Clinical trial NCT02936037
Conditions: Multiple Sclerosis
Keywords: progressive multiple sclerosis MS EDSS TW25 multiple sclerosis
Sponsor: MedDay Pharmaceuticals SA
Start date: 2016-12-01; Completion date: 2020-04-23
Enrollment: 642 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to demonstrate the superiority of MD1003 over placebo in the disability of patients suffering from progressive multiple sclerosis and especially those with gait impairment.

Detailed description:

Arms: arm 1: Placebo capsule, 1 capsule tid (morning,noon and evening) for 15 months and up to 27 months. arm 2: MD1003 capsule, 1 capsule tid (morning,noon and evening) for 15 months and up to 27 months.
Interventions: intervention 1: MD1003 100mg capsule intervention 2: PLACEBO
Intervention descriptions: intervention 1: None intervention 2: an inactive substance

Protocol documents:
Prot_000.pdf: 
 
NOTICE: Part of all the information in this document may be unpublished and should be treated as 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 




 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
2/119 
CONFIDENTIAL 
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) 
 
 
 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
3/119 
CONFIDENTIAL 
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 
 
 
 
 
 
 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
4/119 
CONFIDENTIAL 
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. 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
5/119 
CONFIDENTIAL 
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 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
6/119 
CONFIDENTIAL 
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  
 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
7/119 
CONFIDENTIAL 
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 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
8/119 
CONFIDENTIAL 
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  


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
9/119 
CONFIDENTIAL 
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 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
10/119 
CONFIDENTIAL 
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 
 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
11/119 
CONFIDENTIAL 
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 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
12/119 
CONFIDENTIAL 
 
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 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
13/119 
CONFIDENTIAL 
 
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 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
14/119 
CONFIDENTIAL 
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 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
15/119 
CONFIDENTIAL 
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.  
 
 
 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
16/119 
CONFIDENTIAL 
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) 
 
 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
17/119 
CONFIDENTIAL 
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) 
 
 
 
 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
18/119 
CONFIDENTIAL 
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.  


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
19/119 
CONFIDENTIAL 
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): 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
20/119 
CONFIDENTIAL 
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
-0.1
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)


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
21/119 
CONFIDENTIAL 
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. 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
22/119 
CONFIDENTIAL 
• 
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. 
-0.14
-0.12
-0.1
-0.08
-0.06
-0.04
-0.02
0
0.02
0.04
0.06
0.08
0.1
0months
3months
6months
9months 12months
MD1003(n=24)
Placebo(n=7)
-0.18
-0.16
-0.14
-0.12
-0.1
-0.08
-0.06
-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 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
23/119 
CONFIDENTIAL 
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: 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
24/119 
CONFIDENTIAL 
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. 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
25/119 
CONFIDENTIAL 
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.  


 
SPI2 study 
 
CLINICAL TRIAL PROTOCOL 
 
 
 
Version 4 dated 12-Nov-2018 
 
 
                                                         26/119 
 
 
 
 
                       CONFIDENTIAL 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
27/119 
CONFIDENTIAL 
 
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. 
 
 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
28/119 
CONFIDENTIAL 
 
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  


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
29/119 
CONFIDENTIAL 
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” 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
30/119 
CONFIDENTIAL 
 
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 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
31/119 
CONFIDENTIAL 
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.  


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
32/119 
CONFIDENTIAL 
 
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 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
33/119 
CONFIDENTIAL 
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. 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
34/119 
CONFIDENTIAL 
 
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.  


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
35/119 
CONFIDENTIAL 
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). 
 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
36/119 
CONFIDENTIAL 
• 
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. 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
37/119 
CONFIDENTIAL 
 
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. 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
38/119 
CONFIDENTIAL 
 
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. 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
39/119 
CONFIDENTIAL 
 
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. 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
40/119 
CONFIDENTIAL 
 
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. 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
41/119 
CONFIDENTIAL 
 
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. 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
42/119 
CONFIDENTIAL 
 
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.  


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
43/119 
CONFIDENTIAL 
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 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
44/119 
CONFIDENTIAL 
• 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 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
45/119 
CONFIDENTIAL 
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 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
46/119 
CONFIDENTIAL 
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 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
47/119 
CONFIDENTIAL 
• 
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 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
48/119 
CONFIDENTIAL 
• 
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 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
49/119 
CONFIDENTIAL 
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 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
50/119 
CONFIDENTIAL 
• 
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 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
51/119 
CONFIDENTIAL 
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) 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
52/119 
CONFIDENTIAL 
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) 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
53/119 
CONFIDENTIAL 
• 
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. 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
54/119 
CONFIDENTIAL 
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) 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
55/119 
CONFIDENTIAL 
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. 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
56/119 
CONFIDENTIAL 
 
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 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
57/119 
CONFIDENTIAL 
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.  


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
58/119 
CONFIDENTIAL 
 
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 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
59/119 
CONFIDENTIAL 
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. 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
60/119 
CONFIDENTIAL 
 
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 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
61/119 
CONFIDENTIAL 
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. 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
62/119 
CONFIDENTIAL 
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. 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
63/119 
CONFIDENTIAL 
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.” 
 
 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
64/119 
CONFIDENTIAL 
 
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. 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
65/119 
CONFIDENTIAL 
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. 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
66/119 
CONFIDENTIAL 
• 
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. 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
67/119 
CONFIDENTIAL 
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). 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
68/119 
CONFIDENTIAL 
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 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
69/119 
CONFIDENTIAL 
• 
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. 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
70/119 
CONFIDENTIAL 
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 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
71/119 
CONFIDENTIAL 
 
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 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
72/119 
CONFIDENTIAL 
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. 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
73/119 
CONFIDENTIAL 
• 
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). 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
74/119 
CONFIDENTIAL 
• 
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. 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
75/119 
CONFIDENTIAL 
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.  


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
76/119 
CONFIDENTIAL 
• 
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. 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
77/119 
CONFIDENTIAL 
 
 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  
 
 
 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
78/119 
CONFIDENTIAL 
 
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. 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
79/119 
CONFIDENTIAL 
9 
BIBLIOGRAPHIC REFERENCES 
Bradl M, Lassmann H (2009) Progressive multiple sclerosis. Semin Immunopathol 31: 455-65 
Chakraborty G, Ledeen R (2003) Fatty acid synthesizing enzymes intrinsic to myelin. Brain Res Mol 
Brain Res 112: 46-52 
Chataway J, Schuerer N, Alsanousi A, Chan D, MacManus D, Hunter K, Anderson V, Bangham CR, 
Clegg S, Nielsen C, Fox NC, Wilkie D, Nicholas JM, Calder VL, Greenwood J, Frost C, Nicholas R 
(2014) Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple 
sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet 383: 2213-21 
Confavreux C, Vukusic S (2006) Natural history of multiple sclerosis: a unifying concept. Brain : a 
journal of neurology 129: 606-16 
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-
blind, controlled trial. Lancet 373: 732-8 
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 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
80/119 
CONFIDENTIAL 
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 
mutations inhibit thiamine transport via hTHTR2: biotin is not a substrate for hTHTR2. Am J Physiol 
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 
disease-targeted health-related quality-of-life measures for multiple sclerosis. J Clin Epidemiol 50: 557-
69 
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 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
81/119 
CONFIDENTIAL 
10 APPENDICES 
Annex 1: Revised Mc Donald criteria 
 
 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
                                                                                                                          82/119 
 
 
                                                  CONFIDENTIAL 
Annex 2: Neurostatus 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
                                                                                                                          83/119 
 
 
                                                  CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
                                                                                                                          84/119 
 
 
                                                  CONFIDENTIAL 
 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
                                                                                                                          85/119 
 
 
                                                  CONFIDENTIAL 
 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
                                                                                                                          86/119 
 
 
                                                  CONFIDENTIAL 
 
 
 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
                                                                                                                          87/119 
 
 
                                                  CONFIDENTIAL 
 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
                                                                                                                          88/119 
 
 
                                                  CONFIDENTIAL 
 
 
 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
                                                                                                                          89/119 
 
 
                                                  CONFIDENTIAL 
 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
                                                                                                                          90/119 
 
 
                                                  CONFIDENTIAL 
 
 
 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
91/119 
CONFIDENTIAL 
Annex 3: Relapse assessment questionnaire 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
92/119 
CONFIDENTIAL 
 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
93/119 
CONFIDENTIAL 
 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
94/119 
CONFIDENTIAL 
Annex 4: SPI2 Patient Alert Card 
 
 
 
 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
95/119 
CONFIDENTIAL 
Annex 5: Multiple Sclerosis Quality of Life-54 (MSQOL-54) 
 
 
 
 
 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
96/119 
CONFIDENTIAL 
 
 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
97/119 
CONFIDENTIAL 
 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
98/119 
CONFIDENTIAL 
 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
99/119 
CONFIDENTIAL 
 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
100/119 
CONFIDENTIAL 
 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
101/119 
CONFIDENTIAL 
 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
102/119 
CONFIDENTIAL 
 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
103/119 
CONFIDENTIAL 
 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
104/119 
CONFIDENTIAL 
 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
105/119 
CONFIDENTIAL 
 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
106/119 
CONFIDENTIAL 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
107/119 
CONFIDENTIAL 
 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
108/119 
CONFIDENTIAL 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
109/119 
CONFIDENTIAL 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
110/119 
CONFIDENTIAL 
 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
111/119 
CONFIDENTIAL 
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 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
112/119 
CONFIDENTIAL 
Annex 7: Columbia-Suicide Severity Rating Scale (C-SSRS) 
 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
113/119 
CONFIDENTIAL 
 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
114/119 
CONFIDENTIAL 
 
 
 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
115/119 
CONFIDENTIAL 
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. 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
116/119 
CONFIDENTIAL 
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. 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
117/119 
CONFIDENTIAL 
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, 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
118/119 
CONFIDENTIAL 
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. 


 
SPI2 study 
CLINICAL TRIAL PROTOCOL 
Version 4 dated 12-Nov-2018 
 
 
119/119 
CONFIDENTIAL 
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. 

SAP_001.pdf: 
CONFIDENTIAL
Project Document Effective Date: Date of last signature
Parexel International
MedDay Pharmaceuticals 
MD1003CT2016-01 MS-SPI2
Effect of MD1003 in progressive multiple sclerosis: a randomized double blind placebo-
controlled study
Statistical Analysis Plan for Final Analysis of Study Part 1
Final Version 7.0
Parexel Project Number: 229829


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 2 of 61


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 3 of 61
Parexel SIGNATURE PAGE
Signatures below confirm that the review process was developed in accordance with SOP-
GDO-WW-019 and that it approved for release.
This document has been approved and signed electronically on the final page by the 
following:
 
Signatory
Peter Jakobs
Author:
Project Role: Biostatistician


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 4 of 61
TABLE OF CONTENTS
1 INTRODUCTION ............................................................................................................9
2 STUDY OBJECTIVES...................................................................................................10
2.1 Primary Objective................................................................................................10
2.2 Secondary Objectives ..........................................................................................10
2.3 Exploratory Objectives........................................................................................10
3 INVESTIGATIONAL PLAN.........................................................................................10
3.1 Overall Study Design and Plan............................................................................10
3.1.1 Visits Schedule and Evaluations................................................................11
3.1.2 Randomization...........................................................................................12
3.1.3 Timing of Statistical Analysis ...................................................................12
3.2 Efficacy Endpoints ..............................................................................................12
3.2.1 Primary Efficacy Endpoint ........................................................................12
3.2.2 Secondary Efficacy Endpoints...................................................................13
3.2.2.1 Time to 12-Weeks Confirmed EDSS progression .......................13
3.2.2.2 Clinical Global Impression of Improvement at Visit M15 ..........13
3.2.2.3 Percentage Change from Baseline in TW25 at visit M15............14
3.2.3 Exploratory Efficacy Endpoints ................................................................14
3.2.3.1 Exploratory Brain MRI Efficacy Endpoints.................................14
3.2.3.2 Remote Monitoring of Ambulatory Activity ...............................14
3.2.3.3 MSQOL-54 and CAREQOL-MS.................................................15
3.2.3.4 Kurtzke Functional Systems Scores.............................................15
3.2.3.5 Symbol Digit Modalities Test ......................................................15
3.2.3.6 Neurofilament Blood Concentration............................................16
3.3 Safety Endpoints..................................................................................................16
3.3.1 Extent of Exposure ....................................................................................16
3.3.2 Adverse Events ..........................................................................................16
3.3.3 Relapses .....................................................................................................16
3.3.4 Safety Brain MRI Endpoints .....................................................................16
3.3.5 Clinical Laboratory Tests ..........................................................................17
3.3.6 ECG Endpoints ..........................................................................................17
3.3.7 Columbia-Suicide Severity Rating Scale...................................................17
3.3.8 Vital Signs .................................................................................................18
3.4 Definition of Other Variables Used in the Statistical Analysis...........................18
3.4.1 Geographical Regions................................................................................18
3.4.2 MS Disease History ...................................................................................18
3.4.3 Demographics and Baseline Characteristics..............................................18
3.4.4 Previous and Concomitant Medications and Procedures...........................19
3.4.5 Duration of Study ......................................................................................20
3.4.6 Study Treatment Compliance ....................................................................20
3.4.7 Study Treatment Interruptions...................................................................21
3.4.8 Protocol Deviations ...................................................................................22
3.5 Analysis Sets........................................................................................................22
3.5.1 Screened Analysis Set................................................................................22


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 5 of 61
3.5.2 Intent-To-Treat Analysis Set .....................................................................22
3.5.3 Modified Intent-To-Treat Analysis Set .....................................................23
3.5.4 Full Analysis Set........................................................................................23
3.5.5 Per-Protocol Analysis Set..........................................................................23
3.5.6 Safety Analysis Set....................................................................................23
3.5.7 Roles of the Analysis Sets .........................................................................23
4 STATISTICAL METHODS...........................................................................................24
4.1 Data Quality Assurance.......................................................................................24
4.2 Data Summary Format.........................................................................................24
4.3 Software...............................................................................................................24
4.4 Study Subjects .....................................................................................................25
4.4.1 Disposition of Subjects..............................................................................25
4.4.2 Protocol Deviations ...................................................................................25
4.5 Analysis Sets........................................................................................................25
4.6 Demographic and Other Baseline Characteristics...............................................26
4.7 Previous and Concomitant Medications and Procedures ....................................26
4.8 Efficacy Evaluation .............................................................................................26
4.8.1 Analysis and Data Conventions.................................................................26
4.8.1.1 Multi-Center Studies ....................................................................26
4.8.1.2 Handling of Missing Data ............................................................26
4.8.1.3 Multiple Comparisons/Multiplicity..............................................27
4.8.1.4 Interim Analyses ..........................................................................28
4.8.1.5 Subgroup Analyses.......................................................................28
4.8.2 Analysis of the Primary Efficacy Endpoint...............................................28
4.8.2.1 Main Statistical Analysis..............................................................28
4.8.2.2 Handling of Missing Values in the Main Analysis ......................29
4.8.2.3 First Sensitivity Analysis for Handling of Subjects with 12-Weeks 
Confirmed EDSS Progression ................................................................30
4.8.2.4 Sensitivity Analyses for Handling of Missing Values .................31
4.8.2.5 Sensitivity Analyses in the Context of the Estimand Concept.....35
4.8.2.6 Additional Analyses Related to the Primary Efficacy Endpoint..37
4.8.2.7 Subgroup Analyses.......................................................................37
4.8.3 Analysis of Secondary Efficacy Endpoints ...............................................38
4.8.3.1 Time to 12-Weeks Confirmed EDSS Progression .......................38
4.8.3.2 Analysis of Clinical Global Impression of Improvement ............43
4.8.3.3 Analysis of TW25 ........................................................................46
4.8.4 Analysis of Exploratory Efficacy Endpoints .............................................48
4.8.4.1 Analysis of Exploratory Brain MRI Endpoints............................48
4.8.4.2 Analysis of Remote Monitoring of Ambulatory Activity............48
4.8.4.3 Analysis of MSQOL-54 and CAREQOL-MS .............................49
4.8.4.4 Analysis of Kurtzke Functional System Scores...........................49
4.8.4.5 Analysis of Symbol Digit Modalities Test...................................49
4.8.4.6 Analysis of Neurofilament Blood Concentration.........................49
4.9 Safety Evaluation.................................................................................................50
4.9.1 Analysis of Extent of Exposure .................................................................50
4.9.2 Analysis of Duration of Study ...................................................................50


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 6 of 61
4.9.3 Analysis of Adverse Events.......................................................................50
4.9.4 Deaths, Serious Adverse Events, and Other Significant Adverse Events .51
4.9.5 Analysis of Relapses..................................................................................51
4.9.6 Analysis of Safety Brain MRI Endpoints ..................................................52
4.9.7 Analysis of Clinical Laboratory Tests .......................................................52
4.9.8 Analysis of ECG results.............................................................................52
4.9.9 Analysis of the Columbia-Suicide Severity Rating Scale .........................52
4.9.10
Analysis of Vital Signs ......................................................................52
4.10
Other Analyses...........................................................................................53
4.10.1
Treatment Assignment Questionnaire ...............................................53
4.10.2
Study Treatment Compliance ............................................................53
4.10.3
Study Treatment Interruptions...........................................................53
4.11
Changes in the Conduct of the Study or Planned Analysis .......................54
5 REFERENCES ...............................................................................................................57
6 ADDITIONAL ANALYSES FOR EUROPEAN MEDICINES AGENCY 
FOLLOWING SCIENTIFIC ADVICE.............................................................................58


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 7 of 61
LIST OF ABBREVIATIONS
AE
Adverse event
ATC
Anatomical Therapeutic Chemical
ATP
Adenosine triphosphate
BMI
Body mass index
CAC
Clinical Adjudication Committee
CAREQOL-MS
Caregiver Health-Related Quality of Life in Multiple Sclerosis
eCRF
electronic Case Report Form
CI
Confidence interval
CGI-I
Clinical Global Impression of Improvement
CGI
Clinician’s Global Impression of Improvement
CSR
Clinical Study Report
C-SSRS
Columbia-Suicide Severity Rating Scale
DMT
Disease modifying therapy
DSMB
Data Safety Monitoring Board
ECG
Electrocardiography
EDSS
Expanded Disability Status Scale
EMA
European Medicines Agency
FAS
Full Analysis Set
FCS
Fully Conditional Specification
ICH
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
ITT
Intent-To-Treat
MedDRA
Medical Dictionary for Regulatory Activities
MITT
Modified Intent-To-Treat
MRI
Magnetic resonance imaging
MRS
Magnetic Resonance Spectroscopy
MS
Multiple sclerosis
MSQOL-54
Multiple Sclerosis Quality of Life-54
NAA/CR
N-acetylaspartate / creatine ratio
NA/AUS
North America / Australia
PPS
Per-Protocol Set
PMS
Progressive multiple sclerosis
PPMS
Primary progressive multiple sclerosis
PT
Preferred Term
RRMS
Relapsing-remitting multiple sclerosis
SAE
Serious adverse event
SAP
Statistical Analysis Plan


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 8 of 61
SD
Standard deviation
SDMT
Symbol Digit Modalities Test
SGI
Subject’s Global Impression of Improvement
SOC
System Organ Class
SPMS
Secondary progressive multiple sclerosis
TEAE
Treatment emergent adverse event
TW25
Timed 25-Foot Walk


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 9 of 61
1
INTRODUCTION
Multiple sclerosis (MS) is a common neurological disease affecting more than 2 million 
people worldwide. It is an inflammatory autoimmune disease that damages the myelin of 
the central nervous system causing neurological impairment and, in many cases, severe 
disability.
Approximately 85% of all patients present with relapsing-remitting MS (RRMS), 
characterized by unpredictable acute episodes of neurological dysfunction (or ‘relapses’), 
followed by variable recovery and periods of clinical stability. The remaining 15% of 
patients develop a sustained deterioration of their neurological function from symptom 
outset, termed primary progressive MS (PPMS). Over the chronic course of RRMS, 
approximately 50% of patients develop sustained deterioration with or without 
superimposed relapses; this form is called secondary progressive MS (SPMS). Progressive 
MS (PMS) includes both PPMS and SPMS.  
Biotin, an essential co-enzyme for the production of adenosine triphosphate (ATP) by 
mitochondria, showed beneficial effects in patients with PMS when given in doses of 300 
mg per day in open-label and double-blind trials. The current phase 3 study 
MD1003CT2016-01 MS-SPI2 has been designed to confirm these results (for MD1003 
containing 100 mg Biotin to be taken three times a day) in PMS subjects without clinical 
evidence of a relapse in the previous 2 years.
This Statistical Analysis Plan (SAP) describes the planned final analyses for the 
randomized, double-blind, placebo-controlled study phase (comparing MD1003 to 
matching placebo) to be included in the Clinical Study Report (CSR).
This SAP covers study Part 1 and is based upon the following study documents:
Study Protocol, version 4.0 (12 November 2018)
electronic Case Report Form (eCRF) version 8.0 (18 Feb 2018)
Data Safety Monitoring Board (DSMB) Charter, version 1.0 (04 May 2017).


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 10 of 61
2
STUDY OBJECTIVES
2.1
Primary Objective
The primary objective is to confirm the superiority of MD1003 at 300 mg/day over placebo 
to clinically improve patients with inactive PMS.
2.2
Secondary Objectives
Secondary objectives include: 
demonstration of increased time to 12-weeks confirmed Expanded Disability Status 
Scale (EDSS) progression for MD1003 compared to placebo
comparison of MD1003 and placebo in clinical global impression of improvements 
assessed by investigators and subjects
comparison of MD1003 and placebo in subjects’ physical performance
assessment of subjects’ safety when treated with MD1003 in comparison to placebo. 
2.3
Exploratory Objectives
Exploratory objectives include comparisons of MD1003 and placebo in brain Magnetic 
resonance imaging (MRI) measurements, neurological tests as well as subjects’ and 
caregivers’ health-related quality of life.
3
INVESTIGATIONAL PLAN
3.1
Overall Study Design and Plan
It was planned to randomize approximately 600 subjects (in approximately 90 centers 
located in North America, Europe and Australia); 642 subjects were actually randomized 
in 90 centers.


MedDay Pharmaceuticals 
 
MD1003CT2016-01 MS-SPI2 
 
 
 
 
        Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
      Final Version 7.0
Effective Date: 05 Sep 18
 
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
             Page 11 of 61
3.1.1
Visits Schedule and Evaluations
M-1
M0
M3
M6
M9
M12
M15
M18
M21
M24
M27
Unscheduled 
Visits
Early Study 
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
Follow-up 
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
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 dosage
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
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 (Electrocardiography)
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


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 12 of 61
3.1.2
Randomization
At randomization visit M0, eligible subjects were centrally randomized to one of the two 
study treatments MD1003 or placebo. The underlying randomization list was generated 
with a 1:1 randomization ratio and stratified by center (study site) and MS disease history 
(SPMS / PPMS). The stratified randomization, however, was introduced by a study 
protocol amendment (protocol version 3.0). A small number of subjects (less than 5%) 
were randomized without any stratification under study protocol version 2.0.
3.1.3
Timing of Statistical Analysis
The statistical analysis of the randomized, double-blind, placebo-controlled study phase 
will be performed when all subjects have ended the double-blind period (planned to last 
from 15 to 27 months depending on the subject’s date of randomization), i.e., all 6 
conditions below are met:
1. All randomized subjects had their M15 visit or terminated the study
2. All subjects complete the next scheduled visit after condition 1 has been met; exceptions 
are subjects who have
a. had their study termination visit or
b. withdrawn their informed consent or
c. been declared as lost to follow-up or
d. been withdrawn from the study or
e. deceased
3. Relevant data has been entered by site personnel and data has been transferred from 
external vendors (except unblinded randomization data)
4. Cleaning and reconciliation of relevant data has been performed
5. The agreed status of the database has been applied
6. Unblinded randomization data has been received and passed a quality control.
3.2
Efficacy Endpoints
3.2.1
Primary Efficacy Endpoint
The primary efficacy endpoint is a composite criterion which can be met in one of two 
ways: through confirmed improvement in EDSS or Timed 25-Foot Walk (TW25). The 
composite captures the improvement in ambulation which constitutes the main impaired 
function in subjects with progressive MS. Since the ambulation score in the EDSS scoring 
system can be somewhat insensitive to changes, the addition of a clinically meaningful 
decrease in TW25 may be more sensitive to demonstrate improvement of ambulation.  


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 13 of 61
In more detail, the two criteria are:
a decrease from baseline in EDSS at visit M12 confirmed at visit M151: decrease of at 
least 1 point for baseline EDSS up2 to 5.5 and of at least 0.5 point for baseline EDSS 6 
to 6.5
or 
a decrease from baseline in TW25 of at least 20%3 at visit M12 confirmed at visit M154 
with
baseline EDSS is defined as the lowest (best) EDSS obtained at visits M-1 and M0. 
baseline TW25 is defined as the lowest (best) mean of TW25 attempts performed at the 
visits M-1 and M0, respectively, i.e., 
(mean of TW25 attempts at M - 1, mean of TW25 attempts at M0)
TW25 at visit M12 is defined as the mean of TW25 attempts at visit M12 
TW25 at visit M15 is defined as the mean of TW25 attempts at visit M15. 
3.2.2
Secondary Efficacy Endpoints
3.2.2.1
Time to 12-Weeks Confirmed EDSS progression
12-weeks EDSS progression is defined as an increase of at least 1 point for baseline EDSS 
up5 to 5.5 and of at least 0.5 point for baseline EDSS 6 to 6.5 with respective confirmation 
12 weeks later (with time windows of ± 10 days up to 1 year after randomization, ± 15 days 
afterwards). The baseline EDSS value is defined as in Section 3.2.1. 
Date of 12-weeks confirmed EDSS progression will be the first date of an EDSS 
progression (as defined above) that is confirmed 12 weeks later. Handling of missing 
scheduled EDSS assessments and censoring are described in Section 4.8.3.1. 
Time to 12-weeks confirmed EDSS progression will be calculated as date of 12-weeks 
confirmed EDSS progression (or censoring) minus date of randomization plus 1; it will be 
expressed in weeks.
1 i.e., defined EDSS decrease from baseline observed at visit M12 and at visit M15
2 “EDSS 3.5 to 6.5 at inclusion” has been one of the inclusion criteria, but there may be few subjects with 
baseline EDSS (lowest EDSS obtained at visit M-1 and M0) slightly below 3.5; “up to 5.5 or below” is 
therefore used as baseline EDSS range for at least 1 point decrease
3 No rounding of the TW25 decrease will be done before comparing it to 20%, i.e., a decrease in TW25 of 
19.89% (or any other value < 20%) is not sufficient for fulfilling the TW25 criterion 
4 i.e., defined TW25 decrease from baseline observed at visit M12 and at visit M15
5 Same rationale as for footnote 2 


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 14 of 61
3.2.2.2
Clinical Global Impression of Improvement at Visit M15
The Clinical Global Impression of Improvement (CGI-I) is a 7-point scale that requires the 
clinician (CGI) and the subject (SGI) to assess how much the subject's disease has 
improved or worsened relative to the status at study baseline. It has the following 
categories: 
1 very much improved
2 much improved
3 minimally improved
4 no change
5 minimally worse
6 much worse
7 very much worse.
CGI and SGI will be recorded at M15, M27 and early study termination visit.
3.2.2.3
Percentage Change from Baseline in TW25 at visit M15
Baseline TW25 is defined as the lowest mean of TW25 attempts performed at the visits 
M-1 and M0, respectively, i.e., 
.
(mean of TW25 attempts at M - 1, mean of TW25 attempts at M0)
TW25 at visit M15 is defined as the mean of TW25 attempts at visit M15. 
Percentage change from baseline in TW25 at visit M15 is defined as
% 
=
× 100%
i.e., negative values indication improvements.
3.2.3
Exploratory Efficacy Endpoints
3.2.3.1
Exploratory Brain MRI Efficacy Endpoints
Brain MRIs will be performed at visits M0, M6, M15, M27 and unscheduled visits in case 
of a relapse. 
Exploratory brain MRI efficacy endpoints for visits M6 and M15 are 
whole brain volume
change from baseline in thalamic volume
percent change from baseline in brain volume
change from baseline in cortical grey matter volume
change from baseline in brain water content by Pseudo T2 relaxation time
change from baseline in N-acetylaspartate / creatine ratio (NAA/Cr) in a subset of sites 
acquiring Magnetic Resonance Spectroscopy (MRS) (non-conventional sequences).


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 15 of 61
3.2.3.2
Remote Monitoring of Ambulatory Activity
Remote monitoring of ambulatory activity will be assessed at visits M0 and each follow-
up visits from M3 to M27, at the early study termination visit and at unscheduled visits. 
Exploratory efficacy endpoints are
average daily step count based on a 21 days period prior to the scheduled (M0 or post-
baseline) visit recording steps continuously in the natural environment as part of routine 
daily activity;  average is defined as the sum of daily steps from valid days within such 
a 21 days period divided by the number of valid days; a “valid” day is defined as a day 
with at least 130 steps. At least 3 valid days are required for a visit to be included in the 
statistical analysis. 
change from baseline in average daily step count.
3.2.3.3
MSQOL-54 and CAREQOL-MS
The Multiple Sclerosis Quality of Life 54 (MSQOL-54) and Caregiver Health-Related 
Quality of Life in Multiple Sclerosis (CAREQOL-MS) will be used at visits M0, M15 and 
M27 and at the early study termination visit.
MSQOL-54 summary scores (physical health, mental health) will be derived from 
individual items (Vickrey 1995, Vickrey 1997).
CAREQOL-MS sub-scores (physical stress/global health, social integration, emotion, need 
for assistance/emotional reactions) will be derived from individual items (Benito-León 
2001).
Exploratory efficacy endpoints are 
change from baseline at visit M15 in MSQOL-54 summary scores
change from baseline at visit M15 in CAREQOL-MS sub-scores.
3.2.3.4
Kurtzke Functional Systems Scores
Kurtzke Functional Systems Scores will be determined at M-1, M0 and each follow-up 
visits from M3 to M27, at the early study termination visit and at unscheduled visits.
Exploratory efficacy endpoints are 
change from baseline at visit M15 in Kurtzke Functional Systems Scores
change from baseline at visit M15 in (Kurtzke total) EDSS.
3.2.3.5
Symbol Digit Modalities Test
The Symbol Digit Modalities Test (SDMT) will be performed at M0, M15 and M27 visits 
and at the early study termination visit.  
Exploratory efficacy endpoints are 
change from baseline at visit M15 in SDMT score as a continuous change and as 
categorical change using the following categories:
o decrease of at least 4 digits
o -4 digits < change < 4 digits


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 16 of 61
o increase of at least 4 digits.
3.2.3.6
Neurofilament Blood Concentration
During the double-blind study part, blood samples for neurofilament concentrations will 
be taken at visits M-1, M6, M12, M15, M27 and analyzed in a central laboratory. 
Exploratory endpoints related to neurofilament blood concentration are the absolute 
changes from baseline (M-1) in neurofilament blood concentration at visits M6, M12, M15 
and M27.
3.3
Safety Endpoints  
3.3.1
Extent of Exposure
Extent of exposure will be expressed in months and calculated as
date of last intake of study treatment
date of first intake of study treatment + 1
365.25 12
.
3.3.2
Adverse Events
Adverse events (AEs) will be coded using the agreed version of the Medical Dictionary for 
Regulatory Activities (MedDRA).
Treatment-emergent adverse events (TEAEs) will be defined as those AEs that 
start on or after the date of first dose of study treatment and not later than the date of 
last dose of study treatment
or worsen in severity on or after the date of first dose of study treatment and no later 
than the date of last dose of study treatment. 
AEs with missing or partially missing onset dates will be assumed to be treatment-
emergent, unless there is clear evidence (through comparison of partial dates) to suggest 
that the adverse event started prior to the first dose of study treatment.
3.3.3
Relapses
The investigators will report relapses by a relapse form to the Clinical Adjudication 
Committee (CAC) for validation and MedDRA coding purposes.
The CAC will review protocol-defined, non-protocol-defined and suspected relapses and 
will classify these as either relapse or no relapse.
3.3.4
Safety Brain MRI Endpoints
Brain MRIs will be performed at visits M0, M6, M15, M27 and at unscheduled visits in 
case of a relapse. 
Safety brain MRI endpoints for visits M6 and M15 are:
•
number of new or enlarging T2-weighted lesions
•
presence of at least one new or enlarging T2-weighted lesion


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 17 of 61
•
number of gadolinium-enhancing T1-weighted lesions
•
presence of at least one gadolinium-enhancing T1-weighted lesion
•
volume of T2-weighted lesions
•
volume of non-enhancing T1-weighted lesions.
3.3.5
Clinical Laboratory Tests
Laboratory tests will be performed at visits M-1, M6, M15, M27, at the early study 
termination visit and at unscheduled visits.
Creatinine clearance will be calculated by using the formula (Cockcroft & Gault 1976):
[mL/min] =
(140
[years]) ×
[kg]
[
]
( × 0.85 if female)
Laboratory test results will be classified as normal or abnormal according to the applicable 
laboratory’s normal ranges (these may depend on the subject’s age, sex, race and the date 
when the laboratory examines the sample). 
3.3.6
ECG Endpoints
ECGs will be performed at visits M0, M15, M27, at the early study termination visit and 
at unscheduled visits. At visit M0, a triplicated ECG will be performed, and the mean of 
the 3 ECG results will be used. From the 3 clinical interpretations performed by the 
investigator and the Cardiac Safety Core Laboratory, the last one by the Cardiac Safety 
Core Laboratory will be used for data analysis. For post-baseline ECGs, the clinical 
assessment provided by the Cardiac Safety Core Laboratory will be used for data analysis. 
Corrected QT interval will be calculated by using Fridericia’s formula
= 3
ECG endpoints for visit M15 and the early study termination visit are 
intervals PR, QRS, QT and QTcF and changes from baseline
categories for QTcF: 
 ms, >450 ms, >480 ms and >500 ms
categories for QTcF changes: 
 ms, >30 ms and >60 ms.
3.3.7
Columbia-Suicide Severity Rating Scale
Suicidal ideation and behavior will be assessed at visits M-1, M0 and each follow-up visits 
from M3 to M27, at the early study termination visit and at unscheduled visits using the 
Columbia-Suicide Severity Rating Scale (C-SSRS).
The total score of the C-SSRS can be 10 at maximum and will be derived as follows:
each ‘Yes’ to the questions 1, 2, 3, 4, 5 of Suicidal Ideation, and each ‘Yes’ to the 
questions Actual attempt, Interrupted Attempt, and Aborted attempt.  Preparatory acts 
or behaviors and Actual Suicide of Suicidal Behavior will count as 1 and the sum of all 
these 10 items will give the total score.   


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 18 of 61
sub-scales reflecting ideation and behavior will also be derived separately. 
at screening, the total score will be 9 at the maximum since the last question ‘Actual 
suicide’ will never be Yes.
3.3.8
Vital Signs
The following vital signs will be recorded at visits M-1, M0 and each follow-up visits from 
M3 to M27, at the early study termination visit and at unscheduled visits: 
body weight
body temperature
heart rate
systolic and diastolic blood pressure.
3.4
Definition of Other Variables Used in the Statistical Analysis
3.4.1
Geographical Regions
There will be two geographical regions defined as follows:
North America / Australia (NA/AUS): Canada, United States of America, Australia
Europe: Belgium, Hungary, Poland, Turkey, Czech Republic, Germany, Italy, Spain, 
Switzerland, United Kingdom.
3.4.2
MS Disease History
For statistical analysis, the following data sources for MS disease history (PPMS or SPMS) 
will be used:
eCRF data for subjects for whom disease history is available in the eCRF
Interactive web response system data for subjects for whom disease history is not 
available in the eCRF.
3.4.3
Demographics and Baseline Characteristics
Age in years at time of consent is collected. If missing, it will be calculated as the number 
of complete years between a subject's birth date and the date of informed consent. Age will 
also be presented in classes: 18 to <=25, 26 to <=40, 41 to <=55 and 56 to <=65 and >65. 
Body mass index (BMI) will be calculated as 
[kg/m2] =
[kg]
(
[m])2
In the summary of disease history, time since first appearance of the first symptom 
attributable to MS in years will be calculated as: 
date of informed consent
date of first symptom attributable to MS + 1 
365.25


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 19 of 61
Time since initial diagnosis of MS, time since last EDSS progression, time since last 
relapsing episode (if applicable), and time since discontinuation of fampridine (if 
applicable) will be calculated in the same way.
In case of partial date of first appearance of MS or initial diagnosis of MS (only year 
available or year and month), the earliest possible date will be used (e.g., 1st of January or 
first day of the month). In case of partial date of last EDSS progression, last relapsing 
episode or discontinuation of fampridine (only year available or year and month), the 
earliest possible date in the past will be used (e.g., 1st of January or first day of the month).
Medical history and current medical conditions will be coded using the latest available 
version of the MedDRA dictionary. In case of partial or completely missing start date and 
end date, if this is not possible to decide whether the medical condition is past or current 
(ongoing is also missing), then it will be considered current.
3.4.4
Previous and Concomitant Medications and Procedures
Previous and concomitant medications will be coded using the latest available version of 
the World Health Organization Drug Dictionary.
Medications and procedures will be classified either as previous or concomitant where 
previous includes medications that stopped prior to the date of randomization 
concomitant includes medications that are continuing at the date of randomization and 
medications that started at or after the date of first study treatment dose.
Medication start and stop dates will be compared to the date of randomization to allow 
medications to be classified as either previous or concomitant. If medication start or stop 
dates are missing or partial, the dates will be compared as far as possible with the date of 
randomization. Medications will be assumed to be concomitant, unless there is clear 
evidence to suggest that the medication stopped prior to the date of randomization.
Medications will be assessed by a sponsor physician as either disease modifying therapy 
(DMT), medication for MS symptoms or none of these. For DMTs, the following more 
detailed categories are defined:
previous DMTs (DMTs that stopped prior to the date of randomization)
DMT already present at the date of randomization
DMT started after the date of randomization dose.
Following rules will be applied when counting previous / concomitant medications:
if a subject receives the same previous / concomitant medication (i.e., same 
Anatomical Therapeutic Chemical (ATC) level 1, ATC level 4 and preferred name) 
more than once, they are only counted once under the count for that ATC level 1, ATC 
level 4 and preferred name
if a subject receives more than one previous / concomitant medication in a particular 
ATC class, they will only be included once in the count for the ATC class, but will 
appear in the count for each applicable preferred term within the ATC class.


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 20 of 61
3.4.5
Duration of Study
Duration of study will be expressed in months and calculated as
date of last visit or contact
date of  informed consent + 1 
365.25 12
3.4.6
Study Treatment Compliance
Compliance with study treatment will be calculated 
(1) for the double-blind study phase up to the M15 visit (including) and 
(2) for the overall double-blind study phase. 
For each of these two intervals, the following variables are derived on the subject level:
study treatment duration in days based on data from the study medication compliance 
pages of the eCRF:
(1)
(1) = date of last study treatment  intake up to the M15 visit (incl)
                     
date of first study treatment intake in the double - blind study phase 
+ 1
(2)
(2)
= date of last study treatment intake in the double - blind study phase
                     
date of first study treatment intake in the double - blind study phase 
+ 1
total number of capsules dispensed based on data from the study medication 
compliance pages of the eCRF:
(1)
(1) = sum of numbers of capsules dispensed prior to the M15 visit
(2)
(2) = sum of numbers of capsules dispensed prior to the last visit of 
                  the double - blind study phase
total number of capsules returned based on data from the study medication compliance 
pages of the eCRF: 
(1)
(1) = sum of numbers of capsules returned up to the M15 visit (incl)
(2)
(2) = sum of numbers of capsules returned in the double - blind study
phase 
study treatment compliance expressed in percentages (note subjects are supposed to 
take 3 capsules per day): 
(1)
(1) =
(1)
(1)
3 ×
(1) × 100
(2)
.
(2) =
(2)
(2)
3 ×
(2) × 100


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 21 of 61
In addition, the following categorical study treatment compliance variables on the subject 
level will be derived:
(1) for the double-blind study phase up to the M15 visit (including) using the following 
categories:
o
STC(1) < 70%
o
70%  STC(1)  80%
o
80% < STC(1) < 120%
o
120%  STC(1)  130%
o
STC(1) > 130%. 
(2) for the overall double-blind study phase, using the following categories:
o
STC(2) < 70%
o
70%  STC(2)  80%
o
80% < STC(2) < 120%
o
120%  STC(2)  130%
o
STC(2) > 130%. 
3.4.7
Study Treatment Interruptions
Data for study treatment interruptions will be taken from the from the study treatment 
interruption part of the medication compliance pages of the eCRF. 
Study treatment interruptions will be determined 
(1) for the double-blind study phase up to the M15 visit (including) and 
(2) for the overall double-blind study phase. 
For each of these two intervals, the following variables are derived:
number of study treatment interruptions (derived on the subject level)
duration of study treatment interruptions (derived on the interruption level)
(1)
(1) = date of study treatment  restarted 
                       
date of last study treatment intake + 1
(for a study treatment interruption with date of last study treatment intake is  
date of the M15 visit and date of study treatment restarted is > date of the M15 
visit date, then the latter will be replaced by the M15 visit date)
(2)
(2) = date of study treatment  restarted 
                       
date of last study treatment intake + 1
In addition, the following categorical variables related to study treatment interruptions will 
be derived on the subject level:
(1) for the double-blind study phase up to the M15 visit (including) using the following 
categories:
o
no study treatment interruption
o
at least one study treatment interruption 


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 22 of 61
(2) for the overall double-blind study phase, using the following categories:
o
no study treatment interruption
o
at least one study treatment interruption. 
3.4.8
Protocol Deviations
Major protocol deviations are those deviations from the protocol likely to have an impact 
on the perceived efficacy and/or safety of study treatments. 
Major protocol deviations for this study (and any action to be taken regarding the exclusion 
of subjects or affected data from specific statistical analyses, see Section 3.5) have been 
defined in the Protocol Deviation Specification document. Updates of the Protocol 
Deviation Specification document are allowed only before general unblinding for the final 
statistical analysis. 
Of interest is the intake of off-study biotin as biotin is available as a food supplement in 
several countries. Biotin plasma concentrations will be measured from samples taken at 
visits M-1, M6, M12, M15 and M27 (or at early study termination) during the placebo-
controlled study phase. Biotin plasma concentrations will be measured at a central 
laboratory not informed about the randomized study treatment and the results will be made 
available only after database lock and general unblinding for the final statistical analysis. 
For subjects randomized to placebo, any biotin plasma concentration above 75 ng/ml is 
considered indicative for off-study intake of biotin and constitutes a major protocol 
deviation. 
Similarly, if the visit M-1 biotin level exceeds 75 ng/ml in subjects randomized to MD1003, 
this is considered a major protocol deviation.
3.5
Analysis Sets
Decisions of inclusion of subjects in analysis sets described below will be made prior to 
unblinding of study treatments, documented by Parexel and approved by MedDay. For 
potential major protocol deviations for which final assessment requires knowledge of the 
randomized study treatment (see Section 3.4.6 for the example of off-study biotin intake 
for patients randomized to placebo), the respective analysis set will only be finally 
determined after general unblinding. The rules described in the SAP will be followed.
3.5.1
Screened Analysis Set
The Screened Analysis Set consists of all subjects who were assigned a subject number.
3.5.2
Intent-To-Treat Analysis Set
The Intent-To-Treat (ITT) Analysis Set comprises all subjects to whom study treatment 
was randomized. Statistical analyses will be based on study treatment groups as per 
randomization and MS disease history stratum used for the randomization (where 
applicable), irrespective of the study treatment actually received.


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 23 of 61
3.5.3
Modified Intent-To-Treat Analysis Set
The Modified Intent-To-Treat (MITT) Analysis Set is a subset of the ITT Analysis Set: 
subjects randomized to placebo with any biotin plasma concentration above 75 ng/ml 
at visits mentioned in Section 3.4.8 are excluded from the MITT Analysis Set 
subjects randomized to MD1003 with any biotin plasma concentration above 75 ng/ml 
at visit M-1 are excluded from the MITT Analysis Set.
3.5.4
Full Analysis Set
The Full Analysis Set (FAS) is a subset of the ITT Analysis Set, consisting of subjects 
who:
received at least one dose of study treatment
and had at least one EDSS or TW25 assessment at visits M-1 or M0
and had at least one post-baseline EDSS or TW25 assessment prior to study treatment 
discontinuation in the randomized double-blind study phase. 
3.5.5
Per-Protocol Analysis Set 
The Per-Protocol Analysis Set (PPS) is a subset of the ITT Analysis Set, consisting of 
subjects who: 
did not discontinue study treatment prior to visit M15 
and had at least one EDSS or TW25 assessment at visits M-1 or M0
and have EDSS or TW25 assessment at visits M12 and M15
and have no major protocol deviations up to M15 visit (this includes off-study biotin 
use in subjects randomized to placebo).
3.5.6
Safety Analysis Set
The Safety Analysis Set comprises all subjects who received at least one dose of study 
treatment. 
Statistical analyses will be based on study treatment subjects actually received: if a subject 
has received any dose of MD1003 or any biotin plasma concentration has been above 
75 ng/dl, the subject will be assigned to the MD1003 treatment group within the Safety 
Analysis Set; otherwise the subject will be assigned to the placebo treatment group.
3.5.7
Roles of the Analysis Sets
The main analysis of the primary efficacy endpoint will be based on the ITT Analysis Set; 
sensitivity analyses based on the MITT Analysis Set, the FAS and the PPS will be 
performed to assess the robustness of conclusions to the choice of analysis set. 
Analyses of secondary efficacy endpoints will be based on ITT Analysis Set (main 
analysis) and MITT Analysis Set as a sensitivity analysis. Analyses of exploratory efficacy 
endpoints will be based on the ITT Analysis Set.
Analyses of safety will be based on the Safety Analysis Set.


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 24 of 61
4
STATISTICAL METHODS
4.1
Data Quality Assurance
All tables, figures and listings to be included in the CSR will be independently checked for 
consistency, integrity and in accordance with PAREXEL’s Standard Operation Procedures.
4.2
Data Summary Format
Continuous data will be summarized in terms of the number of subjects, mean, standard 
deviation (SD), median, minimum, maximum and number of observations, unless 
otherwise stated, e.g., additional lower and upper quartiles. The minimum and maximum 
will be reported to the same number of decimal places as the raw data recorded in the 
database. The mean, median, lower quartile and upper quartile will be reported to one more 
decimal place than the raw data recorded in the database. The SD will be reported to two 
more decimal places than the raw data recorded in the database. In general, the maximum 
number of decimal places reported shall be four for any summary statistic.
Categorical data will be summarized in terms of the number of subjects providing data at 
the relevant time point (n), number of subjects with missing data, frequency counts and 
percentages. Percentages will be presented to one decimal place. Percentages will not be 
presented for zero counts. Percentages will be calculated using n as the denominator. 
Changes from baseline in categorical data will be summarized using shift tables where 
appropriate.
P-values greater than or equal to 0.0001, in general, will be presented to four decimal 
places. P-values less than 0.0001 will be presented as “<0.0001”. Confidence intervals 
(CIs) will be presented to one more decimal place than the raw data.
For laboratory tests for which a detection limit exists, values below the detection limit (e.g.. 
< 0.35 kU/L) will be considered as equal to the limit (e.g., = 0.35) in the statistical analyses 
(except in listings where the reported value will be presented). When repeated analyses 
were performed for laboratory tests for a same visit, due to non-evaluable sample or in 
order to confirm results, the latest values will be taken into account in the statistical 
analyses (except in listings where all reported test results will be presented).
4.3
Software
Statistical outputs for inclusion into the CSR will predominantly be generated using SAS® 
version 9.3 or a later version in a validated environment (some planned statistical analyses 
require SAS® version 9.4).


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 25 of 61
4.4
Study Subjects
4.4.1
Disposition of Subjects
The number of subjects screened for entry into the study and the number and percentage 
of subjects with screening failures by major reasons will be summarized based on the set 
of all screened subjects.
The following summaries for disposition of subjects will be provided by study treatment 
group and overall for the ITT Analysis Set:
number and percentage of subjects randomized on the study level per geographical 
region, country and site
number and percentage of subjects randomized by disease history (PPMS/SPMS) and 
per DMT present at baseline (including its combinations)
number and percentage of subjects randomized by disease history (PPMS/SPMS) and 
within geographical region and country 
number and percentage of randomized subjects not treated with any study treatment and 
primary reason for not getting treated 
number and percentage of subjects prematurely discontinuing study treatment and 
primary reason for premature discontinuation of study treatment 
number and percentage of subjects prematurely discontinuing the study and primary 
reason for premature discontinuation of study 
number and percentage of subjects by visit 
number and percentage of subjects withdrawing informed consent.
Listings of eligibility details, randomization details, visit dates, study treatment 
discontinuation details (including reason for study treatment discontinuation) and 
withdrawal/study completion details (including reason for study discontinuation and 
duration of treatment prior to study discontinuation) will be provided.
4.4.2
Protocol Deviations
A summary of number and percentage of subjects with a major protocol deviation and type 
of protocol deviation will be provided by study treatment group for the ITT Analysis Set. 
A listing of all major protocol deviations by subject will be produced.
4.5
Analysis Sets
The following summaries on analysis sets will be provided:
number and percentage of subjects in the Screened Analysis Set and ITT Analysis Set 
(Screened Analysis Set)
number and percentage of subjects in ITT Analysis Set, MITT Analysis Set, FAS, PPS 
and Safety Analysis Set by study treatment group and overall (ITT Analysis Set).
A listing to include site and subject identifier, inclusion/exclusion flag for each analysis 
set, reason for exclusion from an analysis set (if applicable), randomized and actual study 
treatment will be provided. 


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 26 of 61
4.6
Demographic and Other Baseline Characteristics
The following summaries of demographic and baseline characteristics will be based on the 
ITT analysis set and provided by study treatment group and overall:
demographics age, sex, race, ethnicity, height, weight and BMI (for all subjects and 
separately for PPMS subjects and SPMS subjects) 
MS disease history (for all subjects and separately for PPMS subjects and SPMS 
subjects)
childbearing status (for female subjects) and contraception method 
previous medical and surgical history by MedDRA System Organ Class (SOC) and 
Preferred Term (PT)
continuing medical conditions by MedDRA SOC and PT
pattern of progression by disease history (PPMS/SPMS) and by DMT  present at the 
date of randomization.
4.7
Previous and Concomitant Medications and Procedures
The following summaries will be provided by study treatment group and overall based on 
the ITT Analysis Set:
previous DMTs 
DMTs already present at the date of randomization
DMTs already present at the date of randomization by disease history (SPMS/PPMS)
DMTs started after the date of randomization
DMTs started after the date of randomization, by disease history (SPMS/PPMS)
previous medications for MS symptoms 
concomitant medications for MS symptoms
other concomitant therapies
concomitant procedures.
4.8
Efficacy Evaluation
4.8.1
Analysis and Data Conventions
4.8.1.1
Multi-Center Studies
Given the high number of centers with only few subjects per center, it has been decided to 
use geographical region (defined in Section 3.4.1) instead of center as stratification variable 
in statistical analysis procedures.
4.8.1.2
Handling of Missing Data
The description of handling missing data in the statistical analysis of primary and 
secondary efficacy endpoints is integrated in Sections 4.8.2 and 4.8.3.
Analyses of exploratory efficacy endpoints will be based on available data only. 


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 27 of 61
Analyses of safety endpoints will be based on available data, except for safety data where 
partial or missing data will be imputed by a “worst case approach”, for example:
assume an AE is TEAE if AE onset / end dates are missing or inconclusively incomplete
impute missing causality to study medication by “related”
impute missing AE severity as “severe”. 
4.8.1.3
Multiple Comparisons/Multiplicity
Testing of null hypotheses for secondary efficacy endpoints may only be started if the null 
hypothesis for the primary efficacy endpoint on the ITT Analysis Set of all PMS subjects 
will have been rejected. 
If the latter will be the case, then the following sequential conditional testing procedure 
will be applied to restrict the one-sided family-wise type-I-error probability for secondary 
efficacy endpoints by 0.025:
1. The null hypothesis for time to 12-weeks confirmed EDSS progression will be tested as 
described in Section 4.8.3.1: 
if the null hypothesis cannot be rejected (upper limit of a two-sided 95% Wald-type 
CI limit for the hazard ratio  1), then the test procedure for secondary efficacy 
endpoints stops here
if the null hypothesis is rejected (upper limit of a two-sided 95% Wald-type CI limit 
for the hazard ratio < 1), then the test procedure for secondary efficacy endpoints 
continues with step 2 below.
2. The null hypothesis for CGI at visit M15 will be tested as described in Section 4.8.3.2: 
if the null hypothesis for CGI at visit M15 cannot be rejected (one-sided p-value of 
the stratified van Elteren test  0.025), then the test procedure for secondary efficacy 
endpoints stops here
if the null hypothesis for CGI at visit M15 is rejected (one-sided p-value of the 
stratified van Elteren test < 0.025), then the test procedure continues with step 3 
below.
3. The null hypothesis for SGI at visit M15 will be tested as described in Section 4.8.3.2: 
if the null hypothesis for SGI at visit M15 cannot be rejected (one-sided p-value of 
the stratified van Elteren test  0.025), then the test procedure for secondary efficacy 
endpoints stops here
if the null hypothesis for SGI at visit M15 is rejected (one-sided p-value of the 
stratified van Elteren test < 0.025), then the test procedure for secondary efficacy 
endpoints continues with step 4 below
4. The null hypothesis for percentage change in TW25 from visit M0 to visit M15 will be 
tested as described in Section 4.8.3.3 (with one-sided significance level 0.025) and the 
test procedure for secondary efficacy endpoints ends. 
In the analysis of the primary efficacy endpoint for subgroups based on MS disease history 
and subgroups based on geographical regions, a null hypothesis may only be rejected if the 


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 28 of 61
null hypothesis for the primary efficacy endpoint on the ITT Analysis Set of all PMS 
subjects will have been rejected.  
4.8.1.4
Interim Analyses
A Data Safety Monitoring Board (DSMB) will meet approximately every three months and 
review predefined interim analysis results. The DSMB maintains the ability to call for ad 
hoc sessions at any time.
Following each DSMB meeting, a notification will be provided to the Sponsor with a 
recommendation for study conduct. 
4.8.1.5
Subgroup Analyses
To assess the treatment effect and the homogeneity of treatment effect of the primary and secondary 
efficacy endpoints, subgroup analyses defined by the following baseline characteristics will be 
performed (based on the imputation method used for the main analysis):
MS disease history: SPMS or PPMS
geographical region: North America / Australia or Europe
EDSS at baseline: “up to 5.5” or “6 or above”
age:  overall median or > overall median
sex: female or male
concomitant physical therapy: no or yes
BMI:  overall median or > overall median
use of rituximab or ocrelizumab at the date of randomization: no or yes
use of other DMTs at the date of randomization: no or yes
use of anti-spasticity drugs at the date of randomization: no or yes.
Details on the methods for subgroup analyses are provided in Sections 4.8.2.7 (for the 
primary efficacy endpoint) and 4.8.3 (for the secondary efficacy endpoints).  
4.8.2
Analysis of the Primary Efficacy Endpoint
4.8.2.1
Main Statistical Analysis
The main analysis of the primary efficacy endpoint will be based on the ITT Analysis Set.
A logistic regression model with categorical fixed factors 
randomized study treatment (MD1003, placebo)
disease history (SPMS, PPMS)
geographical region (NA/Australia, Europe) 
will be used to estimate and test the study treatment effect expressed as corresponding 
response probability odds ratio (a value >1 indicates a positive effect of MD1003 compared 
to placebo).
The null hypothesis within the logistic regression model will be
H0: response probability odds ratio related to study treatment  1


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 29 of 61
and the alternative hypothesis will be
HA: response probability odds ratio related to study treatment > 1.
The response probability odds ratio related to study treatment will be estimated together 
with a two-sided 95% profile likelihood CI and the null hypothesis will be rejected if the 
lower CI limit is larger than 1 (this constitutes a one-sided test with significance level 
0.025). 
For descriptive purposes, the estimated effect size for MD1003 for the primary efficacy 
endpoint will be converted (by using overall response probability estimates for each study 
treatment group) from the response probability odds ratio point estimate above to point 
estimates as response probability ratio and response probability difference.
In addition to overall statistical significance for the primary outcome, both elements of the 
composite criterion should be consistent with the overall outcome, i.e., each component 
analysis must display a numerical advantage favoring the MD1003 treatment group but are 
not required to demonstrate statistical significance. 
In case of less than 1% responders in at least one of the study treatment groups, a 
conditional exact logistic regression will be performed: an exact two-sided 95% CI for the 
response probability odds ratio will be obtained and the null hypothesis will be rejected if 
the lower CI limit is larger than 1 (this constitutes a one-sided test with significance level 
0.025). In addition, an exact one-sided p-value will be reported.
The sample size has been determined to have a power of >90% to reject the null hypothesis 
with the test procedure described above if assuming response probabilities of 2% for 
placebo and 12% for MD1003. Note that in the previous MS-SPI study, the response 
probabilities were estimated as 0% for placebo and 12.6% for MD1003.
4.8.2.2
Handling of Missing Values in the Main Analysis
Detailed rules for handling of missing EDSS and/or TW25 values at visits Months 12 and 
15 in the main analysis (Section 4.8.2.1) of the primary efficacy endpoint are included in 
Table 1 below:
Table 1: Handling of missing values for the main analysis of the primary efficacy endpoint
Baseline
Month 12
Month 15
EDSS
TW25
EDSS
TW25
EDSS
TW25
Primary efficacy 
endpoint
missing 
missing6
any
any
any
any
non-response
missing
present
any
any
any
any
depends on TW25
present
missing7 
any
any
any
any
depends on EDSS
present
present
missing
missing
any
any
non-response
6 there is no subject with both baseline EDSS and baseline TW25 missing
7 there is no subject with missing baseline TW25


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 30 of 61
Baseline
Month 12
Month 15
EDSS
TW25
EDSS
TW25
EDSS
TW25
Primary efficacy 
endpoint
present
present
any
any
missing
missing
non-response
present
present
missing
any
any
missing
non-response
present
present
any
missing
missing
any
non-response
present
present
missing
present
any
present
depends on TW25
present
present
any
present
missing
present
depends on TW25
present
present
present
missing
present
any
depends on EDSS
present
present
present
any
present
missing
depends on EDSS
The rationale for this single-imputation method of handling missing data (in essence: if 
missing data makes it impossible to determine the primary endpoint, then it will be imputed 
as “non-response”) is that – considering the progressing population randomized for this 
study with almost no hope for spontaneous improvement over 15 months – non-response 
is the most likely outcome. The method may become anti-conservative if more subjects 
randomized to placebo will have an imputed non-response and there is a non-zero response 
probability for placebo.
4.8.2.3
First Sensitivity Analysis for Handling of Subjects with 12-Weeks Confirmed 
EDSS Progression
The main analysis will be repeated with the following modification of the primary efficacy 
endpoint definition (additional to the criteria specified in Section 3.2.1): 
a subject will be handled as a non-responder in this sensitivity analysis, if 
the subject fulfilled the TW25 improvement criteria of the primary efficacy endpoint 
but not the EDSS improvement criteria of the primary efficacy endpoint (see Section 
3.2.1)  and
the subject experienced a 12-weeks confirmed EDSS progression (as defined in Section 
3.2.2.1) at any time during the double-blind study phase.


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 31 of 61
4.8.2.4
Sensitivity Analyses for Handling of Missing Values
Missing primary efficacy endpoint values are caused by combinations of missing baseline 
EDSS8 and missing EDSS and TW25 values at M12 or M15 visits as described below in 
Table 2. 
Table 2: Sources for missing primary efficacy endpoint values 
Baseline
Month 12
Month 15
EDSS
TW25
EDSS
TW25
EDSS
TW25
Primary efficacy
endpoint
Missing
present
any
missing
any
any
missing
Missing
present
any
any
any
missing
missing
present
present
missing
missing
any
any
missing
present
present
any
any
missing
missing
missing
present
present
missing
any
any
missing
missing
present
present
any
missing
missing
any
missing
Sensitivity analyses will be performed for the primary efficacy endpoint to explore the 
influence of missing primary efficacy endpoint data (due to missing EDSS and/or missing 
TW25 at visits M12 and M15) and methods for handling these missing values on the 
treatment effect. 
Tipping-point sensitivity analysis
Graphical displays, based on the “tipping-point” analysis introduced by Yan 2009, will be 
used to visualize the results of a set of sensitivity analyses (using different single 
“response” / “non-response” imputations for missing primary efficacy endpoint values) for 
comparison of the two study treatments. All possible combinations of single imputations 
of missing primary efficacy endpoint values as “response” or “non-response” in the 
MD1003 and placebo group will be evaluated by logistic regression with study treatment 
as the only factor.  
Figure 1 below is an example graphic taken from Campbell 2011 with 8 missing endpoint 
values in the “Treatment Group” (so one could impute 0 to 8 successes) and 11 missing 
endpoint values in the “Control group” (so one could impute 0 to 11 successes), leading to 
a matrix of (9 times 12 =) 108 combinations to be tested for statistical significance; in the 
example, 10 combinations around the “worst case” (all missing values in the “Control 
Group” were imputed as successes and all missing value in the “Treatment Group” were 
imputed as failures.
8 there is no subject with missing baseline TW25


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 32 of 61
Figure 1 Example for a tipping point analysis summary display
“Enhanced tipping-point displays” (Liublinska 2014) will be provided as compact 
summaries of conclusions drawn from different alternative assumptions.
Multiple imputation sensitivity analysis
This section is following Berglund & Heeringa 2014; this reference will also be used for 
implementation of the approach in SAS.
General approach
Multiple imputation methods replace each missing primary efficacy endpoint value with a 
set of m=10 (somewhat more than the default of 5 in SAS PROC MI) plausible values 
(based on a model predicting values for a missing data point based on available data). This 
set of values represents the uncertainty about the correct value to be imputed. The multiply 
imputed datasets (generated by SAS PROC MI) are then analyzed by the statistical 
procedure (only for asymptotic logistic regression and using the maximum likelihood 
parameter estimates and their standard errors) as complete datasets, followed by combining 
the results from these analyses (by using SAS PROC MIANALYZE). 
Prediction model
The prediction model attempts to predict the primary efficacy endpoint (“response” or 
“non-response”) based on available data (variables) that may have an influence on the 
primary efficacy endpoint. 
The proposed prediction model for the primary efficacy endpoint is a logistic regression 
model with the following covariates:
randomized study treatment: MD1003 or placebo


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 33 of 61
MS disease history: SPMS or PPMS
geographical region NA/AUS or Europe
baseline EDSS: “up to 5.5” or “6 or above”
baseline TW25 (continuous covariate)
age at visit M-1 (continuous covariate)
sex: female or male
BMI at visit M-1 (continuous covariate)
physical therapy after date of randomization and prior to visit M15 assessments: no or 
yes
anti-spasticity drugs after date of randomization and prior to visit M15 assessments: no 
or yes
DMT at date of randomization: no or yes
DMT after date of randomization and prior to visit M15 assessments:
o discontinuation of all DMT (in subjects with DMT present at date of randomization)
o initiation of DMT (in subjects without DMT present at date of randomization)
o or none of the above
corticosteroid treatment after date of randomization and prior to visit M15 assessments: 
no or yes
at least one MS relapse (confirmed by the adjudication committee) with onset after date 
of randomization and prior to visit M15 assessments: no or yes
TW25 at visits M3, M6, M9 (continuous covariate)
EDSS at visits M3, M6, M9: “up to 5.5” or “6 or above”.
Algorithm for the multiple imputation of missing values
Within the Bayesian framework, the task of imputing missing values is achieved by 
drawing random values from the posterior predictive distribution of the missing primary 
efficacy endpoint data (predicted by the logistic regression prediction model specified 
above). This posterior predictive distribution is a function of the observed data and 
regression parameters (or function of regression parameters).
As a monotone missing pattern cannot be expected (for example: there may be subjects 
with a missing TW25 value at visit M3 but a TW25 available at visit M12), the fully 
conditional specification (FCS) method will be used for dealing with arbitrary non-
monotone missing data patterns. The FCS is based on an iterative algorithm; at each 
iteration and for each variable of the prediction model, there is a
prediction step (P-step): the current (iteration) values of the observed and imputed 
values are used to derive the predictive distribution of the missing values
and an imputation step (I-step): updated imputations are generated by draws from the 
predictive distribution defined by the updated logistic regression model.
When the last variable in the sequence (this is the primary efficacy endpoint) has been 
imputed, the algorithm cycles again through each variable, repeating the chain of 


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 34 of 61
regression estimation and imputation draw steps. These cycles are repeated 10 times and 
finally there will m=10 draws from the predictive distribution for each missing primary 
efficacy endpoint value.
Analyzing multiply imputed datasets
Individual statistical analysis (as described in Section 4.8.2.1) will be performed for each 
of the m=10 imputed (complete) datasets and the results will be stored in a single well-
specified output file. In particular, with multiple imputations per missing value, m different 
point and variance estimates for the log odds ratio related to study treatment will be 
computed.
Estimation and inference for multiply imputed datasets
As a final step, the m=10 estimates obtained in the individual statistical analyses of the 
multiply imputed (complete) datasets will be combined for making statistical inference. 
Let 
 denote the point and variance estimates for the log odds ratio related to study 
and
treatment from the i-th imputed complete data set, i=1, 2,…,m.  Then the point estimate for 
the log odds ratio related to study treatment from multiple imputations, , is the average 
of the m imputed (complete) datasets estimates:
=
1
= 1
.
Let 
 denote the average of the m (“within-imputation”) variance estimates
=
1
= 1
and  the estimated (“between-imputation”) variance of the point estimates
=
1
1
= 1
(
)2 .
Then the total variance V of the multiple imputation estimate 
for the log odds ratio related 
to study treatment is estimated as
=
+ (1 +
1)
.
 and  will be used for testing null hypothesis stated in Section 4.8.2.1 and constructing 
two-sided 95% CIs for the log odds ratio related to study treatment:
test statistic
=
is approximately distributed as a t-distribution with degrees of freedom equal to
= (
1) 1 + (1 +
1)
2


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 35 of 61
and the two-sided 95% CI for the log odds ratio related to study treatment is calculated 
as
(
0.975,
,
+
0.975,
).
Finally, the exponential function will be used for transforming point estimates and CI limits 
from the log odds ratio scale to the odds ratio scale.
Sensitivity analyses based on the MITT Analysis Set, FAS and PPS
Sensitivity analyses of the primary efficacy endpoint
based on the MITT Analysis Set
based on those subjects in the FAS for whom EDSS or TW25 is available at M12 and 
M15 and 
based on the PPS (the PPS, by definition, excludes subjects with missing primary 
efficacy endpoint data) 
will be performed.
Note that the last two analyses are “completers analyses”: hence, no handling of missing 
data is required – the results, however, are only valid under the strong assumption of 
“missing completely at random”.
4.8.2.5
Sensitivity Analyses in the Context of the Estimand Concept
The section refers to the draft International Council for Harmonisation (ICH) E9 (R1) 
Addendum on Estimands and Sensitivity Analysis (ICH 2017).
Estimand
For this study, the following description of estimand attributes is provided:
A. Population: subjects fulfilling inclusion/exclusion criteria for “non-relapsing but 
progressing multiple sclerosis (primary or secondary)”
B.
Variable: improvement on EDSS or TW25 (details as defined in Section 3.2.1) at visit 
M12 and visit M15
C.
Expected intercurrent events are: 
events (occurring after the date of randomization and up to the M15 visit) related 
to the inflammatory component of MS: 
o any MS relapse confirmed by the Adjudication Committee
o any new gadolinium enhancing T1-weighted lesion
o any new or enlarging T2-weighted lesion
discontinuation of all DMT present at date of randomization and prior to visit M15 
assessments (in subjects with DMT at date of randomization)
initiation of DMT prior to visit M15 assessments (in subjects without DMT at date 
of randomization) 
corticosteroid treatment after date of randomization and prior to visit M15 
assessments  
end of study treatment prior to visit M15 assessments


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 36 of 61
D. Population-level summary: proportions of responders for each study treatment and 
logistic regression analysis results for comparing them between study treatments 
(details described in Sections 4.8.2.1 and 4.8.2.2).
Treatment policy strategy
Intercurrent events will be handled according to the treatment policy strategy, i.e., the 
intention to treat principle. Indeed, because of the distinct mechanism of action of MD1003 
which targets neuro-degeneration (and not inflammation), it is considered that the 
occurrence of intercurrent events (as listed above under C) are assumed not to be related to 
the study treatments and, therefore, not relevant for the assessment of the effect of MD1003 
compared to placebo. All measurements, regardless of intercurrent events other than 
premature end of study, are planned to be collected throughout the study. The value for the 
variable of interest will be used regardless of whether intercurrent events have occurred, 
and for subjects with premature end of study methods for handling missing data are 
specified in previous Sections 4.8.2.1 and 4.8.2.2. 
The estimand described by the treatment-policy strategy is the effect “MD1003 + any 
intercurrent events” versus “placebo + any intercurrent events”. Thus, dependent on the 
frequency of intercurrent events in both treatment arms, this estimand will capture a 
mixture of the effects of treatment and intercurrent events. 
The estimand is therefore the effect of treatment conditions on the response probabilities 
in the targeted patient population, regardless of whether intercurrent events (as defined 
above in C) had occurred.
Sensitivity analyses related to the estimand concept
The robustness of the estimate derived for the estimand under the treatment policy strategy 
will be further assessed using pre-planned sensitivity analyses that will explore the 
potential influence of the following intercurrent events (as defined in more detail above) 
on the primary efficacy endpoint:
subgroup analysis by occurrence of at least one MS relapse confirmed by the 
Adjudication Committee: no / yes
subgroup analysis by at least one gadolinium enhancing T1-weighted lesion: no / yes
subgroup analysis by at least one new or enlarging T2-weighted lesion: no / yes
subgroup analysis by “active disease” defined by at least one MS relapse confirmed by 
the Adjudication Committee or at least one gadolinium enhancing T1-weighted lesion 
or at least one new or enlarging T2-weighted lesion: no / yes
logistic regression analysis as described in Sections 4.8.2.1 and 4.8.2.2 with additional 
factor “active disease” and its interaction with study treatment
subgroup analysis for “DMT subgroups” defined by 
o discontinuation of all DMT present (in subjects with DMT present at date of 
randomization)
o initiation of DMT (in subjects without DMT present at date of randomization)
o or none of the above


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 37 of 61
logistic regression analysis as described in Sections 4.8.2.1 and 4.8.2.2 but with 
additional factor “DMT” (as defined above) and its interaction with study treatment
subgroup analysis by treatment with corticosteroid: no / yes
logistic regression analysis as described in Sections 4.8.2.1 and 4.8.2.2 but with 
additional factor “corticosteroid treatment” and its interaction with study treatment
subgroup analysis by end of study treatment prior to visit M15: no / yes
logistic regression analysis as described in Sections 4.8.2.1 and 4.8.2.2 but with 
additional factor “end of study treatment prior to visit M15” and its interaction with 
study treatment. 
4.8.2.6
Additional Analyses Related to the Primary Efficacy Endpoint
The logistic model described in Section 4.8.2.1 will be used to analyze each component 
(EDSS, TW25) of the primary efficacy endpoint separately. In case of less than 1% 
responders in at least one of the study treatment groups, a conditional exact logistic 
regression will be performed. The handling of missing data for each component will follow 
the logic described in Section 4.8.2.2.  
Number and percentage of subjects with  
EDSS or TW25 improvement
EDSS improvement
TW25 improvement
will be presented by visit and study treatment group, including two-sided 95% CIs for 
response probabilities to assess the development over time. For this “by visit” summary, 
only confirmation at the subsequent visit will be considered as a response, i.e., M3 
confirmed M6, M6 confirmed at M9, M9 confirmed at M12, M12 confirmed at M15, M15 
confirmed at M18, M18 confirmed M21, M21 confirmed at M24, M24 confirmed at M27.
4.8.2.7
Subgroup Analyses
A specific subgroup analysis will be performed for the subgroups defined by MS disease 
history (SPMS or PPMS) by using the logistic regression model of the primary efficacy 
endpoint separately for SPMS and PPMS subjects in the ITT Analysis Set. The two 
separate logistic regression analyses9 will now have the factors study treatment group and 
geographical region and will provide the
point estimate for the response probability odds ratio related to study treatment
two-sided 95% profile likelihood CI for that odds ratio 
separately for SPMS subjects and for PPMS subjects. 
Respective null hypotheses will be rejected if the respective lower CI limit is larger than 1, 
but only if the null hypothesis for the primary efficacy endpoint based on the ITT Analysis 
Set of all PMS subjects will have been rejected. 
9 conditional exact logistic regression in case of less than 1% responders in at least one of the study treatment 
groups


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 38 of 61
A forest-plot displaying odds ratios comparing study treatment groups and related two-
sided 95% confidence intervals will be provided for all subgroups defined in Section 
4.8.1.5.
4.8.3
Analysis of Secondary Efficacy Endpoints
Multiplicity regarding testing of null hypotheses for secondary efficacy endpoints will be 
handled according to the sequential conditional testing procedure described in Section 
4.8.1.3.
4.8.3.1
Time to 12-Weeks Confirmed EDSS Progression
Main analysis
The main analysis will be performed for the ITT analysis set.
Time to 12-weeks confirmed EDSS progression will be graphically presented using Kaplan 
Meier curves. If available, Q1 and median time to 12-weeks confirmed EDSS progression 
and 95% CIs for each study treatment group will be estimated according to the method by 
Brookmeyer & Crowley 1982.
A proportional hazards regression model stratified by MS disease history and geographical 
region will be used to estimate and test the effect of MD1003 relative to placebo on time 
to 12-weeks confirmed EDSS regression. 
The model and its assumptions are described by: 
(
) =
exp(
)
h(.)
hazard function as a function of time t relative to date of randomization, study 
treatment of subject j in stratum k and the unknown regression parameter 
h0k(t)
unspecified baseline hazard function for stratum k at time t
xjk
study treatment for subject j in stratum k 
unknown model parameter (the log hazard ratio) for the study treatment effect 
(MD1003 relative to placebo) on the log-scale, to be estimated
The hazard ratio is a multiplicative constant  = exp( ) comparing the hazard function for 
12-weeks confirmed EDSS progression in the MD1003 treatment group to the hazard 
function for 12-weeks confirmed EDSS progression in the placebo treatment group. The 
latter is the baseline hazard function, which is allowed to vary across the four strata. 
However, the hazard ratio comparing treatments is assumed to be common across strata. A 
hazard ratio < 1 indicates decreased hazard for 12-weeks confirmed EDSS progression in 
the MD1003 study treatment group compared to the placebo treatment group.
The null hypothesis within the stratified proportional hazard regression model will be
H0: hazard ratio   1
and the alternative hypothesis will be
HA: hazard ratio  < 1.


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 39 of 61
The hazard ratio will be estimated together with a two-sided 95% Wald-type CI, and the 
null hypothesis will be rejected if the upper Wald-type CI limit is smaller than 1 (in 
addition, a one-sided Wald-test p-value will be reported). Ties will be handled by the 
“exact” method.
Summaries for 12-weeks confirmed time to EDSS progression by study treatment group 
will include:
Kaplan-Meier plot
number and percentage of subjects having a 12-weeks confirmed EDSS progression, 
number and percentage of subjects censored, 
estimated Q1 and median time to 12-weeks confirmed EDSS progression and two-sided 
95% CI, if available
progression-free probabilities at months 6, 9, 12, 15 and 18 estimated by the Kaplan-
Meier method and its two-sided 95% CIs using the log-log transformation 
results of a stratified proportional hazards regression analysis (hazard ratio and its two-
sided 95% CI)
Kaplan Meier plots by study treatment group will also be provided by disease history 
(SPMS/PPMS) and by geographical region.
Handling of missing data in the main analysis 
For the analysis of time to 12-weeks confirmed EDSS progression, there are 3 types of 
“missing data”:
A. administrative censoring caused by a subject completing the double-blind study phase 
without a 12-weeks confirmed EDSS progression and without any missing scheduled 
EDSS assessment: this constitutes administrative censoring and time to 12-weeks 
confirmed EDSS progression will be censored at the date of the last available scheduled 
EDSS assessment
example1: 5 at baseline, 5 at M3, 5 at M6, 5.5 at M9, 5 at M12, 5.5 at M15, 5.5 at M18, 
5.5 at M21 
example2: 5 at baseline, 5 at M3, 5 at M6, 5.5 at M9, 5 at M12, 5.5 at M15, 5.5 at M18, 
6 at M21
In both examples, M21 was the final visit of the double-blind study phase as this study 
phase was closed according to the rules specified in Section 3.1.3 
 both examples are 
handled as censored at the M21 visit date
B. a subject prematurely discontinues the double-blind study phase without a 12-weeks 
confirmed EDSS progression and without any missing scheduled EDSS assessment 
prior to his/her end of double-blind study phase: time to 12-weeks confirmed EDSS 
progression will be censored at the date of the last available scheduled EDSS 
assessment
example1: 5 at baseline, 5.5 at M3, 6 at M6, all subsequent EDSS assessments missing 
example2: 5 at baseline, 5.5 at M3, 5.5 at M6, all subsequent EDSS assessments 
missing
 
 both examples are handled as censored at the M6 visit date


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 40 of 61
C. a subject has one or more missing scheduled EDSS assessments prior to the his/her end 
of the double-blind study phase
C1 – a 12-weeks confirmed EDSS progression occurred prior to the first of such 
missing scheduled EDSS assessments: the missing EDSS assessments are 
irrelevant for the determination of the endpoint for such a subject, so no action 
required 
example1: 5 at baseline, 6 at M3, 6 at M6, missing at M9, missing at M12, 6 at M15 
 handled as 12-weeks confirmed EDSS progression at the M3 visit date
example2: 5 at baseline, 6 at M3, 6 at M6, missing at M9, 5.5 at M12 
 handled 
as 12-weeks confirmed EDSS progression at the M3 visit date
C2 – the previous and subsequent scheduled EDSS assessments are available and 
at most one of them constitute a relevant EDSS increase (as defined in Section 
3.2.2.1): the missing scheduled EDSS assessment(s) is/are or is/are viewed as 
irrelevant for the determination of the endpoint 12-weeks confirmed EDSS 
progression for such a subject (it can only occur at a visit later than those with 
missing EDSS assessments)
example1: 5 at baseline, 5.5 at M3, missing at M6, 5.5 at M9 
 missing EDSS assessment at M6 is irrelevant
example2: 5 at baseline, 5.5 at M3, missing at M6, missing at M9, 6 at M12 
 missing EDSS assessments at M6 and M9 are viewed as irrelevant; earliest time 
point for a 12-weeks confirmed EDSS progression can be M12 (if there would be 
a confirmation at M15)
example3: 5 at baseline, 6 at M3, missing at M6, 5.5 at M9 
 missing EDSS assessment at M6 is viewed to be irrelevant as EDSS 5.5 at M9 
does not constitute a relevant EDSS increase (as defined in Section 3.2.2.1); earliest 
time point for a 12-weeks confirmed EDSS progression can be M12 (if there would 
be a confirmation at M15) 
C3 – the previous and subsequent scheduled EDSS assessments are available and 
both of them constitute a relevant EDSS increase (as defined in Section 3.2.2.1): 
the missing scheduled EDSS assessment(s) is/are irrelevant, the subject is handled 
as having a  12-weeks confirmed EDSS progression at the earlier of the two visit 
dates
example1: 5 at baseline, 6 at M3, missing at M6, 6 at M9 
 missing EDSS assessment at M6 is irrelevant, 12-weeks confirmed EDSS 
progression at the M3 visit date
example2: 5 at baseline, 6 at M3, missing at M6, missing at M9, 6 at M12 
 missing EDSS assessments at M6 and M9 are irrelevant, 12-weeks confirmed 
EDSS progression at the M3 visit date.


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 41 of 61
First sensitivity analysis with additional censoring rule
The main analysis will be repeated with the following additional censoring rule: 
if a subject meets the EDSS-based response criteria at M12 and M15 for the primary 
efficacy endpoint (see Section 3.2.1), then the subject is not considered as having 12-
week confirmed EDSS progression
that subject’s time to 12-weeks confirmed EDSS progression will be censored at the 
date of the last EDSS assessment at a scheduled visit in the double-blind study phase 
regardless of whether the criteria of 12-week confirmed EDSS progression are met or 
not. 
Sensitivity analyses for handling of missing values
As censoring rules for handling missing values of types A and B may introduce informative 
censoring and too long censored observation times, the following alternative rules for types 
A and B will be used to assess such potential bias by a sensitivity analysis (censoring for 
EDSS improvements at M12 and M15 will not be applied):
A. administrative censoring caused by a subject completing the double-blind study phase 
without a 12-weeks confirmed EDSS progression and without any missing scheduled 
EDSS assessment: this constitutes administrative censoring and time to 12-weeks 
confirmed EDSS progression will be censored at the date of the last available scheduled 
EDSS assessment not constituting a relevant EDSS increase (as defined in Section 
3.2.2.1)
example1: 5 at baseline, 5 at M3, 5 at M6, 5.5 at M9, 5 at M12, 5.5 at M15, 5.5 at M18, 
5.5 at M21 
example2: 5 at baseline, 5 at M3, 5 at M6, 5.5 at M9, 5 at M12, 5.5 at M15, 5.5 at M18, 
6 at M21
In both examples, M21 was the final visit of the double-blind study phase as this study 
phase was closed according to the rules specified in Section 3.1.3 
 example 1 handled 
as censored at the M21 visit date, example 2 handled as censored at the M18 visit date
B. a subject prematurely discontinues the double-blind study phase without a 12-weeks 
confirmed EDSS progression and without any missing scheduled EDSS assessment 
prior to his/her end of double-blind study phase: 
B1 – the last available scheduled EDSS assessment constitutes a relevant EDSS 
increase (as defined in Section 3.2.2.1): the subject will be handled as having a 12-
weeks confirmed EDSS progression and the date of the 12-weeks confirmed EDSS 
progression will be the date of the last available scheduled EDSS assessment
example: 5 at baseline, 5.5 at M3, 6 at M6, all subsequent EDSS assessments 
missing 
 handled as 12-weeks confirmed EDSS progression at the M6 visit date
B2 – the last available scheduled EDSS assessment does not constitute a relevant 
EDSS increase (as defined in Section 3.2.2.1): this will be handled as censored 
subject, and the censoring date will be the date of the last available scheduled EDSS 
assessment
example: 5 at baseline, 5.5 at M3, 5.5 at M6, all subsequent EDSS assessments 
missing 
 handled as censored at the M6 visit date.


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 42 of 61
Multiple imputation sensitivity analysis
Censoring for EDSS improvements at M12 and M15 will not be applied for this sensitivity 
analysis. The same general approach for multiple imputation as outlined in Section 4.8.2.4 
will be followed. The proposed prediction model for missing EDSS assessments, 
dichotomized as either “relevant EDSS increase from baseline” (as defined in Section 
3.2.2.1) or “no relevant EDSS increase from baseline” is a logistic regression model with 
the following covariates:
randomized study treatment: MD1003 or placebo
MS disease history: SPMS or PPMS
geographical region NA/AUS or Europe
baseline EDSS: “5.5 or below” or “6 or above”
baseline TW25 (continuous covariate)
age at visit M-1 (continuous covariate)
sex: female or male
BMI at visit M-1 (continuous covariate)
physical therapy after date of randomization and prior to the date of the first missing 
EDSS assessment: no or yes
anti-spasticity drugs after date of randomization and prior to the date of the first missing 
EDSS assessment: no or yes
DMT at date of randomization: no or yes
DMT after date of randomization and prior to the date of the first missing EDSS 
assessment:
o discontinuation of all DMT (in subjects with DMT present at date of randomization)
o initiation of DMT (in subjects without DMT present at date of randomization)
o or none of the above
corticosteroid treatment after date of randomization and prior to the date of the first 
missing EDSS assessment: no or yes
at least one MS relapse (confirmed by the adjudication committee) with onset after date 
of randomization and prior to the date of the first missing EDSS assessment: no or yes
TW25 (continuous covariate) at the scheduled visit with the first missing EDSS 
assessment; if also missing, then the latest available TW25 at a previous scheduled visit
relevant EDSS increase (as per SAP Section 3.2.2.1) at M3 Visit: no or yes
relevant EDSS increase (as per SAP Section 3.2.2.1) at M6 Visit: no or yes
relevant EDSS increase (as per SAP Section 3.2.2.1) at M9 Visit: no or yes
relevant EDSS increase (as per SAP Section 3.2.2.1) at M12 Visit: no or yes
relevant EDSS increase (as per SAP Section 3.2.2.1) at M15 Visit: no or yes
relevant EDSS increase (as per SAP Section 3.2.2.1) at M18 Visit: no or yes
relevant EDSS increase (as per SAP Section 3.2.2.1) at M21 Visit: no or yes


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 43 of 61
relevant EDSS increase (as per SAP Section 3.2.2.1) at M24 Visit: no or yes
relevant EDSS increase (as per SAP Section 3.2.2.1) at M27 Visit: no or yes.
The algorithm for the multiple imputation of missing EDSS assessments will be FCS as 
described in Section 4.8.2.4 and the multiply imputed datasets will be analyzed by the 
stratified proportional hazards model. The multiple imputation point estimate and two-
sided 95% CI for the log hazard ratio will be obtained (similar as described in Section 
4.8.2.4 for the log odds ratio) and finally transformed to point estimate and CI for the 
multiple imputation hazard ratio.
Sensitivity analysis based on the MITT Analysis Set
Sensitivity analysis based on the MITT Analysis Set (otherwise following the main 
analysis) will be conducted.
Subgroup analyses
A specific subgroup analyses will be performed for the subgroups defined by MS disease 
history (SPMS or PPMS): there will be analyses (Kaplan-Meier plots and proportional 
hazards regression model) of time to 12-weeks confirmed EDSS progression (as per the 
main analysis) separately for SPMS and PPMS subjects in the ITT Analysis Set. The two 
separate proportional hazard regression analyses will now be stratified by geographical 
region and will provide the
point estimate for the hazard ratio related to study treatment
two-sided 95% CI for that hazard ratio 
separately for SPMS subjects and for PPMS subjects. 
Respective null hypotheses will be rejected if the respective lower CI limit is larger than 1, 
but only if the null hypothesis for time to 12-weeks confirmed EDSS progression based on 
the ITT Analysis Set of all PMS subjects will have been rejected. 
A forest-plot displaying hazard ratios comparing study treatment groups and related two-
sided 95% CIs for the hazard ratios will be provided for all subgroups defined in Section 
4.8.1.5.
4.8.3.2
Analysis of Clinical Global Impression of Improvement
The following summaries will be provided by study treatment group:
number and percentage of subjects for each CGI category
number and percentage of subjects for each SGI category.  
Let 
, 
, 
 and 
 denote the probabilities for 
category i, i=1,..,7 of CGI and SGI for MD1003 and placebo, respectively, at visit M15.
Null hypothesis for CGI at visit M15 is stated as
0, 
: the distributions in both study treatment groups are the same, i.e.,
=
 for all = 1,..,6


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 44 of 61
with alternative hypothesis for CGI at visit M15
: 
the distribution in the MD1003 treatment group is stochastically strictly smaller 
(less) than the distribution in the placebo treatment group, i.e.,
= 1
= 1
for all = 1,..,6  and
= 1
>
= 1
for at least one in {1,..,6}.
Null hypothesis for SGI at visit M15 is stated as
0, 
: the distributions in both study treatment groups are the same, i.e.,
=
 for all = 1,..,6
with alternative hypothesis for SGI at visit M15
: the distribution in the MD1003 treatment group is stochastically
strictly smaller (less)
than the distribution in the placebo treatment group, i.e.,
= 1
= 1
for all = 1,..,6  and
= 1
>
= 1
for at least one in {1,..,6}.
CGI and SGI at visit M15 will be compared between study treatment groups using the non-
parametric one-sided van Elteren test stratified by MS disease history and geographical 
region (one-sided significance level 0.025). The one-sided van Elteren test is a stratified 
version of the one-sided Wilcoxon (Mann-Whitney) test: ranks and Wilcoxon scores will 
be generated separately within each stratum and the four by-stratum statistics will be 
weighted by the stratum sizes.
In addition, MD1003 and placebo will be compared by the terms P(CGIMD1003 < CGIplacebo) 
and P(SGIMD1003 < SGIplacebo). For example, P(CGIMD1003 < CGIplacebo) can be interpreted as 
the probability of achieving a better CGI outcome (lower CGI score) for a randomly chosen 
subject of the MD1003 group compared to a randomly chosen subject of the placebo group.  
These quantities are estimated by comparing CGI (SGI) at visit M15 for all nMD1003 subjects 
to CGI (SGI) at visit M15 of all mplacebo subjects: counting the pairs where CGI (SGI) in 
the MD1003 group is better (smaller) and dividing this count by the number of all pairs: 
nMD1003×mPlacebo. Two-sided 95% CIs for P(CGIMD1003 < CGIplacebo) and P(SGIMD1003 < 
SGIplacebo) will be provided as well.


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 45 of 61
Handling of missing data in the main analysis 
The general multiple imputation approach as outlined in Section 4.8.2.4 will be applied. 
The proposed prediction model for missing CGI (SGI) values at visit M15, is a logistic 
regression model with the following covariates:
randomized study treatment: MD1003 or placebo
MS disease history: SPMS or PPMS
geographical region NA/AUS or Europe
baseline EDSS: “up to 5.5” or “6 or above”
baseline TW25 (continuous covariate)
age at visit M-1 (continuous covariate)
sex: female or male
BMI at visit M-1 (continuous covariate)
physical therapy after date of randomization and prior to visit M15 assessment: no or 
yes
anti-spasticity drugs after date of randomization and prior to visit M15 assessment: no 
or yes
DMT at date of randomization: no or yes
DMT after date of randomization and prior to the date of visit M15 assessment:
o discontinuation of all DMT (in subjects with DMT present at date of randomization)
o initiation of DMT (in subjects without DMT present at date of randomization)
o or none of the above
corticosteroid treatment after date of randomization and prior to visit M15 assessment: 
no or yes
at least one MS relapse (confirmed by the adjudication committee) with onset after date 
of randomization up to visit M15 assessment: no or yes
TW25 at visits M3, M6, M9, M12 (continuous covariate)
EDSS at visits M3, M6, M9, M12, M15: “up to 5.5” or “6 or above”.
A refinement of the prediction model may be proposed at the Blinded Data Review Meeting 
prior to unblinding of the randomization.
Derivation of multiple imputation p-value based on the stratified van Elteren test  
The algorithm for the multiple imputation of missing CGI (SGI) values at visit M15 will 
be FCS as described in Section 4.8.2.4 and the multiply imputed datasets will be analyzed 
by van Elteren tests stratified by MS history and geographical region: the difference 
between observed stratified sum of Wilcoxon scores and the expected stratified sum of 
Wilcoxon scores together with its standard deviation will be obtained from each multiply 
imputed dataset. The combination of these results and the final derivation of multiple 
imputation p-values for CGI (SGI) will be performed in analogy to the description in 
Section 4.8.2.4.


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 46 of 61
Derivation of multiple imputation probability estimates  
For each multiply imputed dataset, the estimate for P(CGIMD1003 < CGIplacebo) its standard 
deviation will be obtained. The combination of these results and the final derivation of 
multiple imputation point estimate and two-sided 95% CI for P(CGIMD1003 < CGIplacebo) will 
be performed in analogy to the description in Section 4.8.2.4. The same applies for 
P(SGIMD1003 < SGIplacebo).
Sensitivity analyses based on the MITT Analysis Set
A sensitivity analysis based on the MITT Analysis Set will be performed.
Subgroup Analysis
A forest-plot displaying P(SGIMD1003 < SGIplacebo) estimates comparing study treatment 
groups, the related two-sided 95% CIs and the one-sided p-value of the stratified van 
Elteren test will be provided for the subgroups defined in Section 4.8.1.5. The same applies 
for CGI.
4.8.3.3
Analysis of TW25
A summary of TW25 values and percentage changes from baseline will be provided by 
visit and study treatment group. Note:  If a subject performed only one of the two TW25 
attempts at a visit, then the available TW25 value will be used as the subject’s mean value 
for that visit.
Null hypothesis for percentage change in TW25 from baseline (defined in 3.2.2.3) to visit 
M15 is stated as
the distributions in both study treatment groups are the same
0: 
with alternative hypothesis:
the distribution in the MD1003 treatment group is stochastically strictly smaller (less) 
: 
than the distribution in the placebo treatment group, i.e.,
(%change in TW
)
(%change in TW
) for all  and
(%change in TW
) >
(%change in TW
) for some 
The percentage change in TW25 from baseline to visit M15 will be compared between 
study treatment groups using the non-parametric one-sided van Elteren test stratified for 
MS disease history and geographical region (same approach as described in Section 
4.8.3.2, one-sided significance level 0.025). 
In addition, the Hodges-Lehman point estimate for shift of distributions and its two-sided 
95% CI will be provided.
Handling of missing data in the main analysis 
If both TW25 values at a visit are missing due to inability to perform the trials because of 
MS worsening, then the following single imputation rule will be applied:
the maximum TW25 value observed in the ITT Analysis Set (at any scheduled visit 
and in any study treatment group) will be identified


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 47 of 61
impute that value + 1 second for the missing TW25 value at that visit.
For remaining missing TW25 values, the general multiple imputation approach as outlined 
in Section 4.8.2.4 will be applied. The proposed prediction model for missing TW25 values 
at visit M15, is a linear regression model with the following covariates:
randomized study treatment: MD1003 or placebo
MS disease history: SPMS or PPMS
geographical region NA/AUS or Europe
baseline EDSS: “up to 5.5” or “6 or above”
baseline TW25 (continuous covariate)
age at visit M-1 (continuous covariate)
sex: female or male
BMI at visit M-1 (continuous covariate)
physical therapy after date of randomization and prior to visit M15 assessment: no or 
yes
anti-spasticity drugs after date of randomization and prior to visit M15 assessment: no 
or yes
DMT at date of randomization: no or yes
DMT after date of randomization and prior to the date of visit M15 assessment:
o discontinuation of all DMT (in subjects with DMT present at date of randomization)
o initiation of DMT (in subjects without DMT present at date of randomization)
o or none of the above
corticosteroid treatment after date of randomization and prior to visit M15 assessment: 
no or yes
at least one MS relapse (confirmed by the adjudication committee) with onset after date 
of randomization and prior to visit M15 assessment: no or yes
TW25 at visits M3, M6, M9, M12 (continuous covariate)
EDSS at visits M3, M6, M9, M12, M15: “up to 5.5” or “6 or above”.
A refinement of the prediction model may be proposed at the Blinded Data Review Meeting 
prior to unblinding of the randomization.
The algorithm for the multiple imputation of missing TW25 values at visit M15 will be 
FCS as described in Section 4.8.2.4 (an additional condition is that negative TW25 
imputations must be avoided: in case a negative TW25 value is predicted by the regression 
model, it will be replaced by the minimum observed value in the respective study treatment 
group). The percentage change in TW25 from baseline to visit M15 will be calculated for 
all subjects with multiply imputed TW25 values at visit M15.
Derivation of multiple imputation p-value based on the stratified van Elteren test  
The multiply imputed datasets will be analyzed by van Elteren tests stratified by MS history 
and geographical region: the difference between observed stratified sum of Wilcoxon 


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 48 of 61
scores and the expected stratified sum of Wilcoxon scores together with its standard 
deviation will be obtained from each multiply imputed dataset. The combination of these 
results and the final derivation of multiple imputation p-value for percentage change in 
TW25 from baseline to visit M15 will be performed in analogy to the description in Section 
4.8.2.4.
Derivation of multiple imputation location shift estimates  
For each multiply imputed dataset, the Hodges-Lehmann point estimate for location shift 
and its standard deviation will be obtained. The combination of these results and the final 
derivation of multiple imputation point estimate and two-sided 95% CI for the location 
shift in percentage change in TW25 from baseline to visit M15 will be performed in 
analogy to the description in Section 4.8.2.4.
Sensitivity analyses based on the MITT Analysis Set
A sensitivity analysis based on the MITT Analysis Set will be performed.
Subgroup Analysis
A forest-plot displaying Hodges-Lehmann location shift estimates comparing study 
treatment groups, related two-sided 95% CIs and the one-sided p-value of the stratified van 
Elteren test will be provided for the subgroups defined in Section 4.8.1.5.
4.8.4
Analysis of Exploratory Efficacy Endpoints
Analysis of exploratory efficacy endpoints will be based on the ITT Analysis Set.
4.8.4.1
Analysis of Exploratory Brain MRI Endpoints
Exploratory brain MRI data will be summarized by visit and study treatment group.  The 
respective endpoints, defined in Section 3.2.3.1, will be analyzed by the non-parametric 
van Elteren test stratified by MS disease history and geographical region. 
4.8.4.2
Analysis of Remote Monitoring of Ambulatory Activity
A summary of average daily step counts and changes from baseline in average daily step 
counts will be provided by visit and study treatment group.
The change from baseline in average daily step counts will be compared between study 
treatment groups using a mixed model repeated measures approach with fixed effects
MS disease history
geographical region
study treatment group
month of study visit
visit-by-study treatment group interaction
and random subject effect.
The covariance matrix for the random subject effect will be block diagonal (with each 
block corresponding to a subject) with unstructured non-zero block diagonal elements as 


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 49 of 61
defaults. An alternative structure for the block diagonal part of the covariance matrix for 
the random subject effect is the spatial power law structure in order to reduce the number 
of parameters to be estimated. Akaike’s Information Criteria and Schwarz’ Bayesian 
Criterion are used to assist in the selection process for the covariance structure. A 
converging model with the better criterion value could be used as justification for using 
that covariance structure. 
Hypotheses related to study treatment are expressed as linear combinations of fixed effects 
given above. Least squared means point estimates and two-sided 95% CIs will be provided.
4.8.4.3
Analysis of MSQOL-54 and CAREQOL-MS
MSQOL-54 summary scores and CAREQOL-MS sub-scores as well as changes from 
baseline will be summarized by visit and study treatment group. Changes from baseline to 
visit M15 will be analyzed by the non-parametric van Elteren test stratified by MS disease 
history and geographical region. 
4.8.4.4
Analysis of Kurtzke Functional System Scores
Descriptive summaries of Kurtzke Functional System Scores and change from baseline 
will be presented by visit and study treatment group.
Change from baseline to visit M15 will be analyzed for each Kurtzke Functional System 
Score by the non-parametric van Elteren test stratified by MS disease history and 
geographical region. 
4.8.4.5
Analysis of Symbol Digit Modalities Test
SDMT as well as changes from baseline (including the categorized version defined in 
Section 3.2.3.5) will be summarized by visit and study treatment group. SDMT at visit 
M15 and changes from baseline to visit M15 will be analyzed by the non-parametric van 
Elteren test stratified by MS disease history and geographical region.
4.8.4.6
Analysis of Neurofilament Blood Concentration
Neurofilament blood concentration as well as absolute change from baseline will be 
summarized by visit and study treatment group.
Absolute changes from baseline in neurofilament blood concentration will be compared between 
study treatment groups using a mixed model repeated measures approach with fixed effects
MS disease history
geographical region
DMT at date of randomization (no or yes)
study treatment group
month of study visit
visit-by-study treatment group interaction
and random subject effect.
The covariance matrix for the random subject effect will be block diagonal (with each 
block corresponding to a subject) with unstructured non-zero block diagonal elements as 


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 50 of 61
defaults. An alternative structure for the block diagonal part of the covariance matrix for 
the random subject effect is the spatial power law structure in order to reduce the number 
of parameters to be estimated. Akaike’s Information Criteria and Schwarz’ Bayesian 
Criterion are used to assist in the selection process for the covariance structure. A 
converging model with the better criterion value could be used as justification for using 
that covariance structure. 
Hypotheses related to study treatment are expressed as linear combinations of fixed effects 
given above. Least squared means point estimates and two-sided 95% CIs will be provided.
4.9
Safety Evaluation
All safety summaries and analyses will be based on the Safety Analysis Set. Listings will 
include raw and derived safety data.
4.9.1
Analysis of Extent of Exposure
A summary of the duration of treatment will be provided by study treatment group.  
4.9.2
Analysis of Duration of Study
A summary of the duration of study (length of follow-up) will be provided by study 
treatment group.  
4.9.3
Analysis of Adverse Events
The following summaries will be provided:
overall summary of the number and percentage of subjects reporting any TEAE, any 
TEAE causally related to study medication, any TEAE causally related to study 
procedure, any serious TEAE, any serious TEAE causally related to study medication, 
any TEAE leading to treatment discontinuation, any TEAE leading to death and number 
of deaths (the number of respective AEs will also be reported)
number and percentage of subjects reporting a TEAE by treatment group, SOC, and PT
number and percentage of subjects reporting a TEAE by treatment group, severity, SOC 
and PT
number and percentage of subjects reporting a treatment-emergent adverse event by 
treatment group, causality to study treatment, SOC and PT
number and percentage of subjects reporting a treatment-emergent adverse event by 
treatment group, causality to study procedure, SOC and PT.
Adverse event summaries will be ordered in terms of decreasing incidence for SOC, and 
PT within SOC, in the MD1003 treatment group, and then similarly by decreasing 
frequency in the Placebo group, and then alphabetically for SOC, and PT within SOC.
For each subject and each adverse event, the worst severity recorded will be attributed and 
used in the by-severity summaries. Similarly, the worst causality (most related to 
treatment) will be attributed and used in the by-causality summaries. If severity or causality 
is missing, the worst case will be assumed.


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 51 of 61
4.9.4
Deaths, Serious Adverse Events, and Other Significant Adverse Events
The following summaries will be provided:
number and percentage of subjects reporting treatment emergent SAEs by treatment 
group, SOC, and PT
number and percentage of subjects reporting treatment emergent SAEs assessed as 
causally related to study medication by treatment group, SOC, and PT
number and percentage of subjects reporting TEAEs leading to death by treatment 
group, SOC, and PT
number and percentage of subjects reporting TEAEs leading to study treatment 
discontinuation by treatment group, SOC, and PT
number and percentage of subjects reporting a TEAEs of suicidal ideation or behavior 
by treatment group, SOC, and PT.
In particular, the following listings will be provided:
listing of all deaths that occurred during the study
listing of all SAEs
listing of all AEs leading to discontinuation of study treatment
listing of all AEs of suicidal ideation or behavior.
4.9.5
Analysis of Relapses
Annualized rates of relapses reported by investigators will be calculated by study treatment 
group as shown below: 
=
365.25
For each subject, “days at risk for a relapse” is defined as date of subject’s last visit in the 
double-blind study part minus the date of randomization + 1”. The “sum of days at risk for 
a relapse” is the sum across all subjects of the respective study treatment group. 
The annualized relapse rates based on only relapses confirmed by the Adjudication 
Committee will also be calculated accordingly.
The following summaries of relapses reported by investigators will be provided by study 
treatment group:
number and percentage of subjects with at least one relapse 
Kaplan-Meier curve for time from randomization date to onset date of subject’s first 
relapse
number of relapses per subject
total number of relapses and for those relapses:
o type of relapse (protocol defined, non-protocol defined and suspected relapse)
o number and percentage of relapses treated with steroid
annualized relapse rate (all, protocol defined, non-protocol defined and suspected 
relapse).


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 52 of 61
Further summaries related to relapses will be provided by study treatment group:
Kaplan-Meier curve for time from randomization to onset date of subject’s first relapse 
confirmed by the Adjudication Committee
annualized rate of relapses confirmed by the Adjudication Committee
relapse interpretation compared between investigator and Adjudication Committee.
4.9.6
Analysis of Safety Brain MRI Endpoints
Safety Brain MRI endpoints will be summarized descriptively by visit and study treatment 
group.
4.9.7
Analysis of Clinical Laboratory Tests
The following summaries will be provided by laboratory test and study treatment group:
laboratory test value and change from baseline by visit
number and percentage of subjects experiencing the worst of normal, abnormal not 
clinically meaningful or abnormal clinically meaningful laboratory test result as 
determined by the Site Investigator
number and percentage of subjects shifting from baseline category to worst post-
baseline value (categories of normal, abnormal not clinically significant, or abnormal 
clinically significant laboratory test result). 
4.9.8
Analysis of ECG results
The following summaries of ECG reporting will be provided:
ECG parameter and change from baseline by treatment group and time point
number and percentage of subjects with QT or QTc intervals exceeding predefined 
upper limit (>450ms, >480ms and >500ms), the number and percentage of subjects with 
change from baseline in QT or QTc intervals exceeding predefined upper limit ( >30ms, 
>60ms) and the combination of these 2 conditions
number and percentage of subjects with ECG abnormalities by treatment group
shift table for ECG abnormalities from baseline by treatment group.
A listing of ECG data with abnormal values flagged will be provided. 
4.9.9
Analysis of the Columbia-Suicide Severity Rating Scale
The following summaries will be provided by visit and study treatment group:
C-SSRS total score and change from baseline
suicidal ideation and suicidal behavior component scores.
4.9.10  Analysis of Vital Signs
The following summaries of vital signs (including BMI) will be provided by visit and study 
treatment group:
vital sign and change from baseline


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 53 of 61
number and percentage of subjects experiencing normal, abnormal not clinically 
significant, or abnormal clinically significant vital sign.
4.10 Other Analyses
4.10.1 Treatment Assignment Questionnaire
Treatment assignment questionnaire is performed at the end of the randomization period 
or at study termination visit to assess whether the subject and the investigator guessed 
which treatment the subject was receiving.
The following tables will be presented by study treatment group
a comparison table of the subject versus the investigator interpretation of study 
treatment
a table of the subject and investigator interpretation of study treatment by whether or 
not the subject had an adverse event.
A listing of the treatment assignment questionnaire will be provided.
4.10.2 Study Treatment Compliance
The following tables will be presented by study treatment group:
summary of study treatment compliance in the double-blind study phase up to the M15 
visit (including)
summary of study treatment compliance in the overall double-blind study phase.
A listing of compliance results by subject will be provided. 
4.10.3 Study Treatment Interruptions
The following tables will be presented by study treatment group.
For the double-blind study phase up to the M15 visit (including):
summary of number of study treatment interruptions per subject
summary of subjects with no / at least one study treatment interruption
summary of durations of study treatment interruptions.
For the overall double-blind study phase:
summary of number of study treatment interruptions per subject
summary of subjects with no / at least one study treatment interruption
summary of durations of study treatment interruptions.
A listing of study treatment interruptions by subject will be provided, including the reason 
for study treatment interruption. 


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 54 of 61
4.11 Changes in the Conduct of the Study or Planned Analysis
Study Protocol 4 (dated 12-Nov-2018) has been the last study protocol version prior to this 
final version of the SAP. There were no changes in the conduct of the study since then, but 
there was a mistake in Study Protocol 4: the randomization was in fact stratified by disease 
history and center (study site), not by disease history and geographical region as stated.
Relevant changes in the planned statistical analyses of primary and secondary efficacy 
endpoints are summarized in Table 3 below.
Table 3: Relevant changes in planned statistical analyses from last study protocol version to final SAP
Study Protocol version 4 
Final SAP 6.0
Justification for change
Intent-to-treat population
Intent-to-treat analysis set
Changed per ICH terminology
Not included
Modified intent-to-treat 
analysis set
Included to allow sensitivity 
analyses excluding subjects with 
high biotin plasma 
concentrations at baseline or 
post-baseline (the latter if 
randomized to placebo)
Full analyzable set
Full analysis set
Changed per ICH terminology
Per Protocol population
Per-protocol analysis set
Changed per ICH terminology 
and criteria more specific for the 
primary efficacy endpoint 
Two-sided significance 
levels of 0.05
One-sided significance 
levels of 0.025
Study objective is demonstration 
of MD1003’s superiority over 
placebo, i.e., a clearly one-sided 
hypothesis setting; one-sided 
approach simplifies the 
sequential conditional testing 
procedure for the multiple 
secondary efficacy endpoints
Not included
First sensitivity analysis of 
the primary efficacy 
endpoint for handling of 
subjects with 12-weeks 
confirmed EDSS 
progression
Analysis requested by the FDA 
and implemented as first 
sensitivity analysis of the 
primary efficacy endpoint
Only single imputation  of 
missing primary efficacy 
endpoint data (as non-
responders)
Additional sensitivity 
analyses (tipping point and 
multiple imputation) for 
handling of missing primary 
efficacy endpoint data
Allowing more insight in the 
effect of single imputation in the 
main analysis of the primary 
efficacy endpoint
Multiple imputation for 
secondary efficacy 
endpoints described only 
vaguely 
Much more detailed 
description for handling of 
missing secondary efficacy 
endpoint data (including 
Allowing a consistent approach 
across primary and secondary 
efficacy endpoints, in particular 
regarding multiple imputation 


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 55 of 61
Study Protocol version 4 
Final SAP 6.0
Justification for change
multiple imputation models); 
for TW25 change from 
baseline, a rule for visits 
with both TW25 trials 
missing due to inability 
caused by MS worsening has 
been introduced
models); considering available 
information on the reason for 
missing TW25 values
Logistic regression with 
factors MS history and 
center
Logistic regression with 
factors MS history and 
geographical region
As the number of centers is too 
large for the number of subjects, 
replacing factor center by 
geographical region stabilizes the
statistical analysis. 
Not included
Use of a conditional exact 
logistic regression analysis 
in case of less than 1% 
responders in at least one of 
the study treatment groups 
Results of the asymptotic logistic 
regression analysis may not be 
valid with such a sparse response 
probability 
Handling of intercurrent 
events (relapses and 
steroid treatment during 
the study) only briefly 
mentioned
More extended and detailed 
sensitivity analyses within 
the “estimand” framework as 
described in the ICH E9 
Addendum
Update according to new 
regulatory guidelines
Not included
First sensitivity analysis of 
time to 12-weeks confirmed 
EDSS progression for 
handling of subjects with  
EDSS improvement at M12 
and M15
Analysis requested by the FDA 
and implemented as first 
sensitivity analysis of this 
secondary efficacy endpoint
Secondary efficacy 
endpoints CGI, SGI and 
TW25 change from 
baseline to M15 visit 
analyzed by van Elteren 
test stratified by MS 
history
Secondary efficacy 
endpoints CGI, SGI and 
TW25 change from baseline 
to M15 visits analyzed by 
van Elteren test stratified by 
MS history and geographical 
region
Consistency with randomization 
and analysis of primary and other
secondary efficacy endpoints
Not included
Additional analyses related 
to the primary efficacy 
endpoint and analysis of 
time to 24-weeks confirmed 
EDSS progression
Requested by the EMA
In addition, for the exploratory efficacy endpoints related to remote monitoring of 
ambulatory activity, the relevant period prior to each post-baseline visit has been extended 
from 7 to 21 days, but only including “valid” days with at least 130 steps and requiring at 


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 56 of 61
least 3 valid days for a visit to be included in the statistical analysis. This approach has 
been recommended by the investigator coordinator to stabilize the endpoint.


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 57 of 61
5
REFERENCES
Benito-León J, Rivera-Navarro J, Guerrero AL, de Las Heras V, Balseiro J, Rodríguez E, 
Belló M, Martínez-Martín P; caregiver quality of life in multiple sclerosis (CAREQOL-
MS) Study Group. The CAREQOL-MS was a useful instrument to measure caregiver 
quality of life in multiple sclerosis. J Clin Epidemiol 2011; 64; 675-686 
Berglund P, Heeringa S. Multiple Imputation of Missing Data Using SAS. SAS Institute 
Inc. 2014
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics 
1982; 38; 29-41
Campbell G, Pennello G, Yue L. Missing data in the regulation of medical devices. Journal 
of Biopharmaceutical Statistics 2011; 21; 180-195
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron 1976; 16; 31-41
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use: Draft ICH E9 (R1) Addendum on Estimands and Sensitivity Analysis in 
Clinical Trials to the Guideline on Statistical Principles for Clinical Trials. 2017
Liublinska V, Rubin DB. Sensitivity analysis for a partially missing binary outcome in a 
two-arm randomized clinical trial. Statistics in Medicine 2014; 33; 4170-4185
Vickrey BG, Hays RD, Genovese BJ, Myers LW, Ellison GW. Comparison of a generic to 
disease-targeted health-related quality-of-life measures for multiple sclerosis. J Clin 
Epidemiol 1997; 50; 557-569
Vickrey BG, Hays RD, Harooni R, Myers LW, Ellison GW. A health-related quality of life 
measure for multiple sclerosis. Qual Life Res 1995; 4; 187-206
Yan X, Lee S, Li N. Missing data handling methods in medical device clinical trials. 
Journal of Biopharmaceutical Statistics 2009; 19; 1085-1098


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 58 of 61
6
ADDITIONAL ANALYSES FOR EUROPEAN MEDICINES AGENCY 
FOLLOWING SCIENTIFIC ADVICE
In addition to analyses described in the previous sections of this SAP, analyses described 
in this section will be provided to European Medicines Agency (EMA) as advised in a 
Scientific Advice provided in February 2019.
Additional analyses related to the primary efficacy endpoint 
Analyses (descriptively and by applying statistical methods described in Sections 4.8.2.1 
and 4.8.2.2) assessing the durability of MD1003’s effect and the potential impact of 
discordant EDSS versus TW25 outcomes at visits M12 and M15 for:
TW25 or EDSS improvement (as defined in Section 3.2.1) at M12 confirmed at M1810 
TW25 or EDSS improvement (as defined in Section 3.2.1) at M9 confirmed at M1511 
modified primary efficacy endpoint considering subjects with discordant responses as 
failures; a discordant response is defined as:
o response on EDSS at M12 and M15 but worsening (increase in TW25 by more than 
20% compared to baseline) of TW25 at M12 and M15 visits
o or response on TW25 at M12 and M15 but worsening (increase in EDSS from 
baseline as defined for the EDSS related secondary endpoint) of EDSS at M12 and 
M15 visits.
Additional sensitivity analysis related to secondary efficacy endpoints
Time to 24-weeks confirmed EDSS progression will be analyzed (in addition to time to 12-
weeks confirmed EDSS progression).  
24-weeks EDSS progression is defined as an increase of at least 1 point for baseline EDSS 
up to 5.5 and of at least 0.5 point for baseline EDSS 6 to 6.5 with respective confirmation 
12 and 24 weeks later (with time windows of ± 10 days up to 1 year after randomization, 
± 15 days afterwards). The baseline EDSS value is defined as in Section 3.2.1.
Date of 24-weeks confirmed EDSS progression will be the first date of an EDSS 
progression (as defined above) that is confirmed 12 and 24 weeks later. Handling of 
missing data EDSS assessments and censoring are described further below. Time to 24-
weeks confirmed EDSS progression will be calculated as date of 24-weeks confirmed EDSS 
progression (or censoring) minus date of randomization plus 1; it will be expressed in weeks.
10 i.e., defined EDSS or TW25 decrease from baseline observed at visit M12 and at visit M18
11 i.e., defined EDSS or TW25 decrease from baseline observed at visit M9 and at visit M15


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 59 of 61
For the main analysis of time to 24-weeks confirmed EDSS progression, there are 3 types 
of “missing data”:
A. administrative censoring caused by a subject completing the double-blind study phase 
without a 24-weeks confirmed EDSS progression and without any missing scheduled 
EDSS assessment: this constitutes administrative censoring and time to 24-weeks 
confirmed EDSS progression will be censored at the date of the last available scheduled 
EDSS assessment
example1: 5 at baseline, 5 at M3, 5 at M6, 5.5 at M9, 5 at M12, 5.5 at M15, 5.5 at M18, 
5.5 at M21 
example2: 5 at baseline, 5 at M3, 5 at M6, 5.5 at M9, 5 at M12, 5.5 at M15, 5.5 at M18, 
6 at M21
example3: 5 at baseline, 5 at M3, 5 at M6, 5.5 at M9, 5 at M12, 5.5 at M15, 6 at M18, 
6 at M21
In all 3 examples, M21 was the final visit of the double-blind study phase when this 
study phase was closed according to the rules specified in Section 3.1.3 
 all 3 
examples  are handled as censored at the M21 visit date 
B. a subject prematurely discontinues the double-blind study phase without a 24-weeks 
confirmed EDSS progression and without any missing scheduled EDSS assessment 
prior to his/her end of double-blind study phase: time to 24-weeks confirmed EDSS 
progression will be censored at the date of the last available scheduled EDSS 
assessment
example1: 5 at baseline, 5.5 at M3, 6 at M6, 6 at M9, all subsequent EDSS assessments 
missing 
example2: 5 at baseline, 5.5 at M3, 5.5 at M6, 6 at M9, all subsequent EDSS 
assessments missing
example3: 5 at baseline, 5.5 at M3, 5.5 at M6, 5.5 at M9, all subsequent EDSS 
assessments missing
 all 3 examples are handled as censored at the M9 visit date
C. a subject has one or more missing scheduled EDSS assessments prior to the his/her end 
of the double-blind study phase
C1 – a 24-weeks confirmed EDSS progression occurred prior to the first of such 
missing scheduled EDSS assessments: the missing EDSS assessments are 
irrelevant for the determination of the endpoint for such a subject, so no action 
required 
example: 5 at baseline, 6 at M3, 6 at M6, 6 at M9, missing at M12, missing at M12, 
5 at M15 
 handled as 24-weeks confirmed EDSS progression at M3 visit date
C2 – the previous and subsequent scheduled EDSS assessments are available and 
at most one of them constitute a relevant EDSS increase (as defined in Section 
3.2.2.1): the missing scheduled EDSS assessment is or is viewed as irrelevant for 
the determination of the endpoint 24-weeks confirmed EDSS progression for such 
a subject (it can only occur at a visit later than those with missing EDSS 
assessments)
example1: 5 at baseline, 5.5 at M3, missing at M6, 5.5 at M9 
 missing EDSS assessment at M6 is irrelevant


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 60 of 61
example2: 5 at baseline, 5.5 at M3, missing at M6, missing at M9, 5.5 at M12 
 missing EDSS assessments at M6 and M9 are irrelevant
example3: 5 at baseline, 5.5 at M3, missing at M6, missing at M9, 6 at M12 
 missing EDSS assessments at M6 and M9 are viewed as irrelevant; earliest time 
point for a 24-weeks confirmed EDSS progression can be M12 (if there would be 
confirmations at M15 and M18)
example4: 5 at baseline, 6 at M3, missing at M6, missing at M9, 5.5 at M12 
 missing EDSS assessments at M6 and M9 are viewed to be irrelevant as EDSS 
5.5 at M12 does not constitute a relevant EDSS increase (as defined in Section 
3.2.2.1); earliest time point for a 24-weeks confirmed EDSS progression can be 
M15 (if there would be confirmations at M18 and M21) 
C3 – the previous and subsequent scheduled EDSS assessments are available and 
both of them constitute a relevant EDSS increase (as defined in Section 3.2.2.1): 
the missing scheduled EDSS assessment(s) is/are viewed as irrelevant, the subject 
is handled as having a  24-weeks confirmed EDSS progression at the earlier of the 
two visit dates
example1: 5 at baseline, 6 at M3, missing at M6, 6 at M9 
 missing EDSS assessment at M6 is viewed as irrelevant, 24-weeks confirmed 
EDSS progression at M3 visit date
example2: 5 at baseline, 6 at M3, missing at M6, missing at M9, 6 at M12 
 missing EDSS assessments at M6 and M9 are viewed as irrelevant, 24-weeks 
confirmed EDSS progression at M3 visit date.
The analysis of time to 24-weeks confirmed EDSS progression will be performed for the ITT 
analysis set:
graphically presented using Kaplan Meier curves by study treatment group
if available, Q1 and median time to 24-weeks confirmed EDSS progression and 95% 
CIs for each study treatment group will be estimated according to the method by 
Brookmeyer & Crowley 1982
a proportional hazards regression model stratified by MS disease history and 
geographical region will be used to estimate and test the effect of MD1003 relative to 
placebo on time to 24-weeks confirmed EDSS regression
Kaplan Meier plots by study treatment group will also be provided by disease history 
(SPMS/PPMS) and by geographical region. 
Sensitivity analysis for handling of missing values
As censoring rules above for missing values of types A and B may introduce informative 
censoring and too long censored observation times, the following alternative rules for types 
A and B will be used to assess such potential bias by a sensitivity analysis:
A. administrative censoring caused by a subject completing the double-blind study phase 
without a 24-weeks confirmed EDSS progression and without any missing scheduled 
EDSS assessment: this constitutes administrative censoring and time to 24-weeks 
confirmed EDSS progression will be censored at the date of the last available scheduled 


MedDay Pharmaceuticals
 
MD1003CT2016-01 MS-SPI2
 
 Statistical Analysis Plan
TP-GDO-WW-016-07
CONFIDENTIAL
Final Version 7.0
Effective Date: 05 Sep 18
Project Document Effective Date: Date of last signature
Related to: SOP-GDO-WW-019
Page 61 of 61
EDSS assessment not constituting a relevant EDSS increase (as defined in Section 
3.2.2.1)
example1: 5 at baseline, 5 at M3, 5 at M6, 5.5 at M9, 5 at M12, 5.5 at M15, 5.5 at M18, 
5.5 at M21. 
example2: 5 at baseline, 5 at M3, 5 at M6, 5.5 at M9, 5 at M12, 5.5 at M15, 5.5 at M18, 
6 at M21.
example3: 5 at baseline, 5 at M3, 5 at M6, 5.5 at M9, 5 at M12, 5.5 at M15, 6 at M18, 
6 at M21
In all 3 examples, M21 was the final visit of the double-blind study phase when this 
study phase was closed according to the rules specified in Section 3.1.3 
 example 1 
handled as censored at the M21 visit date, example 2 handled as censored at the M18 
visit date, example 3 handled as censored at the M15 visit date 
B. a subject prematurely discontinues the double-blind study phase without a 12-weeks 
confirmed EDSS progression and without any missing scheduled EDSS assessment 
prior to his/her end of double-blind study phase: 
B1 – the last two available scheduled EDSS assessments both constitute a relevant 
EDSS increase (as defined in Section 3.2.2.1): the subject will be handled as having 
a 24-weeks confirmed EDSS progression and the date of the 24-weeks confirmed 
EDSS progression will be the date of the earlier of the two last available scheduled 
EDSS assessments
example: 5 at baseline, 5.5 at M3, 6 at M6, 6 at M9, all subsequent EDSS 
assessments missing 
 handled as 24-weeks confirmed EDSS progression at the 
M6 visit date
B2 – the last available scheduled EDSS assessment constitutes a relevant EDSS 
increase (as defined in Section 3.2.2.1) and the previous scheduled EDSS 
assessment does not constitute a relevant EDSS increase: the subject will be 
handled as having a 24-weeks confirmed EDSS progression and the date of the 24-
weeks confirmed EDSS progression will be the date of the last available scheduled 
EDSS assessment
example: 5 at baseline, 5.5 at M3, 5.5 at M6, 6 at M9, all subsequent EDSS 
assessments missing 
 handled as 24-weeks confirmed EDSS progression at the 
M9 visit date
B3 – the last available scheduled EDSS assessment does not constitute a relevant 
EDSS increase (as defined in Section 3.2.2.1): this will be handled as censored 
subject, and the censoring date will be the date of the last available scheduled EDSS 
assessment
example: 5 at baseline, 5.5 at M3, 5.5 at M6, 5.5 at M9, all subsequent EDSS 
assessments missing 
 handled as censored at M9 visit date


PAREXEL International Electronic Signature Page 
This page is the manifestation of the electronic signature(s) used in compliance with PAREXEL 
International’s electronic signature policies and procedures and in compliance with applicable regulations. 
UserName: Jakobs, Peter (jakobsp) 
Title:  Senior Director, Biostatistics, GDO 
Date: Monday, 10 February 2020, 03:56 PM   GMT Standard Time 
Meaning: Document contents approved. 
================================================
Document ID: 564453413 - Name at Publication: 229829 SAP 20200210 7.0.docx
This document contains a total of 62 pages including any signature page/s.