMUS database 
and local database of the investigating centres), the inclusion and non-inclusion criteria will be 
checked by the patient’s neurologist.  
During a routine consultation or a dedicated teleconsultation, the neurologist or the investigating 
Clinical Research Associate (CRA) will propose that the patient take part in the study. If agreed, a 
letter of information will be given to each patient (in person or by email in the case of 
teleconsultation). If the patient so wishes, a reflection period will be granted. In this case, patients 
will be contacted by telephone by the CRA regarding any questions they may have about the 
protocol. If the patient agrees to take part, the non-objection will be recorded in the patient’s medical 
file. 
 
2- Inclusion 
Patients will then be able to complete the study questionnaires either on paper (sent and returned 
to the care centre in a pre-stamped envelope given to the patient) or in the form of an online survey 
(a link to the survey will be available via an invitation sent to the patient by email, using the secure 
Lime Survey system on the platform of Prof Delphine Grynberg’s Research Unit). Questionnaires 
take an estimated 1h to complete. 
If the questionnaires are completed in paper format, they will be returned by the patient to the care 
centre to check that they have been completed correctly and that anonymity has been preserved. 
They will then be scanned and sent to a member of Prof Delphine Grynberg’s Research Unit for 
input.) 
In both cases, the confidentiality of the data will be respected thanks to an identification code made 
up of information known by the patient (e.g. year of birth, first letter of the investigating centre) which 
will make it possible to match the patient’s clinical data (from the pseudonymised EDMUS database) 
with their answers to the questionnaires (from the "questionnaires" database via Limesurvey). The 
correspondence table between the study identification code and the identity of the participants will 
be kept in the care centre. An investigator file will be kept in a locked cabinet in the department, 
accessible only to investigators. This file contains a list of correspondences between nominative 
data and the patient anonymisation code. Data protection and secure storage will be implemented 
in accordance with the recommendations of the General Data Protection Regulation (GDPR) under 
the supervision of the Clinical Research and Innovation Delegation of CHU Caen. 
 
3- Follow-up 
Participants will be asked to complete these questionnaires again, either on computer or on paper 
(sent either during a routine consultation or by post with a pre-stamped return envelope) in the time 
of event (TE) (=Th-F) and at the end of the study (T1). 
If TE < 18 months after T0 inclusion, then T1=T0+24 months (patient participation of 24 months). 
If 18 months ≤ TE ≤ 24 months after T0 inclusion, then T1=TE+6 months (patient participation 
between 24 and 30 months). 
 

 
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Definition of therapeutic failure (Th-F): Change or discontinuation of the DMT decided by the 
treating neurologist, linked to a progression of the disease characterised by inflammatory activity 
(clinical and/or radiological) and/or progression of the disease unrelated to inflammatory activity.  
The following events will not be considered:  
- 
Change or discontinuation of the DMT due to an adverse event, discomfort and/or 
compliance difficulties and/or failure to comply with clinical and biological monitoring,  
- 
Discontinuation due to pregnancy after inclusion,  
- 
Discontinuation due to an unrelated intercurrent medical condition (e.g. cancer). 
 
Questionnaires in paper form will be received in the original investigating centre for verification of 
completion. They will then be scanned and transmitted securely for centralisation to: Delphine 
Grynberg, SCALab Laboratory, Université de Lille (Pont de Bois site) - Rue du Barreau, BP 60149, 
59653 Villeneuve d’Ascq Cedex, France. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
In-person visit 

 
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Calendar of summary: 
 
Ratings 
Selection  
(D-14 to D0) 
T0  
(D0) 
TE  
(Th-F) 
T1* 
(End of study) 
Enlightened information  
X 
 
 
 
Collection of non-objection 
X 
 
 
 
Eligibility criteria verification 
X 
 
 
 
Questionnaires completion 
 
X 
X 
X 
Demographic and clinical data 
(EDMUS) 
 
X 
X 
X 
* If TE < 18 months after T0 inclusion, then T1=T0+24 months. If 18 months ≤ TE ≤ 24 months after T0 inclusion, then T1=TE+6 
months. 
 
 
DESCRIPTION OF THE DATA TO BE COLLECTED 
 
Clinical data is collected at routine follow-up visits, retrospectively at the first visit and prospectively 
thereafter. The mandatory clinical data set includes demographic and socioeconomic characteristics, 
relapses and disability, as well as disease-modifying therapies (start and stop dates with reasons for 
stopping). 
 
Demographic and clinical data: data from the EDMUS database 
- 
Age, gender, education level (number of years), marital status, household composition, 
employed or not, full-time/part-time employment, disability/early retirement. 
- 
At inclusion: duration of disease, number of relapses in the year and in the two years 
preceding the start of treatment, EDSS, comorbidities (number of significant pathologies), 
smoking, overweight (BMI), measurement of fatigue with the EMIF MS questionnaire during 
other self-assessments (short questionnaire of 21 questions). 
- 
During follow-up care (as part of the normal course of treatment): EDSS, number of clinical 
attacks, MRI data as reported in the EDMUS software. 
 
PROM data: data from the "questionnaires" database via Limesurvey 
- 
Quality of life: The International Multiple Sclerosis Quality of Life Questionnaire (MusiQoL) is 
a multidimensional, self-administered questionnaire that has been developed internationally 
(including a French version). It comprises 31 questions describing nine dimensions (daily 
activities, psychological well-being, relationships with friends, symptoms, relationships with 
family, relationships with the healthcare system, emotional and sexual life, adaptation, and 
rejection). The study of internal structural validity, external validity, reproducibility and 
acceptability indicates that the tool meets generally accepted standards. The simultaneous 
participation of several countries in the development process provides a common 
assessment tool, which is useful for international research projects. 
- 
Psychological distress: Anxiety and depression symptoms will be assessed using the 
Hospital Anxiety and Depression Scale (HADS) validated in French. It contains 14 items 
divided into two dimensions (anxiety and depression). This questionnaire has already been 
used with MS patients and has shown good psychometric indicators. 
- 
Measure of well-being: ICECAP-A (ICEpop CAPability measure for Adults) is a measure of 
the capability of the general adult population (18+) intended for use in economic evaluation 

 
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18 
 
and focused on well-being in the broad sense, rather than health. ICECAP-A comprises five 
attributes (attachment, stability, fulfilment, pleasure, autonomy). Qualitative and quantitative 
studies on the validity of ICECAP-A have been carried out and a French translation of 
ICECAP-A has been developed for the general population. 
- 
Activity levels: The self-administered iMTA Productivity Cost Questionnaire (or iPCQ) will be 
used to measure the impact of the disease on market and household activities. This recently 
validated questionnaire, available in French, comprises 18 items. 
 
PREM data: data from the "questionnaires" database via Limesurvey 
- 
Quality of care: MusiCare is the only French-language questionnaire specific to MS for 
assessing the quality of care as perceived by MS patients and their careers. It was developed 
in two standard phases: (i) item generation, based on interviews with patients and carers; 
and (ii) validation, consisting of measures of validity, reliability, external validity, 
reproducibility and responsiveness. The validation process produced a 35-item questionnaire 
with satisfactory internal consistency and stability in 5 different areas describing information, 
quality and coordination of care and medical empathy (information on the disease; 
information on treatments/medical investigations; relations with care teams; access to care; 
reception in care facilities). The external validity test revealed the expected associations 
between MusiCare scores and socio-demographic and clinical data. The questionnaire 
showed good reproducibility. 
 
Socioeconomic status:  
- 
This item will be assessed using individual measures of socioeconomic position (highest 
degree of education, occupation). 
As shown in the figure below, each patient will complete the questionnaire at inclusion (T0) and two 
years later, at the end of the study (T1). Patients in therapeutic failure will complete the 
questionnaires as soon as possible after confirmation of Th-F and no later than 4 weeks after the 
occurrence of this event (TE). If the event occurs during the last 6 months of the 2-year follow-up 
period after patient inclusion, the T1 end-of-study visit will be conducted 6 months after the TE visit. 
As a result, these patients can be monitored for a maximum of 30 months.  
 
 

 
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STATISTICAL METHODOLOGY 
 
Based on published works and our experience, we have set a participation rate of 50% to 70% and 
a 2-year Th-F rate of 15% to 20%. For a total number of patients that could be of around 300, we 
hope to recruit between 150 and 210 patients to the study, including 23 to 30 patients with a Th-F at 
2 years of around 15% and 32 to 42 patients with a Th-F at 2 years of 20%. With these numbers, 
considering a power of 80% and a type 1 error of 5% (two-tailed Student t-test), it will be possible to 
highlight an effect size (standardised difference) of around 0.6, corresponding to an effect size value 
between moderate and high, corresponding to a threshold generally accepted as the minimal 
clinically important difference for quality of life. 
 
The MusiQoL scale values obtained for the control group (group without Th-F) and the group with 
Th-F are summarised in the following table: 
Group 
MusiQoL scale (T0) 
MusiQoL scale (T1) 
Th-F 
x1 
y1 
Without Th-F (Control) 
x2 
y0 
To meet the main objective, the following will be assessed:  
▪ 
the absolute difference at T1 (y1-y0) 
▪ 
the difference between the changes (y1-x1) - (y0-x0) = c1 - c0 
The Student t-test will be performed after verification of the homoscedasticity hypothesis. The effect-
size (Cohen’s d) will be calculated by the difference divided by the combined (pooled) standard 
deviation. This can be interpreted conventionally: a d around 0.2 is described as a "weak" effect, 0.5 
as "medium" and 0.8 as "strong". The statistical analysis will be done globally but also in relation to 
a group without Th-F-bis constructed from propensity score matching (PSM) between Th-F patients 
and patients without Th-F. The propensity score will be estimated using multivariate logistic 
regression based on various factors collected at admission; these can be very different due to the 
disparity in numbers between the two groups with or without Th-F formed at the end of the study 
Several special cases that may affect the study will be considered: 
- if the method of filling out the questionnaires (paper or electronic) leads to a difference, it will be 
considered in the analysis 
- patients who have multiple therapeutic failures should be a very small number; these will remain in 
the study and their profile will be analysed to highlight possible differences with patients who had 
only one therapeutic failure.  
- for patients who, for any reason other than therapeutic failure, need to modify or discontinue or 
stop treatment, two cases will occur:  
   - first, this event occurs before the therapeutic failure, they will be excluded from the study and 
replaced,  
   - second, if the event occurs after a therapeutic failure, these patients will remain in the study 
and will be analysed in intention to treat but not in per protocol analysis. 
 
Secondary objectives  
 
The first secondary objective will be studied using an appropriate function, the variation of the PRO 
measurement using time up to Th-F as the interaction terms. Depending on the PRO indicator 
studied, the regression will be either a linear regression, an ordered logistical regression or a Poisson 
regression. All the PRO measurements and associated models used in this study are presented in 
the following table (Table 1). Variation in patient-reported outcomes will be the primary outcome. 
These models allow us to measure the association between patient-reported outcomes, 
socioeconomic status and variation in PROs. In these models, the time elapsed until Th-F could be 
considered as an interaction term. The inclusion of such an interaction term would allow us to test 
the hypothesis that the time between the Th-F and the end of the study has an influence on the 
evaluation of PROs.  

 
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Δ𝑃𝑅𝑂0,1=(𝕀𝑒,[𝑡1-𝑡𝑒],𝑃𝑅𝑂0,𝑃𝑅𝐸0,𝑆𝑆𝐸,𝑍0, 𝑍1, interaction terms) 
With 𝑡0∶inclusion 𝑡1∶end of follow-up (𝑡1=𝑡0+2) 𝑡𝑒 𝑡𝑖𝑚𝑒 𝑡𝑜 𝑡ℎ𝑒𝑟𝑎𝑝𝑒𝑢𝑡𝑖𝑐 𝑓𝑎𝑖𝑙𝑢𝑟𝑒 𝑇ℎ-𝐹 
𝕀𝑒 Th-F indicator Yes=1; 0 either([𝑡1- 𝑡𝑒] = 0 if 𝕀𝑒=0)  
𝑃𝑅𝑂𝑡∶Patient reported outcome at t  
𝑃𝑅𝐸𝑡∶ patient reported experiment at t  
Δ𝑃𝑅𝑂𝑡,′∶ variation between PRO at t & t’ 
𝑆E𝑆∶∶ socioeconomic status 
𝑍𝑡∶ other variables (demographic, clinical) 
 
The probability of having a Th-F during follow-up will be studied using logistic regression (Th-F=1 if 
Th-F during follow-up, 0 otherwise). In the model, the explanatory variables will be PRO and PRE at 
inclusion, and socioeconomic status. 
Assessment of the impact of Th-F at time of event (TE) between inclusion of T0 and T1 (2-year 
follow-up) on PROMs and PREMs, compared to values at T0 (group of patients with Th-F only) will 
follow a procedure similar to that proposed for the main objective but for one group only on the 
difference before/after. Note that for the MusiCare scale, the analysis will be done according to the 
following 5 areas: Information on disease, Information on medical treatments/ investigations, 
Relations with care teams, Access to care, Reception in care facilities. Each item is rated from 1 
(strongly agree) to 5 (do not know). 
In all analyses, the influence of missing values will be studied. If the missing data is not completely 
random, multiple imputation will be carried out in accordance with international guidelines on missing 
data. All models will be calculated using standard statistical software (SAS 9.4 and STATA). 
 
 
PRO  
Variable type  
Regression method  
Quality of life (MusiQoL)  
one global index score 
between 0 and 100  
Linear regression  
ordered logistic regression  
Psychological distress 
(HADS)  
two scores (anxiety and 
depression) between 0 and 
21  
Linear regression  
ordered logistic regression  
Well-being/capabilities 
(ICECAP-A)  
one score between 0 and 1  Linear regression  
ordered logistic regression  
Activity level (iPCQ)  
 
Percentage of people 
becoming inactive, number 
of days of inactivity, 
productivity losses (market 
and domestic activity) - 
positive or zero value  
Multinomial logistic 
regression  
Poison regression  
Generalized linear model 
(GLM)  
Quality of care (MusiCare) 
one global index score 
between 0 and 100 
Linear regression  
ordered logistic regression 

 
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VIGILANCE 
 
During the course of the trial, the investigator must:  
• 
report adverse drug reactions to the Regional Pharmacovigilance Centre (CRPV) 
• 
report any adverse reactions linked to a medical device or to the procedure for fitting a 
medical device to the local materials vigilance correspondent 
• 
notify the establishment’s quality department in the event of an adverse reaction related to 
care. 
 
 
PARTICIPATION IN THE STUDY 
 
• 
Duration of participation for a participant: 30 months maximum 
• 
Details of the tests to be carried out: participants will be asked to complete 5 questionnaires 
at 3 points in the study (T0, TE, T1). These questionnaires will be completed during a routine 
consultation or sent home by post with a return envelope or on a dedicated electronic platform 
(LimeSurvey). 
• 
Period of exclusion from any further trials: No exclusion period 
• 
Possibility to take part in other trials at the same time: no 
• 
Compensation payments. Participants will not be compensated  
• 
Locations where the study will be carried out: Participants will be included and monitored in 
each centre 
5 participating centres : CRC-SEP, CHU Rouen Normandie, CHU Amiens, CHU Lille, GHICL. 
 
 
All research participants must be covered by the social security system. 
 
 
RIGHTS OF ACCESS TO DATA AND SOURCE DOCUMENTS 
 
Patient information: 
In accordance with the Data Protection Act and Act no. 2002-303 of 4 March 2002, patients may at 
any time exercise their right to access and correct the data collected. A patient’s participation in the 
research, as well as the procedures for obtaining their non-objection and for providing information 
about the research, is specified in the patient’s medical file. CHU CAEN NORMANDIE will keep 
patients informed of the overall results of this research at the end of the study. 
 
 
DATA PROCESSING AND STORAGE OF DOCUMENTS AND RESEARCH DATA 
 
Insofar as such research is conducted in the context of strict legislative and regulatory requirements 
in accordance with standardised methodologies, CHU CAEN NORMANDIE undertakes to adopt and 
comply with Deliberation No. 2018-154 of 3 May 2018 approving a reference methodology relating 
to the processing of personal data implemented in the context of research in the field of health that 
does not require the express or written consent of the data subject (MR-003) - Declaration 
number 2011519 V0. 

 
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This automated processing of health data complies with the European Regulation of 27 April 2016 
on the protection of individuals with regard to the processing of personal data and on the free 
movement of such data. 
The investigator coordinating the study undertakes to carry out the research in accordance with this 
reference methodology and to keep the source documents for a period of 15 years: ultrasound 
examination reports, biological examinations, clinical observations in the patient’s medical file, etc. 
 
 
REGULATORY CONSIDERATIONS AND INVESTIGATOR OBLIGATIONS 
 
Regulatory considerations: 
The medical procedures for this trial comply with the most recent recommendations of the 
Declaration of Helsinki and Law no. 2012-300 of 5 March 2012 and its implementing decree no. 
2016-1537 of 16 November 2016. 
 
The sponsor or their representatives: 
• 
Provide the investigating centres with the instructions and documents they need to 
conduct the trial (protocol, data collection booklets), 
• 
May organise a set-up session to train investigators and study coordinators (at this 
session, all sections of the protocol will be reviewed, the completion of case report forms 
will be explained, as well as study procedures), 
• 
Be available for consultation at all times and maintain contact with the investigating 
centre’s staff by post, telephone and/or fax, 
• 
Examine and evaluate the data in the case report form and look for any errors in data 
collection. 
 
Investigator obligations: 
The investigator undertakes to accept quality assurance audits carried out by the sponsor or 
inspections carried out by the health authorities. 
The investigator also undertakes to provide the sponsor with the following information: 
- 
ClinicalTrials registration number (NCT number): https://clinicaltrials.gov/ 
- 
Date of first inclusion in the study 
- 
Annual update (calendar year) of the number of inclusions 
- 
Date of last inclusion in the study 
- 
Date of last follow-up visit for the last patient in the study 
 
 
LEGAL AND ETHICAL CONSIDERATIONS 
 
Informing participants: 
The patient will be informed of the purpose of the research, the progress and duration of the study, 
the benefits, potential risks and constraints of the study and the opinion given by the CPP. They may 
exercise their right to object. 
 

 
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Request for an opinion from the CPP: 
"Non-interventional research," as stated in Article L. 1121-1 of the Public Health Code (Law no. 2012-
300 of 5 March 2012 and its implementing decree no. 2016-1537 of 16 November 2016) will be 
subject to the opinion of a CPP. 
The CPP must approve the protocol and the enlightened information document.  
 
Substantial changes: 
Any changes to the protocol must be submitted to the CPP for authorisation. 
 
Declaration of start/end of trial: 
The sponsor will declare the start and end of inclusion in the study to the CPP.  
 
 
PUBLICATION RULES  
 
All study data are the exclusive property of the sponsor. Any publication relating to these may only 
be made after validation by the sponsor and the methodologist, where applicable. 
Any person designated as an author must be competent to do so, and investigators are bound by 
the law to professional secrecy. According to the International Committee of Medical Journal Editors 
(ICMJE), each author must have participated sufficiently in the work to take responsibility for all or 
part of the content. The credibility of the authorship of the article is based on 3 essential contributions: 
• 
the design and method and/or analysis and interpretation of results, 
• 
the drafting of the article or critical revisions with significant involvement in the intellectual 
content, 
• 
the final approval of the published version. 
 
Order of authors (coordinating investigator(s), methodologist, primary investigators of the 
participating centres):  
The order will take into account the participation of the various investigators in the trial (number of 
patients included and evaluable) and those who make a significant contribution during the course of 
the trial. 
The source of funding will be indicated. 
In the case of ancillary studies, their results may only be published with the agreement of the sponsor 
and the methodologist, and only after publication of the main study, which must be cited. 
The coordinating investigator will sign the final clinical trial report, thereby indicating their agreement 
with the analyses, results and conclusions of the report. 
The results will be presented at conferences and published. 
These publications and presentations will be discussed with all the investigators taking part in the 
trial.  
 
 
 
 

 
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BIBLIOGRAPHY 
 
1 Update of the ECTRIMS/EAN Guidelines on the Treatment of Multiple Sclerosis. Montaban X, on 
behalf of the steering, Committee. ECTRIMS, Vienna 2021; ECTRIMS/EAN session 
 
2 Ayrignac X, Bigaut K, Pelletier J, de Seze J, Demortiere S, Collongues N, Maarouf A, Pinna F, 
Aouinti S, Carra Dallière C, Kremer, L, Charif M, Picot MC, Labauge P. First line therapeutic failure: 
Predictive factors in a cohort of 863 relapsing-remitting MS patients. Mult Scler Relat Disord. 2021 
Feb;48:102686. 
 
3 D'Amico E, Haase R, Ziemssen T. Review: Patient-reported outcomes in multiple sclerosis care. 
Mult Scler Relat Disord. 2019 Aug; 33:61-66.  
 
4 Lebrun-Frenay C, Kobelt G, Berg J, Capsa D, Gannedahl M; European Multiple Sclerosis Platform. 
New insights into the burden and costs of multiple sclerosis in Europe: Results for France. Mult Scler. 
2017 Aug; 23(2_suppl): 65-77 
 
5 Okunrintemi V, Khera R, Spatz ES, Salami JA, Valero-Elizondo J, Warraich HJ, Virani SS, 
Blankstein R, Blaha MJ, Pawlik TM, Dharmarajan K, Krumholz HM, Nasir K. Association of Income 
Disparities with Patient-Reported Healthcare Experience. J Gen Intern Med. 2019 Jun;34(6):884-
892.  
 
6 OECD (2019), Health at a Glance 2019: OECD Indicators, OECD Publishing, Paris, 
https://doi.org/10.1787/4dd50c09-en. 
 
7 Calocer F, Dejardin O, Kwiatkowski A, Bourre B, Vermersch P, Hautecoeur P, Launoy G, Defer G. 
Socioeconomic deprivation increases the risk of disability in multiple sclerosis patients. Mult Scler 
Relat Disord. 2020 May;40:101930.  
 
8 Lelorain, S., Moreaux, C., Christophe, V., Weingertner, F., & Bricout, H. (2019). Cancer care 
continuity: A qualitative study on the experiences of French healthcare professionals, patients and 
family caregivers. International Journal of Care Coordination, 22(2), 58-68.  
 
9 Haute Autorité de Santé. Health technology assessment at the HAS: the role of quality of life. Saint-
Denis La Plaine: HAS; 2018 
 
10 Vernay D., Gerbaud L., Biolay S. et al. Quality of life and multiple sclerosis: validation of the 
French version of a self-questionnaire, the SEP-59. Rev Neurol 2000;156(3):247-63 
 
11 Honarmand, K., & Feinstein, A. (2009). Validation of the Hospital Anxiety and Depression Scale 
for use with multiple sclerosis patients. Multiple Sclerosis Journal, 15(12), 1518-1524. 
 
12 Al-Janabi H, Flynn TN, Coast J. Development of a self-report measure of capability well-being for 
adults: the ICECAP-A. Qual Life Res. 2012 Feb;21(1):167-76. 

 
This document is the property of CHU Caen – Any use, reproduction and modification is subject to the owner’s agreement.   
25 
 
 
13 Bouwmans C, Krol M, Severens H, Koopmanschap M, Brouwer W, Hakkaart-van Roijen L. The 
iMTA Productivity Cost Questionnaire: A Standardized Instrument for Measuring and Valuing Health-
Related Productivity Losses. Value Health. 2015 Sep; 18(6): 753-8. 
 
14 Veillard D, Baumstarck K, Edan G, Debouverie M, Wiertlewski S, De Sèze J, Clavelou P, Pelletier 
J, Verny C, Chauvin K, Cosson ME, Loundou A, Auquier P. Assessing the experience of the quality 
of care of patients living with multiple sclerosis and their caregivers: The MusiCare questionnaire. 
Eur J Neurol. 2021 Mar;28(3):910-920. 
 
15 Pornet C, Delpierre C, Dejardin O, Grosclaude P, Launay L, Guittet L, Lang T, Launoy G: 
Construction of an adaptable European transnational ecological deprivation index: the French 
version. J Epidemiol Community Health 2012; 66:982-989.  
 
 
 
 
 

 
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APPENDICES 
 
APPENDIX 1 : DISEASE MODIFYING TREATMENTS FOR MULTIPLE SCLEROSIS 
 
Moderate efficacy DMTs  
Dimethyl Fumarate 
Diroximel Fumarate 
Glatiramer Acetate 
Interferon Beta 
Peginterferon Beta 
Teriflunomide 
 
High efficacy DMTs 
Cladribine 
Fingolimod 
Mitoxantrone 
Natalizumab 
Ocrelizumab 
Ofatumumab 
Ponesimod 
Rituximab* 
 
* : DMT used without French marketing authorisation but with a strong consensus in the MS experts’ 
community.