Effect of MD1003 in Progressive Multiple Sclerosis: a Randomized Double Blind Placebo Controlled Study
Phase: PHASE3
Conditions: Multiple Sclerosis
Sponsor: MedDay Pharmaceuticals SA

 
NOTICE: Part of all the information in this document may be unpublished and should be treated as 
the confidential property of MEDDAY, not divulged to unauthorized persons in any form, including 
publications and presentations, without the written consent of MEDDAY. 
Effect of MD1003 in progressive multiple sclerosis: 
a randomized double-blind placebo-controlled study 
 
CLINICAL TRIAL PROTOCOL 
 
Version No: 4 
Dated 12-Nov-2018 
Short title:  
SPI2 
Product: 
MD1003 
Protocol No:  
MD1003CT2016-01MS-SPI2 
EudraCT No:  2016-000700-29 
IND Number:  118798 
SPONSOR: 
MEDDAY PHARMACEUTICALS SA 
Address:  
24-26 rue de la pépinière 
75008 Paris 
France 
Tel:  + 33 (0)1 80 40 14 00 
Fax:  + 33 (0)1 81 51 66 77 

 
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SPONSOR SIGNATURE 
The study protocol of the clinical trial “Effect of MD1003 in progressive multiple sclerosis: a 
randomized double-blind placebo-controlled study” version 4 dated 12 Nov 2018 was subjected to 
critical review and the information it contains is consistent with current knowledge of the risks and 
benefits of the investigational product. My signature, in conjunction with the signature of the 
investigator, confirms the agreement of both parties that the clinical study will be conducted in 
accordance with the protocol and all applicable laws and regulations including, but not limited to, the 
International Conference on Harmonisation (ICH) Guideline for Good Clinical Practice (GCP), the 
Code of Federal Regulations (CFR), the ethical principles that have their origins in the Declaration of 
Helsinki, and applicable privacy laws. 
Name 
Title 
Date 
Signature 
Frederic Sedel, MD, 
PhD 
Chief Scientific Officer 
12-Nov-2018 
 
Frederick 
Munschauer, MD 
Global Head of Medical  
12-Nov-2018 
 
Prof. Bruce Cree, 
MD, PhD, MAS 
Coordinating Investigator 
12-Nov-2018 
 
 
CRO and designees 
Monitoring, data management, statistical analysis: Parexel International (Dublin, Ireland) 
Cardiac Safety Central Laboratory: Banook (Nancy, France) 
Core Imaging Laboratory: NeuroRx (Montreal, Canada) 
Clinical Central Laboratory: Eurofins (Lancaster, USA/Breda, The Netherlands/Singapore, Asia) 
Independent Biotin Assay Laboratory: Atlanbio (Saint Nazaire, France) 
 
 
 

 
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INVESTIGATOR SIGNATURE 
My signature, in conjunction with the signature of the sponsor, confirms the agreement of both parties 
that the clinical study will be conducted in accordance with the protocol and all applicable laws and 
regulations including, but not limited to, the International Conference on Harmonisation (ICH) 
Guideline for Good Clinical Practice (GCP), the Code of Federal Regulations (CFR), the ethical 
principles that have their origins in the Declaration of Helsinki, and applicable privacy laws. 
I have fully discussed the objectives of this study and its contents with the sponsor's representatives. I 
agree to conduct this study according to the protocol and its amendments and to comply with the 
requirements of the patient ethical, legal and safety considerations. 
Nothing in this document is intended to limit the authority of a physician to provide emergency medical 
care under applicable regulations. 
Name 
Title 
Date 
Signature 
 
Principal Investigator 
 
 
 
 
 
 

 
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STUDY SUMMARY 
Study Protocol Title 
Effect of MD1003 in progressive multiple sclerosis: a randomized double-
blind placebo-controlled study 
Short title 
SPI2 
Clinical Phase 
Phase III 
Study Protocol Number MD1003CT2016-01MS-SPI2 
EudraCT Number 
2016-000700-29 
Methodology and study 
design 
PART 1:  
Total duration of Part 1 is 27 months. The randomized double-blind 
placebo-controlled period ranges from 15 to 27 months depending upon 
the randomization date of an individual patient. 
Once the last month 15 evaluation of the study has been completed, patients 
will switch to the active drug at the next planned visit. Participants and 
study personnel will remain blinded as to the original treatment 
assignment. 
Maximum duration of double-blind period per patient will be no longer 
than 27 months. 
PART 2: 
At the last evaluation of Part 1 (Visit 11/Month 27) all participants will be 
offered active treatment in an open label extension for 39 additional months 
(From V11/M27 to V18/M66).  
The purpose of the active drug extension is to further define the safety of 
MD1003. 
Study Centers 
Coordinating investigator: Prof. Bruce CREE, UCSF, USA 
Investigational centers: 90 centers located in North America 
(USA/Canada), Europe and Australia. 
Steering committee:  
Prof. Fred LUBLIN, New York, USA; 
Prof. Bruce CREE, San Francisco, USA; 
Prof. Gary CUTTER, Birmingham, USA; 
Prof. Jerry WOLINSKY, Houston, USA; 
Prof. Mark FREEDMAN, Ottawa, Canada; 
Prof. Giancarlo COMI, Milan, Italy; 
Prof. Gavin GIOVANNONI, London, UK; 
Prof. Hans-Peter HARTUNG, Düsseldorf, Germany. 
 
Data Safety Monitoring Board: 
Prof. Stephen REINGOLD, Salisbury, USA; 
Prof. Pierre DUQUETTE, Montreal, Canada; 
Prof. Tobias DERFUSS, Basel, Switzerland; 
Prof. Franz FAZEKAS, Graz, Austria; 
Prof. Maria Pia SORMANI, Genoa, Italy. 

 
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Objectives 
 
Primary objective 
To demonstrate the superiority of MD1003, 300 mg/day, over placebo to 
clinically improve patients with progressive multiple sclerosis (MS). 
 
Secondary objectives 
To evaluate the safety of MD1003 
Number of patients 
Approximately 600 patients divided into 2 groups:  
- 
Group 1 (300 patients): Placebo 
- 
Group 2 (300 patients): MD1003, 300 mg/day 
Diagnosis and inclusion 
criteria  
1. Patient aged 18-65 years old 
2. Signed and dated written informed consent form in accordance with 
local regulations: having freely given their written informed consent to 
participate in the study 
3. Diagnosis of primary or secondary progressive MS fulfilling revised 
McDonald criteria (2010) and Lublin criteria (2014) 
4. Documented evidence of clinical disability progression within the 2 
years prior to inclusion, i.e. a) progression of EDSS during the past 
two years of at least 1 point sustained for at least 6 months if inclusion 
EDSS is from 3.5 to 5.5 or at least 0.5 point increase  sustained for at 
least 6 months if inclusion EDSS is from 6 to 6.5 or b) increase of 
TW25 by at least 20% in the last two years sustained for at least 6 
months or c) other well-documented objective worsening validated by 
the Adjudication Committee 
5. EDSS at inclusion from 3.5 to 6.5 
6. TW25 < 40 seconds at inclusion visit  
7. Kurtzke pyramidal functional subscore ≥2 defined as “minimal 
disability: patient complains of motor-fatigability or reduced 
performance in strenuous motor tasks (motor performance grade 1) 
and/or BMRC grade 4 in one or two muscle groups” 
Exclusion criteria 
1. Clinical evidence of a relapse in 24 months prior to inclusion  
2. Treatment with any product containing biotin as single ingredient 
within six months prior to inclusion (multivitamin supplementation 
authorized if biotin < 1mg per day) 
3. Concomitant treatment with fampridine at inclusion or in the 30 days 
prior to inclusion 
4. New immunosuppressive/immunomodulatory drug initiated less than 
90 days prior to inclusion 
5. Treatment with botulinum toxin (except for cosmetic purposes) 
initiated within 6 months prior to inclusion 
6. In-patient rehabilitation program within the 3 months prior to inclusion 
7. Pregnancy, breastfeeding or women with childbearing potential 
without acceptable form of contraception 

 
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8. Men unwilling to use an acceptable form of contraception 
9. Any general chronic handicapping/incapacitating disease other than 
MS 
10. Any serious disease necessitating biological follow-up with biological 
tests using biotinylated antibodies or substrates 
11. Past history of rhabdomyolysis or metabolic myopathy  
12. Known fatty acids beta oxidation defect 
13. Known hypersensitivity or intolerance to biotin, analogues or 
excipients, patients with rare hereditary problems of galactose 
intolerance, the Lapp lactase deficiency or glucose-galactose 
malabsorption 
14. Patients with hypersensitivity or any contra-indication to gadolinium 
15. Patients with uncontrolled hepatic disorder, renal or cardiovascular 
disease, or cancer 
16. Laboratory tests out of normal ranges considered by the investigator 
as clinically significant with regards to the study continuation 
17. Patients with history or presence of alcohol abuse or drug addiction 
18. Untreated or uncontrolled psychiatric disorders, especially suicidal 
risk assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) 
19. Participation in another research study involving an investigational 
product (IP) in the 90 days prior to inclusion, or planned use during the 
study duration 
20. Patients likely to be non-compliant to the study procedures or for 
whom a long-term follow-up seems to be difficult to achieve 
21. Relapse that occurs between inclusion and randomization visit 
Investigational Product MD1003 300 mg/day (100 mg tid).  
Control therapy 
Placebo capsules in placebo arm for at least 15 months and up to 27 months 
depending on the patient randomization date 
Concomitant & 
intercurrent therapies 
• Usual care including immuno-modulators, and immunosuppressive 
drugs including monthly pulses of IV methylprednisolone allowed in 
placebo and treated groups if already treated by these drugs 
• IV methylprednisolone allowed during the trial if relapse without oral 
taper 
• Fampridine not allowed during the study 
• Initiation of botulinum toxin not allowed during the study (except for 
cosmetic purpose) 
• In-patient rehabilitation therapy program not allowed during the study  
 

 
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Duration of 
administration 
PART 1:  
Total duration of Part 1 is 27 months. The randomized double-blind 
placebo-controlled period ranges from 15 to 27 months depending upon 
the randomization date of an individual patient. 
Once the last month 15 evaluation of the study has been completed for all 
subjects, participants will switch to the active drug at the next planned visit 
(V8/M18 or V9/M21 or V10/M24).  After switching to active drug, 
participants and study personnel will remain blinded as to the original 
treatment assignment.  
The maximum duration of double-blind period per patient will be no longer 
than 27 months. 
PART 2: 
At the last evaluation of Part 1 (Visit 11/Month 27) all participants will be 
offered active treatment in an open label extension for 39 additional months 
(From V11/M27 to V18/M66).  
The purpose of the active drug extension is to further define the safety of 
MD1003.    
Evaluation criteria 
• 
Primary efficacy endpoint 
Proportions of patients:  
• 
with decreased EDSS at M12 confirmed at M15 (where 
decreased EDSS is defined as a decrease of at least 1 point if 
initial EDSS from 3.5 to 5.5 and of at least 0.5 point if initial 
EDSS from 6 to 6.5)  
or  
• 
with improved TW25 of at least 20% at M12 confirmed at 
M15  
The baseline score for EDSS will be the lowest (best) value obtained during 
either the inclusion or randomization visit.  
The baseline value for TW25 will be the best mean of the 2 scores obtained 
at either the inclusion or randomization visit (the lowest mean value 
between the 2 visits). 
The TW25 value at visit M12 and M15 is defined as the mean of the two 
TW25 attempts at each visit.  
• 
Secondary efficacy endpoints 
1. Time to EDSS progression confirmed at 12 weeks 
2. Mean difference between treatment arms in CGI at M15 
3. Mean difference between treatment arms in SGI at M15 
4. Mean change in TW25 score between M0 and M15 
• 
Exploratory endpoints 
1. Mean change in Brain MRI measures between M0 and M15:  
a. Percent whole brain volume 
b. Percent thalamic volume 

 
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c. Percent cortical grey matter volume 
 
d. Brain water content evaluated by Pseudo T2 
relaxation time  
e. NAA/Cr in a subset of sites acquiring MRS 
2. Remote monitoring of ambulation 
3. Multiple Sclerosis Quality of Life-54 (MSQOL54) and 
Caregiver health-related quality of life in Multiple Sclerosis 
(CAREQOL-MS) subscores and composite scores 
4. Subscores of the Kurtzke functional score 
5. Symbol Digit Modalities Test (SDMT) 
• 
Safety evaluation 
1. Recording of AEs 
2. Laboratory testing (standard haematology and biochemistry 
panel) 
3. ECG: PR, QRS, QT and RR interval, HR and QTcF, wave 
morphology, rhythm and conduction 
4. Brain MRI: new or enlarging T2 lesions and Gd+ lesions 
5. Columbia-Suicide Severity Rating Scale 
Statistical methodology For the sample size estimation of SPI2, hypotheses were set at 2% for the 
proportion of clinically improved patients in the placebo group and at 12% 
in the MD1003 group. A sample-size of 600 patients will provide a power 
>90% in the global population. 
A logistic regression will be fitted to estimate the treatment effect (odd-
ratio of improved patients) using treatment, disease history (SPMS/PPMS) 
and geographical region as fixed factors (referred as the main logistic 
model in the following parts).  
The main logistic model will then be used for each component of the 
composite outcome (EDSS and TW25 responses), to complement the 
analysis of the main endpoint. 
For the primary endpoint analysis, patients without confirmation of clinical 
response at M12 and M15 will be considered as non-responders (missing 
data will be handled in accordance with the rules specified in the statistical 
analysis plan).  
No multiplicity adjustment is considered for the primary endpoint as there 
is a unique main criterion. Secondary endpoints are hierarchically scaled 
by order of clinical importance. 
Duration of patient 
participation 
PART 1: 28 months (1-month screening plus at least 15-months, but not 
to exceed 27 months of blinded study drug administration)  
PART 2: Open label extension for 39 months (V11/M27 to V18/M66) 
Study duration 
Total study duration: 84 months  
Recruitment period: 17 months recruitment  
PART 1: 28 months (1-month screening period + 27-month patient 
participation) 
PART 2: 39 months from V11/M27 until V18/M66  

 
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LIST OF ABBREVIATIONS 
9-HPT  
 
Nine Hole Peg Test 
ACC 
 
 
Acetyl-CoA Carboxylase 
AE 
 
 
Adverse Event 
ALT 
 
 
Alanine Transaminase 
ANCOVA 
 
Analysis of Covariance 
APPT  
 
Activated Partial Thromboplastin Time 
AST 
 
 
Aspartate Transaminase 
ATP 
 
 
Adenosine Triphosphate 
BBGD  
 
Biotin Basal Ganglia Disease 
BNB 
 
 
Bisnorbiotin 
BSO 
 
 
Biotin Sulfoxide 
CAC 
 
 
Clinical Adjudication Committee  
CSCL  
 
Core Cardiac Safety Laboratory 
CAREQOL-MS  
Caregiver health-related quality of life in Multiple Sclerosis 
eCRF 
 
 
electronic Case Report Form 
CIS 
 
 
Clinically Isolated Syndromes 
C-SSRS 
 
Columbia-Suicide Severity Rating Scale 
CGI 
 
 
Clinical Global Impression assessed by Investigator 
CNS 
 
 
Central Nervous System 
CPT1 
 
 
Carnitine Palmitoyltransferase 1 
DSMB  
 
Data Safety Monitoring Board 
EC 
 
 
Ethics Committee 
ECG 
 
 
Electrocardiography 
EDSS  
 
Expanded Disability Status Scale 
ETDRS  
 
Early Treatment Diabetic Retinopathy Study  
FAS 
 
 
Full Analyzable Set 
FDA 
 
 
Food and Drug Administration 
FIS 
 
 
Fatigue Impact Scale 
FS 
 
 
Functional System 
GCP 
 
 
Good Clinical Practice 
GGT 
 
 
Gamma-Glutamyl Transpeptidase 
GP 
 
 
General Practitioner  
HEENT  
 
Head, Eyes, Ears, Nose, Throat 
H-MRS  
 
Proton Magnetic Resonance Spectroscopy 
ICH 
 
 
International Conference on Harmonisation 
IEC 
 
 
Independent Ethics Committee 

 
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IP 
 
 
Investigational Product  
 
 
IRB 
 
 
Institutional Review Board 
ITT 
 
 
Intent-To-Treat 
IVMP  
 
Intravenous Methylprednisolone 
IWRS  
 
Interactive Web Response System 
LOCF  
 
Last Observation Carried Forward 
MCC 
 
 
3-Methylcrotonyl-CoA Carboxylase 
MRI 
 
 
Magnetic Resonance Imaging 
MRS 
 
 
Magnetic Resonance Spectroscopy 
MS 
 
 
Multiple Sclerosis 
MSQOL 54 
 
Multiple Sclerosis Quality of Life-54 
MSWS  
 
Multiple Sclerosis Walking Scale 
NAA/Cr 
 
N-acetylaspartate / creatine ratio 
NIP 
 
 
Non-Investigational Product 
OLE 
Open Label Extension 
 
ON 
 
 
Optic Neuritis 
PP 
 
 
Per-Protocol 
PC 
 
 
Pyruvate Carboxylase 
PCC 
 
 
Propionyl-CoA Carboxylase 
PPMS  
 
Primary Progressive Multiple Sclerosis 
PT 
 
 
Prothrombin Time 
RBC 
 
 
Red Blood Cell 
RRMS  
 
Relapsing-Remitting Multiple Sclerosis 
SADR  
 
Serious Adverse Drug Reaction 
SAE 
 
 
Serious Adverse Event 
SAP 
 
 
Statistical Analysis plan 
SDMT  
 
Symbol Digit Modalities Test 
SGI 
 
 
Clinical Global Impression assessed by Subject 
SPMS  
 
Secondary Progressive Multiple Sclerosis 
T3 
 
 
Triiodothyronine 
TCA 
 
 
Tricarboxylic Acid 
TSH 
 
 
Thyroid-stimulating Hormone 
TW25  
 
Timed 25-Foot Walk 
USA 
 
 
United States of America 
VA 
 
 
Visual Acuity 
WBC 
 
 
White Blood Cell 
 

 
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TABLE OF CONTENTS 
 
STUDY SUMMARY _______________________________________________________________ 4 
LIST OF ABBREVIATIONS ________________________________________________________ 9 
TABLE OF CONTENTS __________________________________________________________ 11 
Introduction / Rationale ___________________________________________________________ 14 
1 
Study objectives _____________________________________________________________ 22 
1.1 
Primary objective _______________________________________________________ 22 
 
Primary endpoint____________________________________________________________ 22 
 
Primary efficacy measure _____________________________________________________ 23 
 
Secondary objectives _____________________________________________________ 23 
 
Secondary efficacy endpoints __________________________________________________ 23 
 
Exploratory endpoints ________________________________________________________ 23 
 
Safety of MD1003 __________________________________________________________ 23 
2 
Investigational plan __________________________________________________________ 25 
 
Overall study design _____________________________________________________ 25 
 
PART 1: Randomized double-blind placebo-controlled period for 15 to 27 months ________ 27 
 
PART 2: Open Label Extension (39 months) ______________________________________ 28 
 
Number of patients ______________________________________________________ 28 
 
Selection and withdrawal of patients ________________________________________ 28 
 
Inclusion criteria ____________________________________________________________ 28 
 
Exclusion criteria ___________________________________________________________ 30 
 
Contraception ______________________________________________________________ 30 
 
Follow up of pregnancy ______________________________________________________ 31 
 
Patient identification and assignment of patient number _____________________________ 31 
 
Screening failures ___________________________________________________________ 32 
 
Premature discontinuation of treatment __________________________________________ 32 
 
Premature termination or suspension of the study __________________________________ 33 
 
Investigational products, control therapies and administration __________________ 33 
 
Description of investigational product and control arm ______________________________ 33 
 
Packaging and labelling ______________________________________________________ 35 
 
Treatment assignment ________________________________________________________ 35 
 
Randomization and blinding ___________________________________________________ 35 
 
Investigational product shipping, handling and storage ______________________________ 37 
 
Treatments compliance, accountability and return of therapeutic units __________________ 37 
 
Overdose __________________________________________________________________ 38 
 
Destruction ________________________________________________________________ 38 
 
Concomitant treatments __________________________________________________ 38 

 
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Concomitant medication ______________________________________________________ 38 
 
Physical therapy ____________________________________________________________ 39 
 
Visits schedule and evaluations ____________________________________________ 40 
 
Study flow chart Part 1: double-blind period for 15 to 27 months ______________________ 40 
 
Study flow chart Part 2: Open label extension _____________________________________ 41 
 
Evaluations ________________________________________________________________ 42 
 
Efficacy assessments _____________________________________________________ 53 
 
Expanded Disability Status Scale (EDSS) Definition ________________________________ 53 
 
TW25 (Timed 25-Foot Walk) __________________________________________________ 56 
 
Symbol Digit Modalities Test (SDMT) __________________________________________ 56 
 
Remote monitoring of ambulatory activity ________________________________________ 57 
 
Patient reported outcome measures ______________________________________________ 57 
 
Safety assessments _______________________________________________________ 58 
 
Serious and non-serious adverse events monitoring and recording _____________________ 58 
 
Suicide behavior questionnaire: Columbia-Suicide Severity Rating Scale (C-SSRS) _______ 58 
 
Clinical examination _________________________________________________________ 59 
 
Laboratory testing (haematology and biochemistry panel) ____________________________ 60 
 
Electrocardiogram ___________________________________________________________ 60 
 
Brain MRI _________________________________________________________________ 61 
 
Exploratory endpoints assessed by brain MRI ________________________________ 61 
 
Measures of biotin concentration in blood ___________________________________ 62 
 
Measures of neurofilament concentration in blood ____________________________ 62 
3 
Adverse events ______________________________________________________________ 63 
 
Special warning, precaution for use related to interference with laboratory tests ___ 63 
 
Definitions _____________________________________________________________ 64 
 
Handling of Non-Serious Adverse Events ____________________________________ 65 
 
Severity assessment _________________________________________________________ 66 
 
Causality assessment _________________________________________________________ 66 
 
Assessment of seriousness ____________________________________________________ 67 
 
Serious Adverse Events reporting __________________________________________ 67 
 
Sponsor Reporting Requirements to Regulatory Authority _____________________ 68 
4 
Statistical considerations ______________________________________________________ 68 
 
Determination of sample size ______________________________________________ 68 
 
Definition of populations for analysis _______________________________________ 68 
 
Handling of Missing data _____________________________________________________ 69 
 
Multiplicity ________________________________________________________________ 69 
 
Efficacy evaluation ______________________________________________________ 69 

 
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Analysis of the primary endpoint _______________________________________________ 69 
 
Analysis of secondary endpoints________________________________________________ 70 
 
Analysis of exploratory endpoints ______________________________________________ 71 
 
Active drug extension analysis _________________________________________________ 71 
 
Safety evaluation ________________________________________________________ 71 
 
Interim analysis and data safety monitoring committee ________________________ 73 
 
Analysis by subgroups ____________________________________________________ 73 
5 
Prestudy documentation ______________________________________________________ 73 
6 
Informed consent ____________________________________________________________ 74 
7 
Direct Access, data Handling and Record-keeping _________________________________ 74 
 
Investigator ____________________________________________________________ 74 
 
Sponsor ________________________________________________________________ 75 
 
Source document requirements ____________________________________________ 75 
 
The use and completion of electronic Case Report Forms (eCRFs) _______________ 75 
8 
Administrative rules __________________________________________________________ 76 
 
Curriculum vitae ________________________________________________________ 76 
 
Secrecy agreement _______________________________________________________ 76 
 
Protocol amendments ____________________________________________________ 76 
 
Record retention in investigation center(s) ___________________________________ 76 
 
Insurance compensation __________________________________________________ 76 
 
Quality control and assurance _____________________________________________ 77 
 
Ownership of results - Publication __________________________________________ 77 
 
Study Specific Committees ________________________________________________ 77 
 
Scientific and Steering committee ______________________________________________ 77 
 
Adjudication Committee ______________________________________________________ 78 
 
Data Safety Monitoring Board (DSMB) __________________________________________ 78 
9 
Bibliographic references ______________________________________________________ 79 
10 
APPENDICES ______________________________________________________________ 81 
Annex 1: Revised Mc Donald criteria _____________________________________________ 81 
Annex 2: Neurostatus __________________________________________________________ 82 
Annex 3: Relapse assessment questionnaire ________________________________________ 91 
Annex 4: SPI2 Patient Alert Card ________________________________________________ 94 
Annex 5: Multiple Sclerosis Quality of Life-54 (MSQOL-54)__________________________ 95 
Annex 6: Caregiver health-related quality of life in Multiple Sclerosis – CAREQOL-MS _ 111 
Annex 7: Columbia-Suicide Severity Rating Scale (C-SSRS) _________________________ 112 
Annex 8: World Medical Association Declaration of Helsinki (2013 version) ___________ 115 

 
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INTRODUCTION / RATIONALE 
Multiple Sclerosis (MS) is a common neurological disease affecting more than 2 million people 
worldwide. Its prevalence rate varies between races and regions, with an estimated mean of around 
1/1,000 in Europe and United States of America. 
MS is an inflammatory autoimmune disease that damages the myelin of the central nervous system 
(CNS) causing neurological impairment and, in many cases, severe disability (Noseworthy et al., 2000). 
The aetiology of MS remains unknown. It is generally believed that MS is mediated by a complex 
interplay between host genetic factors and environmental exposures, such as viral infection and 
hypovitaminosis D (Sotgiu et al., 2004). 
Approximately 85% of all patients present with relapsing-remitting (RRMS), which is characterized 
by unpredictable acute episodes of neurological dysfunction named relapses, followed by variable 
recovery and periods of clinical stability. 
Around 15% of all patients develop a sustained deterioration of their neurological function from the 
beginning; i.e. primary progressive multiple sclerosis (PPMS) (Bradl & Lassmann, 2009). 
Within 15 years more than 50% of patients who presented with a RR form develop sustained 
deterioration with or without superimposed relapses; this form is called secondary progressive (SPMS). 
Conversion of RRMS to secondary progressive presentations of MS is an age-dependent process with a 
rate estimated at 2-3% per year (Confavreux & Vukusic, 2006). 
The term “relapsing MS” includes 1) RRMS, and 3) clinically isolated syndromes (CIS) who show 
dissemination of lesions in time and space on magnetic resonance imaging (MRI) scans according to the 
2010 revised McDonald’s criteria (Lublin et al., 2014, Polman et al., 2011). All the disease modifying 
therapies approved so far in MS are intended to treat relapsing forms of MS. Prevention and/or 
modification of relapses as well as prevention or delay of the accumulation of lesions and disability due 
to relapses have constituted the main goals in the treatment of relapsing multiple sclerosis. 
In relapsing MS, lymphocytes and monocytes of the peripheral adaptive immune system infiltrate 
perivascular brain and spinal cord tissue causing focal inflammation that can be identified on imaging 
as acute contrast enhancing lesions. The histopathological hallmark of these lesions is injury to 
oligodendroglia cells that wrap axons in myelin, the cell membrane that enhances electrical resistance 
and allows salutatory conduction through the central nervous system. Axons themselves are typically 
relatively spared and this feature helps distinguish multiple sclerosis from tissue destructive processes. 
Thus in this relapsing, inflammatory phase, MS is considered to be an inflammatory demyelinating 
disease. The focal inflammation resolves over weeks and gliosis follows resulting in the hardened 
plaques described at autopsy.   
The term “progressive MS” includes both PPMS and SPMS (Lublin et al., 2014). Progressive MS can 
be “active” when clinical relapses and/or MRI activity (contrast-enhancing lesions; new and 
unequivocally enlarging T2 lesions) occur. Progressive MS is said to be “not-active” in the absence of 
clinical relapses or MRI inflammatory activity.  
Both inflammatory and neurodegenerative processes contribute to progressive MS with a continuum 
between progressive active forms where inflammation still exist and not-active forms where the axonal 
degenerative process predominates without overt signs of focal inflammation. To date most therapeutic 
approaches of progressive MS focused on the inflammatory component with little success (Ontaneda et 
al., 2015). In contrast the axonal degenerative process, which is far less well understood, has been the 
focus of only a few trials (Chataway et al., 2014, Kapoor et al., 2010). 
At the cellular level, it has been hypothesized that progressive axonal degeneration might be linked 
to/driven by secondary energy failure. Indeed, it is believed that, in the normal condition, myelin 
insulation reduces the energy demand during impulse propagation because adenosine triphosphate 
(ATP) is needed to reform the resting membrane potential only at the Ranvier nodes. Demyelinated 

 
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fibers are placed at an energetic disadvantage because of increased ionic leaks across the denuded axon 
membrane, resulting in an increased energy demand for ion pumping. In addition, energy production 
may be compromised owing to mitochondrial disruption and Na+-K+-ATPase- mediated ion transport 
may be reduced in many demyelinated axons in the MS brain that could bias these axons towards a state 
of ‘virtual hypoxia’. The resulting mismatch between energy supply and demand could result in 
degeneration (Luessi et al., 2012, Stys et al., 2012). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The figure above illustrates the increased axonal demand as a result from axonal demyelination. Nerve 
impulses in myelinated axons propagate between the nodes of Ranvier. The transient opening of voltage-
gated Na+ ion channels triggers depolarization. Repolarization is achieved through voltage-gated K+ 
ion channels, which restore electrical conditions, followed by restoration of the ionic distribution by the 
ATP-dependent Na+/K+ ATPase pump. ATP consumption is greatly increased in demyelinated axons 
due to redistribution of ion channels along the length of the denuded axon. 
 
1. Vitamin H/Biotin: mechanism of action 
Vitamin H, more commonly known as biotin, is part of the water-soluble B complex vitamin group. 
Biotin is an essential nutrient that acts as a carboxyl (CO2) transporter in carboxylation reactions. In 
mammals, biotin serves as a cofactor for four carboxylases involved in the metabolism of carbohydrates, 
amino acids and fatty acids: (1) pyruvate carboxylase (PC), (2) 3-methylcrotonyl-CoA carboxylase 
(MCC), (3) propionyl-CoA carboxylase (PCC) and (4) acetyl-CoA carboxylase (ACC) (Tong, 2013). 
Three out of these four reactions lead to production of Krebs cycle intermediates that are central in 
Sedel et al, Neuropharmacology submission 2015 
26 
 
Figure 2. Increased axonal energy demand as a result from axon demyelination. Nerve 
impulses in myelinated axons propagate between the nodes of Ranvier. Depolarization of 
the membrane is triggered by the transient opening of voltage-gated Na+ ion channels. 
Repolarization is achieved through voltage-gated K+ ion channels, which restore electrical 
conditions, followed by restoration of the ionic distribution by the ATP-dependent Na+/K+ 
ATPase pump. ATP consumption is greatly increased in demyelinated axons due to 
redistribution of ion channels along the length of the denuded axon.  
 
 
 

 
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aerobic energy production. In addition, ACC is the rate-limiting enzyme for fatty acids synthesis and is 
expressed at high level in oligodendrocytes. It is hypothesized that activation of ACC by high doses of 
biotin could stimulate remyelination. 
Besides its role as a co-factor, biotin may regulate genes encoding enzymes or transporters involved 
in its own metabolism or other cell functions (Zempleni et al., 2009). However, this physiological role 
of biotin remains unclear. 
High doses of biotin are expected to be the first therapeutic approach having an impact on progressive 
MS by reversing the “virtual hypoxia” phenomenon and triggering remyelination (Sedel et al., 2015a, 
Sedel et al., 2015b). 
Target 1, increasing the amount of ATP in the diseased neurons: Reversing the virtual hypoxia 
phenomenon.   
• 
It is hypothesized that the treatment with high-dose biotin reverses the state of virtual hypoxia 
through its role as a cofactor for PC, MCC, and PCC. These three enzymes are central to aerobic energy 
production and generate intermediates for the tricarboxylic acid (TCA) cycle. All three of these enzymes 
are expressed in astrocytes and neurons. PC catalyzes the conversion of pyruvate to oxaloacetate, thus 
serving an essential anaplerotic role by replenishing the 4-carbon “backbone” of the TCA cycle. PCC 
generates methylmalonyl-CoA from propionyl-CoA, which is then converted to succinyl-CoA by 
methylmalonyl-CoA mutase. MCC plays a role in the metabolism of leucine and ultimately leads to 
production of acetyl- CoA. Thus, these three biotin-dependent carboxylases feed the TCA cycle at three 
different entry points: oxaloacetate, succinate and acetyl-CoA, and could be expected to increase the 
levels of cellular ATP. By increasing the available intraneuronal pool of ATP, high-dose biotin may 
reduce demyelinated neural dysfunction and the adverse effects of hypoxia.  
• 
 
The first evidence that high doses of biotin (5 to 10 mg/Kg/day) could have an 
advantage to low doses (0.014 mg mg/Kg/day) was supported by previous experience in “Biotin basal 
ganglia disease” (BBGD), a disorder of energy metabolism. BBGD is caused by mutations in the 
thiamine transporter THTR2 (Debs et al., 2010, Ozand et al., 1998, Zeng et al., 2005). A thiamine defect 
is expected to block the Krebs cycle (Subramanian et al., 2006). High doses of Biotin (about 5-10 
mg/kg/day) showed potential efficacy in this orphan neurological disease. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The figure describes how biotin increases ATP production in axonal mitochondria (Sedel et al., 2015b). 
Sedel et al, Neuropharmacology submission 2015 
Figure 3. Biotin increases ATP production in axonal mitochondria (Fernandez-Mejia, 
2005) 
 
 

 
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Target 2: Triggering remyelination 
A second biotin-dependent pathway that occurs in the cytoplasm through the biotin-dependent ACC1 
and ACC2 may play a role in myelin repair. This pathway is key in the regulation of fatty acid synthesis 
(Tong, 2013). ACC1 and ACC2 are key regulators of membrane lipid synthesis including myelin 
synthesis (Chakraborty & Ledeen, 2003). In the CNS, ACC1 and 2 are mostly expressed in 
oligodendrocytes (Chakraborty & Ledeen, 2003). Furthermore, ACC can be detected in purified myelin 
(Chakraborty & Ledeen, 2003). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The figure summarizes how biotin activates myelin formation in oligodendrocytes through its role as 
a cofactor for ACC (Sedel et al., 2015a). 
 
2. Clinical evidence for biotin as a potential treatment for progressive MS 
1) Pilot, open-label study in patients with progressive MS 
Twenty-three consecutive patients with progressive MS were treated with high doses of biotin ranging 
from 100 mg to 600 mg/day (median= 300 mg/day divided in three doses) in a compassionate use 
protocol (Sedel et al., 2015b). Treatment duration was 2 to 36 months (mean treatment duration = 9.2 
months). Patients were followed in three different MS-reference centers in France. Most of the patients 
had been treated with medications that failed to improve their neurological condition including monthly 
pulses of intravenous methylprednisolone (IVMP), cyclophosphamide, azathioprine or fampridine that 
are sometimes used in empiric treatment of progressive MS. None of these drugs were initiated during 
the period of treatment with biotin, except consecutive pulses of IVMP in case of superimposed MS 
relapses. 
Fourteen patients were classified as PPMS and 9 as SPMS. Four patients had permanent visual loss 
following optic neuropathies; one patient had progressive lateral hemianopia caused by involvement of 
the optic radiations and 18 patients had progressive paraparesis or tetraparesis related to spinal cord 
involvement. 
Overall, 21/23 patients with progressive MS (91.3%) exhibited clinical improvement with high doses 
of biotin evidenced with clinical, electrophysiological and proton magnetic resonance spectroscopy (H-
MRS) data. In all cases, clinical improvement appeared 2 to 8 months (mean=3 months) following 
Sedel et al, Neuropharmacology submission 2015 
25 
 
Figures and Tables 
 
Figure 1. Biotin activates myelin formation in oligodendrocytes through its role as a 
cofactor for ACC (Chakraborty et al., 2003) 
 
 
 
 

 
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treatment initiation. Only 2 patients with severe tetraparesis did not show positive response to treatment, 
possibly related to short duration of treatment exposure (8 and 7 months respectively). However, one 
patient with a severe tetraparesis appeared to benefit after only 8 months of treatment. The dose of 300 
mg/day was associated with the best clinical efficacy. In addition, treatment appeared to be safe: 
transient diarrhoea, the only minor adverse effect, was noted in 2 patients. One patient died at 73 years 
old, from cardiac failure three years after treatment onset, but this was not attributed to treatment. No 
symptoms of cardiac dysfunction were observed in the 22 other patients. MS relapse frequency was 
similar to that observed before treatment in the four patients who experienced at least one relapse. 
 
2) Randomized, double-blind, placebo-controlled trial in adult patients with progressive MS 
(MS-SPI) 
MS-SPI the first randomized, double-blind study conducted by MedDay was intended to demonstrate 
the superiority of D-Biotin 300 mg/day over placebo in clinical confirmed improvement of patients with 
not active progressive multiple sclerosis (PPMS or SPMS) based on EDSS and timed 25-foot walk 
(TW25) measures. This was a 12-month double-blind randomized placebo-controlled Phase 2b/3 trial 
that compared MD1003 (D-Biotin 300 mg/day) with placebo followed by a 12 month-extension phase 
during which the placebo was switched to the active drug (during the extension phase patients and 
clinicians remained blinded to the treatment received during the double-blind phase). D-Biotin was 
administered orally at a dose of 100 mg thrice daily (morning, noon, evening). Eligible patients were 18 
to 75 years of age with PPMS or SPMS that fulfilled revised McDonald (Polman et al., 2011) and Lublin 
(Lublin & Reingold, 1996) criteria with clinical evidence of spastic paraparesis (walking disability due 
to cortico-spinal tracts involvement). Patients with clinical or radiological evidence of inflammatory 
disease activity within the previous year were excluded. All patients had a baseline EDSS of 4.5 to 7 
with evidence of disease progression during the previous two years (an increase of EDSS of ≥1 point if 
EDSS was 4.5–5.5 and ≥0.5 point if EDSS was 6–7). The primary endpoint was the proportion of 
patients with a clinical improvement in either EDSS or timed 25-foot walk (TW25) scores at month 9 
(and confirmed at month 12) compared with the best EDSS/TW25 values recorded between screening 
and randomization visits. Clinical improvement was defined as a decrease of ≥0.5 points or ≥ 1 point 
for EDSS (if baseline score was 6–7 or 4.5–5.5, respectively) or a decrease of ≥20% for TW25 score. 
Secondary endpoints were the mean change in EDSS from randomization to month 12; the proportion 
of patients with EDSS progression from randomization to month 9 (confirmed at month 12); mean 
change in TW25 (randomization to month 12); the clinical global impression of change score evaluated 
by the investigator (CGI) and the subject (SGI) at month 12; and mean change in MS walking scale 
(MSWS), fatigue impact scale (FIS), EDSS subscores, 9-hole peg test (9-HPT), and SF-36 score 
(randomization to month 12). 
Thirteen (12.6%) patients treated with MD1003 achieved clinical improvement in MS-related 
disability at month 9, confirmed at month 12, compared with none of the placebo-treated patients 
(p=0.0051). Most of the patients (10 out of 13) responded on the EDSS sub-score while 5 responded on 
the TW25 sub-score (2 patients responded on both). Results were similar for the primary endpoint on a 
per-protocol basis (N=129): 14.9% of patients in the intervention group responded and none in the 
control group (p=0.0093). The percentages of responders were 9.5% in the PPMS subgroup and 14.7% 
in the SPMS subgroup. 
In the extension phase, the proportion of responders at M18 confirmed at M24 in the placebo/biotin 
group, i.e. the patients who were receiving their first biotin intakes, was 7.14%, i.e. slightly lower than 
the biotin group proportion of the responders at M6 confirmed at M9 that was 10.68%. The proportion 
of responders in the biotin-biotin sequence group was 13.19%, i.e. stable. At month 24 (end of the 
extension phase)14/91 (15.4%) patients initially treated with MD1003 and 5/42 (11.9%) patients 
initially treated with placebo had reduced MS-related disability.  

 
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On the other hand, the proportion of patients with worsened EDSS scores (confirmed at two visits) 
increased at a faster rate in the placebo group compared to the biotin group: at M9 (confirmed at M12), 
it reached 13.64% and 4.21%, respectively. This result was not statistically significant (p=0.0727). At 
M18 (confirmed at M24), the proportion continued to increase in the biotin/biotin group, reaching 
9.88%; the increase was also observed in the placebo/biotin group but at a faster rate, and reached 
31.71%, this result was found statistically significant (p=0.0045) indicating that early treatment with 
biotin decreased the rate of disease’s progression. 
As a result, mean EDSS scores decreased during the study in the biotin group, but increased in the 
placebo group. The changes from baseline at M9 and at M12 were statistically different in the biotin 
group compared to the placebo group: p=0.0223 at M9 and p=0.0139 at M12. At M12, once the patients 
included in the placebo group had been switched to biotin for the extension phase, the increase of the 
mean EDSS change from baseline, that had been observed in the double-blind phase, stopped and 
remained constant until the M24 assessment (+0.13 at M12 versus +0.15 at M24). In the patients who 
had already been receiving biotin during the double-blind phase, the mean change EDSS (from baseline) 
remained relatively stable over 24 months (-0.03 at month 12 versus +0.04 at month 24). This indicates, 
that the 12-month delay in initiating active treatment in the placebo/biotin group resulted in a higher 
level of disability compared to the 24-month of active treatment administration in the biotin/biotin 
group. 
Results of patient reported outcome measures also showed statistically significant differences in favor 
of the biotin group for the Clinician and Subject Global Impression of change Scales (CGI and SGI): 
the mean (SD) CGI was better in the biotin group compared to the placebo group: 4.05 (0.81) versus 
4.62 (0.75), and this difference was statistically significant (p<0.0001). Similarly, the mean (SD) SGI 
was better in the biotin group compared to the placebo group: 4.27 (1.05) versus 4.76 (0.89), and this 
difference was statistically significant (p=0.0094). During the extension phase, the CGI and SGI were 
relatively stable in the biotin/biotin group between M12 and M24. In the placebo/biotin group, once the 
patients had switched to biotin, CGI and SGI improved. As a result, at M24, the mean CGI (SD) and 
SGI were identical in the biotin/biotin group and in the placebo/biotin group: 4.17(0.97) versus 
4.21(0.75) for CGI (p=0.9270); and 4.47(1.07) versus 4.41(0.87) for SGI (p=0.7207). 
Compared to previous trials in progressive MS, the effect size of MD1003 on mean EDSS progression 
is better than any drug tested so far in primary or secondary progressive MS (based on published data 
only): 

 
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Mean change EDSS in the MS-SPI in the context of previous published trials in PPMS and SPMS 
involving>6000 patients. 
 
The incidence and distribution of adverse events (AEs) were similar in both study arms during the 
double-blind phase. Most (97%) AEs observed in the intervention group were of mild-or-moderate 
intensity. The only serious AE (SAE) reported in more than one patient was MS relapse observed in 4 
(3.9%) patients in the intervention group and 4 (7.8%) patients in the control group. Three serious AEs 
were possibly related to MD1003: MS relapse, mucocutaneous rash, and hypoglycaemia in a diabetic 
patient treated with insulin. Allergic reaction, such as mucocutaneous rash, is a known side effect 
reported with medicines containing biotin and is considered as an identified risk with MD1003. 
One patient died during the study: a suicide in a patient randomized to MD1003 that was considered 
as unrelated to treatment by the investigator. 
Five cases of apparent biological hyperthyroidism were recorded as AEs, one of whom underwent 
thyroidectomy. Among these, 4 cases were without clinical symptoms and it was subsequently 
determined that they were due to abnormal thyroid function laboratory tests arising from biotin 
interference with the immunoassays using a biotinylated reagent. This results in falsely low values with 
sandwich immunoassays and false elevations with competitive immunoassays (Kwok et al., 2012, 
Wijeratne et al., 2012).  
Brain MRI (T2 sequence) identified new MS lesions in 11 (23.4%) MD1003-treated and in 3 (13.0%) 
placebo-treated patients (p=0.356). Four MD1003-treated patients had enlarging lesions (0 [0%] in 
placebo-treated patients; p=0.3). Two patients had at least one post-gadolinium enhancing lesion on T1 
sequence in the MD1003 group versus none in the placebo group (p=1.0). 
In the extension phase, one case of myopathy with muscular lipidosis was reported in a patient after 6 
months of treatment with MD1003. The patient recovered progressively. A causal relationship with the 
study drug is plausible considering that biotin by stimulating ACC should increase the levels of its end-
product, malonyl-CoA. High levels of malonyl-CoA are known to inhibit carnitine palmitoyltransferase 
1 (CPT1), which is responsible for long-chain fatty acid transport into mitochondria for further 
degradation, resulting in reduced fatty acid beta-oxidation (Foster, 2012, McGarry et al., 1978). 
Consequently, it is theoretically possible that high doses of biotin could result in lipid storage myopathy 
under specific circumstances not identified in this single patient (CPT1 gene analysis did not reveal any 
mutation or polymorphism). 
-0.2
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0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
M3
M6
M9
M12
M18
M24
M36
Mean change from baseline 
Post-treatment visit
Placebo
MD1003
Overall literature placebo
Overall literature active
Olympus placebo (PPMS, n=147)
Olympus active (ritux, PPMS, n=292)
Impact placebo (SPMS, n=219)
Impact active (INFb, SPMS, n=217)
Promise placebo (PPMS, n=316)
Promise active (GA, PPMS, n=627)
MS-STAT placebo (SPMS, n=70)
MS-STAT active (simvastatin, SPMS, n=7)
MBP8298 placebo DR2/4+ (n=261)
MBP8298 active DR2/4+ (n=267)
MBP8298 placebo DR2/4-(n=58)
MBP8298 active DR2/4-(n=52)
Lamotrigine placebo (n=59)
Lamotrigine active (n=61)
Andersen placebo (n=178)
Andersen active (IFNb, n=186)
European placebo (SPMS, n=358)
European active (IFNb, SPMS, n=360)
North american placebo (SPMS, n=308)
North american treatment 250 mc (IFNb, SPMS, n=317)
North american treatment 160 mc (IFNb, SPMS, n=314)
Cladribine placebo (PPMS&SPMS, n=54)
Cladribine treatment 0.7 mk/kg (PPMS&SPMS, n=53)
Cladribine treatment 2.1 mg/kg (PPMS&SPMS, n=52)
IgIV placebo (SPMS, n=159)
IgIV active (SPMS, n=159)

 
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3) Randomized, double-blind, placebo-controlled trial in adult patients suffering from chronic 
visual loss after optic neuritis related to multiple sclerosis (MS-ON) 
This study was intended to demonstrate the effects of high doses of biotin in MS patients with 
permanent visual loss following optic neuritis (ON). 
Study population: Eligible patients were 18 to 75 years of age with MS that fulfilled revised 
International Panel criteria (Polman et al., 2011) and unilateral or bilateral optic neuropathy with a visual 
acuity (VA) of the worst (diseased) eye ≤5/10 confirmed at 6 months. (Early Treatment Diabetic 
Retinopathy Study (ETDRS) score ≤ 72). All patients had evidence of visual acuity worsening in the 
last three years either following an optic neuritis relapse or in the context of chronic progressive optic 
neuritis. Patients with an optic neuritis relapse in the 6 months prior to inclusion were excluded. 
Study design: This was a 6-month double-blind, 2:1 randomized, placebo-controlled trial that 
compared MD1003 (biotin 300 mg/day) with placebo. Treatment duration was 24 weeks followed by a 
pre-planned extension phase where the placebo was switched to the active. Biotin was administered 
orally at a dose of 100 mg thrice daily (morning, noon, evening). All usual patient treatments were 
allowed throughout the study, including immunomodulatory and immunosuppressive drugs providing 
these therapies were initiated ≥3 months before inclusion (≥1 month for fampridine). Intravenous 
methylprednisolone without oral taper was allowed upon MS relapse. 
Assessments and endpoints: The primary endpoint was the mean change in best corrected visual acuity 
(logMAR) at 100% contrast between baseline and month 6 of the diseased eye (where the diseased eye 
is defined as the eye with the worst visual acuity (<5/10) at baseline and with evidence of worsening 
during the past three years). 
Secondary endpoints were the proportion of patients with improvement of VA of the diseased eye of 
at least 0.3 logMAR; the proportion of patients with improvement of bilateral VA from <5 to ≥5/10 at 
100% contrast; the proportion of eyes with reappearance of P100 waves or improvement of P100 
latencies≥10 ms at M6 (or M12 for the extension phase); the clinical global impression at M6 and M12 
evaluated by the clinician (CGI) and by the patient (SGI); the mean change in NEIFVQ-25 (functional 
vision questionnaire) between baseline and M6 (or M12 for the extension phase); and the mean change 
in SF36 between baseline and M6 (or M12 for the extension phase). 
Safety was investigated by comparing the incidence of AEs and laboratory/ electrocardiography (ECG) 
findings between study arms. 
Statistical analysis: We compared differences in mean absolute change in VA using analysis of 
covariance (ANCOVA) with a 0.05 two-sided significance level with adjustment on baseline values. 
Baseline patient demographic characteristics were generally well balanced between study arms, 
regarding age, sex, age of onset, and duration of the disease. Patients either suffered from visual loss 
following an optic neuritis relapse (ON relapses, n=62) or from chronic progressive optic neuritis 
(progressive ON, n=31). A greater proportion of patients with progressive ON were attributed to the 
active arm (37%) as compared to the placebo arm (25%). 
Primary endpoint: 
Overall, there was no significant difference in the mean change of visual acuity amongst treatment 
groups (p=0.6581). 
Prospectively defined subgroup analyses identified that only patients with progressive ON might have 
benefited from MD1003 while no effect was observed in the largest subgroup of patients with non-
progressive ON following a relapse:  
• 
In the subgroup of patients with progressive ON, 100% contrast VA of the diseased eye 
improved by a mean of 3 letters in the active arm versus worsening by 1.5 letters in the placebo 
arm. The evolution of other important endpoints was consistent with the improvement of 100% 
contrast VA. 

 
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• 
MD1003 had no effect at all in the subgroup of patients with non-progressive ON subsequent 
to a relapse: the 100% contrast visual acuity improved by 3 letters in both active and placebo 
arms. 
 
 
Pre-planned subgroup analyses of the MS-ON trial. After 6 months, patients having received the placebo 
were switched to the active drug for 6 months. The data suggest that MD1003 is able to reverse 
progression in patients with progressive visual loss (right panel). In contrast no effect is detected in the 
subgroup of patients with non-progressive visual loss following a relapse (optic neuritis sequelae, left 
panel). 
Biotin was well tolerated, with a similar safety profile to placebo. No drug related safety issues were 
identified confirming the limited risk of exposure to MD1003. During the double-blind phase of the 
study, 9 patients (13.8%) in the MD1003 group experienced a MS relapse versus 1 patient (3.6%) in the 
placebo group. 
Overall, results of the open label and double-blind phases of MS-SPI and MS-ON studies showed 
a beneficial effect of high-dose biotin in patients with progressive MS. The SPI2 study is 
anticipated to confirm these results in a larger international trial. 
1 
STUDY OBJECTIVES 
1.1 
Primary objective 
The primary objective of the SPI2 study is to confirm the superiority of MD1003 at 300 mg/day over 
placebo to clinically improve patients with not active progressive MS. 
 
Primary endpoint 
The primary endpoint is a composite criterion which can be met in one of two ways: either through 
confirmed improvement in the EDSS score or in TW25.  
The composite criterion includes either 
• 
a decreased EDSS at M12 confirmed at M15 (decrease of at least 1 point if baseline EDSS is 
from 3.5 to 5.5 and of at least 0.5 point if baseline EDSS is from 6 to 6.5) compared to baseline 
EDSS 
or  
• 
an improved TW25 of at least 20% at M12 confirmed at M15 compared to baseline TW25. 
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0months
3months
6months
9months 12months
MD1003(n=24)
Placebo(n=7)
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-0.04
-0.02
0
0.02
0.04
0.06
0.08
0.1
0months 3months 6months 9months12months
MD1003(n=41)
Placebo(n=21)
Progressive chronic ON 
Non Progressive chronic ON 
(LogMar+/-SEM) 
(LogMar+/-SEM) 
Worsening 
Improving 

 
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The baseline score for EDSS will be the lowest (best) value obtained during either the inclusion or 
randomization visits. For the TW25, the baseline value will be the best mean of the 2 values obtained at 
either the inclusion or randomization visits (the lowest mean value between these 2 visits).  
The TW25 value at visit M12 is defined as the mean of the two TW25 attempts at visit M12. The TW25 
value at visit M15 is defined as the mean of the two TW25 attempts at visit M15. 
 
Primary efficacy measure 
The primary efficacy measure is the comparison of the proportion of patients achieving either composite 
criterion at M12 confirmed at M15 across treatment groups. 
 
Secondary objectives 
 
Secondary efficacy endpoints 
Secondary endpoints will be assessed at the end of the placebo-controlled phase. Secondary endpoints 
are listed hierarchically: 
1. Time to EDSS progression confirmed at 12 weeks; 
2. Mean difference between treatment arms in CGI at M15; 
3. Mean difference between treatment arms in SGI at M15; 
4. Mean change in TW25 score between M0 and M15; 
5. Mean change in TW25 score between M0 and the last visit in double-blind phase of any 
particular patient (M15, M18, M21, M24 or M27 or Early Termination). 
 
Exploratory endpoints  
1. Brain MRI measurements will assess the following endpoints between M0 and M15 (and 
between M0 and M27 and every year until the end of the study): 
a. 
Percent whole brain volume change 
b. 
Percent thalamic volume change 
c. 
Percent cortical grey matter volume change 
d. 
Brain water content by Pseudo T2 relaxation time change 
e. 
NAA/Cr in a subset of sites acquiring MRS 
2. Remote monitoring of ambulatory activity between M0 and M15 (and between M0 and M27 
and every year until the end of the study) 
3. Mean change in the Multiple Sclerosis Quality of Life-54 (MSQOL54) and Caregiver 
health-related quality of life in Multiple Sclerosis (CAREQOL-MS) subscores and 
composite scores between M0 and M15 (and between M0 and M27 and every year until the 
end of the study) 
4. Mean change in subscores of the Kurtzke functional score between M0 and M15 (and 
between M0 and M27 and every year until the end of the study) 
5. Mean change in Symbol Digit Modalities Test (SDMT) between M0 and M15 (and between 
M0 and M27) 
 
Safety of MD1003 
Safety of MD1003 will be assessed by: 
1. Recording of AEs at each visit 
2. Laboratory testing (standard haematology and biochemistry panel) including: 

 
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a. CBC with differential: 
i. Number and types of white blood cells (WBCs) 
ii. Number of red blood cells (RBCs) 
iii. Red cell distribution width (RDW) 
iv. Haematocrit 
v. Haemoglobin 
vi. Mean corpuscular volume (MCV) 
vii. Mean corpuscular haemoglobin 
viii. Platelet count 
b. Metabolic panel (fasting): 
i. 
BUN 
ii. 
CO2 (carbon dioxide/bicarbonate) 
iii. 
Creatinine, estimated creatinine clearance rate using Cockcroft-Gault formula 
iv. 
Glucose 
v. 
Serum chloride 
vi. 
Serum potassium 
vii. 
Serum sodium 
c. Hepatic function panel: 
i. 
Aspartate transaminase (AST) 
ii. 
Alanine transaminase (ALT) 
iii. 
Bilirubin 
iv. 
Gamma-glutamyl transpeptidase (GGT) 
v. 
Alkaline phosphatase 
d. Lipid panel (fasting) 
i. 
Total cholesterol 
ii. 
Triglycerides 
iii. 
HDL cholesterol 
iv. 
LDL cholesterol 
e. Thyroid panel  
i. 
Thyroid-stimulating hormone (TSH) 
ii. 
Free triiodothyronine (T3 free) 
3. ECG at M0, M15, M27, M42, M54, and M66: PR, QRS, QT and RR interval, HR and 
QTcF, wave morphology, rhythm and conduction 
4. Brain MRI at M0, M6, M15, M27, M42, M54, and M66: 
a. Comparison of proportion of patients with at least one new/enlarging T2-weighted MS 
lesion at M6 and M15 in group 2 (300 mg/day) versus group 1 (placebo) 
b. Comparison of proportion of patients with at least one gadolinium enhancing lesion on 
the T1-weighted sequence at M6 and M15 in group 2 (300 mg/day) versus group 1 
(placebo) 
c. Mean number of gadolinium enhancing lesions on the T1-weighted sequence at M6 and 
M15 in group 2 (300 mg/day) versus group 1 (placebo) 
d. Mean number of new enlarging T2-weighted lesions per patient at M6 and M15 in group 
2 (300 mg/day) versus group 1 (placebo) 
e. Mean of T2-weighted lesion volume per patient at M6 and M15 in group 2 (300 mg/day) 
versus group 1 (placebo) 
f. Mean of non-enhancing T1-weighted lesion volume per patient at M6 and M15 in group 
2 (300 mg/day) versus group 1 (placebo) 
5. C-SSRS score: Suicidal ideation and behavior will be assessed during this trial at each visit 
using the suicide behavior questionnaire Columbia-Suicide Severity Rating Scale. 

 
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2 
INVESTIGATIONAL PLAN 
 
Overall study design 
PART 1:  
The duration of Part 1 is 27 months. The randomized double-blind placebo-controlled period ranges 
from 15 to 27 months depending upon the randomization date of an individual patient. 
Once the last month 15 evaluation of the study has been completed, patients will switch to the active 
treatment at the next planned visit. Patients and study personnel will remain blinded as to the original 
treatment arm until the last V11/M27 visit of the study has been completed. 
 
PART 2: 
At the last evaluation of Part 1 (Visit 11/Month 27) all participants will be offered active treatment in 
an open label extension for 39 additional months (From V11/M27 to V18/M66).  
The purpose of the active drug extension is to further define the safety of MD1003.  
 
The total duration of the study (Part 1 + Part 2) is 66 months. If the study fails to meet the primary 
outcome measure or is terminated by either the Sponsor or upon DSMB recommendation, then all 
patients in both Part 1 and Part 2 will undergo an Early Termination Visit (see section 2.6.3.4) as soon 
as practicable and the study drug discontinued.  

 
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PART 1: Randomized double-blind placebo-controlled period for 15 to 27 months 
 
Part 1 is a randomized double-blind placebo-controlled period for 15 to 27 months. The blinded placebo-
controlled phase will last for at least 15 months but no longer than 27 months and will end when the last 
month 15 evaluation for the last-enrolled study subject has been completed. 
Patients who complete 15 months will be maintained on their original treatment assignment (MD1003 
versus placebo) for a maximum of 27 months or until the last Month 15 evaluation of the study is 
completed, whichever comes first. Patients and study personnel will remain blinded as to the original 
treatment assignment. 
Once the last month 15 evaluation for all study subjects has been completed, patients will switch to the 
active drug at the next planned study visit (V8/M18 or V9/M21 or V10/M24 depending on their 
randomization date). Patients will remain blinded to their original treatment arm until the last V11/M27 
visit of the study has been completed. 
Maximum study duration per patient for Part 1 will be no longer than 27 months. 
 
 

 
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PART 2: Open Label Extension (39 months) 
 
Part 2 is an open label extension for 39 months. All patients who completed 27 months (V11/M27) will 
be offered active treatment in an open label extension from V11/M27 to V18/M66.  
The maximum study duration per patient for Part 1 and Part 2 will be no longer than 66 months (27 + 
39 months). 
 
Number of patients 
The study will include approximately 600 patients at 90 centers located in North America, Australia and 
Europe divided into 2 groups:  
- 
Group 1 (300 patients): placebo, three times a day 
- 
Group 2 (300 patients): MD1003, 300 mg/day given as 100 mg three times a day. 
 
Selection and withdrawal of patients 
 
Inclusion criteria 
1. Patient aged 18-65 years old 
2. Signed and dated written informed consent form in accordance with local regulations: having 
freely given their written informed consent to participate in the study  

 
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3. Diagnosis of primary or secondary progressive MS fulfilling revised McDonald criteria (2010) 
and Lublin criteria (2014) 
4. Documented evidence of clinical disability progression within the 2 years prior to inclusion, 
i.e. a) progression of EDSS during the past two years of at least 1 point sustained for at least 
6 months if inclusion EDSS is from 3.5 to 5.5 or at least 0.5 point increase sustained for at 
least 6 months if inclusion EDSS is from 6 to 6.5 or b) increase of TW25 by at least 20% in 
the past two years sustained for at least 6 months or c) other well-documented objective 
worsening validated by the Adjudication Committee 
5. EDSS score 3.5 to 6.5 at inclusion defined as follows: 
 
3.5: 
Fully ambulatory but with moderate disability in one functional system 
(one FS grade 3) and mild disability in one or two FS (one / two FS grade 2) and 
others 0 or 1; or fully ambulatory with two FS grade 3 (others 0 or 1); or fully 
ambulatory with five FS grade 2 (others 0 or 1) 
 
4.0: 
Ambulatory without aid or rest for > 500 meters; up and about some 
12 hours a day despite relatively severe disability consisting of one FS grade 4 
(others 0 or 1) or combinations of lesser grades exceeding limits of previous steps 
 
4.5: 
Ambulatory without aid or rest for > 300 meters; up and about much 
of the day, characterized by relatively severe disability usually consisting of one 
FS grade 4 and combination of lesser grades exceeding limits of previous steps 
 
5.0: 
Ambulatory without aid or rest for > 200 meters (usual FS equivalents 
include at least one FS grade 5, or combinations of lesser grades usually 
exceeding specifications for step 4.5) 
 
5.5: 
Ambulatory without aid or rest for >100 meters 
 
6.0: 
Unilateral assistance (cane or crutch) required to walk at least 100 
meters with or without resting 
 
6.5: 
Constant bilateral assistance (canes or crutches) required to walk at 
least 20 meters without resting 
Within the 4.5 to 6.5 range, the EDSS relies mainly on the Ambulatory Score: 
 2: ≥300 meters, but <500 meters, without help or assistance (EDSS 4.5) 
 3: ≥200 meters, but <300 meters, without help or assistance (EDSS 5.0) 
 4: ≥100 meters, but <200 meters, without help or assistance (EDSS 5.5) 
 5: Walking range <100 meters without assistance (EDSS 6.0) 
 6: Unilateral assistance, ≥50 meters (EDSS 6.0) 
 7: Bilateral assistance, ≥120 meters (EDSS 6.0) 
 8: Unilateral assistance, <50 meters (EDSS 6.5) 
 9: Bilateral assistance, ≥5 meters, but <120 meters (EDSS 6.5) 
6. TW25<40 seconds at inclusion visit  
7. Kurtzke pyramidal functional subscore ≥2 defined as “minimal disability: patient complains of 
motor-fatigability or reduced performance in strenuous motor tasks” (motor performance 
grade 1) and/or BMRC grade 4 in one or two muscle groups” 

 
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Exclusion criteria 
1. Clinical evidence of a relapse in 24 months prior to inclusion 
2. Treatment with any product containing biotin as single ingredient within six months prior to 
inclusion (multivitamin supplementation authorized if biotin < 1mg per day) 
3. Concomitant treatment with fampridine at inclusion or in the 30 days prior to inclusion 
4. New immunosuppressive/immunomodulatory drug initiated less than 90 days prior to 
inclusion 
5. Treatment with botulinum toxin (except for cosmetic purposes) initiated within 6 months prior 
to inclusion 
6. In-patient rehabilitation program within the 3 months prior to inclusion 
7. Pregnancy, breastfeeding or women with childbearing potential without acceptable form of 
contraception 
8. Men unwilling to use an acceptable contraceptive method 
9. Any general chronic handicapping/incapacitating disease other than MS 
10. Any serious disease necessitating biological follow up with biological tests using biotinylated 
antibodies or substrates 
11. Past history of rhabdomyolysis/metabolic myopathy  
12. Known fatty acids beta oxidation defect 
13. Known hypersensitivity or intolerance to biotin, analogues or excipients, patients with rare 
hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose 
malabsorption 
14. Patients with hypersensitivity or contra-indication to gadolinium 
15. Patients with uncontrolled hepatic disorder, renal or cardiovascular disease, or cancer 
16. Laboratory tests out of normal ranges considered by the investigator as clinically significant 
with regards to the study continuation 
17. Patients with history or presence of alcohol abuse or drug addiction 
18. Untreated or uncontrolled psychiatric disorders, especially suicidal risk assessed by Columbia-
Suicide Severity Rating Scale (C-SSRS) 
19. Participation in another research study involving an investigational product (IP) in the 90 days 
preceding inclusion, or planned use during the study duration 
20. Patients likely to be non-compliant to the study procedures or for whom a long-term follow-
up seems to be difficult to achieve 
21. Relapse that occurs between inclusion and randomization visit 
 
Contraception 
Both male and female patients who are not either surgically sterile (tubal ligation/obstruction or removal 
of ovaries or uterus) or post-menopausal (no spontaneous menstrual periods for at least one year 
confirmed by a negative hormone panel) must commit to using one highly effective method (such as 

 
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intrauterine device, sterilisation of one of the partners, hormonal birth control methods) plus one 
supplementary barrier method (such as condom, diaphragm) with a spermicide for the duration of the 
study and for two months after the treatment termination (or 90 days according to local regulations).  
Birth control methods which are considered as highly effective (low failure rate less than 1% per year) 
when used consistently and correctly include: 
• 
Established use of oral, injected or implanted hormonal methods of contraception; 
• 
Placement of an intrauterine device or intrauterine system; 
• 
Female bilateral tubal ligation; 
• 
Vasectomized partner; 
• 
Sexual abstinence: When this is in line with the preferred and usual lifestyle of the patient. 
Note: Periodic abstinence (e.g. calendar ovulation, thermal, post-ovulation methods) and 
withdrawal are not highly effective methods of contraception. 
 
Supplementary barrier methods of birth control include: 
• 
Male or female condom with spermicidal foam/gel/film/cream/suppository; 
• 
Cap, diaphragm or sponge with spermicidal foam/gel/film/cream/suppository. 
Pregnancy testing: For women of childbearing potential, a highly sensitive serum HCG test will be 
added to the biological safety panels, and the patient will be asked to perform a monthly urinary test 
during the study and for up to three months after study termination, using kits provided by the sponsor.  
 
Follow up of pregnancy 
A female subject must immediately inform the investigator if she becomes pregnant during the study 
and discontinues the study treatment. The investigator should report all pregnancies to the sponsor on 
the form provided. Monitoring of the subject should continue until the conclusion of the pregnancy and 
until 3 months after the birth of the baby following local regulation. 
If the female pregnant partner of the male subject agrees to provide information regarding her pregnancy, 
she will be asked to sign the pregnant partner consent form template. In addition, the following 
information will be collected from the pregnant partner: relevant medical history, details of any previous 
pregnancies including outcome and any complications, details about the current pregnancy, any drugs 
taken during your pregnancy, the outcome of the pregnancy, details of the birth and delivery, details 
about the health of the baby until 3 months after the birth. This information will only be collected in the 
event that the female partner of a male subject participating in this study becomes pregnant during the 
male subject’s participation in this study. 
 
Patient identification and assignment of patient number 
Patients will be numbered sequentially. Each patient in the study must be assigned a unique subject 
number and must keep that number throughout the study even if he or she transfers to another site. A 
patient who is included but not randomized may be re-screened at a later time, only upon sponsor 
validation. An inclusion number must never be reassigned for any reason. The investigator must 
maintain a patient master log linking the patient number to the patient’s name. The investigator must 
follow all applicable privacy laws in order to protect a patient’s privacy and confidentiality. Information 
that could identify a patient will be masked on material received by the sponsor. 
The allocation of patient number will be done through the EDC using the Interactive Web Response 
System (IWRS) at the first visit (V1/Inclusion visit) in chronological order of signature of the informed 
consent form in the study. Once patient numbers are assigned, they cannot be reassigned.  

 
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Screening failures 
Patients who sign an informed consent form but fail to meet the eligibility criteria are defined as 
screening failures. For all screening failures, the investigator is asked to maintain a screening log that 
documents the patient number, reason (s) for screening failure and justification for rescreening if 
applicable. A copy of this log should be retained in the investigator’s study file. The demography, the 
eligibility and end of trial forms will be completed and returned to the sponsor for screening failures. 
 
Premature discontinuation of treatment 
The treatment may be prematurely and definitively discontinued for a participant for one of the 
following reasons: 
• 
Adverse event: clinical or laboratory event that in the medical judgement of the investigator 
for the best interest of the patient are grounds for discontinuation 
• 
Occurrence of pregnancy 
• 
Withdrawal of consent: patient desires to withdraw from further participation in the study in 
the absence of a medical need to withdraw determined by the investigator.  
The reason of consent withdrawal should be documented on the eCRF when available. 
• 
Suicidal risk evaluated by suicidal risk assessed by Columbia-Suicide Severity Rating 
Scale (C-SSRS) 
The investigator should record the primary reason and the date of the premature discontinuation of the 
treatment in the electronic case report form (eCRF). 
In the event that a patient discontinues or is withdrawn from the treatment and/or from the study, the 
investigator will notify the sponsor and when possible the safety and efficacy determinations designated 
under the final visit will be obtained on the last day on which the patient receives the investigational 
product or as soon as possible thereafter. 
 
Withdrawal from the treatment 
Patients who discontinue study treatment for any reason will be encouraged by sites to remain on study 
for all remaining study evaluations and procedures according to regular visits schedule. Follow-up visits 
should continue for as long as possible with scheduled investigations at V6/M12 and V7/M15 for an 
ITT analysis. 
 
Withdrawal from the study 
Subjects who desire to withdraw from further participation in the study in the absence of a medical need 
will be asked to attend for an early termination visit where all protocol evaluations & procedures (or at 
least safety assessments) will be performed.  
Although a subject is not obliged to give his/her reason(s) for withdrawing prematurely from the study, 
the investigator should make a reasonable effort to ascertain the reason(s), while fully respecting the 
subject's rights. 
 
Lost to Follow Up 
In case a patient is lost to follow up every effort should be made to confirm that the patient has decided 
to withdraw his consent. At least three calls on different days and times should be performed with 

 
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leaving a voice message if possible. If attempts to contact the patient fail, a registered letter should be 
sent to the patient’s residence. Depending on the country regulation, the investigator should contact the 
primary care physician/general practitioner to obtain any recent information on the patient.  
All attempts to contact or obtain information on the patient should be documented in source documents. 
 
Premature termination or suspension of the study 
If the trial is terminated prematurely or suspended for any reason, the investigator/institution should 
promptly inform the trial subjects, should assure appropriate therapy and follow-up for the subjects, and, 
where required by the applicable regulatory requirement(s), should inform the regulatory authority(ies).  
In addition: 
- If the investigator terminates or suspends a trial without prior agreement of the sponsor, the 
investigator should inform the institution, where required by the applicable regulatory requirements, and 
the investigator/institution should promptly inform the sponsor and the IRB/IEC and should provide the 
sponsor and the IRB/IEC a detailed written explanation of the termination or suspension. The 
investigator will coordinate with the sponsor to return all IP vials, and other study materials.  
- If the sponsor terminates or suspends a trial, the investigator should promptly inform the institution, 
where required by the applicable regulatory requirements, and the investigator/institution should 
promptly inform the IRB/IEC and provide the IRB/IEC a detailed written explanation of the termination 
or suspension. 
- If the IRB/IEC terminates or suspends its approval/favorable opinion of a trial, the investigator should 
inform the institution, where required by the applicable regulatory requirements, and the 
investigator/institution should promptly notify the sponsor and provide the sponsor with a detailed 
written explanation of the termination or suspension. 
Whether the trial is completed or prematurely terminated, the sponsor should ensure that the clinical 
trial/study reports are prepared and provided to the regulatory agency(ies) as required by the applicable 
regulatory requirement(s). 
If the study fails to meet the primary outcome measure or is terminated by either the Sponsor or upon 
DSMB recommendation, then all patients in both Part 1 and Part 2 will undergo an Early Termination 
Visit (see section 2.6.3.4) as soon as practicable and the study drug discontinued.  
 
Investigational products, control therapies and administration 
Investigational products and control therapies will be administered only to patients who have provided 
informed consent. 
 
Description of investigational product and control arm 
 
Investigational products 
Investigational products units will be supplied by the sponsor or designee. 
▪ 
MD1003 capsules 
The investigational product will consist in capsules of 100 mg MD1003 and excipients (lactose). 
 
Control arm 
▪ 
Placebo capsules 
This formulation consists of lactose powder as placebo. 

 
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Dose regimen 
The dose regimen will be 1 capsule three times a day (tid, one in the morning, one at noon, one in the 
evening) in a fasted state (before meal times) as a slight food effect has been established in 
pharmacokinetics studies. Capsules have to be swallowed with a glass of water with a minimum of 4 
hours between each intake and at least one hour before mealtime.  
• 
Group 1 (placebo): one placebo capsule tid 
• 
Group 2 (MD1003, 300 mg/day): one capsule of MD1003 tid 
 
 
Summary of known and potential risks and benefits, if any to human subjects 
• 
Expected benefits 
Preventing or reversing the development of pathology should reduce the severity of the clinical 
expression of the disease, especially with regard to motor performances, quality of life. 
Benefit on the quality of life of relatives taking care of the patient is also expected. 
• 
Potential risks 
o Teratogenicity 
During the non-clinical development with MD1003, a risk for teratogenicity has been identified in a 
reproduction study in rabbits at doses corresponding to those used in humans. Therefore, correct 
contraception measures should be undertaken during treatment with MD1003 and in case of pregnancy, 
the treatment with MD1003 should be discontinued. 
o Intolerance to lactose 
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, 
the Lapp lactase deficiency or glucose-galactose malabsorption should not take MD1003. 
o Laboratory tests errors - Interference with immunoassays 
Biotin may interfere with some assays used in clinical analyzers that are based on a biotin/streptavidin 
interaction leading to laboratory reporting errors. Therefore, special consideration must be given to 
patients requiring laboratory tests such as thyroid functions, pregnancy tests, and troponin, but 
erroneious results may also occur for a large number of tests used in the diagnosis and monitoring of 
cardiovascular, neoplastic, hemotologic, infectious, endocrine, bone and inflammatory diseases (See 
Section 3.1 for more details). 
o Hypoglycaemia in diabetic patients  
In the clinical studies with MD1003, one patient with Type 1 diabetes who was receiving insulin 
experienced episodes of hypoglycaemia approximately 1 year after initiating MD1003. These ceased 
when MD1003 was stopped and recurred on re-challenge. A potential influence of MD1003 on the effect 
of insulin cannot be ruled out and the patient’s dose of insulin may need to be adjusted.  
o Relapses 
Across the double-blind placebo-controlled phases of the two clinical studies evaluating MD1003 in MS 
patients, a similar proportion of patients treated with MD1003 (6.5%) and placebo (6.2%) reported MS 
relapses in the progressive MS population whereas in the relapsing remitting MS population, the 
proportion was higher in the MD1003 group (13.3%) compared to the placebo group (7.1%). MD1003 
is only being studied in non-relapsing progressive forms of MS.  

 
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o Dermatologic reactions 
In the double-blind placebo-controlled phases of the clinical studies, the drug reactions of blister, eczema 
and mucocutaneous rash occurred in three different patients treated with MD1003, each event occurring 
in only 1 patient (0.6% for each drug reaction). No patients in the placebo group reported these events.  
o Myopathy 
In the open label extension phases of the previous studies, myopathy occurred in one patient (0.4%) 5 
months after initiation of MD1003 from which he fully recovered when MD1003 was stopped. The 
investigations performed (electromyography and muscular lipidosis observed after muscle biopsy), 
indicated a lipid storage myopathy. A causal relationship with MD1003 cannot be ruled out as biotin 
could result in lipid storage myopathy by inhibiting the fatty acids beta-oxidation pathway. 
 
Packaging and labelling 
The sponsor or designee will prepare and ship IP to the study pharmacist or to the Principal Investigator 
where appropriate. Each IP vial will be labelled according to local regulation requirements. For all 
randomized patients, the treatment will be dispensed by the hospital pharmacy (where applicable) the 
quantity of vials needed to cover the period until the next visit.  
The capsules will be supplied in vials containing 90 capsules each corresponding to one month of 
treatment. The same colour will be used for placebo and active drug bottles. 
In addition to the legal requirements label, a label indicating the treatment number and the treatment 
period will be attached to each vial. 
 
Treatment assignment 
At M0, patients will be randomly assigned to receive either placebo (group 1) or active drug 300 mg/day 
(group 2) for at least 15 months and no longer than 27 months.  
The blinded placebo-controlled phase will last for at least 15 months and no longer than 27 months and 
will end when the last month 15 evaluation for all study subjects has been completed. 
Once the last month 15 evaluation has been completed, all patients will switch to the active drug at the 
next scheduled visit. Participants and study personnel will remain blinded as to the original treatment 
assignment even after switching to active treatment. 
At the V11/M27 evaluation, an open label extension (patients under active drug) will be offered to 
participants for 39 additional months. 
Dispensation of the correct treatment during the double-blind period (Part 1) and the open-label 
extension (Part 2) will be automatically programmed by IWRS.  
 
Randomization and blinding 
• 
Randomization 
At randomization visit (V2/M0), all eligible patients will be randomized to one of the two treatment 
arms. The randomization will be done in 1:1 ratio stratified by geographical region, and by disease 
history (PPMS or SPMS). 
The treatment numbers will be provided at each visit by an Interactive Web Response System (IWRS). 
 

 
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• 
Blinding 
This study is a double-blind study. Each product, active or placebo, will be supplied in size one capsules 
having the same appearance. 
The capsules will contain the same quantity of white powder, with the same appearance and taste 
(MD1003 has no taste). 
Placebo capsules will thus contain 100 mg more lactose in replacement of MD1003. 
Investigators have no contact with the biostatistician in charge of the randomization list. 
The treating physician is distinct from the blinded rater. The latter has no information about biological 
results or any potential adverse events reported by the patient in connection with the treatment received.  
The treating physician will be responsible amongst others for supervising the study drug administration, 
recording and treating AEs, monitoring safety assessments including laboratory parameters, and for the 
physical examination and all other assessments except EDSS and TW25. The blinded rater will be 
responsible for all EDSS and TW25 assessments including the one performed at inclusion visit (V1/M-
1) and those performed at any unscheduled visits required because of new or changing symptoms 
potentially related to MS.  
Throughout the study, the blinded rater will remain blind to the subject’s treatment, laboratory data, 
adverse event profile, and any changes in the safety assessments. Both the treating physician and the 
subject will be informed of the importance of not discussing these issues with the blinded rater to prevent 
unblinding. The blinded rater should only communicate with the subjects on matters related to their 
neurological status and should remind the subjects at each visit not to discuss other matters related to 
their treatment with him/her. The blinded rater should not have access to the eCRF, except for the EDSS 
and TW25 pages, and restricted access to the patient’s files/reports. 
Every effort must be made to minimize the communication between the blinded rater and the treating 
physician and Study Coordinators.  
A special agreement for respecting the blinding procedure must be signed by all personnel involved in 
this study prior to the initiation of the study. The Sponsor will provide the blinding agreement. 
The treating physician and the blinded rater will not have access to measures of MD1003 in blood at 
V4/M6, V6/M12, V7/M15 and V11/M27. 
The treating physician and the blinded rater as well as patients will have no access to the randomization 
list until the end of the study, once the last 27-month evaluation of the study has been completed. This 
ensures that patients and physicians and raters will remain double-blinded during the study regarding 
whether a patient would have received the active or the placebo during the initial placebo-controlled 
phase of the study. 
The investigator should ensure that the code is broken only in case of emergency with, if possible, prior 
contact to sponsor to explain why the unblinding is necessary. The investigator should promptly 
document and explain to the sponsor any premature unblinding (e.g., accidental unblinding, unblinding 
due to a serious adverse event) of the IP. 
In order to control potential exposure to biotin prior to inclusion and during the study for patients of the 
placebo group, biotin serum level and its two main metabolites: bisnorbiotin (BNB) and biotin sulfoxide 
(BSO) will be measured in all patients at inclusion, V4/M6, V6/M12, V7/M15 and V11/M27. The 
samples will be collected and transferred all along the study to an independent laboratory (Atlanbio, 
France), where analyses will be performed blindly, under control of the Central Clinical Laboratory. 
Results of these analyses will not be disclosed to any participant prior to data base locking. 

 
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Investigational product shipping, handling and storage  
IP will be shipped directly to the pharmacist (if applicable) designated by the Investigator after required 
regulatory and legal documents have been received by the sponsor or designee. 
Upon receipt of the investigation products shipment, the pharmacist or the principal investigator will 
verify the condition and quantity of the study supplies, including inspection of document per instructions 
in the Pharmacy Binder. Room temperature during shipment (ie. +59°F to +77°F (+15°C to +25°C) for 
this study will be required. 
The sealed Investigational Product (IP) bottles must not be opened until they are used for administration.  
Once unpacked and inspected, IP or control arm must be stored at room temperature, ie. +59°F to +77°F 
(+15°C to +25°C). The pharmacist must store the sealed investigation products in a secured area with 
access restricted to authorized personnel only. The IP must be stored as indicated.  
Deviations from the storage requirements, including any actions taken, must be documented and 
reported to the sponsor or designee.  Once a deviation is identified, the IP must be quarantined and not 
used until the sponsor provides documentation of permission to use the IP. 
Once the IP has been allocated and dispensed to the patient, it must be maintained at room temperature, 
i.e. +59°F to +77°F (+15°C to +25°C). The details on how to manage IP at site will be also provided in 
a separate drug manual (Investigator Manual CTS).  
IP shipment to patient homes should be avoided as much as possible and should remain exceptional. 
Sponsor written approval is required and shipment can occur only under the following conditions: 
- 
Evidence of what was packed for the subject 
- 
Quality Control of the content of the shipment 
- 
Delivery signature receipt 
- 
Adequate and qualified couriers should be used (temperature tracker) 
- 
Information letter should accompany the shipment 
- 
Investigator must contact the patient to check good treatment receipt 
- 
Investigator must check that the posology of the treatment is clearly understood 
- 
All of the above must be documented in the medical file of the patient 
 
Treatments compliance, accountability and return of therapeutic units 
Regulatory agencies require accounting for the disposition of all IP received by each clinical site. 
Information on drug disposition required by law consists of the date received; date dispensed, quantity 
dispensed, and the patient to whom the drug was allocated and dispensed. The investigator is responsible 
for the accounting for all unused IP and all used IP containers through the pharmacist if applicable. The 
pharmacist or the principal investigator uses this information to maintain an accurate and complete 
dispensing and inventory record supplied by the sponsor or designee. At the completion or termination 
of the study, a final drug accountability review and reconciliation must be completed; any discrepancies 
must be investigated, and their resolution documented. 
All unused IP must be returned to the sponsor/contract distribution center with the appropriate form. 
IP will be dispensed by the pharmacy where applicable and the date of the dispensation will be 
documented in the patient’s record in addition to the eCRF.  
The remaining study medication will be checked at each visit by the investigator and the pharmacist 
before completing the drug dispensation records. 
The remaining study medication, labels and dispensing records will be checked by the monitor to verify 
accurate dose dispensing. 

 
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Overdose 
The Sponsor has established specific rules regarding compliance and management compliance 
deviation. Please find below the compliance ranges defined: 
• 
Compliance <70%: it is considered as major deviation to the protocol 
• 
Compliance between [70%; 80% [: it is considered as minor deviation to the protocol 
• 
Compliance between [120%; 130]: it is considered as minor deviation to the protocol 
• 
Compliance > 130%: it is considered as major deviation and an adverse event “overdosing” 
should be reported.  See section 4. Adverse event for more information. 
 
Destruction 
Remaining study medication and packaging of used and non-used IP will be returned to the sponsor or 
its designee for destruction.  
Recording of destruction operations should be carried out in such a manner that all operations may be 
accounted for. The records will be kept by the sponsor. This destruction will be done only after the 
finalization of the clinical trial and the compilation of the final study report, only upon approval of the 
Sponsor. 
 
Concomitant treatments 
Concomitant treatment is defined as any medication or physical therapy that is ongoing at inclusion or 
started during the trial. 
 
Concomitant medication 
For this study, concomitant medication is defined as any medication that is taken at the same time as the 
first administration of IP and will be recorded on the concomitant medication page of eCRF. 
All usual treatments of the patient are authorized for the duration of the study, such as immuno-
modulators, and immunosuppressive drugs including monthly pulses of IV methylprednisolone for 
patients already treated by these drugs. All of these drugs have to be initiated at least 3 months prior to 
inclusion and maintained at the same dose as much as possible, except IV methylprednisolone which 
may be used for relapses.  
During the study, initiation or change of any of these drugs or DMT is not allowed, but this is not a 
reason to withdraw a patient. In case initiation or change of DMT is decided by the investigator, the 
following should be respected: 
• 
Document accordingly, in source documents and eCRF 
• 
Report as a protocol deviation  
• 
Make every effort to keep patients in the study at least until the V7/M15 visit  
• 
Continue or discontinue MD1003 should be discussed with Medical Monitors and Sponsor 
CMO 
Intravenous methylprednisolone is authorized during the trial in case of MS relapse, without oral taper. 
Follow up visits must be scheduled before infusions. 
As far as possible, visits have to be scheduled before steroids infusions rather than after. 
All medications will be recorded in the eCRF and the patient’s source documents. 

 
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Physical therapy 
If the patient has previously followed a continuous physical therapy program at least 3 months prior to 
inclusion, this program should be maintained throughout the duration of the study and should not be 
discontinued. Intensive new in-patient rehabilitation therapy program is not allowed within the 3 months 
prior to inclusion and during the trial since it could impact EDSS assessments. 

 
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Visits schedule and evaluations 
 
Study flow chart Part 1: double-blind period for 15 to 27 months 
 
M-1 
M0 
M3 
M6 
M9 
M12 
M15 
M18 
M21 
M24 
M27 
Unscheduled 
Visits  
Early 
Termination 
Visit 
 
Inclusion 
visit V1 
Randomization 
visit V2 
Follow-up 
visit V3 
Follow-up 
visit V4 
Follow-up 
visit V5 
Follow-up 
visit V6 
Follow up 
visit V7 
Follow up 
visit V8 
Follow up 
visit V9 
Follow up 
visit V10 
Final 
double-
blind visit 
V11 
 
 
STUDY WINDOWS*** 
+/- 15 
days 
 
+/-10 days 
+/- 10 days 
+/- 10 days 
+/- 10 days 
+/- 15 days 
+/- 15 days 
+/- 15 days 
+/- 15 days 
+/- 15 days 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Inclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization  
 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographic Data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical examination* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EDSS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TW25 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ambulatory activity monitoring 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MS relapse questionnaire 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SDMT 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
CGI-I (SGI & CGI) 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
MSQOL54 / CAREQOL-MS 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
Laboratory testing** 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
Blood-based pregnancy testa 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
Biotin blood level 
X 
 
 
X 
 
X 
X 
 
 
 
X 
 
X 
Neurofilament blood level 
X 
 
 
X 
 
X 
X 
 
 
 
X 
 
X 
ECG 
 
Xb 
 
 
 
 
X 
 
 
 
X 
X 
X 
Brain MRI 
 
X 
 
X 
 
 
X 
 
 
 
X 
Xc 
 
Concomitant medication / 
therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study medication dispensation 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Patient alert card dispensation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Compliance check 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs reporting 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Treatment assignment 
questionnaire 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
a: for women of childbearing potential; in addition, a urinary pregnancy test will be performed each month during the study and for 3 months after termination  
b: triplicated ECG 
c: in case of relapse 
*: physical examination and vital signs / **: CBC with differential, Metabolic panel (fasting), Hepatic function panel and Lipid panel (fasting) / *** One month is equal to 28 days. 

 
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Study flow chart Part 2: Open label extension  
 
M30 
M36 
M42 
M48 
M54 
M60 
M66 
Unscheduled 
Visits  
Early 
Termination 
Visit 
 
Follow-up visit 
V12 
Follow-up visit 
V13 
Follow-up visit 
V14 
Follow-up visit 
V15 
Follow-up visit 
V16 
Follow-up visit 
V17 
Final OLE visit 
V18 
 
 
STUDY WINDOWS*** 
+/-15 days 
+/- 15 days 
+/- 15 days 
+/- 15 days 
+/- 15 days 
+/- 15 days 
+/- 15 days 
 
 
Informed consent 
 
 
 
 
 
 
 
 
 
Inclusion criteria 
 
 
 
 
 
 
 
 
 
Exclusion criteria 
 
 
 
 
 
 
 
 
 
Randomization  
 
 
 
 
 
 
 
 
 
Demographic Data 
 
 
 
 
 
 
 
 
 
Clinical examination* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EDSS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TW25 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ambulatory activity monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MS relapse questionnaire 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SDMT 
 
 
 
 
 
 
 
 
X 
CGI-I (SGI & CGI) 
 
 
X 
 
X 
 
X 
 
X 
MSQOL54 / CAREQOL-MS 
 
 
X 
 
X 
 
X 
 
X 
Laboratory testing** 
 
 
X 
 
X 
 
X 
X 
X 
Blood-based pregnancy testa 
 
 
X 
 
X 
 
X 
X 
X 
Biotin blood level 
 
 
X 
 
X 
 
X 
 
X 
Neurofilament blood level 
 
 
X 
 
X 
 
X 
 
X 
ECG 
 
 
X 
 
X 
 
X 
X 
X 
Brain MRI 
 
 
X 
 
X 
 
X 
Xc 
 
Concomitant medication / therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study medication dispensation 
X 
X 
X 
X 
X 
X 
X 
 
 
Patient alert card dispensation  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Compliance check 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Treatment assignment questionnaire 
 
 
 
 
 
 
 
 
 
 
a: for women of childbearing potential; in addition, a urinary pregnancy test will be performed each month during the study and for 3 months after termination 
b: triplicated ECG 
c: in case of relapse 
*: physical examination and vital signs / **: CBC with differential, Metabolic panel (fasting), Hepatic function panel and Lipid panel (fasting) / *** One month is equal to 28 days. 

 
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Evaluations 
The treating physician will be responsible for collecting the following information: informed consent 
and background information, concomitant therapies, any adverse event, current medical status, 
laboratory testing results, ECG interpretation, inclusion/exclusion criteria, SDMT, MSQOL-54, 
CAREQOL-MS, CGI-I (both clinician and subject), C-SSRS, and end of randomized period treatment 
assignment questionnaire. 
A blinded rater, independently from the treating physician, will perform the following evaluations: 
Neurostatus EDSS and/or TW25. The blinded rater for the EDSS and/or for TW25 is not necessarily a 
physician: the investigator may delegate the responsibility of the blinded rater to an individual qualified 
by training and experience, such as a nurse practitioner (NP) or a physician assistant (PA – applicable 
in USA). A blinded rater performing EDSS must be Neurostatus level C certified. 
A separate central core lab different from treating physicians & blinded raters will perform the MRI and 
ECG analyses. 
As far as possible, visits have to be scheduled before steroids infusions rather than after. 
 
Evaluations Part 1: Double-blind phase for 15 to 27 months 
2.6.3.1.1 
Visit 1 (M-1): Inclusion visit 
During the inclusion visit, the investigator will check inclusion/exclusion criteria and, after having 
obtained informed consent for study participation, will record the following information into the 
eCRF: 
• 
Informed consent 
• 
Medical history: major illnesses, previous surgery/operation and allergies 
• 
Multiple Sclerosis history with Pattern of Progression  
• 
Concomitant therapies recording including usual dose regimen of studied disease therapy  
• 
Clinical examination including vital signs 
• 
Demographic data (including racial/ethnicity data according to local regulations) 
• 
Check inclusion criteria 
• 
Check non-inclusion criteria 
• 
EDSS 
• 
TW25 
• 
C-SSRS 
• 
SPI2 patient alert card dispensed to patient with next visit date indicated on it 
The investigator will organize blood sampling and transfer to the Central Clinical Laboratory of the 
safety panel following the Operating Manual, the results to be available for the inclusion: 
• 
Safety panel includes: 
o CBC with differential 
o Metabolic panel (fasting) 
o Hepatic function panel 
o Lipid panel (fasting) 
o Blood-based pregnancy test: highly sensitive HCG pregnancy test in women of 
childbearing potential 
• 
A serum sample for biotin and neurofilament level assessment will be stored at -20° on site 
and transferred to an independent laboratory before end of the enrolment period.  

 
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The investigator should plan the MRI so that the results are available prior to the V2/M0 visit to insure 
image quality.   
The patient will be provided with ambulatory activity monitoring device (Fitbit ®) and instructions for 
use. 
The patient will be assigned with an inclusion number automatically provided by the IWRS system. 
This unique inclusion number will not be re-allocated in case of screen failure. 
2.6.3.1.2 
Visit 2 (M0): Randomization visit 
If the patient fulfils all inclusion/exclusion criteria at this visit, the patient will be randomized. Then, 
the investigator/study coordinator will record the following information into the eCRF: 
• 
Any adverse event occurred before the randomization visit 
• 
MS relapse assessment questionnaire (specific form, Cf. Annex 3) 
• 
Concomitant medication and therapies 
• 
Clinical examination including vital signs 
• 
EDSS 
• 
TW25 
• 
C-SSRS 
• 
SDMT 
• 
MSQOL-54 / CAREQOL-MS 
• 
Ambulatory activity monitoring data collection 
• 
Urinary-based pregnancy test (If applicable) 
• 
Brain MRI 
• 
ECG 12 derivations (triplicate) 
• 
SPI2 patient alert card dispensed to patient with next visit date indicated on it 
The investigator will fill a "drug delivery form" for the hospital pharmacy (where applicable) to dispense 
study medication. 
The patient will be supplied with the study medication dispensed by the hospital pharmacy or the 
principal investigator where applicable. Four vials for a total of three months of treatment will be 
dispensed. The patient will be asked to take one capsule from the vial in the morning, one capsule at 
noon and one capsule in the evening. Capsules have to be swallowed with a glass of water with a 
minimum of 4 hours between each intake and at least one hour before mealtime.  
2.6.3.1.3 
Visit 3 (M3): Follow up visit  
The investigator will record the following information into the eCRF: 
• Adverse events 
• MS relapse assessment questionnaire (specific form, Cf. Annex 3) 
• Concomitant medication and therapies 
• Compliance evaluation since the previous visit  
• Clinical examination including vital signs 
• EDSS 
• TW25 
• C-SSRS 
• Ambulatory activity monitoring data collection 

 
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• Urinary-based pregnancy test results of the period V2/M0 to V3/M3 
• SPI2 patient alert card dispensed to patient with next visit date indicated on it 
The investigator should ideally plan to carry out the brain MRI of the V4/M6 visit on the same day. 
However, if this is not possible, the MRI should be performed as per the permitted window within the 
protocol (+/-10 days). 
2.6.3.1.4 
Visit 4 (M6): Follow-up visit 
The investigator will record the following information into the eCRF: 
• Adverse events 
• MS relapse assessment questionnaire (specific form, Cf. Annex 3) 
• Concomitant medication and therapies 
• Compliance evaluation since the previous visit 
• EDSS 
• TW25 
• C-SSRS 
• Ambulatory activity monitoring data collection 
• Brain MRI 
• Urinary-based pregnancy test results of the period V3/M3 to V4/M6 
• SPI2 patient alert card dispensed to patient with next visit date indicated on it 
The investigator will perform blood sampling and shipment to the Central Clinical Laboratory of the 
safety panel following the Operating Manual: 
• Safety panel includes: 
o CBC with differential 
o Metabolic panel  
o Hepatic function panel 
o Lipid panel (fasting) 
o Blood-based pregnancy test: highly sensitive HCG pregnancy test in women of 
childbearing potential 
o Thyroid panel: TSH, T3 free  
• 
A serum sample for biotin and neurofilament level assessment will be stored at -20° on site 
and transferred at the end of the study to an independent laboratory. The date and time of the 
last biotin intake will be collected in the eCRF. 
2.6.3.1.5 
Visit 5 (M9): Follow-up visit 
The investigator will record the following information into the eCRF: 
• Adverse events 
• MS relapse assessment questionnaire (specific form, Cf. Annex 3) 
• Concomitant medication and therapies 
• Compliance evaluation since the previous visit 
• Clinical examination including vital signs 
• EDSS 
• TW25 
• C-SSRS 
• Ambulatory activity monitoring data collection 
• Urinary-based pregnancy test results of the V4/M6-V5/M9 period 
• SPI2 patient alert card dispensed to patient with next visit date indicated on it 

 
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2.6.3.1.6 
Visit 6 (M12): Follow up visit 
The investigator will record the following information into the eCRF: 
• Adverse events 
• MS relapse assessment questionnaire (specific form, Cf. Annex 3) 
• Concomitant medication and therapies 
• Compliance evaluation since the previous visit 
• Clinical examination including vital signs 
• EDSS 
• TW25 
• C-SSRS 
• Ambulatory activity monitoring data collection 
• Urinary-based pregnancy test results of the V5/M9-V6/M12 period 
• SPI2 patient alert card dispensed to patient with next visit date indicated on it 
• A serum sample for biotin and neurofilament level assessment will be stored at -20° on site 
and transferred at the end of the study to an independent laboratory. The date and time of the 
last biotin intake will be collected. 
The investigator will plan the brain MRI of the V7/M15 visit ideally on the same day. However, if it is 
not possible, the MRI should be performed as per the permitted window within the protocol (+/- 15 
days). 
2.6.3.1.7 
Visit 7 (M15): Follow-up visit 
The investigator will record the following information into the eCRF: 
• 
Adverse events 
• 
MS relapse assessment questionnaire (specific form, Cf. Annex 3) 
• 
Concomitant medication and therapies 
• 
Compliance evaluation since the previous visit 
• 
Clinical examination including vital signs 
• 
EDSS 
• 
TW25 
• 
C-SSRS 
• 
SDMT 
• 
CGI-I (SGI, CGI) 
• 
MSQOL-54 / CAREQOL-MS 
• 
Ambulatory activity monitoring data collection 
• 
Physician and patient treatment assignment questionnaire 
• 
Brain MRI 
• 
ECG 12 derivations (single) 
• 
Urinary-based pregnancy test results of the V6/M12-V7/M15 period 
• 
SPI2 patient alert card dispensed to patient with next visit date indicated on it 
The investigator will perform blood sampling and shipment to the Central Clinical Laboratory of the 
safety panel following the Operating Manual: 
• Safety panel includes: 
o CBC with differential 
o Metabolic panel  
o Hepatic function panel 

 
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o Lipid panel (fasting) 
o Blood-based pregnancy test: highly sensitive HCG pregnancy test in women of 
childbearing potential 
o Thyroid panel: TSH, T3 free 
• 
A serum sample for biotin and neurofilament level assessment will be stored at -20° on site 
and transferred at the end of the study to an independent laboratory. The date and time of the 
last biotin intake will be collected. 
Patients who have completed 15 months will be kept on the blinded study drug until the last Month 
15 evaluation for all study subjects has been completed but not more than 27 months.  
Once the last month 15 evaluation of the study has been completed, patients will switch to the 
active drug at the next planned study visit (V8/M18 or V9/M21 or V10/M24 depending on their 
randomization date). Participants and study personnel will remain blinded as to the original 
treatment assignment. 
Dispensation of the active drug to all patients will be triggered automatically by IWRS at the last 
V7/M15 evaluation of the study and for all subsequent visits. 
2.6.3.1.8 
Visit 8 (M18): Follow-up visit 
The investigator will record the following information into the eCRF: 
• 
Adverse events 
• 
MS relapse assessment questionnaire (specific form, Cf. Annex 3) 
• 
Concomitant medication and therapies 
• 
Compliance evaluation since the previous visit 
• 
Clinical examination including vital signs 
• 
EDSS 
• 
TW25 
• 
C-SSRS 
• 
Ambulatory activity monitoring data collection 
• 
Urinary-based pregnancy test results of the V7/M15-V8/M18 period 
• 
SPI2 patient alert card dispensed to patient with next visit date indicated on it 
The patient will be provided with the study drug dispensed by the hospital pharmacy or the Principal 
Investigator where applicable and will be treated with the active drug once the last V7/M15 evaluation 
of the study has been completed. Alternatively, the patient will remain on double-blind. 
2.6.3.1.9 
Visit 9 (M21): Follow-up visit  
The investigator will record the following information into the eCRF: 
• 
Adverse events 
• 
MS relapse assessment questionnaire (specific form, Cf. Annex 3) 
• 
Concomitant medication and therapies 
• 
Compliance evaluation since the previous visit 
• 
Clinical examination including vital signs 
• 
EDSS 
• 
TW25 
• 
C-SSRS 

 
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• 
Ambulatory activity monitoring data collection 
• 
Urinary-based pregnancy test results of the V8/M18-V9/M21 period 
• 
SPI2 patient alert card dispensed to patient with next visit date indicated on it 
The patient will be provided with the study drug dispensed by the hospital pharmacy or the Principal 
Investigator where applicable and will be treated with the active drug once the last V7/M15 evaluation 
of the study has been completed. Alternatively, the patient will remain on double-blind. 
2.6.3.1.10 Visit 10 (M24): Follow-up visit 
The investigator will record the following information into the eCRF: 
• 
Adverse events 
• 
MS relapse assessment questionnaire (specific form, Cf. Annex 3) 
• 
Concomitant therapies 
• 
Compliance evaluation since the previous visit 
• 
Clinical examination including vital signs 
• 
EDSS 
• 
TW25 
• 
C-SSRS 
• 
Ambulatory activity monitoring data collection 
• 
Urinary-based pregnancy test results of the V9/M21-V10/M24 period 
• 
SPI2 patient alert card dispensed to patient with next visit date indicated on it 
The patient will be provided with the study drug dispensed by the hospital pharmacy or the Principal 
Investigator where applicable and will be treated with the active drug once the last V7/M15 evaluation 
of the study has been completed. Alternatively, the patient will remain on double-blind. 
The investigator should ideally plan the brain MRI of the V11/M27 visit on the same day. However, if 
it is not possible, the MRI should be performed as per the permitted window within the protocol (+/- 15 
days) 
2.6.3.1.11 Visit 11 (M27): Final double-blind visit of part 1 
The investigator will record the following information into the eCRF: 
• 
Informed consent for part 2 (Open Label Extension) 
• 
Adverse events 
• 
MS relapse assessment questionnaire (specific form, Cf. Annex 3) 
• 
Concomitant medication and therapies 
• 
Compliance evaluation since the previous visit 
• 
Clinical examination including vital signs 
• 
EDSS 
• 
TW25 
• 
C-SSRS 
• 
SDMT 
• 
CGI-I (SGI, CGI) 
• 
MSQOL54 / CAREQOL-MS 
• 
Ambulatory activity monitoring data collection 
• 
Brain MRI  
• 
ECG 12 derivations (single) 
• 
Urinary-based pregnancy test results of the V10/M24-V11/M27 period 

 
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• 
SPI2 patient alert card dispensed to patient with next visit date indicated on it 
The investigator will perform blood sampling and shipment to the Central Clinical Laboratory of the 
safety panel following the Operating Manual: 
• Safety panel includes: 
o CBC with differential 
o Metabolic panel  
o Hepatic function panel 
o Lipid panel (fasting) 
o Blood-based pregnancy test: highly sensitive HCG pregnancy test in women of 
childbearing potential 
o Thyroid panel: TSH, T3 free 
• A serum sample for biotin and neurofilament level assessment will be stored at -20° on site 
and transferred at the end of the study to an independent laboratory. The date and time of the 
last biotin intake will be collected. 
At this visit, participants will be offered entry into an open label extension (OLE) where all 
patients will be treated with active drug (MD1003) until the end of the study (V18/M66). Four 
vials for a total of 3 months of treatment will be dispensed to the patient. 
Dispensation of the active drug at the V11/M27 visit and for subsequent OLE (Part 2) visits will 
be automatically programmed by IWRS. 
Patients and study personnel will remain blinded to the original treatment arm until the last 
V11/M27 visit of the study has been completed.  
The randomization list of each site will be communicated once the last V11/M27 visit of the study 
for all subjects has been completed. 
If a patient decides not to participate in the OLE, he should be followed-up for 30 days after receiving 
the last dose of study medication and any AEs, which occur during this time, should be reported in the 
eCRF and followed up until resolution or stabilization of the AE or SAE. 
The investigator will remind women of child bearing potential not willing to enter the OLE to perform 
a monthly urinary pregnancy test for a period up to 3 months following the treatment discontinuation 
and inform the site immediately in case of positive result in order to organize an additional visit. 
 
Evaluations Part 2: Open-label extension phase 
2.6.3.2.1 
Visit 12 (M30): Follow up visit of part 2 (OLE) 
The investigator will record the following information into the eCRF: 
• Adverse events 
• MS relapse assessment questionnaire (specific form, Cf. Annex 3) 
• Concomitant medication and therapies 
• Compliance evaluation since the previous visit 
• Clinical examination including vital signs 
• EDSS 
• TW25 
• C-SSRS 
• Ambulatory activity monitoring data collection 
• Urinary-based pregnancy test results of the V11/M27-V12/M30 period 
• SPI2 patient alert card dispensed to patient with next visit date indicated on it 

 
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Seven vials for a total of six months of treatment will be dispensed to the patient. 
2.6.3.2.2 
Visit 13 (M36): Follow-up visit 
The investigator will record the following information into the eCRF: 
• Adverse events 
• MS relapse assessment questionnaire (specific form, Cf. Annex 3) 
• Concomitant medication and therapies 
• Compliance evaluation since the previous visit 
• Clinical examination including vital signs 
• EDSS 
• TW25 
• C-SSRS 
• Ambulatory activity monitoring data collection 
• Urinary-based pregnancy test results of the V12/M30-V13/M36 period 
• SPI2 patient alert card dispensed to patient with next visit date indicated on it 
The investigator will plan the brain MRI of the V14/M42 visit ideally on the same day. However, if it 
is not possible, the MRI should be performed as per the permitted window within the protocol (+/- 15 
days). 
2.6.3.2.3 
Visit 14 (M42): Follow-up visit 
The investigator will record the following information into the eCRF: 
• 
Adverse events 
• 
MS relapse assessment questionnaire (specific form, Cf. Annex 3) 
• 
Concomitant medication and therapies 
• 
Compliance evaluation since the previous visit 
• 
Clinical examination including vital signs 
• 
EDSS 
• 
TW25 
• 
C-SSRS 
• 
CGI-I (SGI, CGI) 
• 
MSQOL-54 / CAREQOL-MS 
• 
Ambulatory activity monitoring data collection 
• 
Brain MRI 
• 
ECG 12 derivations (single) 
• 
Urinary-based pregnancy test results of the V13/M36-V14/M42 period 
• 
SPI2 patient alert card dispensed to patient with next visit date indicated on it 
The investigator will perform blood sampling and shipment to the Central Clinical Laboratory of the 
safety panel following the Operating Manual: 
• Safety panel includes: 
o CBC with differential 
o Metabolic panel  
o Hepatic function panel 
o Lipid panel (fasting) 
o Blood-based pregnancy test: highly sensitive HCG pregnancy test in women of 
childbearing potential 
o Thyroid panel: TSH, T3 free 

 
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• 
A serum sample for biotin and neurofilament level assessment will be stored at -20° on site 
and transferred at the end of the study to an independent laboratory. The date and time of the 
last biotin intake will be collected. 
2.6.3.2.4 
Visit 15 (M48): Follow-up visit 
The investigator will record the following information into the eCRF: 
• Adverse events 
• MS relapse assessment questionnaire (specific form, Cf. Annex 3) 
• Concomitant medication and therapies 
• Compliance evaluation since the previous visit 
• Clinical examination including vital signs 
• EDSS 
• TW25 
• C-SSRS 
• Ambulatory activity monitoring data collection 
• Urinary-based pregnancy test results of the V14/M42-V15/M48 period 
• SPI2 patient alert card dispensed to patient with next visit date indicated on it 
The investigator will plan the brain MRI of the V16/M54 visit ideally on the same day. However, if it 
is not possible, the MRI should be performed as per the permitted window within the protocol (+/- 15 
days). 
2.6.3.2.5 
Visit 16 (M54): Follow-up visit 
The investigator will record the following information into the eCRF: 
• 
Adverse events 
• 
MS relapse assessment questionnaire (specific form, Cf. Annex 3) 
• 
Concomitant medication and therapies 
• 
Compliance evaluation since the previous visit 
• 
Clinical examination including vital signs 
• 
EDSS 
• 
TW25 
• 
C-SSRS 
• 
CGI-I (SGI, CGI) 
• 
MSQOL-54 / CAREQOL-MS 
• 
Ambulatory activity monitoring data collection 
• 
Brain MRI 
• 
ECG 12 derivations (single) 
• 
Urinary-based pregnancy test results of the V15/M48-V16/M54 period 
• 
SPI2 patient alert card dispensed to patient with next visit date indicated on it 
The investigator will perform blood sampling and shipment to the Central Clinical Laboratory of the 
safety panel following the Operating Manual: 
• Safety panel includes: 
o CBC with differential 
o Metabolic panel  
o Hepatic function panel 
o Lipid panel (fasting) 
o Blood-based pregnancy test: highly sensitive HCG pregnancy test in women of 
childbearing potential 

 
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o Thyroid panel: TSH, T3 free 
• 
A serum sample for biotin and neurofilament level assessment will be stored at -20° on site 
and transferred at the end of the study to an independent laboratory. The date and time of the 
last biotin intake will be collected. 
2.6.3.2.6 
Visit 17 (M60): Follow-up visit 
The investigator will record the following information into the eCRF: 
• Adverse events 
• MS relapse assessment questionnaire (specific form, Cf. Annex 3) 
• Concomitant medication and therapies 
• Compliance evaluation since the previous visit 
• Clinical examination including vital signs 
• EDSS 
• TW25 
• C-SSRS 
• Ambulatory activity monitoring data collection 
• Urinary-based pregnancy test results of the V16/M54-V17/M60 period 
• SPI2 patient alert card dispensed to patient with next visit date indicated on it 
The investigator will plan the brain MRI of the V17/M60 visit ideally on the same day. However, if it 
is not possible, the MRI should be performed as per the permitted window within the protocol (+/- 15 
days). 
2.6.3.2.7 
Visit 18 (M66): Final visit of OLE 
The investigator will record the following information into the eCRF: 
• 
Adverse events 
• 
MS relapse assessment questionnaire (specific form, Cf. Annex 3) 
• 
Concomitant medication and therapies 
• 
Compliance evaluation since the previous visit 
• 
Clinical examination including vital signs 
• 
EDSS 
• 
TW25 
• 
C-SSRS 
• 
CGI-I (SGI, CGI) 
• 
MSQOL-54 / CAREQOL-MS 
• 
Ambulatory activity monitoring data collection 
• 
Brain MRI 
• 
ECG 12 derivations (single) 
• 
Urinary-based pregnancy test results of the V17/M60-V18/M66 period 
• 
SPI2 patient alert card dispensed to patient with next visit date indicated on it 
The investigator will perform blood sampling and shipment to the Central Clinical Laboratory of the 
safety panel following the Operating Manual: 
• Safety panel includes: 
o CBC with differential 
o Metabolic panel  
o Hepatic function panel 
o Lipid panel (fasting) 

 
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o Blood-based pregnancy test: highly sensitive HCG pregnancy test in women of 
childbearing potential 
o Thyroid panel: TSH, T3 free 
• 
A serum sample for biotin and neurofilament level assessment will be stored at -20° on site 
and transferred at the end of the study to an independent laboratory. The date and time of the 
last biotin intake will be collected. 
The investigator will remind women of child bearing potential to perform a monthly urinary pregnancy 
test for a period up to 3 months following the treatment discontinuation and inform the site immediately 
in case of positive result in order to organize an additional visit. During this visit the investigator will 
complete a pregnancy follow-up form and initiate the follow-up of the patient up to the delivery 
whatever its outcome. 
Participants should be followed-up for 30 days after receiving the last dose of study medication and any 
AEs, which occur during this time, should be reported in the eCRF and followed up until resolution or 
stabilization of the AE or SAE. 
 
Unscheduled Visit (when required)  
In case of relapses or whenever required by the patient or investigator, the patient can attend an 
unscheduled visit where the investigator will record the following information into the eCRF: 
• 
Adverse events 
• 
MS relapse assessment questionnaire (specific form, Cf. Annex 3) 
• 
Concomitant medication and therapies 
• 
Clinical examination including vital signs 
• 
EDSS 
• 
TW25 
• 
C-SSRS 
• 
Ambulatory activity monitoring data collection 
• 
Brain MRI in case of relapse 
• 
ECG 12 derivations 
• SPI2 patient alert card dispensed to patient with next visit date indicated on it 
The investigator will perform blood sampling and shipment to the Central Clinical Laboratory of the 
safety panel following the Operating Manual: 
• Safety panel includes: 
o CBC with differential 
o Metabolic panel  
o Hepatic function panel 
o Lipid panel (fasting) 
o Blood-based pregnancy test: highly sensitive HCG pregnancy test in women of 
childbearing potential 
o Thyroid panel: TSH, T3 free  
 
Early Termination Visit (when applicable)  
In case of early termination, the patient should attend an early termination visit where the investigator 
will record the following information into the eCRF: 
• 
Adverse events 
• 
MS relapse assessment questionnaire (specific form, Cf. Annex 3) 

 
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• 
Concomitant medication and therapies 
• 
EDSS 
• 
TW25 
• 
C-SSRS 
• 
SDMT 
• 
CGI-I (SGI, CGI) 
• 
MSQOL-54 / CAREQOL-MS 
• 
Ambulatory activity monitoring data collection 
• 
Physician and patient treatment assignment questionnaire (not applicable for open-label 
extension) 
• 
ECG 12 derivations (single) 
The investigator will perform blood sampling and shipment to the Central Clinical Laboratory of the 
safety panel following the Operating Manual: 
• Safety panel includes: 
o CBC with differential 
o Metabolic panel  
o Hepatic function panel 
o Lipid panel (fasting) 
o Blood-based pregnancy test: highly sensitive HCG pregnancy test in women of 
childbearing potential 
o Thyroid panel: TSH, T3 free 
• 
A serum sample for biotin and neurofilament level assessment will be stored at -20° on site 
and transferred at the end of the study to an independent laboratory. The date and time of the 
last biotin intake will be collected. 
The investigator will remind women of child bearing potential to perform a monthly urinary pregnancy 
test for a period up to 3 months following the treatment discontinuation and inform the site immediately 
in case of positive result in order to organize an additional visit. 
Participants should be followed-up for 30 days after receiving the last dose of study medication and any 
AEs, which occur during this time, should be reported in the eCRF and followed up until resolution or 
stabilization of the AE or SAE. 
 
Efficacy assessments 
For efficacy assessment, all scales and questionnaires will be provided and have to be used for this study 
unless site specific versions are approved by the sponsor. 
 
Expanded Disability Status Scale (EDSS) Definition  
Neurostatus EDSS (Cf. Annex 2) will be used during the study to rate neurological impairment in 
multiple sclerosis patients. The Neurostatus is a modification by Kappos of the original Kurtzke scale. 
It eliminates some ambiguities especially for the ambulation score. 
Kurtzke’s Expanded Disability Status Scale (EDSS) is a scale for assessing neurologic impairment in 
MS (Kurtzke, 1983) including: 1) a series of scores in each of eight functional systems, and 2) the EDSS 
steps (ranging from 0 [normal] to 10 [death due to MS]). The functional systems are visual, brain stem, 
pyramidal, cerebellar, sensory, bowel & bladder, cerebral, and other functions. 

 
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EDSS steps 4.5 to 7.5 are defined by the impairment to ambulation and rely on a specific ambulatory 
score:  
Expanded disability status scale: 
0: 
Normal neurological exam (all FS grade 0) 
1.0: 
No disability, minimal signs in one FS (one FS grade 1) 
1.5: 
No disability, minimal signs in more than one FS (more than one FS grade 1) 
2.0: 
Minimal disability in one FS (one FS grade 2, others 0 or 1) 
2.5: 
Minimal disability in two FS (two FS grade 2, others 0 or 1) 
3.0: 
Moderate disability in one FS (one FS grade 3, others 0 or 1) though fully ambulatory; 
or mild disability in three or four FS (three / four FS grade 2, others 0 or 1) though fully 
ambulatory 
3.5: 
Fully ambulatory but with moderate disability in one FS (one FS grade 3) and mild 
disability in one or two FS (one / two FS grade 2) and others 0 or 1; or fully ambulatory with 
two FS grade 3 (others 0 or 1); or fully ambulatory with five FS grade 2 (others 0 or 1) 
4.0: 
Ambulatory without aid or rest for > 500 meters; up and about some 12 hours a day 
despite relatively severe disability consisting of one FS grade 4 (others 0 or 1) or combinations 
of lesser grades exceeding limits of previous steps 
4.5: 
Ambulatory without aid or rest for > 300 meters; up and about much of the day, 
characterized by relatively severe disability usually consisting of one FS grade 4 and 
combination of lesser grades exceeding limits of previous steps 
5.0: 
Ambulatory without aid or rest for > 200 meters (usual FS equivalents include at least 
one FS grade 5, or combinations of lesser grades usually exceeding specifications for step 4.5) 
5.5: 
Ambulatory without aid or rest for >100 meters 
6.0: 
Unilateral assistance (cane or crutch) required to walk at least 100 meters with or 
without resting (see chapter 8, Ambulation) 
6.5: 
Constant bilateral assistance (canes or crutches) required to walk at least 20 meters 
without resting (see chapter 8, Ambulation) 
7.0: 
Unable to walk 5 meters even with aid, essentially restricted to wheelchair; wheels 
self and transfers alone; up and about in wheelchair some 12 hours a day 
7.5: 
Unable to take more than a few steps; restricted to wheelchair; may need some help in 
transferring and in wheeling self 
8.0: 
Essentially restricted to bed or chair or perambulated in wheelchair, but out of bed 
most of day; retains many self-care functions; generally has effective use of arms 
8.5: 
Essentially restricted to bed much of the day; has some effective use of arm(s); retains 
some self-care functions 
9.0: 
Helpless bed patient; can communicate and eat 
9.5: 
Totally helpless bed patient; unable to communicate effectively or eat/swallow 
10: 
Death due to MS 
Ambulation score rated from 0 to 12: 
0: 
Unrestricted 
1: 
Fully ambulatory 
2: 
≥300 meters, but <500 meters, without help or assistance (EDSS 4.5 or 5.0) 
3: 
≥200 meters, but <300 meters, without help or assistance (EDSS 5.0) 
4: 
≥100 meters, but <200 meters, without help or assistance (EDSS 5.5) 
5: 
Walking range <100 meters without assistance (EDSS 6.0) 
6: 
Unilateral assistance, ≥50 meters (EDSS 6.0) 
7: 
Bilateral assistance, ≥120 meters (EDSS 6.0) 
8: 
Unilateral assistance, <50 meters (EDSS 6.5) 
9: 
Bilateral assistance, ≥5 meters, but <120 meters (EDSS 6.5) 

 
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10: 
Uses wheelchair without help; unable to walk 5 meters even with aid, essentially 
restricted to wheelchair; wheels self and transfers alone; up and about in wheelchair some 12 
hours a day (EDSS 7.0) 
11: 
Uses wheelchair with help; unable to take more than a few steps; restricted to 
wheelchair; may need some help in transferring and in wheeling self (EDSS 7.5) 
12: 
essentially restricted to bed or chair or perambulated in wheelchair, but out of bed 
most of day; retains many self-care functions; generally has effective use of arms (EDSS 8.0) 
 
EDSS requirements and measurement method 
EDSS including ambulatory part must be completed at each visit and recorded using Neurostatus scoring 
sheet.  
The reported walking distance must be a measured value and not declarative or a rounded value. The 
ambulation should be done in an inside hallway of sufficient length (At least 30m) with a reliable 
consistent method of measurement. The site should ensure that patients are assessed at approximately 
the same time of day whenever possible (Morning vs afternoon visit can impact EDSS assessment).  
The following measuring methods are allowed: 
• 
Measuring wheel 
• 
Marks in the corridor associated with any other complementary methods (measuring tape or 
wheel to measure the distance between 2 marks…) allowing to report the most accurate distance 
• 
Any other measuring method that allow to report an accurate and reliable walking distance. 
The measuring method used should be documented in source documents. 
Patient reported distance values cannot replace the measurements performed at each study visit on site. 
If a patient is fully ambulatory or unrestricted, the blinded rater should ensure that the patient walks 
more than the 500 meters threshold in order to avoid any ambiguity in the EDSS score.  
 
EDSS assistive device 
As the frame of reference for the primary endpoint is improvement, there are instances in which patients 
may need to be tested, safely, without assistance. For example, patients using a cane or walker to 
ambulate should be examined safely with less assistance (e.g. from bilateral assistance to unilateral 
assistance) or no assistance (from unilateral assistance to no assistance). 
Remember that all patients must be evaluated the same way all along the study from the screening date. 
The blinded rater will perform the neurological examination, document the Kurtzke Functional Systems 
(KFS) scores and ambulation score, then assess EDSS.  
Every effort will be made to ensure that there is no change in the blinded rater throughout the course of 
the study for any individual patient or at least the same rater for V1/M-1, V2/M0, V6/M12, and V7/M15. 
Blinded raters will receive training in performing EDSS assessments prior to the beginning of the study 
and must have successfully passed an examination on performance of the Neurostatus EDSS 
examination within 24 months of participation. A blinded rater is not necessarily a physician but can be 
a study nurse as long as trained to perform the EDSS and Neurostatus level C certified. In case of a 
change of blinded rater during the study, the new blinded rater should acknowledge and approve the 
previous EDSS score for all concerned patients. 

 
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Definition of EDSS improvement and worsening 
For the EDSS, the baseline value will be the best of the 2 scores obtained at either the inclusion or 
randomization visits. 
According to baseline EDSS, an improvement will be defined as follows: 
• 
EDSS from 3.5 to 5.5: decrease of at least 1 point 
• 
EDSS at or above 6: decrease of at least 0.5 point 
 
According to baseline EDSS, a worsening will be defined as follows: 
• 
EDSS from 3.5 to 5.5: increase of at least 1 point 
• 
EDSS at or above 6: increase of at least 0.5 point 
 
TW25 (Timed 25-Foot Walk)  
The TW25 is a widely used outcome measure of leg function/ambulation. It has been validated in 
progressive MS trials (Goodman et al., 2009).  
In this test the patient should walk 7.62 meters (25 feet) as quickly, but safely, as possible without 
running. The course on which the test is walked, such as a hallway, should be clearly marked and free 
of obstructions. Patients are permitted to use their own assistive device or the best assistive device that 
might be necessary. 
If a device is necessary (EDSS above 6), at the inclusion visit, the device should be used as well during 
all the subsequent follow-up visits even if the patient improved.  
The timed-walk test should be performed twice, the time being recorded in seconds to the nearest one-
tenth of a second, starting as the lead foot passes the start line and ending as the lead foot passes the 
finish line.  
The two values of TW25 will be entered in the eCRF. Please document any condition that could affect 
the realization of the test.  
The TW25 will be performed at each visit by the blinded rater. A blinded rater is not necessarily a 
physician but can be a study nurse as long as trained to perform the TW25 test. 
 
Definition of TW25 improvement and worsening 
For the TW25, the baseline value will be the best mean of the 2 scores obtained at either the inclusion 
or randomization visits (the lowest mean between the 2 visits). An improvement is defined as a TW25 
decreased by at least 20% and a worsening is defined as an increase of 20%. 
The TW25 value at visit M12 is defined as the mean of the two TW25 attempts at visit M12. The TW25 
value at visit M15 is defined as the mean of the two TW25 attempts at visit M15.  
 
Symbol Digit Modalities Test (SDMT)  
The SDMT measures the time to pair abstract symbols with specific numbers. The test requires elements 
of attention, visual perceptual processing, working memory, and cognitive/psychomotor speed. The 
SDMT is a measure of divided attention, visual scanning and motor speed. This measure involves a 
coding key consisting of 9 abstract symbols, each paired with a number ranging from 1 to 9. The subject 

 
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is required to scan the key and write down the number corresponding to each symbol as fast as possible. 
The number of correct substitutions within 90 seconds is recorded. In the written version of the test the 
subject fills in the numbers that correspond to the symbols. In the oral version the examiner records the 
numbers spoken by the subject. The score is the number of correctly coded items from 0-110 in 90 
seconds. 
The written form from Western Psychological Services (WPS) will be used in the trial. The oral version 
can be used in the study if the patient has upper extremity impairment. If a patient switches from written 
to oral version during the study, it should be documented accordingly.   
 
Remote monitoring of ambulatory activity 
Remote monitoring of ambulatory activity will be performed using a Fitbit device. The key variable will 
be the average daily step count over 1-week period recorded continuously in the natural environment as 
part of routine daily activity. This is the measure most frequently used in physical activity trials as it has 
good face validity and has ample validation against research grade accelerometers. Other variables that 
can also be measured using this kind of device include: estimated active minutes per day; estimated 
distance walked; estimated stairs climbed (# of floors); estimated energy expenditure (calories burned); 
sleep (awake vs. restless vs. asleep). 
Participants will be trained by the investigational team on the set-up, use and maintenance of the device 
and asked to wear the device as much as possible for the duration of the study. These devices have the 
ability to be motivational by setting daily step count goals. To minimize the influence of motivational 
factors on ambulatory activity levels, the daily “goal” on the device will be set low (i.e. 500 steps/day) 
or at least standardized, although participants can be taught how to change the settings to their liking 
(these settings do not affect the number of steps stored by the device). 
The site should encourage the patients to keep wearing the Fitbit device during Part 2 of the study. 
 
Patient reported outcome measures 
Patient reported outcome measures will be collected to compare the patient outcomes in active and 
placebo groups. 
The following instruments will be administered: 
• 
Subject Global Impression of Improvement scale (SGI) 
• 
Multiple Sclerosis Quality of Life-54 (MSQOL-54) 
• 
Caregiver health-related quality of life in Multiple Sclerosis (CAREQOL-MS) 
 
Clinical Global Impression of Improvement scale (CGI-I)  
The Clinical Global Impression of Improvement scale (CGI-I) is a 7-point scale that requires the 
clinician and the patient to assess how much the patient's illness has improved or worsened relative to 
the baseline state at the beginning of the intervention and rated as: 1, very much improved; 2, much 
improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much 
worse. 
The CGI-I will be assessed by the patient (subject global impression, SGI) and by the clinician (clinician 
global impression, CGI) at V7/M15, V11/M27, V14/M42, V16/M54, and V18/M66.  

 
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Multiple Sclerosis Quality of Life-54 (MSQOL-54)  
The MSQOL-54 is a multidimensional health-related quality of life measure that combines both generic 
and MS-specific items into a single instrument (Vickrey et al., 1997, Vickrey et al., 1995). The 
developers utilized the SF-36 as the generic component to which 18 items were added to tap MS-specific 
issues such as fatigue, cognitive function, etc. This 54-item instrument generates 12 subscales along 
with two summary scores, and two additional single-item measures. The subscales are: physical 
function, role limitations-physical, role limitations-emotional, pain, emotional well-being, energy, 
health perceptions, social function, cognitive function, health distress, overall quality of life, and sexual 
function. The summary scores are the physical health composite summary and the mental health 
composite summary. The single item measures are satisfaction with sexual function and change in 
health. 
 
Caregiver health-related quality of life in Multiple Sclerosis (CAREQOL-MS)  
In 2011, Benito-León et al. published the first specific questionnaire for assessing the QoL of carers of 
patients with MS: Caregiver Health-Related Quality of Life in Multiple Sclerosis (CAREQOL-MS). It 
consists of 24 items comprising four subscales: physical stress/global health, social integration, emotion, 
and the need for assistance/emotional reactions. Questionnaire items were derived from a literature 
review and the views of patients, caregivers, and experts. They are scored on a 5-point Likert-type scale 
(higher scores reflecting worse HRQoL). A significant correlation was observed between the 
CAREQOL-MS score and carers’ age and patients’ EDSS scores. The average standard error for the 
subscales ranged from 2.01 to 2.43. The scale was free of floor or ceiling effects. For subscales, 
Cronbach’s alpha coefficient ranged from 0.80 to 0.90. These results gave evidence for the usefulness 
and satisfactory psychometric properties of the questionnaire CAREQOL-MS (see Appendix 4). 
Therefore, CAREQOL-MS will be completed if patient has a caregiver. In the event the subject’s 
caregiver changes during the course of the study, this would be considered as a protocol deviation and 
should be reported appropriately. 
 
 Safety assessments 
Serious AE will be reported immediately to the Pharmacovigilance Unit of the sponsor within 24h after 
awareness from investigational team. 
 
Serious and non-serious adverse events monitoring and recording 
All adverse events will be recorded throughout the study from signature of the informed consent form. 
 
Suicide behavior questionnaire: Columbia-Suicide Severity Rating Scale (C-SSRS)  
The C-SSRS (both Baseline and Since Last Visit paper versions) will be administered to the patient and 
scored by a qualified, trained rater. Additional detailed information concerning administration, scoring 
and recording may also be provided by the Rater Training Vendor. Training is recommended for clinical 
practice before completing the C-SSRS. 
 
Inclusion  
Suicidal ideation and behaviour will be assessed at inclusion visit using the Baseline C-SSRS. The 
Baseline C-SSRS should be administered by trained raters.  Subjects with a history of suicidal ideation 
as evidenced by answering “yes” to questions 4 or 5 on the suicidal ideation portion of the C-SSRS 

 
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completed at the inclusion visit or history of a suicide attempt regardless of the attempt date (per the C-
SSRS) will not be included.  
There is no predefined C-SSRS score to exclude a patient from participating in the trial. However, only 
patients who are not judged to be at serious risk for self-harm during the course of the trial may be 
included in the trial; others must be excluded from trial participation and receive appropriate clinical 
care to ensure their safety. 
 
Follow up visits  
Suicidal ideation and behaviour will be assessed during this trial using the Since Last Visit C-SSRS. 
The Since Last Visit C-SSRS should be administered by trained raters at each visit, as indicated in the 
flow chart, as well as at unscheduled visits as clinically indicated. Site staff should review the contents 
of the C-SSRS for completeness and then transcribe the data to the eCRF. Patients who at any time 
during this trial report an AE of suicidal ideation or behaviour, either between visits or during visit 
interviews, must be assessed by trained raters and reviewed by an M.D. or a clinician Ph.D. Patients 
who report suicidal ideation with intent, with or without a plan or method (i.e., a positive response to 
Items 4 or 5 in the assessment of suicidal ideation on the C-SSRS) or suicidal behaviour must be 
evaluated that day by a psychiatrist or other trained mental health professional who is a licensed 
psychologist, social worker or nurse practitioner (or comparable professional qualification in countries 
outside the United States). Only patients whose suicidal ideation is passive, who expressly deny any 
intent to act, and who, after evaluation, are not judged to be at serious risk for self-harm during the 
course of the trial may continue in the trial; others must be discontinued from trial participation and 
receive appropriate clinical follow-up care to ensure their safety. All reports of suicidal ideation or 
behaviour must be reported as an AE and as an event of special interest Sites are to indicate which health 
care professionals are to be responsible for acute care on-site and to specify referral center(s) to be used 
for further evaluation. The C-SSRS (both Baseline and Since Last Visit paper versions) will be 
administered to the patient and scored by a qualified, trained rater. Additional detailed information 
concerning administration, scoring and recording may also be provided by the Rater Training Vendor. 
Training is recommended for clinical practice before completing the C-SSRS. 
 
Clinical examination 
 
Physical examination 
The physical examination comprises a routine medical examination including neurological and 
cognitive assessments.  The following body systems will be examined: HEENT (head, eyes, ear, nose, 
and throat), urological, cardiovascular, respiratory, lymphatic, gastrointestinal, musculoskeletal, 
dermatological, and venous system.  
 
Vital signs 
The following vital signs will be assessed at each visit (except when mentioned): 
• Systolic (SBP) and diastolic (DBP) blood pressure (mmHg); 
• Heart rate (beats per minute [bmp]); 
• Body temperature (°C); 
• Height* (cm) and weight (kg).  
*Height will be assessed and recorded only at V1/M-1. 
Blood pressure (SBP and DBP) and heart rate will be measured using a semi-automatic blood pressure 
recording device with an appropriate cuff size. Supine blood pressure and heart rate will be measured 
after the patient has rested in a supine position for at least 5 minutes. 
Body temperature will be measured until a stable reading is obtained. 

 
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Laboratory testing (haematology and biochemistry panel)  
Laboratory testing (standard haematology and biochemistry panel) including: 
• CBC with differential: 
o Number and types of white blood cells (WBCs) 
o Number of red blood cells (RBCs) 
o Red cell distribution width (RDW) 
o Haematocrit 
o Haemoglobin 
o Mean corpuscular volume (MCV) 
o Mean corpuscular haemoglobin 
o Platelet count 
• Metabolic panel (fasting): 
o BUN 
o CO2 (carbon dioxide/bicarbonate) 
o Creatinine 
o Estimated creatinine clearance rate using Cockcroft-Gault formula 
o Glucose 
o Serum chloride 
o Serum potassium 
o Serum sodium 
• Hepatic function panel: 
o Aspartate transaminase (AST) 
o Alanine transaminase (ALT) 
o Bilirubin 
o Gamma-glutamyl transpeptidase (GGT) 
o Alkaline phosphatase 
• Lipid panel (fasting): 
o Total cholesterol 
o Triglycerides 
o HDL cholesterol 
o LDL cholesterol 
• Contraceptive method monitoring in women of childbearing potential 
o Highly sensitive HCG pregnancy test 
• 
Monthly urinary pregnancy tests  
• 
Thyroid panel:  
o Thyroid-Stimulating Hormone (TSH) 
o Free Triiodothyronine (T3 free)  
 
Electrocardiogram 
Digital ECG will be recorded during Part 1 at V2/M0 (triplicated ECG), V7/M15, V11/M27, during Part 
2 at V14/M42, V16/M54, and V18/M66 to assess the potential of MD1003 to delay cardiac 
repolarization. All ECG records should be electronically sent to the Core Cardiac Safety Laboratory 
(CCSL). In case the electronic submission of the ECG is not possible, the original paper ECG trace 
should be sent to the CCSL. 
The assessment will be performed by the CCSL and include testing the effects on the QT/QTc interval 
as well as the other ECG parameters (RR, PR, QRS intervals, wave morphology, rhythm and 
conduction). 
QTc interval will be calculated using Fridericia’s correction: QTc = QT/RR0.33 

 
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The QT/QTc interval data will be assessed both as analyses of central tendency (e.g., means, medians) 
and categorical analyses. 
For central tendency, the effect of MD1003 on the QT/QTc interval will be analysed using the largest 
time-matched mean difference between the drug and placebo (baseline-adjusted) over the collection 
period. 
For categorical analysis, QT/QTc interval data will be based on the number and percentage of patients 
meeting or exceeding some predefined upper limit values: 
• 
Absolute QTc interval prolongation  
o QTc interval > 450 
o QTc interval > 480 
o QTc interval > 500 
• 
Change from baseline in QTc interval: 
o QTc interval increases from baseline >30 
o QTc interval increases from baseline >60 
• 
Statements regarding other ECG anomalies (rhythm, conduction, repolarisation) and their 
change from baseline will be reported and analysed 
 
Brain MRI  
Brain MRI using conventional sequences (T2 and T1 pre and post gadolinium injection) will be 
performed during Part 1 at V2/M0, V7/M15, V11/M27, during Part 2 at V14/M42, V16/M54, and 
V18/M66. Safety of MD1003 will be assessed by analysing: 
• 
Comparison of proportion of patients with at least one new/enlarging T2-weighted MS lesion 
at M6 and M15 in group 2 (300 mg/day) versus group 1 (placebo) 
• 
Mean number of new/enlarging T2-weighted MS lesions per patient at M6 and M15 in group 2 
(300 mg/day) versus group 1 (placebo) 
• 
Comparison of proportion of patients with at least one gadolinium enhancing lesion on the T1-
weighted sequence at M6 and M15 in group 2 (300 mg/day) versus group 1 (placebo) 
• 
Mean number of gadolinium enhancing lesions on the T1-weighted sequence at M6 and M15 
in group 2 (300 mg/day) versus group 1 (placebo) 
• 
Mean of T2-weighted lesion volume per patient at M6 and M15 in group 2 (300 mg/day) versus 
group 1 (placebo) 
• 
Mean of non-enhancing T1-weighted lesion volume per patient at M6 and M15 in group 2 (300 
mg/day) versus group 1 (placebo) 
 
Exploratory endpoints assessed by brain MRI 
The brain MRI will be supervised and analysed centrally by a Core Imaging Laboratory. Technical 
specifications will be described in a separate MRI Manual containing scanner-specific console 
instructions for acquisition, as well as data transfer requirements.  
As a pre-requisite, all sites will be trained to perform and transfer to Core Imaging Laboratory a dummy 
run before first patient enrolled. Site will be authorized to start enrolment upon Approval Letter from 
Core Imaging Laboratory receipt. 
During the study, DICOM images will be transferred to the Core Imaging Laboratory. After Quality 
Control, analyses will be performed blindly. 

 
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The brain MRI also will assess the following endpoints between V2/M0 and V7/M15, between V2/M0 
and V11/M27, and between V2/M0 and each MRI time point during the open label extension:  
• 
Percent thalamic volume change 
• 
Percent whole brain volume change 
• 
Percent cortical grey matter volume change 
• 
Brain water content by Pseudo T2 relaxation time change 
• 
NAA/Cr in a subset of sites acquiring MRS 
 Measures of biotin concentration in blood 
Since biotin is available as a food supplement in several countries, the absence (or low level) of biotin 
intake will be checked at inclusion by measuring biotin plasma concentration. 
Other measures will be performed at V4/M6, V6/M12, V7/M15, V11/M27 or at early termination during 
the placebo-controlled phase to check compliance in patients treated by MD1003 and to check for 
absence of “off label” biotin intake in patients having received the placebo. Additionally, biotin 
measures will be performed in Part 2 at V14/M42, V16/M54, and V18/M66 or at early termination to 
assess compliance. 
The biotin assay will be performed blindly in an independent central laboratory which has no contact 
with the investigators. A plasma level above 75 ng/ml will be considered as an important exposure. This 
threshold corresponds to the lowest concentration value observed during the previous clinical trials with 
high doses biotin at steady state. 
Pre-treatment samples will be dosed before the end of the enrolment period (i.e. after 3 months of 
enrolment) to check the proportion of “off label” use of high dose biotin in the placebo group. The 
double-blind will be maintained by the central laboratory and individual results will be disclosed to 
Steering Committee only in case of protocol violation, allowing to envision the patient’s withdrawal and 
replacement before the end of the enrolment period. 
Biotin and its main metabolites (BNB and BSO) measures of V4/M6, V6/M12 and V7/M15 samples 
will be performed at the end of the study with no access to data prior to database lock. The placebo 
patients found as biotin positive (above the 75 ng/ml threshold) will be considered as a protocol violation 
and withdrawn from the FAS and PP analysis. 
The treating and evaluating physicians will not have access to the results before the end of the study at 
V11/M27. 
 Measures of neurofilament concentration in blood 
The purpose of the neurofilament assay is to serve as an independent assessment of neuroinflammation. 
Neurofilament concentrations will be measured in Part 1 at V1/M-1, V4/M6, V6/M12, V7/M15, 
V11/M27 and in Part 2 at V14/M42, V16/M54, and V18/M66. 
The neurofilament concentration will be performed blindly in an independent central laboratory which 
has no contact with the investigators. 
The treating and evaluating physicians will not have access to the results before the end of the study at 
V11/M27. 

 
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3 
ADVERSE EVENTS 
 
Special warning, precaution for use related to interference with laboratory tests 
Biotin may interfere with some immunoassay methods that use a biotinylated reagent i.e. based on a 
biotin/streptavidin interaction. Therefore special consideration must be given to patients requiring 
biological tests outside the Central Laboratory used in the study. The impacted laboratory tests include 
those for anaemia, cardiac, fertility, pregnancy, hormonal, oncology, bone metabolism, inflammation 
biomarkers, infectious disease antigens and antibody titration. Some immunohistochemistry methods 
used in diagnostic pathology may also be affected. The following needs to be taken into account: 
• Only biotin/streptavidin-free analyzers and kits are suitable for performing immunoassays. 
• To avoid misleading results, clinical laboratories should be informed that the patient is taking 
high dose biotin so that appropriate analyzers can be used to ensure accuracy and reliability. 
• When interpreting laboratory test results performed outside the study in a patient treated with 
MD1003, it is necessary to contact the laboratory to verify if the treatment with high biotin doses 
interferes with the method used. If this is the case, the test should be repeated using an alternative 
method. 
• Tests that are sometimes required in an emergency situation can be distorted by biotin. They 
include, but are not limited to, HCG, BNP, CPK, CPKMB, D-dimer, troponin, cortisol, 
procalcitonin TSH, T3/T4, HIV serology.  
• The results can be falsely high, but also falsely low, dependant on the type of assay used: 
o Competitive assays are used for low molecular weight molecules (such as T3, T4, cortisol, 
testosterone, 25OH vitamin D, ...) with a risk of falsely high results 
o Sandwich assays are used for high molecular weight molecules (such as TSH, troponin, 
ACTH, βHCG, PSA ...) with a risk of falsely low results 
• Patients and their caregiver should be informed about the risk of interference with some diagnostic 
and laboratory tests and are strongly advised to carry with them at all times the SPI2 patient alert 
card summarizing this information. The patient alert card should be given to patients at inclusion. 
At each visit, the investigator should verify that the patient understands this important warning 
and redistribute a new copy of the alert card to the patient. This card should be presented to all 
healthcare professionals that the patient sees, including in an emergency situation. 
• General Practitioner (GP) letter: If a patient has consented to it, a letter must be sent to patient’s 
GP to inform them that their patient is potentially taking high dose biotin and of the potential risk 
of laboratory interferences due to biotin. During the study the blinded rater will and must remain 
blinded from all biological tests dosed outside the Clinical Central Laboratory. 
In case of a laboratory test performed outside of SPI2 routine safety assessments, the site must verify 
whether the laboratory results were affected by biotin interferences. The site should immediately check 
the model of the analyser used and perform a re-test in a laboratory using suitable analysers. The CSM 
can provide sites with the closest location of a laboratory equipped with a suitable analyser upon request. 
If any treatment has been initiated following laboratory results outside of the study, the site should 
immediately ask the patient to stop the corrective treatment in case this diagnosis was based on non-
reliable laboratory results.  
If it is confirmed that the laboratory results were impacted by interferences, the initial verbatim of the 
AE reported in the eCRF should be replaced by “False [initial AE verbatim] due to interferences with 
biotin.” 
 
 

 
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Definitions 
Adverse Event (AE): 
Any untoward medical occurrence in a patient or clinical investigation patient administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this treatment. 
An adverse event can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding, for example), symptom or disease temporally associated with the use of an 
investigational product, whether or not considered related to the IP. 
Examples of AEs include, but are not limited to, the following: 
• 
Abnormal test findings (i.e. laboratory interferences)  
• 
Hypersensitivity 
• 
Progression/worsening of underlying disease 
• 
Drug abuse 
• 
Drug dependency 
• 
Protocol-related adverse event (see definition below) 
• 
Additionally, they may include the signs or symptoms resulting from 
• 
Drug overdose 
• 
Drug withdrawal 
• 
Drug misuse 
• 
Drug interactions 
• 
Exposure during pregnancy 
• 
Exposure via breastfeeding 
• 
Medication error 
A protocol-related adverse event is an AE occurring during a clinical study that is not related to the IP 
but is considered to be related to the research conditions, i.e., related to the fact that a patient is 
participating in the study. For example, a protocol-related AE may be an untoward event related to a 
medical procedure required by the protocol like for example, ocular injuries due to the instillation 
procedure. 
Serious Adverse Event (SAE): 
A serious adverse event (SAE) is any untoward medical occurrence that, at any dose: 
• 
Results in death 
• 
Is life-threatening, (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the patient was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death if more severe.) 
• 
Requires hospitalization or prolongation of existing hospitalization 
• 
Results in disability/incapacity 
• 
Is a congenital anomaly/birth defect 
• 
Medical or scientific judgment should be exercised in deciding whether reporting is appropriate 
in other situations, such as important medical events that may not be immediately life 
threatening or result in death or hospitalization but may jeopardize the patient or may require 
medical or surgical intervention to prevent one of other outcomes listed in the above definition.  
These should also be considered serious. 
• 
In this study, all MS relapses (as defined below) will be considered as a SAE. Study treatment 
should be maintained as much as possible. 
o All MS relapses (as defined below) reported by investigators will be recorded in an MS 
relapse form (annex 3) which will be communicated to and assessed by the Adjudication 
Committee for diagnosis validation. 

 
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MS relapses 
The following definitions should be used for relapses: 
• 
Protocol-defined relapse:  
o appearance of a new symptom or worsening of an old symptom, attributable to MS 
o symptoms lasting at least 24 hours 
o absence of fever or infection 
o preceded by stability or improvement for at least 30 days 
o subject seen within 7 days of onset 
o change of at least 0.5 on EDSS or 1 pt on 2 FS or 2 pts on 1 FS since the last visit 
• 
Non protocol-defined relapse: same as above but the subject was not seen within 7 days of onset 
• 
Suspected relapse: Relapse that fails to meet the above situations but may have been a relapse 
– i.e. all circumstances point to relapse, but no change in the EDSS. 
It is asked to the sites to interview patients at each visit using the relapse assessment questionnaire in 
order to record all reports of possible relapses. This form will be submitted and reviewed by the Clinical 
Adjudication Committee in case of protocol-defined, non-protocol-defined and suspect relapses. The 
event fulfilling the “Not a relapse” criteria should NOT be submitted to the Clinical Adjudication 
Committee. 
Medication Errors 
In this protocol, a reportable medication error includes the following: 
 
• 
The administration of an unassigned treatment. 
• 
Inadvertent or accidental exposure to an investigational product with or without an AE. 
Whether or not the medication error is accompanied by an AE, as determined by the investigator, the 
medication error and, if applicable, any associated adverse event(s) is captured on an adverse event (AE) 
eCRF (refer to Adverse Event Reporting section for further details).  
Important:  
• 
All AE/SAE associated or not to the IPs shall be notified to the Sponsor Pharmacovigilance 
Unit. 
• 
SAR suspected to be related to an interaction between an IP and a Non-Investigational Product 
(NIP) should be reported. 
 
Handling of Non-Serious Adverse Events 
All AEs encountered during the clinical study (from signature of informed consent) will be reported on 
the eCRF.  
• 
All AEs and SAEs must be recorded on patient’s source documents.  
• 
All AEs and SAEs for patients who receive a treatment assignment code will be recorded in the 
eCRFs. During the active reporting period specified above, all AEs will be reported on the AE 
page(s) of the eCRF. It should be noted that the form for collection of SAE information is not 
the same as the AE eCRF. Where the same data are collected, the forms must be completed in 
a consistent manner. For example, the same AE term should be used on both forms. AEs should 
be reported using concise medical terminology on the eCRFs as well as on the form for 
collection of SAE information. 

 
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• 
Each AE is to be assessed to determine if it meets the criteria for SAEs. If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate. 
• 
Withdrawal due to AE should be distinguished from withdrawal due to insufficient response, 
according to the definition of AE noted earlier, and recorded on the appropriate AE eCRF page. 
In case of confirmed laboratory interferences, the initial AE should be replaced on the eCRF 
using the following verbatim “False [initial AE] due to laboratory interferences with laboratory 
test”. 
The information to be entered in the eCRF will include: 
• 
The time of onset of any AE or the worsening of a previously observed AE 
• 
The specific type of reaction in standard medical terminology 
• 
The duration of the AE (start and stop dates) 
 
Severity assessment 
The severity of the adverse event (AE). The severity should be rated as: 
• 
Mild: discomfort noted, but no disruption of normal daily activity. 
• 
Moderate: discomfort noted of sufficient severity to reduce or adversely affect normal activity. 
• 
Severe: incapacitating, with inability to work or perform normal daily activity. 
 
Causality assessment 
An assessment of the relationship of the adverse event (AE) to the study medication, i.e., according to 
the definitions below: 
• 
Definite: a clinical event, including laboratory test abnormality, occurring in a plausible time 
relationship to drug administration, and which cannot be explained by concurrent disease or 
other drugs or chemicals. The event must be pharmacologically or phenomenologically 
plausible, and its clinical response to withdrawal of the drug (dechallenge) should be clinically 
plausible. It must also be confirmed by a satisfactory rechallenge procedure.  
• 
Probable/likely: a clinical event in which a relationship to the IP seems probable because of 
such factors as a clear temporal association with the use of the IP, lack of alternative 
explanations for the event or other factors. 
• 
Possible: the essential distinctions between ‘Probable’ and ‘Possible’ are that in the latter case 
there may be another equally likely explanation for the event (could also be explained by disease 
or other drugs) and/or there is no information or uncertainty with regard to what has happened 
after stopping. 
• 
Unlikely: a clinical event with a temporal relationship to IP administration that makes a causal 
relationship improbable and / or in which other factors suggesting an alternative aetiology exist. 
Such factors include a known relationship of the adverse event to concomitant drug, the patient’s 
disease state or environmental factors including common infectious diseases. 
• 
Conditional/Unclassified: A clinical event, including laboratory test abnormality, reported as 
an adverse reaction, about which more data is essential for a proper assessment or the additional 
data are under examination. 
• 
Not related: Not suspected to be reasonably related to the IP. A reasonable alternative 
explanation must be available. 
In addition, if the investigator determines an SAE is associated with study procedures, the investigator 
must record this causal relationship in the source documents and eCRF, as appropriate, and report such 
an assessment in accordance with the SAE reporting requirements, if applicable. 

 
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As far as possible, all investigators should follow-up participants with AEs until the event is resolved or 
until, in the opinion of the investigator, the event is stabilized or determined to be chronic. Details of 
AE resolution must be documented in the eCRF and in the source documents. Participants should be 
followed-up for 30 days after receiving the last dose of study medication and any AEs, which occur 
during this time, should be reported according to the procedures outlined above. Any significant changes 
in AEs should be reported even though the patient has completed the study, including the protocol-
required post-treatment follow-up. 
 
Assessment of seriousness 
After the relationship, the seriousness shall be determined by the treating physician according to the 
definition given below: 
Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (SADR): Any untoward medical 
occurrence or effect that at any dose: 
• 
Results in death 
• 
Is life-threatening, (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the patient was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death if more severe.) 
• 
Requires hospitalization or prolongation of existing hospitalization 
• 
Results in disability/incapacity 
• 
Is a congenital anomaly/birth defect 
• 
Medical or scientific judgment should be exercised in deciding whether reporting is appropriate 
in other situations, such as important medical events that may not be immediately life 
threatening or result in death or hospitalization but may jeopardize the patient or may require 
medical or surgical intervention to prevent one of other outcomes listed in the above definition.  
These should also be considered serious. 
• 
In this study, all MS relapses (as defined below) will be considered as a SAE. Study treatment 
should be maintained as much as possible. 
o All MS relapses (as defined below) reported by investigators will be recorded in an MS 
relapse form (annex 3) which will be communicated to and assessed by the Adjudication 
Committee for diagnosis validation and MEDDRA coding purpose. 
 
Serious Adverse Events reporting 
All SAEs and follow-up information must be reported to the sponsor on a SAE form within 24 hours of 
investigator awareness of the event.  
All non-serious AE notified at the same time of serious AE shall be recorded and notified to the 
Pharmacovigilance unit of the sponsor.  
The description of SAE will include a description of the AE with sufficient details to allow for a 
complete medical assessment of the case and independent determination of possible causality. 
Information on other possible causes of the event, such as concomitant medications and illnesses must 
be provided. In the case of a patient death, a summary of available autopsy findings must be submitted 
as soon as possible to the Sponsor or its designated representative. 
All adverse events encountered during the clinical study must be reported on the eCRF as soon as the 
data are available. Therefore, data will be accessible immediately by the sponsor or designee.   
Serious adverse events (SAEs), whether or not associated with study medication administration, will be 
recorded both on the Adverse Event form of the eCRF and the SAE form (available from the eCRF web 
site or from the Investigator’s study files). 

 
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ALL SAEs occurring during this study (from signature of informed consent) and up to 30 days 
after a patient discontinued or completed the study, whether or not related to the administration 
of study medications, must be reported by faxing the completed SAE form, after reviewing the 
report for consistency and accuracy within 24 hours of awareness by the investigator, to the e-
mail address or fax number mentioned on the SAE reporting form (investigator site file).  
As soon as new information is available, a follow-up SAE should be sent to PV immediately and 
the eCRF updated accordingly.  
Medical Assistance 
If there is a need to discuss any medical issues concerning a serious adverse event or to report a serious 
adverse event during the business hours, the sponsor can be contacted through the CRO medical monitor 
(contact details available in the investigator site file). 
 
Sponsor Reporting Requirements to Regulatory Authority 
Adverse event reporting, including suspected serious unexpected adverse reactions, will be carried out 
in accordance with applicable local regulations. 
4 
STATISTICAL CONSIDERATIONS  
 
Determination of sample size  
The sample size is determined in terms of superiority, between group 2 (MD1003 300 mg/day) versus 
group 1 (placebo) according to the primary endpoint, i.e. the proportion of patients with a clinical 
improvement defined as: 
“decreased EDSS at M12 confirmed at M15 (defined as a decrease of at least 1 point if initial 
EDSS from 3.5 to 5.5 and of at least 0.5 point if initial EDSS between 6 and 6.5) or with improved 
TW25 of at least 20% at M12 and M15 compared to the best EDSS and TW25 scores among 
inclusion and randomization visits” 
In the previous MS-SPI study, the improvement percentage was 0% in the placebo group and 12.6% in 
the active arm.  
For the sample size estimation of SPI2, hypotheses were set at 2% for the proportion of clinically 
improved patients in the placebo group and at 12% in the MD1003 group. These hypotheses lead to a 
power >90% with 600 patients. 
 
Definition of populations for analysis 
Safety population 
All patients who receive at least one dose of study medication will be included in the safety analyses. 
Intent-to-treat population (ITT) 
All analyses will be performed according to the intent-to-treat principle, i.e. patients will be analysed 
according to the treatment arm they were assigned to by randomization. The ITT population will include 
all randomized patients. 
Full Analyzable Set (FAS) 
The FAS will include all randomized patients who:  
• 
received at least one dose of study treatment 
• 
and had at least one EDSS and TW25 assessment at visits V1/M-1 or V2/M0 

 
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• 
and had at least one post-baseline EDSS and TW25 assessment prior to study treatment 
discontinuation in the randomized double-blind study phase. 
Per Protocol population (PP) 
All patients of the ITT who receive at least one dose of study medication and with assessment of EDSS 
and TW25 at inclusion, randomization, V6/M12 and V7/M15, and without major protocol deviations. 
Statistical analyses will be performed on the ITT, FAS and PP populations as delineated in the Statistical 
Analysis Plan.   
General considerations 
Planned analyses will be performed using SAS®, version 9.2 or later, SAS Institute, Cary, Northern 
Carolina, USA. Descriptive analyses will be performed. Data will be displayed graphically using 
histograms and boxplots and summarized as follows: continuous variables by descriptive statistics 
(number of patients [N], mean, standard deviation, minimum, median and maximum); categorical data 
by absolute and relative frequencies (n and %).  
Quality assurance of the data and statistical analysis and the development of the statistical part of the 
study report will be made by the sponsor or designee.  
All clinical data recorded as verbatim into the eCRF will be encoded in MedDRA last version. 
 
Handling of Missing data 
For the primary endpoint analysis, patients with missing data precluding evaluation will be considered 
non-responders.  
For the secondary outcome measures, missing data will be adapted using the multiple imputation method 
derived from modelling the respective treatment arms. In sensitivity analyses the multiple imputation 
approach will be used where missing data will be conservatively imputed using the Gaussian distribution 
fitted on the available data of the placebo group at the same time point to that of missing data.  
Details on imputation methods and sensitivity analyses concerning the main and the secondary endpoints 
will be fully described in the SAP of the study. 
 
Multiplicity 
No multiplicity adjustment is considered necessary for the primary endpoint as there is a unique main 
criterion and two arms to be compared; therefore, there is only one confirmatory hypothesis to be tested 
with an alpha risk of 5%. 
However, secondary endpoints are hierarchically scaled by order of clinical importance and maintained 
to a few numbers in order to avoid multiplicity concerns. 
 
Efficacy evaluation 
 
Analysis of the primary endpoint 
The main objective of the trial is to demonstrate the superiority of MD1003 over placebo on the 
progressive multiple sclerosis, comparing the proportion of patients with a clinical improvement 
between the MD1003 and placebo groups. 

 
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A logistic regression will be fitted to estimate the treatment effect (odd-ratio of improved patients) using 
treatment, disease history (SPMS/PPMS), geographical region, and center as fixed factors (referred as 
the main logistic model in the following parts). 
Improvement is defined through the following composite outcome: 
• 
Decreased EDSS at M12 confirmed at M15 (defined as a decrease of at least 1 point if initial 
EDSS from 3.5 to 5.5 and of at least 0.5 point if initial EDSS between 6 and 6.5) compared to 
the best EDSS obtained at either the inclusion or randomization visits 
or  
• 
Improved TW25 of at least 20% at M12 and M15 compared to the best mean of the two TW25 
mean scores obtained at either the inclusion or randomization visits. 
It is required that in addition to overall statistical significance for the primary composite outcome, both 
elements of the composite outcome should be consistent with the overall outcome i.e. each component 
analysis must display a numerical advantage favouring the active arm. The numerical advantage does 
not have to demonstrate statistical significance with a p value < 0.05. 
The main logistic model will then be used for each component of the composite outcome (EDSS and 
TW25 responses) to complement the main analysis of the main endpoint. 
Sensitivity analyses of the main outcome will be further described in the SAP of the study, but they will 
particularly explore the potential influence of the following parameters on the estimate of the treatment 
effect: 
• 
Subjects with and without relapses 
• 
Subjects with and without steroid treatment during the study 
• 
Subjects with and without modification of their disease modifying therapy 
 
Analysis of secondary endpoints 
1. Time to EDSS progression confirmed at 12 weeks (of at least 1 point if initial EDSS from 3.5 
to 5.5 and of at least 0.5 point if initial EDSS from 6 to 6.5) will be graphically presented with 
survival curves. The median time to increase of EDSS and its 95% Confidence Interval in each 
treatment group, as well as the hazard ratio (test/control), will be estimated using a Cox-
regression model using treatment and disease history (SPMS/PPMS) as well as region as fixed 
effects. A patient without progression performing his last double-blind evaluation of the study 
(after the last patient reaches Month 15 or Month 27, whichever comes first) will be censored 
at this date for the purpose of the analysis. 
2. Comparison of CGI-I score (clinical global impression) at M15 evaluated both by the patient 
(SGI) and by the evaluating physician (CGI) will be performed using a Van Elteren test 
(stratified on disease history SPMS/PPMS). 
3. Mean change in TW25 between M0 and M15 will be performed using a Van Elteren test 
(stratified on disease history SPMS/PPMS). 
When applicable, the main endpoints will also be described and compared at M6, M9 and M12, to 
highlight a potential early effect of the treatment. Statistical analyses will be fully predefined in the SAP 
of the study 

 
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Analysis of exploratory endpoints 
All pre-planned analyses will be described in detail within the Statistical Analysis Plan. 
1. The brain MRI outcomes will be analysed between M0 and M15 (and between M0 and M27): 
• 
Mean percent thalamic volume change between M0 and M6, M0 and M15 (and between 
M0 and M27) will be performed using Mann-Whitney U test; 
• 
Mean percent brain volume change between M0 and M6, M0 and M15 (and between M0 
and M27) will be performed using Mann-Whitney U test; 
• 
Mean percent cortical grey matter volume change between M0 and M6, M0 and M15 (and 
between M0 and M27) will be performed using Mann-Whitney U test; 
• 
Mean brain water content by Pseudo T2 relaxation time change between M0 and M6, M0 
and M15 (and between M0 and M27) will be performed using Mann-Whitney U test; 
• 
Mean NAA/Cr change (in a subset of sites acquiring MRS) between M0 and M15 (and 
between M0 and M27) will be performed using Mann-Whitney U test. 
2. Remote monitoring of ambulatory activity between M0 and M15 (and between M0 and M27 
for patients on the double-blinded extension phase). Comparison of daily average step counts 
will be performed using Mann-Whitney U test. In addition, a MMRM (Mixed effect Model 
Repeat Measurement) will be performed as a sensitivity analysis 
3. Mean change in the Multiple Sclerosis Quality of Life-54 (MSQOL-54) and in the Caregiver 
health-related quality of life in Multiple Sclerosis (CAREQOL-MS) subscores and composite 
scores between M0 and M15 (and between M0 and M27 for patients on the extension double-
blinded phase) will be performed using Mann-Whitney U test. 
4. Mean change in subscores of the Kurtzke functional score between M0 and M15 (and between 
M0 and M27 for patients on the extension double-blinded phase) will be performed using Mann-
Whitney U test. 
5. Mean change in Symbol Digit Modalities Test (SDMT) between M0 and M15 (and between 
M0 and M27 for patients on the extension double-blinded phase) will be performed using Mann-
Whitney U test. 
 
Active drug extension analysis  
Patients on active drug in either Part 1 or Part 2 of the study will be followed principally for safety 
considerations. Efficacy measures such as EDSS and TW25 will be explored using descriptive statistics 
and time to major milestones.  
 
Safety evaluation 
The analysis will be based on the safety population and presented by treatment groups concerning the 
comparative phase of the study. An additional analysis will also describe the totality of the data of 
patients under active treatment. Safety analysis of Part 1 and Part 2 will be conducted in a similar 
fashion. More details are given in the study SAP.  
Study treatments exposure 
Exposure of treatments will be summarized for each period of the study (comparative/open). 
Adverse Events 

 
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Adverse events will be summarized by presenting the number and percentage of patients having an 
adverse event, having an adverse event in each body system, and each individual adverse event. 
Concomitant therapy 
All concomitant medications taken during this study will be listed by patient. 
Safety of MD1003 will be assessed by: 
1. Recording of adverse events in the two groups: descriptive analyses will be performed. 
2. Comparison of incidence of abnormal laboratory testing (haematology and biochemistry panel) 
a. CBC with differential 
b. Metabolic panel (fasting) 
c. Hepatic function panel 
d. Lipid panel (fasting) 
e. Thyroid panel 
3. ECG 
The assessment will be performed by the CSCL and include testing the effects on the QT/QTc interval. 
QTc interval will be calculated using Fridericia’s correction: QTc = QT/RR 0.33 
The QT/QTc interval data will be assessed both as analyses of central tendency (e.g., means, medians) 
and categorical analyses. 
For central tendency, the effect of MD1003 on the QT/QTc interval will be analyzed using the largest 
time-matched mean difference between the drug and placebo (baseline-adjusted) over the collection 
period 
For categorical analysis, QT/QTc interval data will be based on the number and percentage of patients 
meeting or exceeding some predefined upper limit values: 
• 
Absolute QTc interval prolongation  
o QTc interval > 450 
o QTc interval > 480 
o QTc interval > 500 
• 
Change from baseline in QTc interval: 
o QTc interval increases from baseline >30 
o QTc interval increases from baseline >60 
• 
Statements regarding other ECG anomalies (rhythm, conduction and repolarization) and their 
change from baseline will be reported and analysed.  
4. Brain MRI: 
Analyses will be performed at each visit: 
• 
Comparison of proportion of patients with at least one new/enlarging T2-weighted MS lesion 
(at M6 and M15 in group 2 (300 mg/day) versus group 1 (placebo): 95% Exact confidence 
intervals and Fisher's exact test. 
• 
Mean number of new/enlarging T2-weighted MS lesions per patient at M6 and M15 in group 2 
(300 mg/day) versus group 1 (placebo): Mann-Whitney U test. 
• 
Comparison of proportion of patients with at least one gadolinium enhancing lesion on the T1-
weighted sequence at M6 and M15 in group 2 (300 mg/day) versus group 1 (placebo): 95% 
Exact confidence intervals and Fisher's exact test. 
• 
Mean number of gadolinium enhancing lesions on the T1-weighted sequence at M6 and M15 
in group 2 (300 mg/day) versus group 1 (placebo): Mann-Whitney U test. 

 
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• 
Mean number of new enlarging T2-weighted lesions per patient at M6 and M15 in group 2 (300 
mg/day) versus group 1 (placebo): Mann-Whitney U test. 
• 
Mean of T2-weighted lesion volume per patient at M6 and M15 in group 2 (300 mg/day) versus 
group 1 (placebo): Mann-Whitney U test. 
• 
Mean of non-enhancing T1-weighted lesion volume per patient at M6 and M15 in group 2 (300 
mg/day) versus group 1 (placebo): Mann-Whitney U test. 
 
Interim analysis and data safety monitoring committee 
No interim analysis is planned as part of this study. 
The principal analysis is planned before the end of the entire trial, on the data collected during the 
double-blind 15-month phase. 
In the extension phase of the study, the active study treatment will be dispensed in an open label fashion. 
Although the study treatment will be unblinded in the final months of the study, the study investigators, 
center staff and patients will remain masked to the prior randomized treatment assignments until the 27-
month study has been completed. 
DSMB can help sponsor and investigators of the study regarding decisions to be taken during the study 
for which independent judgment is desirable. DSMB may for this purpose: 
• 
Recommend continue the study as planned 
• 
recommend further analysis for the interpretation of the safety results; 
• 
recommend minor or major modifications of the protocol based on safety issues and/or for the 
extension phase, made necessary because of the results of this principal analysis; 
• 
recommend early termination of the trial for safety or efficacy reasons 
 
Analysis by subgroups 
Some analyses in subgroups, defined by the following factors, will be performed using forest-plots 
representation, in order to assess the homogeneity of treatment effect concerning the main endpoint and 
the 3 secondary endpoints: 
• 
Region: North America/Australia vs Europe 
• 
Disease history (SPMS/PPMS) 
• 
EDSS at baseline: “3.5 to 5.5” vs “6 or above” 
• 
Age 
• 
Sex 
• 
Disease duration 
• 
Concomitant physical therapy 
• 
BMI 
• 
Use of concomitant Disease Modifying Therapies 
• 
Use of concomitant myorelaxants 
5 
PRESTUDY DOCUMENTATION 
The investigator must provide the sponsor with the following documents BEFORE enrolling any 
patients: 
• 
Completed and signed statement of investigator form (i.e., FDA form 1572). 

 
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All applicable country-specific regulatory forms. 
• 
Current signed and dated curriculum vitae for the principal investigator, sub-investigators, 
determination of eligibility, efficacy, or safety) who are listed on the statement of investigator 
form (i.e., FDA form 1572). 
• 
Copy of the IRB/IEC approval letter for the protocol and informed consent. All advertising, 
recruitment, and other written information provided to the subject must be approved by the 
IRB/IEC.  Written assurance of continuing approval (at least annually) and, where required, a 
copy of the annual progress report submitted to the IRB/IEC must also be provided to the 
sponsor. 
• 
Copy of the IRB/IEC-approved informed consent document to be used. 
• 
If applicable, a list of the IRB/IEC members and their qualifications and a description of the 
committee’s working procedure. 
• 
Copy of the protocol sign-off page signed by the investigator. 
• 
Fully executed Clinical Site Agreement. 
• 
If applicable, a financial disclosure form. 
6 
INFORMED CONSENT 
The investigator is responsible for the safety and protection of the patients by following all applicable 
regulations. These regulations are available upon request from the sponsor or designee. The informed 
consent document(s) used during the informed consent process must be reviewed by the sponsor, 
approved by the IRB/IEC, and available for inspection.  
Before any protocol-required procedures are performed, a subject must: 
• 
Be informed of all pertinent aspects of the study and elements of informed consent. 
• 
Be given time to ask questions and time to consider the decision to participate. 
• 
Voluntarily agree to participate in the study. 
• 
Sign and date an IRB/IEC-approved informed consent document 
The investigator must explain to each patient (or legally authorized representative) the nature of the 
study, its purpose, the procedures involved, the expected duration, the potential risks and benefits 
involved and any discomfort it may entail. Each subject must be informed that participation in the study 
is voluntary and that he/she may withdraw from the study at any time and that withdrawal of consent 
will not affect his/her subsequent medical treatment or relationship with the treating physician. 
This informed consent should be given by means of a standard written statement, in non-technical 
language. The subject should read and consider the statement before signing and dating it and should be 
given a copy of the signed document. 
7 
DIRECT ACCESS, DATA HANDLING AND RECORD-KEEPING 
 
 Investigator  
The investigator will permit study-related monitoring, audits, IRB/IEC review, and regulatory 
inspections by providing direct access to source data and documents. 
All information will be recorded on source documents. The eCRFs must be fully completed and include 
all required data. All eCRF data must be submitted to the sponsor throughout and at the end of the study. 
Remote data capture will be used to record and transmit data electronically to the sponsor or designee. 
The eCRF must be completed within 5 days after each visit. 

 
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If an investigator retires, relocates, or otherwise withdraws from conducting the study, the investigator 
must notify the sponsor to agree upon an acceptable storage solution. Regulatory agencies will be 
notified with the appropriate documentation. An updated statement of investigator form (i.e., US Food 
and Drug Administration [FDA] form 1572) will be filed with the sponsor or designee for any changes 
in the study personnel reported in the current statement of investigator form. 
Investigators must notify their IRB/IEC of protocol violations in accordance with local regulatory and 
IRB/IEC requirements. 
The investigator will allow the monitor to visit the site facilities where the study will take place in order 
to ensure that the site complies with the requirements of the protocol and the GCP. 
 
 Sponsor 
The CRF data are stored in a database and processed electronically. The sponsor or designee reviews 
the data for safety information. The data are reviewed for legibility, completeness, and logical 
consistency. Automated validation programs identify missing data, out-of-range data, and other data 
inconsistencies. Requests for data clarification are forwarded to the investigative site for resolution. 
At regular intervals during the study, the monitor will visit the site, to check the completeness of 
patients’ records, the accuracy of entries on the eCRF, the adherence to protocol and to Good Clinical 
Practice, the progress of enrolment, and to ensure that study medication is being stored and accounted 
for according specifications. 
The investigator and key trial personnel must be available to assists the monitor during these visits. 
 
 Source document requirements 
The investigator must give the monitor direct access to relevant hospital or clinical records, to confirm 
their consistency with the eCRF data entries. 
The consent form will include a statement by which the patients allows the sponsor's duly authorized 
personnel (trial monitoring team) to have direct access to source data which supports data on the 
electronic case report forms. These personnel, bound by professional secrecy, will not disclose any 
personal identity or personal medical information. 
 
 The use and completion of electronic Case Report Forms (eCRFs) 
It is the responsibility of the Investigator to maintain adequate and accurate eCRFs in recording all 
observations and other data pertinent to the clinical investigation on ongoing basis into the eCRFs 
designed by an eCRF provider. 
1. CRFs are implemented electronically (eCRF), using third party software application that is fully 
validated and conforms to regulatory requirements for electronic data capture, where applicable.  
2. The eCRF enables data capture via an on-line system on a personal computer (PC). 
• 
Designated staff at participating sites shall enter data required by the protocol into the eCRF.  
• 
All access to the system is administered by the eCRF administrator and will only be granted after 
appropriate and documented training. A dedicated account (with login and password) will be 
provided at each user by the eCRF administrator. 
• 
Specific guidelines for data completion will be available. 
• 
The data will be recorded via the application into a central database over encrypted lines using the 
SSL (Secure Sockets Layer) protocol.  

 
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Personal health identifiers are stored in the central database in encrypted form. 
• 
All entries and modifications of data are logged in an audit trail. 
• 
Electronic signatures will be used where required. 
• 
Automated validation program check for data discrepancies in the eCRFs will be implemented 
where appropriate. 
8 
ADMINISTRATIVE RULES 
 
 Curriculum vitae 
An updated copy of the curriculum vitae of the investigator will be provided to the sponsor prior to the 
beginning of the study. An updated CV should be collected during the course of the study at least every 
2 years. 
 
 Secrecy agreement 
By signing the protocol, the investigator agrees to keep all information provided by the sponsor in strict 
confidence and to request similar confidentiality from his/her staff and the IRB/EC. Study documents 
provided by the sponsor will be stored appropriately to ensure their confidentiality. 
The information provided by the sponsor to the investigator may not be disclosed to others without direct 
written authorization from the sponsor, except to the extent necessary to obtain informed consent from 
patients who wish to participate in the trial. 
 
 Protocol amendments 
Any change in the study plan requires a protocol amendment. An investigator must not make any 
changes to the study without IRB/IEC and sponsor approval except when necessary to eliminate 
apparent immediate hazards to the patients. A protocol change intended to eliminate an apparent 
immediate hazard to patients may be implemented immediately, but the change must then be 
documented in an amendment, reported to the IRB/IEC within 5 working days, and submitted to the 
appropriate regulatory agency in the required time frame. All protocol amendments must be reviewed 
and approved by the sponsor and investigator. 
 
 Record retention in investigation center(s) 
The investigator shall retain and preserve 1 copy of all data collected or databases generated in the 
course of the study, specifically including but not limited to those defined by GCP as essential, for the 
longer of (a) 2 years after the last marketing authorization for the study drug has been approved or the 
sponsor has discontinued its research with respect to such drug or (b) such longer period as required by 
applicable global regulatory requirements. At the end of such period, the investigator shall notify the 
sponsor in writing of his or her intent to destroy all such material. The sponsor shall have 30 days to 
respond to the investigator’s notice, and the sponsor shall have a further opportunity to retain such 
materials at the sponsor’s expense. 
 
 Insurance compensation 
The sponsor certifies having taken out a liability insurance policy which covers the investigators and his 
co-workers and which is in accordance with the local laws and requirements. 
A certificate of insurance will be provided to the investigator. 

 
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 Quality control and assurance  
The sponsor or designee performs quality control and assurance checks on all clinical studies that it 
sponsors. Before enrolling any patients in this study, sponsor personnel or designee and the investigator 
review the protocol, the investigator’s brochure, the eCRFs and instructions for their completion, the 
procedure for obtaining informed consent, and the procedure for reporting AEs and SAEs. A qualified 
representative of the sponsor will monitor the conduct of the study. During these site visits, information 
recorded in the eCRFs is verified against source documents. 
 
Ownership of results - Publication 
The results from this study are the exclusive property of the sponsor. 
No information concerning the study, or its results may be published or communicated without the prior 
written and signed agreement of the sponsor. 
The sponsor’s decision to publish or otherwise publicly communicate the results of this study will be 
made in accordance with all applicable laws, regulations, and sponsor policies regarding publication 
and communication of clinical study results. 
 
Study Specific Committees  
 
Scientific and Steering committee 
Members: 
• 
Prof. Fred LUBLIN, New York, USA (Chairman); 
• 
Prof. Bruce CREE, San Francisco, USA; 
• 
Prof Gary CUTTER, Birmingham, USA; 
• 
Prof Jerry WOLINSKY, Houston, USA; 
• 
Prof. Mark FREEDMAN, Ottawa, Canada; 
• 
Prof. Giancarlo COMI, Milan, Italy; 
• 
Prof. Gavin GIOVANNONI, London, UK; 
• 
Prof. Hans-Peter HARTUNG, Düsseldorf, Germany 
Missions:  
• 
Defining the study objective, designing the study protocol, and proposing protocol 
amendments during the study.  
• 
Defining the general organization, maintaining the quality of study conduct, 
• 
Analysing the information provided by the Adjudication Committee (AC) and the Data 
Safety Monitoring Board (DSMB), 
• 
Ongoing monitoring of individual toxicities and adverse events,  
• 
Writing study publications  
 
 
 

 
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Adjudication Committee 
For independent adjudication, members are not involved at all as investigators, sub-investigators or any 
tasks related to the recruitment in the SPI2 clinical trial. 
Members: 
• 
Prof. Robert P. LISAK, Detroit, USA (Chairman); 
• 
Dr. Jennifer GRAVES, San Francisco, USA; 
• 
Dr. Stephen KRIEGER, New York, USA; 
• 
Dr. Rana K. ZABAD, Omaha, USA; 
• 
Dr. Scott NEWSOME, Baltimore, USA. 
Missions: 
• 
To validate eligibility of patients especially regarding the documentation of disease 
progression prior inclusion. 
• 
To analyse relapsing episodes and categorize these AEs as per protocol definitions (§ 3.2). 
 
Data Safety Monitoring Board (DSMB) 
DSMB is an independent advisory committee. It will be set-up and managed by the CRO. 
Members: 
• 
Prof. Stephen REINGOLD, Salisbury, USA; 
• 
Prof. Pierre DUQUETTE, Montreal, Canada; 
• 
Prof. Tobias DERFUSS, Basel, Switzerland; 
• 
Prof. Franz FAZEKAS, Graz, Austria; 
• 
Prof. Maria Pia SORMANI, Genoa, Italy 
 
Missions 
• 
To ensure patients safety and rights throughout the study, 
• 
To preserve the scientific and ethical integrity of the study.  
• 
To provide the sponsor with recommendations on the conduct of the study. 
• 
To help sponsor and investigators regarding decisions to be taken during the study when 
independent judgment is desirable, such as:  
- 
recommend further analysis to the interpretation of the results of an interim review of 
data 
- 
recommend minor or major modifications of the protocol became necessary because 
of recruitment, or follow-up testing or, to take account of new scientific data 
- 
recommend early termination of the trial. 
• 
To advise on the continuation of the trial in case of SUSARs. 

 
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9 
BIBLIOGRAPHIC REFERENCES 
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Clegg S, Nielsen C, Fox NC, Wilkie D, Nicholas JM, Calder VL, Greenwood J, Frost C, Nicholas R 
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Confavreux C, Vukusic S (2006) Natural history of multiple sclerosis: a unifying concept. Brain : a 
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Debs R, Depienne C, Rastetter A, Bellanger A, Degos B, Galanaud D, Keren B, Lyon-Caen O, Brice A, 
Sedel F (2010) Biotin-responsive basal ganglia disease in ethnic Europeans with novel SLC19A3 
mutations. Archives of neurology 67: 126-30 
Foster DW (2012) Malonyl-CoA: the regulator of fatty acid synthesis and oxidation. J Clin Invest 122: 
1958-9 
Goodman AD, Brown TR, Krupp LB, Schapiro RT, Schwid SR, Cohen R, Marinucci LN, Blight AR, 
Fampridine MSFI (2009) Sustained-release oral fampridine in multiple sclerosis: a randomised, double-
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Kapoor R, Furby J, Hayton T, Smith KJ, Altmann DR, Brenner R, Chataway J, Hughes RA, Miller DH 
(2010) Lamotrigine for neuroprotection in secondary progressive multiple sclerosis: a randomised, 
double-blind, placebo-controlled, parallel-group trial. Lancet Neurol 9: 681-8 
Kurtzke JF (1983) Rating neurologic impairment in multiple sclerosis: an expanded disability status 
scale (EDSS). Neurology 33: 1444-52 
Kwok JS, Chan IH, Chan MH (2012) Biotin interference on TSH and free thyroid hormone 
measurement. Pathology 44: 278-80 
Lublin FD, Reingold SC (1996) Defining the clinical course of multiple sclerosis: results of an 
international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials 
of New Agents in Multiple Sclerosis. Neurology 46: 907-11 
Lublin FD, Reingold SC, Cohen JA, Cutter GR, Sorensen PS, Thompson AJ, Wolinsky JS, Balcer LJ, 
Banwell B, Barkhof F, Bebo B, Jr., Calabresi PA, Clanet M, Comi G, Fox RJ, Freedman MS, Goodman 
AD, Inglese M, Kappos L, Kieseier BC et al. (2014) Defining the clinical course of multiple sclerosis: 
the 2013 revisions. Neurology 83: 278-86 
Luessi F, Siffrin V, Zipp F (2012) Neurodegeneration in multiple sclerosis: novel treatment strategies. 
Expert Rev Neurother 12: 1061-76; quiz 1077 
McGarry JD, Takabayashi Y, Foster DW (1978) The role of malonyl-coa in the coordination of fatty 
acid synthesis and oxidation in isolated rat hepatocytes. J Biol Chem 253: 8294-300 
Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG (2000) Multiple sclerosis. The New 
England journal of medicine 343: 938-52 
Ontaneda D, Fox RJ, Chataway J (2015) Clinical trials in progressive multiple sclerosis: lessons learned 
and future perspectives. Lancet Neurol 14: 208-223 
Ozand PT, Gascon GG, Al Essa M, Joshi S, Al Jishi E, Bakheet S, Al Watban J, Al-Kawi MZ, Dabbagh 
O (1998) Biotin-responsive basal ganglia disease: a novel entity. Brain : a journal of neurology 121 ( Pt 
7): 1267-79 

 
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Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, Fujihara K, Havrdova E, 
Hutchinson M, Kappos L, Lublin FD, Montalban X, O'Connor P, Sandberg-Wollheim M, Thompson 
AJ, Waubant E, Weinshenker B, Wolinsky JS (2011) Diagnostic criteria for multiple sclerosis: 2010 
revisions to the McDonald criteria. Ann Neurol 69: 292-302 
Sedel F, Bernard D, Mock DM, Tourbah A (2015a) Targeting demyelination and virtual hypoxia with 
high-dose biotin as a treatment for progressive multiple sclerosis. Neuropharmacology  
Sedel F, Papeix C, Bellanger A, Touitou V, Lebrun-Frenay C, Galanaud D, Gout O, Lyon-Caen O, 
Tourbah A (2015b) High doses of biotin in chronic progressive multiple sclerosis: a pilot study. Multiple 
sclerosis and related disorders 4: 159-69 
Sotgiu S, Pugliatti M, Fois ML, Arru G, Sanna A, Sotgiu MA, Rosati G (2004) Genes, environment, 
and susceptibility to multiple sclerosis. Neurobiol Dis 17: 131-43 
Stys PK, Zamponi GW, van Minnen J, Geurts JJ (2012) Will the real multiple sclerosis please stand up? 
Nat Rev Neurosci 13: 507-14 
Subramanian VS, Marchant JS, Said HM (2006) Biotin-responsive basal ganglia disease-linked 
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Cell Physiol 291: C851-9 
Tong L (2013) Structure and function of biotin-dependent carboxylases. Cell Mol Life Sci 70: 863-91 
Vickrey BG, Hays RD, Genovese BJ, Myers LW, Ellison GW (1997) Comparison of a generic to 
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Vickrey BG, Hays RD, Harooni R, Myers LW, Ellison GW (1995) A health-related quality of life 
measure for multiple sclerosis. Qual Life Res 4: 187-206 
Wijeratne NG, Doery JC, Lu ZX (2012) Positive and negative interference in immunoassays following 
biotin ingestion: a pharmacokinetic study. Pathology 44: 674-5 
Zempleni J, Wijeratne SS, Hassan YI (2009) Biotin. Biofactors 35: 36-46 
Zeng WQ, Al-Yamani E, Acierno JS, Jr., Slaugenhaupt S, Gillis T, MacDonald ME, Ozand PT, Gusella 
JF (2005) Biotin-responsive basal ganglia disease maps to 2q36.3 and is due to mutations in SLC19A3. 
Am J Hum Genet 77: 16-26 

 
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10 APPENDICES 
Annex 1: Revised Mc Donald criteria 
 
 

 
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Annex 2: Neurostatus 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Annex 3: Relapse assessment questionnaire 

 
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Annex 4: SPI2 Patient Alert Card 
 
 
 
 

 
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Annex 5: Multiple Sclerosis Quality of Life-54 (MSQOL-54) 
 
 
 
 
 

 
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Annex 6: Caregiver health-related quality of life in Multiple Sclerosis – CAREQOL-MS  
 
Caregiver health-related quality of life (HRQOL) in Multiple Sclerosis – CAREQOL-MS 
Questionnaire* 
1. I worry about the thoughts regarding multiple sclerosis of the person whom I care for. 
2. I reflect about the suffering the limited mobility brings to the person with multiple sclerosis whom 
I care for. 
3. Moving and traveling with the person with multiple sclerosis whom I care for is complicated for 
me. 
4. I worry about the fatigue of the person with multiple sclerosis whom I care for. 
5. The fatigue of the person with multiple sclerosis whom I care for poses a greater physical burden 
to me. 
6. The personal hygiene of the person with multiple sclerosis whom I care for proves complicated. 
7. I feel alone regarding my tasks of caring for, watching, and supporting a person with multiple 
sclerosis. 
8. I believe that my situation might improve through the collaboration of other caregivers. 
9. Caring for a person with multiple sclerosis leaves me with no time for caring for the rest of my 
family. 
10. Multiple sclerosis has affected my social life. 
11. Taking care of a person with multiple sclerosis has meant a change in my lifestyle. 
12. I miss the company of persons outside the family circle who are acquainted with the disease, so 
I can share my current situation with them. 
13. The attitude of the person with multiple sclerosis whom I care for elicits mood changes in me. 
14. The nervousness of the person with multiple sclerosis whom I care for irritates me. 
15. I feel sad as a consequence of the multiple sclerosis of the person whom I care for. 
16. Multiple sclerosis has affected my relationship with my partner, either regarding our sexual or 
emotional relationship. 
17. I believe that some psychological aid would help me provide better care for the person with 
multiple sclerosis. 
18. I have been suffering from sleep disturbances since I learned that the person whom I care for 
suffers from multiple sclerosis. 
19. The evening care of the person with multiple sclerosis whom I care for prevents me from resting 
at night. 
20. I am scared about the progress and the consequences of multiple sclerosis. 
21. My own health has worsened over the course of this year. 
22. Ever since the person whom I care for started suffering from multiple sclerosis, I devote less time 
to my own personal appearance and wellbeing. 
23. The care of the person with multiple sclerosis has affected my work life. 
24. The multiple sclerosis of the person whom I care for has impacted on my family’s financial 
situation 

 
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Annex 7: Columbia-Suicide Severity Rating Scale (C-SSRS) 
 

 
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Annex 8: World Medical Association Declaration of Helsinki (2013 version) 
WMA Declaration of Helsinki - Ethical Principles for Medical Research 
Involving Human Subjects (2013 version) 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 
and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
 
 
Preamble 
1.         The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement 
of ethical principles for medical research involving human subjects, including research on identifiable 
human material and data. 
            The Declaration is intended to be read as a whole and each of its constituent paragraphs should 
be applied with consideration of all other relevant paragraphs. 
2.         Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians. 
The WMA encourages others who are involved in medical research involving human subjects to adopt 
these principles.  
General Principles 
3.         The Declaration of Geneva of the WMA binds the physician with the words, “The health of my 
patient will be my first consideration,” and the International Code of Medical Ethics declares that, “A 
physician shall act in the patient's best interest when providing medical care.” 
4.         It is the duty of the physician to promote and safeguard the health, well-being and rights of 
patients, including those who are involved in medical research. The physician's knowledge and 
conscience are dedicated to the fulfilment of this duty. 
5.         Medical progress is based on research that ultimately must include studies involving human 
subjects. 
6.         The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic interventions 
(methods, procedures and treatments). Even the best proven interventions must be evaluated continually 
through research for their safety, effectiveness, efficiency, accessibility and quality. 
7.         Medical research is subject to ethical standards that promote and ensure respect for all human 
subjects and protect their health and rights. 

 
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8.         While the primary purpose of medical research is to generate new knowledge, this goal can never 
take precedence over the rights and interests of individual research subjects. 
9.         It is the duty of physicians who are involved in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal information of 
research subjects. The responsibility for the protection of research subjects must always rest with the 
physician or other health care professionals and never with the research subjects, even though they have 
given consent. 
10.       Physicians must consider the ethical, legal and regulatory norms and standards for research 
involving human subjects in their own countries as well as applicable international norms and standards. 
No national or international ethical, legal or regulatory requirement should reduce or eliminate any of 
the protections for research subjects set forth in this Declaration. 
11.       Medical research should be conducted in a manner that minimises possible harm to the 
environment. 
12.       Medical research involving human subjects must be conducted only by individuals with the 
appropriate ethics and scientific education, training and qualifications. Research on patients or healthy 
volunteers requires the supervision of a competent and appropriately qualified physician or other health 
care professional. 
13.       Groups that are underrepresented in medical research should be provided appropriate access to 
participation in research. 
14.       Physicians who combine medical research with medical care should involve their patients in 
research only to the extent that this is justified by its potential preventive, diagnostic or therapeutic value 
and if the physician has good reason to believe that participation in the research study will not adversely 
affect the health of the patients who serve as research subjects. 
15.       Appropriate compensation and treatment for subjects who are harmed as a result of participating 
in research must be ensured. 
Risks, Burdens and Benefits  
16.       In medical practice and in medical research, most interventions involve risks and burdens. 
           Medical research involving human subjects may only be conducted if the importance of the 
objective outweighs the risks and burdens to the research subjects. 
17.       All medical research involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and groups involved in the research in comparison with 
foreseeable benefits to them and to other individuals or groups affected by the condition under 
investigation. 
           Measures to minimise the risks must be implemented. The risks must be continuously monitored, 
assessed and documented by the researcher.  
18.       Physicians may not be involved in a research study involving human subjects unless they are 
confident that the risks have been adequately assessed and can be satisfactorily managed. 
           When the risks are found to outweigh the potential benefits or when there is conclusive proof of 
definitive outcomes, physicians must assess whether to continue, modify or immediately stop the study.            
Vulnerable Groups and Individuals 
19.       Some groups and individuals are particularly vulnerable and may have an increased likelihood 
of being wronged or of incurring additional harm. 
           All vulnerable groups and individuals should receive specifically considered protection. 
20.       Medical research with a vulnerable group is only justified if the research is responsive to the 
health needs or priorities of this group and the research cannot be carried out in a non-vulnerable group. 

 
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In addition, this group should stand to benefit from the knowledge, practices or interventions that result 
from the research. 
Scientific Requirements and Research Protocols  
21.       Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources of 
information, and adequate laboratory and, as appropriate, animal experimentation. The welfare of 
animals used for research must be respected. 
22.       The design and performance of each research study involving human subjects must be clearly 
described and justified in a research protocol. 
           The protocol should contain a statement of the ethical considerations involved and should 
indicate how the principles in this Declaration have been addressed. The protocol should include 
information regarding funding, sponsors, institutional affiliations, potential conflicts of interest, 
incentives for subjects and information regarding provisions for treating and/or compensating subjects 
who are harmed as a consequence of participation in the research study. 
           In clinical trials, the protocol must also describe appropriate arrangements for post-trial 
provisions. 
Research Ethics Committees 
23.       The research protocol must be submitted for consideration, comment, guidance and approval to 
the concerned research ethics committee before the study begins. This committee must be transparent 
in its functioning, must be independent of the researcher, the sponsor and any other undue influence and 
must be duly qualified. It must take into consideration the laws and regulations of the country or 
countries in which the research is to be performed as well as applicable international norms and 
standards but these must not be allowed to reduce or eliminate any of the protections for research 
subjects set forth in this Declaration.  
           The committee must have the right to monitor ongoing studies. The researcher must provide 
monitoring information to the committee, especially information about any serious adverse events. No 
amendment to the protocol may be made without consideration and approval by the committee. After 
the end of the study, the researchers must submit a final report to the committee containing a summary 
of the study’s findings and conclusions.  
Privacy and Confidentiality  
24.       Every precaution must be taken to protect the privacy of research subjects and the confidentiality 
of their personal information. 
Informed Consent  
25.       Participation by individuals capable of giving informed consent as subjects in medical research 
must be voluntary. Although it may be appropriate to consult family members or community leaders, 
no individual capable of giving informed consent may be enrolled in a research study unless he or she 
freely agrees. 
26.       In medical research involving human subjects capable of giving informed consent, each potential 
subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts of 
interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the study 
and the discomfort it may entail, post-study provisions and any other relevant aspects of the study. The 
potential subject must be informed of the right to refuse to participate in the study or to withdraw consent 
to participate at any time without reprisal. Special attention should be given to the specific information 
needs of individual potential subjects as well as to the methods used to deliver the information. 
           After ensuring that the potential subject has understood the information, the physician or another 
appropriately qualified individual must then seek the potential subject’s freely-given informed consent, 

 
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preferably in writing. If the consent cannot be expressed in writing, the non-written consent must be 
formally documented and witnessed.       
           All medical research subjects should be given the option of being informed about the general 
outcome and results of the study. 
27.       When seeking informed consent for participation in a research study the physician must be 
particularly cautious if the potential subject is in a dependent relationship with the physician or may 
consent under duress. In such situations the informed consent must be sought by an appropriately 
qualified individual who is completely independent of this relationship. 
28.       For a potential research subject who is incapable of giving informed consent, the physician must 
seek informed consent from the legally authorised representative. These individuals must not be 
included in a research study that has no likelihood of benefit for them unless it is intended to promote 
the health of the group represented by the potential subject, the research cannot instead be performed 
with persons capable of providing informed consent, and the research entails only minimal risk and 
minimal burden. 
29.       When a potential research subject who is deemed incapable of giving informed consent is able 
to give assent to decisions about participation in research, the physician must seek that assent in addition 
to the consent of the legally authorised representative. The potential subject’s dissent should be 
respected. 
30.       Research involving subjects who are physically or mentally incapable of giving consent, for 
example, unconscious patients, may be done only if the physical or mental condition that prevents giving 
informed consent is a necessary characteristic of the research group. In such circumstances the physician 
must seek informed consent from the legally authorised representative. If no such representative is 
available and if the research cannot be delayed, the study may proceed without informed consent 
provided that the specific reasons for involving subjects with a condition that renders them unable to 
give informed consent have been stated in the research protocol and the study has been approved by a 
research ethics committee. Consent to remain in the research must be obtained as soon as possible from 
the subject or a legally authorised representative. 
31.       The physician must fully inform the patient which aspects of their care are related to the research. 
The refusal of a patient to participate in a study or the patient’s decision to withdraw from the study 
must never adversely affect the patient-physician relationship. 
32.       For medical research using identifiable human material or data, such as research on material or 
data contained in biobanks or similar repositories, physicians must seek informed consent for its 
collection, storage and/or reuse. There may be exceptional situations where consent would be impossible 
or impracticable to obtain for such research. In such situations the research may be done only after 
consideration and approval of a research ethics committee. 
Use of Placebo 
33.       The benefits, risks, burdens and effectiveness of a new intervention must be tested against those 
of the best proven intervention(s), except in the following circumstances: 
           Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or 
           Where for compelling and scientifically sound methodological reasons the use of any intervention 
less effective than the best proven one, the use of placebo, or no intervention is necessary to determine 
the efficacy or safety of an intervention  
           and the patients who receive any intervention less effective than the best proven one, placebo, or 
no intervention will not be subject to additional risks of serious or irreversible harm as a result of not 
receiving the best proven intervention.  
           Extreme care must be taken to avoid abuse of this option. 

 
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Post-Trial Provisions 
34.       In advance of a clinical trial, sponsors, researchers and host country governments should make 
provisions for post-trial access for all participants who still need an intervention identified as beneficial 
in the trial. This information must also be disclosed to participants during the informed consent process. 
Research Registration and Publication and Dissemination of Results 
35.       Every research study involving human subjects must be registered in a publicly accessible 
database before recruitment of the first subject. 
36.       Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to 
the publication and dissemination of the results of research. Researchers have a duty to make publicly 
available the results of their research on human subjects and are accountable for the completeness and 
accuracy of their reports. All parties should adhere to accepted guidelines for ethical reporting. Negative 
and inconclusive as well as positive results must be published or otherwise made publicly available. 
Sources of funding, institutional affiliations and conflicts of interest must be declared in the publication. 
Reports of research not in accordance with the principles of this Declaration should not be accepted for 
publication. 
Unproven Interventions in Clinical Practice 
37.       In the treatment of an individual patient, where proven interventions do not exist or other known 
interventions have been ineffective, the physician, after seeking expert advice, with informed consent 
from the patient or a legally authorised representative, may use an unproven intervention if in the 
physician's judgement it offers hope of saving life, re-establishing health or alleviating suffering. This 
intervention should subsequently be made the object of research, designed to evaluate its safety and 
efficacy. In all cases, new information must be recorded and, where appropriate, made publicly 
available.