Collection of Blood Samples From Patients With Relapsing Forms of Multiple Sclerosis (RMS) Who Have Developed Immune Thrombocytopenic Purpura (ITP) After LEMTRADA® Treatment
Phase: PHASE4
Conditions: Multiple Sclerosis
Sponsor: Genzyme, a Sanofi Company

Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: QSD-002434 VERSION N°15.0 (30-NOV-2017) 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 01
COMPOUND: LEMTRADA® /alemtuzumab/GZ402673 
Collection of blood samples from  patients with relapsing forms of Multiple 
Sclerosis (RMS) who have developed Immune thrombocytopenic purpura (ITP) 
after LEMTRADA® treatment 
STUDY NUMBER: ASY15905 
STUDY NAME: LEMTRADA ITP 
Version Number: 
1 
EudraCT  
Not applicable 
IND Number(s) 
Not applicable 
WHO universal trial number: 
Not applicable 
Date: 
24-May-2019
Total number of pages: 
40 
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NAMES AND ADDRESSES OF 
INVESTIGATOR 
 
Name: 
Address: 
 
 
Tel: 
 
E-mail: 
 
 
 
Los Angeles, CA 90094 
 
 
 
 
STUDY MEDICAL 
MANAGER 
Name: 
Address: 
 
 
 
Tel: 
 
E-mail: 
 
GLOBAL STUDY 
MANAGER  
 
 
Name: 
Address: 
 
 
 
Tel: 
 
E-mail: 
 
SPONSOR’S MEDICAL 
OFFICER 
 
Name: 
Address: 
 
 
 
Tel: 
 
E-mail: 
 
SPONSOR 
Company: 
Address: 
 
 
 
 
Genzyme Corporation 
50 Binney Street 
Cambridge, MA 02142 
USA 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
Company: 
Address: 
 
 
 
Tel: 
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
DOCUMENT HISTORY 
 
Document 
Country/Countries 
impacted by amendement 
Date, version 
Amended Clinical Trial Protocol 01 
US 
24-May-2019, version 1 (electronic 1.0) 
Original Protocol 
 
31-Aug-2018, version 1 (electronic 1.0) 
AMENDED PROTOCOL 01 (24-MAY-2019)  
This amended protocol (amendment 01) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union because it modifies the study primary objective. 
OVERALL RATIONALE FOR THE AMENDMENT 
This substantial protocol amendment introduces the following changes due to the modification the 
study primary objective. 
In addition, Sanofi-Genzyme uses this opportunity to edit other sections of the protocol as listed 
below for better clarity. Inconsistencies, typographical and spelling errors throughout the 
document were also corrected. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Title (page 1) 
Title modified to “Collection of blood 
samples” 
Due to change in the main objective of the study 
Names and addresses 
Name and address of the 
investigator was added 
Update 
4.2 Study rationale 
5.1 Primary objective 
9.2.1 Pharmacogenetic 
assessment 
9.2.2 Sampling time 
Update on the main focus (primary 
objective) of the study: collection of 
blood samples for DNA extraction 
The DNA analysis (sequencing) will not be part of this 
study and will be included in a more global biomarker 
project 
4.2 Study rationale 
5.2 Exploratory objective 
First exploratory objective was 
removed 
This objective will not be part of the study 
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Section # and Name 
Description of Change 
Brief Rationale 
6.2.1 Duration of study 
participation for each patient 
9.5.2 Sample blood volume 
12.1 Visit Schedule 
Increase duration and 
implementation  of one additional 
visit, if needed 
To allow to complete blood drawn, if for any safety 
reason all samples cannot bet collected at the initial 
blood draw visit 
7.2 Inclusion criteria 
Removal of “As per label” for 
Lemtrada 
To allow enrollment of RMS patients who developed ITP 
during clinical trials involving Gz402673 (Lemtrada) 
6.1 Description of the study 
Number of sites 
Clarification on the number of site  
Update 
9.5.2 Sample blood volume 
Updated 
 
Addition of a discard tube 
 
Less blood volume 
collection feasible  
 
Need a discard tube before blood DNA sample draw 
To increase subject safety if needed  
9.2.6 Future use of samples 
Detailed description of sample use 
Clarification of the use of samples as the DNA analysis 
(sequencing) will not be part of this study and will be 
included in a more global biomarker project 
11.2 Reasons for study 
withdrawal 
14.2 Informed consent 
“patient’s representative” deleted 
Requested by IRB as not applicable here 
13.7  Analysis of 
pharmacogenetics variables 
Pharmacogenetic statistical analysis 
is not in the scope of this study but 
will be part of a global biomarker 
program 
Update due to modification of study objective 
 
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CLINICAL TRIAL SUMMARY 
COMPOUND: LEMTRADA® 
/alemtuzumab/GZ402673 
STUDY No : ASY15905 
TITLE 
Collection of blood samples from  patients with relapsing  forms of 
Multiple Sclerosis (RMS) who have developed Immune 
thrombocytopenic purpura (ITP) after LEMTRADA® treatment 
INVESTIGATOR/TRIAL LOCATION 
USA; may be expanded to Canada 
STUDY OBJECTIVE(S) 
Primary objective: 
To collect blood samples, in a new cohort of RMS patients  who have 
developed Immune thrombocytopenic purpura (ITP) after LEMTRADA 
treatment, for future DNA analysis as part of a global biomarker project 
assessing pre-identified candidate SNPs associated to the 
development of ITP after LEMTRADA treatment.  
Exploratory objectives: 

To collect from these patients additional serum, plasma,
circulating peripheral blood mononuclear cells (PBMCs), and
RNA samples together with their retrospective demographic
and clinical data related to MS disease and ITP status.
STUDY DESIGN 
Phase IV, single-center, non-randomized study. 
Some retrospective demographic and clinical data will be captured 
through the patient’s physician, patient reporting, and medical records. 
The only intervention will be the blood draws performed during study 
visit(s). 
This study is part of a global biomarker project that aims to collect 
samples from different studies to potentially confirm correlations 
between ITP and other autoimmune conditions and specific single 
nucleotide polymorphism (SNP) genetic set. 
STUDY POPULATION 
Main selection criteria: 
Inclusion criteria: 
I 01. 
Male and female adult patients who have been treated with 
LEMTRADA, with development of ITP subsequent to 
treatment. Patients do not need to be currently on 
LEMTRADA treatment. 
I 02. 
Patients who have signed the study informed consent form 
(ICF). 
Total expected number of patients: 
Approximately 35 
Expected number of sites: 
1 center 
STUDY TREATMENT(s) 
No investigational medicinal product(s) will be administered to 
patients. 
PRIMARY ENDPOINT(S) AND MAIN 
SECONDARY ENDPOINT(S) 
Primary endpoints: DNA will be extracted from peripheral blood 
Exploratory endpoints:  

Peripheral blood will be collected for the preparation of
serum, plasma, and PBMCs, which will be stored for up to
5 years, and RNA, which will be stored up to 15 years after
completion of the study.
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 
Retrospective demographic and clinical data related to MS 
disease and ITP status will be collected for correlative 
analysis. 
Safety: Adverse events and serious adverse events related to study 
procedures during the visit(s).  
ASSESSMENT SCHEDULE 
The study will consist of one single visit which includes a subject 
interview and a blood draw. However, for safety reason and at the 
discretion of the medical team, the blood draw might occur in more 
than one visit, 
Blood draw will be performed to collect samples from which DNA, 
serum, plasma, PBMCs, and RNA will be further extracted. 
Additionally the following data points will be captured if available from 
the prescriber, patient, and/or medical records: 
 
Age/date of birth, gender, race/ethnicity 
 
Body mass index (BMI) if possible, otherwise most recent 
weight and height from medical records 
 
Time since MS symptom onset/ MS diagnosis 
 
Previous MS therapies 
 
Prior history of ITP / coagulation disorders, thyroid or renal 
problems; date of ITP symptoms/diagnosis onset 
 
Prior evidence of other autoimmunity disorders 
 
Symptoms associated with ITP prior to time of diagnosis 
 
Details of laboratory and medical confirmation of ITP clinical 
diagnosis 
 
Treatments and duration to achieve response/resolution of 
ITP 
 
Smoking history 
 
Recent laboratory data (last data available): platelets, thyroid 
function, urinalysis 
 
Present MS clinical status:  
- 
Medical record documentation of time and intensity of 
relapses 
- 
Recent magnetic resonance imaging reports 
- 
Recent (1-2 years) evidence of disability progression 
STATISTICAL CONSIDERATIONS 
 
Sample size determination 
Sample size for this study was based upon empirical considerations. 
No sample size calculation was performed. 
Phamacogenomic analysis 
The statistical analysis of pharmacogenetics variables will be part of a 
global biomarker program and is not in the scope of this study.  
Safety 
Safety analysis (AEs and SAEs) will be based on the review of 
individual values, and descriptive statistics.  
DURATION OF STUDY PERIOD 
(per patient) 
One to 70 days. 
One visit is required for blood draw. However, for safety reason and at 
the discretion of the medical team, the blood draw might occur in more 
than one visit. 
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1 
STUDY FLOW CHART 
 
Assessments  
Screening & 
Inclusion Visita 
Inclusion criteria  
Informed consent 
X 
X 
Patient demography (age, date of birth, gender, race/ethnicity) 
Xb 
Detailed patient history of clinical and pathological characteristics: 
 
Time since MS symptom onset/ MS diagnosis 
 
Previous MS therapies 
 
Prior history of ITP / coagulation disorders, thyroid or renal problems; date of ITP 
symptoms/diagnosis onset 
 
Prior evidence of other autoimmunity disorders 
 
Symptoms associated with ITP prior to time of diagnosis 
 
Details of laboratory and medical confirmation of ITP clinical diagnosis 
 
Treatments and duration to achieve response/resolution of ITP 
 
Smoking history 
 
BMI if possible, otherwise most recent weight and height from medical records 
 
Recent laboratory data (last data available): platelets, thyroid function, urinalysis 
 
Present MS clinical status:  
- 
Medical record documentation of time and intensity of relapses 
- 
Recent MRI reports 
- 
Recent (1-2 years) evidence of disability progression 
Xb 
Blood draw for further pharmacogenetic analysis and sample storage 
Xc 
AE collection 
X 
AE = adverse event; BMI = body mass index; ITP = Immune thrombocytopenic purpura; MRI = magnetic resonance imaging; MS = multiple 
sclerosis. 
a Screening and inclusion visit can be performed the same day or on separate days with a maximum timeframe of 30 days apart. The visit may 
be performed either at the study center or at the patient’s home if he/she cannot reach the study center. The visit will occur late in the day to 
comply with sample management requirements. 
b If available from the prescriber, patient, and/or medical records. 
c One visit is required for blood draw. However, for safety reason and at the discretion of the medical team, the blood draw might occur in more 
than one visit. If a second visit occurs, it must take place within 40 days of the first visit. 
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TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 01 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 3 
DOCUMENT HISTORY ................................................................................................................................... 3 
AMENDED PROTOCOL 01 (24-MAY-2019) .................................................................................................. 3 
OVERALL RATIONALE FOR THE AMENDMENT ........................................................................................ 3 
1 
STUDY FLOW CHART .................................................................................................................... 7 
2 
TABLE OF CONTENTS .................................................................................................................. 8 
2.1 
LIST OF TABLES ........................................................................................................................... 11 
3 
LIST OF ABBREVIATIONS .......................................................................................................... 12 
4 
INTRODUCTION AND RATIONALE ............................................................................................. 13 
4.1 
INTRODUCTION ............................................................................................................................ 13 
4.2 
STUDY RATIONALE...................................................................................................................... 14 
5 
STUDY OBJECTIVES ................................................................................................................... 15 
5.1 
PRIMARY OBJECTIVE .................................................................................................................. 15 
5.2 
EXPLORATORY OBJECTIVES: .................................................................................................... 15 
6 
STUDY DESIGN ............................................................................................................................ 16 
6.1 
DESCRIPTION OF THE STUDY ................................................................................................... 16 
6.2 
DURATION OF STUDY PARTICIPATION .................................................................................... 16 
6.2.1 
Duration of study participation for each patient ............................................................................. 16 
6.2.2 
Determination of end of clinical trial (all patients) .......................................................................... 16 
6.3 
INTERIM ANALYSIS ...................................................................................................................... 16 
7 
SELECTION OF SUBJECTS ........................................................................................................ 17 
7.1 
NUMBER OF SUBJECTS PLANNED............................................................................................ 17 
7.2 
INCLUSION CRITERIA .................................................................................................................. 17 
7.3 
EXCLUSION CRITERIA ................................................................................................................ 17 
8 
STUDY TREATMENTS ................................................................................................................. 18 
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8.1 
INVESTIGATIONAL MEDICINAL PRODUCT ............................................................................... 18 
8.2 
OTHER PRODUCTS ..................................................................................................................... 18 
8.3 
PACKAGING AND LABELING ...................................................................................................... 18 
8.4 
STORAGE CONDITIONS AND SHELF LIFE ................................................................................ 18 
8.5 
RESPONSIBILITIES ...................................................................................................................... 18 
8.6 
CONCOMITANT MEDICATION ..................................................................................................... 18 
8.7 
TREATMENT ACCOUNTABILITY AND COMPLIANCE ............................................................... 18 
9 
ASSESSMENTS ............................................................................................................................ 19 
9.1 
SAFETY ......................................................................................................................................... 19 
9.1.1 
Baseline demographic characteristics ........................................................................................... 19 
9.1.2 
History of clinical and pathological characteristics ......................................................................... 19 
9.1.3 
Safety assessment ......................................................................................................................... 20 
9.2 
PHARMACOGENETICS ................................................................................................................ 20 
9.2.1 
Pharmacogenetic assessment ....................................................................................................... 20 
9.2.2 
Sampling times ............................................................................................................................... 20 
9.2.3 
Number of samples ........................................................................................................................ 20 
9.2.4 
Sample handling procedure ........................................................................................................... 20 
9.2.5 
Sampled blood volume .................................................................................................................. 21 
9.2.6 
Future use of samples ................................................................................................................... 21 
9.2.7 
Sample destruction ........................................................................................................................ 22 
10 
SUBJECT SAFETY ....................................................................................................................... 23 
10.1 
ADVERSE EVENT MONITORING ................................................................................................ 23 
10.2 
DEFINITIONS OF ADVERSE EVENTS......................................................................................... 23 
10.2.1 
Adverse event ................................................................................................................................ 23 
10.2.2 
Serious adverse event ................................................................................................................... 24 
10.3 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING .......................... 24 
10.3.1 
General guidelines for reporting adverse events ........................................................................... 24 
10.3.2 
Guidelines for reporting serious adverse events ........................................................................... 25 
10.4 
OBLIGATIONS OF THE SPONSOR ............................................................................................. 25 
11 
HANDLING OF PATIENT WITHDRAWAL ................................................................................... 26 
11.1 
LIST OF TREATMENT WITHDRAWAL CRITERIA ....................................................................... 26 
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11.2 
REASONS FOR STUDY WITHDRAWAL ...................................................................................... 26 
11.3 
WITHDRAWAL FOLLOW-UP PROCEDURE ................................................................................ 26 
12 
STUDY PROCEDURES ................................................................................................................ 27 
12.1 
VISIT SCHEDULE .......................................................................................................................... 27 
12.1.1 
Screening procedures .................................................................................................................... 27 
12.1.2 
Description of the inclusion visit ..................................................................................................... 27 
12.2 
DEFINITION OF SOURCE DATA .................................................................................................. 27 
13 
STATISTICAL CONSIDERATIONS .............................................................................................. 28 
13.1 
DETERMINATION OF SAMPLE SIZE ........................................................................................... 28 
13.2 
SUBJECT DESCRIPTION ............................................................................................................. 28 
13.3 
ANALYSIS POPULATION ............................................................................................................. 28 
13.4 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ............................................................. 28 
13.5 
EXTENT OF STUDY TREATMENT EXPOSURE AND COMPLIANCE ........................................ 28 
13.6 
PRIOR/CONCOMITANT MEDICATION/THERAPY ...................................................................... 28 
13.7 
ANALYSIS OF PHARMACOGENETIC VARIABLES .................................................................... 29 
13.8 
ANALYSIS OF SAFETY DATA ...................................................................................................... 29 
13.9 
ANALYSIS OF PHARMACOKINETIC DATA ................................................................................. 29 
13.10 
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSIS ........................................................... 29 
13.11 
INTERIM ANALYSIS ...................................................................................................................... 29 
14 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................... 30 
14.1 
ETHICAL AND REGULATORY STANDARDS .............................................................................. 30 
14.2 
INFORMED CONSENT ................................................................................................................. 30 
14.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD (IRB) .................................... 31 
15 
STUDY MONITORING................................................................................................................... 32 
15.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) ....................................................................... 32 
15.2 
RESPONSIBILITIES OF THE SPONSOR ..................................................................................... 32 
15.3 
SOURCE DOCUMENT REQUIREMENTS .................................................................................... 33 
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15.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST ...................................................................................................................................... 33 
15.5 
USE OF COMPUTERIZED SYSTEMS .......................................................................................... 33 
16 
ADDITIONAL REQUIREMENTS ................................................................................................... 34 
16.1 
CURRICULUM VITAE.................................................................................................................... 34 
16.2 
RECORD RETENTION IN STUDY SITE(S) .................................................................................. 34 
16.3 
CONFIDENTIALITY ....................................................................................................................... 34 
16.4 
PROPERTY RIGHTS ..................................................................................................................... 35 
16.5 
DATA PROTECTION ..................................................................................................................... 35 
16.6 
INSURANCE COMPENSATION .................................................................................................... 35 
16.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ................................. 36 
16.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE ............................................................................................................................................ 36 
16.8.1 
By the Sponsor ............................................................................................................................... 36 
16.8.2 
By the Investigator ......................................................................................................................... 37 
16.9 
CLINICAL TRIAL RESULTS .......................................................................................................... 37 
16.10 
PUBLICATIONS AND COMMUNICATIONS ................................................................................. 37 
17 
CLINICAL TRIAL PROTOCOL AMENDMENTS .......................................................................... 38 
18 
BIBLIOGRAPHIC REFERENCES ................................................................................................. 39 
19 
APPENDICES ................................................................................................................................ 40 
 
2.1 
LIST OF TABLES 
Table 1 - Sampled blood volume per patient ................................................................................................ 21 
 
 
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3 
LIST OF ABBREVIATIONS 
 
ADL: 
activity of daily living 
AE: 
adverse event 
ALT: 
alanine aminotransferase 
BMI: 
body mass index 
CNS: 
central nervous system 
CRF: 
case report form 
CTCAE: 
Common Terminology Criteria for Adverse Events 
eCRF: 
electronic case report form 
GCP: 
Good Clinical Practice 
ICF: 
informed consent form 
IMP: 
investigational medicinal product 
IRB: 
Institutional Review Board 
ITP: 
immune thrombocypenic purpura 
MS: 
multiple sclerosis 
NCI: 
National Cancer Institute 
PBMC: 
peripheral blood mononuclear cell 
RMS: 
relapsing multiple sclerosis 
SAE: 
serious adverse event 
SNP: 
single nucleotide polymorphism 
ULN: 
upper limit of normal 
 
 
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INTRODUCTION AND RATIONALE 
4.1 
INTRODUCTION 
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) that 
affects more than 2.3 million people worldwide (1). Its clinical course is typically characterized 
by initial episodes of transient neurological compromise with full recovery, followed by a phase 
of cumulative deficits that may increase with each new episode. Most relapsing patients 
eventually develop secondary progression leading to a constellation of chronic sequelae including 
profound muscle weakness, impaired gait and mobility, bladder and bowel dysfunction, and 
cognitive and visual impairments. MS is believed to arise from the interplay of polygenic 
inherited susceptibility and as yet unidentified environmental agents. Age of onset typically 
ranges from 10 to 59 years, with most cases occurring between 20 and 40 years of age. As with 
most other autoimmune disorders, MS is more than twice as common among women. 
Pathologically, MS is characterized by focal and nonfocal tissue injury of the brain and spinal 
cord due to the complex interplay of inflammation, demyelination, axonal injury, astrocytosis, and 
tissue atrophy. Lymphocytes are believed to play a central role in MS pathogenesis. 
Alemtuzumab (LEMTRADA®) is a humanized monoclonal antibody that binds to CD52, a cell 
surface antigen present at high levels on T and B lymphocytes, and at lower levels on natural 
killer cells, monocytes, and macrophages (2). Alemtuzumab acts through antibody-dependent 
cellular cytolysis and complement-dependent cytotoxicity following cell surface binding to T and 
B lymphocytes. The mechanism by which alemtuzumab exerts its therapeutic effects in MS is 
unknown, but may involve immunomodulation through the depletion and repopulation of 
lymphocytes subsets. It effects rapid and sustained lymphocyte depletion and has shown potent 
efficacy in treatment-naïve as well as treatment-refractory patients with relapsing remitting 
multiple sclerosis (RRMS). Treatment with alemtuzumab 12 mg/day is efficacious in patients 
with RRMS and is associated with clinically meaningful and statistically significant 
improvements in clinical endpoints, imaging endpoints and composite disease measures, 
compared with subcutaneous (SC), high-dose, high-frequency interferon-beta-1a (IFNB-1a). 
The most important adverse reactions are autoimmunity (eg, immune thrombocytopenic purpura 
(ITP), thyroid disorders, nephropathies, cytopenias), infusion-associated reactions, and serious 
infections. Serious events of ITP have been observed in approximately 2% of patients with 
relapsing multiple sclerosis (RMS) treated with alemtuzumab in clinical trials. The onset of ITP 
generally occurred between 14 and 36 months after the first alemtuzumab exposure but might also 
occur later. Fatality in the index case of ITP, which was reported in the Phase 2 study, highlights 
the seriousness of the risks associated with the disorder.  
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4.2 
STUDY RATIONALE 
In a previous analysis on a small number of patients from the Ph3 clinical trial population, a 
specific single nucleotide polymorphism (SNP) genetic set was identified showing a strong 
correlation with development of ITP after treatment by alemtuzumab (unpublished internal data). 
However samples from an independent cohort of post-marketing RMS patients who have 
developed ITP would be needed to confirm these data.  
The current study will focus on the collection of blood samples to extract DNA from patients who 
developed ITP consequently to Lemtrada treatment. The DNA will be subjected to further 
sequencing  pre-identified specific candidate genes of interest to evaluate their polymorphism 
status and correlate these assessments with demographic and clinical data from the patients as 
well as the occurrence of LEMTRADA-induced ITP. DNA sequencing and corresponding 
analysis are not part of this study. 
Complementary to these objectives serum, plasma, peripheral blood mononuclear cells (PBMCs), 
and RNA samples will be collected and stored to be further explored in this patient population to 
potentially identify new safety and LEMTRADA treatment response markers. 
This study is part of a global biomarker project that aims to collect samples from different studies 
to potentially confirm correlations between ITP and other autoimmune conditions and specific 
SNP genetic set. Genomic data collected in other studies from MS patients who are treated with 
LEMTRADA but did not develop any autoimmune condition will be used as controls to validate 
the preliminary findings. The ultimate goal of this global biomarker project is to enhance the 
benefit/risk ratio of LEMTRADA with the objective of discovering a panel of biomarkers to 
predict which patients are at risk of developing auto-immunity events. 
 
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5 
STUDY OBJECTIVES 
5.1 
PRIMARY OBJECTIVE 
To collect blood samples, in a new cohort of RMS patients  who have developed Immune 
thrombocytopenic purpura (ITP) after LEMTRADA treatment, for future DNA analysis as part of 
a global biomarker project assessing pre-identified candidate SNPs associated to the development 
of ITP after LEMTRADA treatment in RMS patients.  
5.2 
EXPLORATORY OBJECTIVES: 
 To collect from these patients additional serum, plasma, circulating PBMCs, and RNA 
samples together with their retrospective demographic and clinical data related to MS 
disease and ITP status 
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6 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE STUDY 
This is a phase 4, single-center, non-randomized study conducted in one site in the USA; the study 
may be expanded to Canada at an undetermined number of sites. No investigational medicinal 
product (IMP) administration will be performed. 
Some retrospective demographic and clinical data will be captured through the patient’s 
physician, patient reporting, and medical records. 
The only intervention will be the blood draw performed during study visit(s). 
6.2 
DURATION OF STUDY PARTICIPATION 
6.2.1 Duration of study participation for each patient 
This duration is from one to 70 days. Screening and visit(s) can be performed the same day or on 
separate days with a maximum timeframe of 30 days apart. One visit is required for blood draw. 
However, for safety reason and at the discretion of the medical team, the blood draw might occur 
in more than one visit. If a second visit occurs, it must take place within 40 days of the first visit. 
The study will be considered completed for a patient at the time he/she completes all the 
scheduled study procedures. 
6.2.2 Determination of end of clinical trial (all patients) 
The end of the clinical trial is defined as the day of last patient last visit. 
6.3 
INTERIM ANALYSIS 
No interim analysis is planned. 
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SELECTION OF SUBJECTS 
7.1 
 NUMBER OF SUBJECTS PLANNED 
Approximately 35 patients 
7.2 
INCLUSION CRITERIA 
I 01. Male and female adult patients who have been treated with LEMTRADA, with 
development of ITP subsequent to treatment. Patients do not need to be currently on 
LEMTRADA treatment. 
I 02. Patients who have signed the study informed consent form (ICF). 
7.3 
EXCLUSION CRITERIA 
None 
 
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STUDY TREATMENTS 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT 
No IMP will be administered to patients. 
8.2 
OTHER PRODUCTS 
Not applicable. 
8.3 
PACKAGING AND LABELING 
Not applicable. 
8.4 
STORAGE CONDITIONS AND SHELF LIFE 
Not applicable. 
8.5 
RESPONSIBILITIES 
Not applicable. 
8.6 
CONCOMITANT MEDICATION 
Not applicable. 
8.7 
TREATMENT ACCOUNTABILITY AND COMPLIANCE 
Not applicable. 
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9 
ASSESSMENTS 
9.1 
SAFETY 
9.1.1 Baseline demographic characteristics 
Baseline demographic characteristics will consist of: 
 
Age (years) 
 
Date of birth 
 
Gender 
 
Race/ethnicity: Subject race (African/American, Caucasian, Asian, Other) and ethnicity 
(“Hispanic” or “Not Hispanic”) will be collected in this study because analysis of results 
according to race/ethnicity are required by several Regulatory Authorities (eg, 
African/American population for FDA in United States). 
9.1.2 History of clinical and pathological characteristics 
History of clinical and pathological characteristics, if available from the prescriber, patient, and/or 
medical records, will consist of:  
 Time since MS symptom onset/MS diagnosis 
 Previous MS therapies 
 Prior history of ITP/coagulation disorders, thyroid or renal problems; date of ITP 
symptoms/diagnosis onset 
 Prior evidence of other autoimmunity disorders 
 Symptoms associated with ITP prior to time of diagnosis 
 Details of laboratory and medical confirmation of ITP clinical diagnosis 
 Treatments and duration to achieve response/resolution of ITP 
 Smoking history 
 Body mass index if possible, otherwise most recent weight and height from medical 
records 
 Recent laboratory data (last data available): platelets, thyroid function, urinalysis 
 Present MS clinical status:  
- 
Medical record documentation of time and intensity of relapses 
- 
Recent magnetic resonance imaging reports 
- 
Recent (1-2 years) evidence of disability progression 
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9.1.3 Safety assessment  
Adverse events (AEs) and serious adverse events (SAEs) related to study procedures will be 
recorded spanning from the signature of the ICF until the end of the study. As there is no 
investigational product administration, assessment of the relationship of AEs or SAEs to 
procedures (ie, blood sampling) will be performed by both the Investigator and the Sponsor. 
9.2 
PHARMACOGENETICS 
9.2.1 Pharmacogenetic assessment 
Samples will be processed for DNA isolation.  
These blood samples will be transferred to a site that will, on behalf of Sanofi, extract DNA. 
Material extracted will remain labelled with the same identifiers used during the study (ie, patient 
ID, sample ID). They will be transferred to a Sponsor site (or a subcontractor site) which can be 
located outside of the country where the study is conducted. DNA and RNA sample collection, 
handling, storage, and future analysis will conform to all applicable national guidance and 
regulations.  
As part of a global biomarker program and outside the scope of this study, this DNA will be 
further subjected to sequencing analysis. Genomic data generated from these samples will be used 
to confirm previous findings of a potential set of SNPs observed in patients with RMS who have 
developed ITP after LEMTRADA treatment.  
The DNA will be stored for up to 15 years from the completion of the clinical study report in the 
US.  
9.2.2 Sampling times 
A blood draw will be collected at the study visit(s) for DNA extraction and sample storage as 
specified in the study flow chart (Section 1).  
Blood will be collected preferably late in the day to comply with sample management 
requirement – overnight shipment of the samples for first morning delivery to the central lab. 
9.2.3 Number of samples 
The number of sample per patient is indicated in Table 1. 
9.2.4 Sample handling procedure 
Special procedures for collection, shipment, processing and storage of samples will be provided in 
the laboratory manual. 
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9.2.5 Sampled blood volume 
A total of 69 ml of whole blood will be collected as shown in Table 1 and under the priority rank 
indicated.  
At the discretion of the medical team, for some patients the collection of 69 ml at one single draw 
may be inappropriate. In such cases, either additional draws may be performed or less blood 
volume may be collected but respecting the priority order indicated in Table 1. 
Table 1 - Sampled blood volume per patient 
Priority 
Type 
Volume per 
sample 
Sample number 
Total 
 
discard tube 
2 mL 
1 
2 mL 
1 
DNA PAXgene tubes 
2.5 mL 
2 
5 mL 
2 
RNA PAXgene tubes 
2.5 mL 
2 
5 mL 
3 
EDTA for PBMCs 
8.5 mL 
5 
42.5 mL 
4 
SST tube 
8.5 mL 
1 
8.5 mL 
5 
K2EDTA tube 
6.0 mL 
1 
6.0 mL 
 
Total  
 
 
69 mL 
PMBC = peripheral blood mononuclear cells. 
9.2.6 Future use of samples 
The DNA samples will be stored for up to 15 years from the completion of the clinical study 
report in the US. A part of this DNA will be used for sequencing analysis. The DNA samples that 
will be unused or left over after testing  may be used for additional research purposes related to 
better understanding MS disease pathogenesis, drug response or activity.  
Additional blood samples collected during this study will be processed for serum, plasma, 
PBMCs, and RNA preparations and stored as described in the laboratory manual. These samples 
may be used for research purpose related to MS disease, ITP status, predictive and safety 
biomarker identification, or LEMTRADA mechanism of action. These samples will remain 
labelled with the same identifiers as the one used during the study (ie, patient ID, sample ID). 
They will be transferred to a Sanofi site (or a subcontractor site), which can be located outside of 
the countries where the study is conducted, and stored for up to 5 years (serum, plasma, PBMCs) 
or 15 years (RNA) after completion of the study.  
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9.2.7 Sample destruction 
If a patient, via written request, asks for destruction of his/her samples, the Sponsor will destroy 
the samples per applicable guidelines; however, any data already generated will not be destroyed. 
The Sponsor will notify the Investigator in writing that the samples have been destroyed. 
However, any analyses of the sample(s) that have already been performed or data generated prior 
to patient’s request will continue to be used as part of the research in this project and will be kept 
by the Sponsor. 
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SUBJECT SAFETY 
The Investigator is the primary person responsible for making all clinically relevant decisions on 
safety issues. 
10.1 
ADVERSE EVENT MONITORING 
All events will be managed and reported in compliance with all applicable regulations, and 
included in the final clinical study report. 
10.2 
DEFINITIONS OF ADVERSE EVENTS 
10.2.1 Adverse event 
An adverse event (AE) is any untoward medical occurrence in a subject which does not 
necessarily have to have a causal relationship with this treatment. 
Adverse events and SAEs related to study procedures will be recorded spanning from the 
signature of the ICF until the end of the study. As there is no investigational product 
administration, assessment of the relationship of AEs or SAEs to procedures (ie, blood sampling) 
will be performed by both the Investigator and the Sponsor. 
Adverse events will be graded according National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) v4.03 and classified by system organ class / preferred term 
according the last available version of the MedDRA dictionary. For AEs not included in the NCI 
CTCAE, the Investigator will be required to assess the intensity of the adverse drug/biologic 
experience using the CTCAE general guideline: 
 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age 
appropriate instrumental activities of daily living (ADL). Instrumental ADL refer to 
preparing meals, shopping for groceries or clothes, using the telephone, managing money, 
etc. 
 
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL. Self-care ADL refer to bathing, dressing and undressing, feeding self, using the 
toilet, taking medications and not bedridden. 
 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
 
Grade 5: Death related to AE. 
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10.2.2 Serious adverse event 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
 Results in death, or 
 Is life-threatening, or 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject 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 it were more severe. 
 Requires inpatient hospitalization or prolongation of existing hospitalization, or 
 Results in persistent or significant disability/incapacity, or 
 Is a congenital anomaly/birth defect, or 
 Is a medically important event: 
- 
Medical and scientific judgment should be exercised in deciding whether expedited 
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 subject or may require medical or surgical intervention to prevent one of 
the other outcomes listed in the definition above. 
Note: Examples of such events are intensive treatment in an emergency room or at 
home for allergic bronchospasm, blood dyscrasias, convulsions, alanine 
aminotransferase (ALT)> 3 x upper limit of normal (ULN) + total bilirubin > 2 x ULN 
or asymptomatic ALT increase > 10 x ULN, or development of drug dependence or 
drug abuse.   
10.3 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING 
10.3.1 General guidelines for reporting adverse events 
All AEs related to study procedures, regardless of seriousness, spanning from the signature of the 
ICF until the end of the study as defined by the protocol, are to be recorded on the corresponding 
page(s) or screen(s) of the case report form (CRF) for included subjects. For screen failed 
subjects, recording in the CRF is only performed in case of SAE occurring during the screening 
period or in case of AE when some screening procedures expose the subject to safety risks 
(eg, any substance administered as pretreatment or for phenotyping, invasive tests performed or 
chronic treatment interrupted). 
Whenever possible, diagnosis or single syndrome should be reported instead of symptoms. The 
Investigator should specify the date of onset, intensity (see definitions in Section 10.2.1), 
corrective treatment/therapy given, additional investigations performed (eg, in the case of 
dermatologic lesions photographs are required), outcome, and Investigator’s/Sponsor’s opinion.  
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In order to ensure the safety of the subjects, the Investigator should take appropriate measures to 
follow all AEs until clinical recovery is complete and laboratory results have returned to normal, 
or until progression has been stabilized, or until death.  This may imply that observations will 
continue beyond the last planned visit per protocol, and that additional investigations may be 
requested by the monitoring team. 
10.3.2 Guidelines for reporting serious adverse events 
In the case of a SAE, the Investigator must immediately: 
 SEND (within 24 hours, preferably by fax or e-mail) the signed and dated corresponding 
page(s) in the CRF to the representative of the monitoring team whose name, fax number, 
and e-mail address appear on the clinical trial protocol. 
 ATTACH the photocopy of all examinations carried out and the dates on which these 
examinations were performed. Care should be taken to ensure that the subject’s identity is 
protected and the subject’s identifiers in the clinical trial are properly mentioned on any 
copy of source document provided to the Sponsor. For laboratory results, include the 
laboratory normal ranges. 
 All further documentation should be sent to the monitoring team within 24 hours of 
knowledge. In addition, every effort should be made to further document within the week 
(7 days) following initial notification any SAE that is fatal or life threatening.  
Any SAE brought to the attention of the Investigator at any time after the end of the study for the 
subject and considered by the Investigator to be caused by the study procedures with a reasonable 
possibility, should be reported to the monitoring team. 
10.4 
OBLIGATIONS OF THE SPONSOR 
The Sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report. 
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11 
HANDLING OF PATIENT WITHDRAWAL 
11.1 
LIST OF TREATMENT WITHDRAWAL CRITERIA 
Not applicable. 
11.2 
REASONS FOR STUDY WITHDRAWAL 
 The patient may withdraw from the study if they decide to do so, at any time and 
irrespective of the reason, or upon the Investigator’s decision or at the specific request of 
the Sponsor.   
 In case of withdrawal, the patient should withdraw consent in writing and, if the patient 
refuses or is physically unavailable, the site should document and sign the reason for the 
patient‘s failure to withdraw consent in writing.  
11.3 
WITHDRAWAL FOLLOW-UP PROCEDURE 
All study withdrawals should be recorded by the Investigator on the appropriate CRF pages or 
screens for electronic CRF (eCRF) when considered as confirmed. 
Patients withdrawn from the study must not be reincluded in the study. Their Subject ID numbers 
must not be reused. 
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STUDY PROCEDURES 
12.1 
VISIT SCHEDULE 
12.1.1 Screening procedures 
The screening and visit(s) can be performed the same day or on separate days with a maximum 
timeframe of 30 days apart.  
The patient will receive information on the study objective(s) and procedures from the 
Investigator. The patient must sign the informed consent prior to any action related to the study. 
The screening visit will include the investigations listed in the Study Flow Chart (Section 1) and 
detailed in Section 9.1. 
Patients who meet all the inclusion criteria will be eligible for inclusion in the study. 
12.1.2 Description of the inclusion visit 
The visit will be performed either at the study center or at the patient’s home if he/she cannot 
reach the study center.  
The visit will occur late in the day to comply with sample management requirements.  
Prior to any assessments an informed consent signed by the patients must be collected. 
Blood draw will be performed and samples collected in the priority order specified in Section 9.2. 
For any safety reason, several blood draw may be needed or less blood volume may be collected 
but respecting the priority order indicated in Table 1.One visit is required for blood draw. 
However, for safety reason and at the discretion of the medical team, the blood draw might occur 
in more than one visit. If a second visit occurs, it must take place within 40 days of the first visit. 
12.2 
DEFINITION OF SOURCE DATA 
All evaluations that are reported in the CRF must be supported by appropriately identified source 
documentation. 
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STATISTICAL CONSIDERATIONS 
For the current study, data from patients with ITP only will be collected. Statistical data 
processing and quality control steps will be performed. Descriptive statistics and sensitivity 
analysis will be provided. 
The formal statistical analysis to find predictive biomarkers for ITP events will be conducted 
retrospectively when data from the control patients (those patients who did not develop ITP) are 
available from other studies. 
Safety analysis of AEs will be based on the review of individual values, and descriptive statistics. 
13.1 
DETERMINATION OF SAMPLE SIZE 
Sample size for this study was based upon empirical considerations. No sample size calculation 
was performed. 
13.2 
SUBJECT DESCRIPTION 
Not applicable. 
13.3 
ANALYSIS POPULATION  
The safety population will consist of all patients included into the study. 
13.4 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Continuous variables (age) and qualitative variables (gender, race/ethnicity) will be summarized 
by descriptive statistics for the safety population. 
13.5 
EXTENT OF STUDY TREATMENT EXPOSURE AND COMPLIANCE 
Not applicable. 
13.6 
PRIOR/CONCOMITANT MEDICATION/THERAPY 
Not applicable. 
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13.7 
ANALYSIS OF PHARMACOGENETIC VARIABLES 
The statistical analysis of pharmacogenetics variables will be part of a global biomarker program 
and is not in the scope of this study.  
13.8 
ANALYSIS OF SAFETY DATA 
The safety evaluation will be based on the review of individual values and descriptive statistics of 
AEs related to study procedures during the study visit.  
13.9 
ANALYSIS OF PHARMACOKINETIC DATA 
Not applicable. 
13.10 PHARMACOKINETIC/PHARMACODYNAMIC ANALYSIS 
Not applicable. 
13.11 INTERIM ANALYSIS 
No interim analysis is planned. 
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ETHICAL AND REGULATORY CONSIDERATIONS 
14.1 
ETHICAL AND REGULATORY STANDARDS 
This clinical trial will be conducted by the Sponsor, the Investigator, delegated Investigator staff 
and Subinvestigator, in accordance with consensus ethics principles derived from international 
ethics guidelines, including the Declaration of Helsinki, and the ICH guidelines for Good Clinical 
Practice (GCP), all applicable laws, rules and regulations. 
14.2 
INFORMED CONSENT 
The Investigator (according to applicable regulatory requirements), or a person designated by the 
Investigator and under the Investigator’s responsibility, should fully inform the patient of all 
pertinent aspects of the clinical trial including the written information giving approval/favorable 
opinion by the ethics committee (Institutional Review Board [IRB]). All participants should be 
informed to the fullest extent possible about the study, in language and terms they are able to 
understand. 
Prior to a patient’s participation in the clinical trial, the electronic ICF should be signed, name 
filled in, and personally dated by the patient, and by the person who conducted the informed 
consent discussion. A copy of the signed and dated ICF will be provided to the patient by e-mail. 
The ICF used by the Investigator for obtaining the patient’s informed consent must be reviewed 
and approved by the Sponsor prior to submission to the appropriate ethics committee (IRB) for 
approval/favorable opinion. 
The electronic ICF and any other written information to be provided to patients should be revised 
whenever important new information becomes available that may be relevant to the subject’s 
consent. Any revised ICF, and information should receive the IRB’s approval/favorable opinion in 
advance of use. The patient should be informed in a timely manner if new information becomes 
available that may be relevant to the patient’s willingness to continue participation in the trial. The 
communication of this information should be documented. In case of study suspension due to 
safety concerns, patient will be informed of this study suspension and the reason for it. Once it is 
confirmed that it is safe for the study to continue, study patients will be asked to confirm their 
agreement to continue the study. 
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14.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD (IRB)  
As required by local regulation, the Investigator or the Sponsor must submit this clinical trial 
protocol to the Health Authorities (Competent Regulatory Authority) and the appropriate IRB, 
and is required to forward to the respective other party a copy of the written and dated 
approval/favorable opinion signed by the chairman with IRB composition. 
The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, ICF, Investigator’s Brochure, Investigator’s curriculum vitae, 
etc.) and the date of the review should be clearly stated on the written IRB approval/favorable 
opinion. 
The Investigator will not start the study before the written and dated approval/favorable opinion is 
received by the Investigator and the Sponsor. 
During the clinical trial, any amendment or modification to the clinical trial protocol should be 
submitted to the Health Authorities (Competent Regulatory Authority), as required by local 
regulation, in addition to the IRB before implementation, unless the change is necessary to 
eliminate an immediate hazard to the patients, in which case the Health Authorities (Competent 
Regulatory Authority) and the IRB should be informed as soon as possible. They should also be 
informed of any event likely to affect the safety of patients or the continued conduct of the clinical 
trial, in particular any change in safety. All updates to the Investigator’s Brochure will be sent to 
the IRB and to Health Authorities (Competent Regulatory Authority), as required by local 
regulation. 
A progress report is sent to the IRB at least annually and a summary of the trial’s outcome at the 
end of the clinical trial. 
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STUDY MONITORING 
15.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) 
The Investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the Sponsor (including security rules). The 
Investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the CRF, discrepancy resolution form , or other appropriate instrument) 
in an accurate and legible manner according to the instructions provided and to ensure direct 
access to source documents to Sponsor representatives. 
If any circuit includes transfer of data, particular attention should be paid to the confidentiality of 
the patient’s data to be transferred. 
The Investigator may appoint such other individuals as he/she may deem appropriate as 
Subinvestigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Subinvestigators shall be appointed and listed in a timely manner. The 
Subinvestigators will be supervised by and work under the responsibility of the Investigator. The 
Investigator will provide them with a copy of the clinical trial protocol and all necessary 
information. 
15.2 
RESPONSIBILITIES OF THE SPONSOR 
The Sponsor of this clinical trial is responsible to regulatory authorities for taking all reasonable 
steps to ensure the proper conduct of the clinical trial as regards ethics, clinical trial protocol 
compliance, and integrity and validity of the data recorded on the CRFs. Thus, the main duty of 
the monitoring team is to help the Investigator and the Sponsor maintain a high level of ethical, 
scientific, technical and regulatory quality in all aspects of the clinical trial. 
At regular intervals during the clinical trial, the site will be contacted, through monitoring visits, 
letters or telephone calls, by a representative of the monitoring team to review study progress, 
Investigator and patient compliance with clinical trial protocol requirements, and any emergent 
problems. These monitoring visits will include but not be limited to review of the following 
aspects: patient informed consent, patient recruitment and follow-up, SAE documentation and 
reporting, AE documentation, and quality of data. 
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15.3 
SOURCE DOCUMENT REQUIREMENTS 
According to the ICH GCP, the monitoring team must check the CRF entries against the source 
documents, except for the preidentified source data directly recorded in the CRF. The ICF will 
include a statement by which the patient allows the Sponsor’s duly authorized personnel, the IRB, 
and the regulatory authorities to have direct access to original medical records which support the 
data on the CRFs (eg, patient’s medical file, appointment books, original laboratory records, etc.). 
These personnel, bound by professional secrecy, must maintained confidentiality of all personal 
identity or personal medical information (according to confidentiality and personal data protection 
rules). 
15.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST 
It is the responsibility of the Investigator to maintain adequate and accurate CRFs (according to 
the technology used) designed by the Sponsor to record (according to Sponsor instructions) all 
observations and other data pertinent to the clinical investigation in a timely manner. All CRFs 
should be completed in their entirety in a neat, legible manner to ensure accurate interpretation of 
data. 
Should a correction be made, the corrected information will be entered in the eCRF overwriting 
the initial information. An audit trail allows identifying the modification.  
Data are available within the system to the Sponsor as soon as they are entered in the eCRF. 
The computerized handling of the data by the Sponsor may generate additional requests 
(discrepancy resolution forms) to which the Investigator is obliged to respond by confirming or 
modifying the data questioned. The requests with their responses will be managed through the 
eCRF. 
15.5 
USE OF COMPUTERIZED SYSTEMS 
The complete list of computerized systems used for the study is provided in a separate document 
which is maintained in the Sponsor and Investigator study files. 
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ADDITIONAL REQUIREMENTS 
16.1 
CURRICULUM VITAE 
A current copy of the curriculum vitae describing the experience, qualification and training of 
each Investigator and Subinvestigator will be signed, dated and provided to the Sponsor prior to 
the beginning of the clinical trial. 
16.2 
RECORD RETENTION IN STUDY SITE(S) 
The Investigator must maintain confidential all study documentation, and take measures to 
prevent accidental or premature destruction of these documents. 
The Investigator should retain the study documents at least 15 years after the completion or 
discontinuation of the clinical trial. 
However, applicable regulatory requirements should be taken into account in the event that a 
longer period is required. 
The Investigator must notify the Sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation. 
If the Investigator’s personal situation is such that archiving can no longer be ensured by him/her, 
the Investigator shall inform the Sponsor and the relevant records shall be transferred to a 
mutually agreed upon designee. 
16.3 
CONFIDENTIALITY 
All information disclosed or provided by the Sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to, the clinical trial 
protocol, personal data in relation to the patients, the CRFs, the Investigator’s Brochure, and the 
results obtained during the course of the clinical trial, is confidential, prior to the publication of 
results. The Investigator and any person under his/her authority agree to undertake to keep 
confidential and not to disclose the information to any third party without the prior written 
approval of the Sponsor. 
However, the submission of this clinical trial protocol and other necessary documentation to the 
IRB is expressly permitted, the IRB members having the same obligation of confidentiality. 
The Subinvestigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Subinvestigators of the confidential nature of the clinical trial. 
The Investigator and the Subinvestigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party’s account. 
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16.4 
PROPERTY RIGHTS 
All information and documents provided by the Sponsor or its designee are and remain the sole 
property of the Sponsor. 
The Investigator shall not and shall cause the delegated Investigator staff /Subinvestigator not to 
mention any information or the Product in any application for a patent or for any other intellectual 
property rights 
All the results, data, documents and inventions, which arise directly or indirectly from the clinical 
trial in any form, shall be the immediate and exclusive property of the Sponsor. 
The Sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, 
develop, market or otherwise use the results of the clinical trial. 
As the case may be, the Investigator and/or the Subinvestigators shall provide all assistance 
required by the Sponsor, at the Sponsor’s expense, for obtaining and defending any patent, 
including signature of legal documents. 
16.5 
DATA PROTECTION 
 The patient’s personal data, which are included in the Sponsor database, shall be treated in 
compliance with all applicable laws and regulations. 
 When archiving or processing personal data pertaining to the Investigator and/or to the 
patients, the Sponsor shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party. 
 The Sponsor also collects specific data regarding Investigator as well as personal data 
from any person involved in the study which may be included in the Sponsor’s databases, 
shall be treated by both the Sponsor and the Investigator in compliance with all applicable 
laws and regulations. 
The data collected in this study will only be used for the purpose(s) of the study. They may be 
further processed if they have been pseudonymized. 
16.6 
INSURANCE COMPENSATION 
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship. This insurance policy is in accordance with local laws and requirements. 
The insurance of the Sponsor does not relieve the Investigator and the collaborators from any 
obligation to maintain their own liability insurance policy. An insurance certificate will be 
provided to the IRB or regulatory authorities in countries requiring this document. 
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16.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES 
For the purpose of ensuring compliance with the clinical trial protocol, GCP, and applicable 
regulatory requirements, the Investigator should permit auditing by or on the behalf of the 
Sponsor and inspection by regulatory authorities. 
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel is bound by professional secrecy, and as 
such will not disclose any personal identity or personal medical information. 
The Investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents. 
As soon as the Investigator is notified of a planned inspection by the authorities, he will inform 
the Sponsor and authorize the Sponsor to participate in this inspection. 
The confidentiality of the data verified and the protection of the patients should be respected 
during these inspections. 
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to the Sponsor. 
The Investigator shall take appropriate measures required by the Sponsor to take corrective 
actions for all problems found during the audit or inspections. 
16.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE 
16.8.1 By the Sponsor 
The Sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including but not limited to the following:  
 The information on the product leads to doubt as to the benefit/risk ratio; 
 Patient enrollment is unsatisfactory; 
 The Investigator has received from the Sponsor all means and information necessary to 
perform the clinical trial and has not included any patient after a reasonable period of time 
mutually agreed upon; 
 Non-compliance of the Investigator or Subinvestigator, delegated staff with any provision 
of the clinical trial protocol, and breach of the applicable laws and regulations or breach of 
the ICH GCP; 
In any case the Sponsor will notify the Investigator of its decision by written notice. 
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16.8.2 By the Investigator 
The Investigator may terminate his/her participation upon 30 days’ prior written notice if the 
study site or the Investigator for any reason becomes unable to perform or complete the clinical 
trial.  
In the event of premature discontinuation of the study or premature close-out of a site, for any 
reason whatsoever, the appropriate IRB and regulatory authorities should be informed according 
to applicable regulatory requirements.  
16.9 
CLINICAL TRIAL RESULTS 
The Sponsor will be responsible for preparing a clinical study report and to provide a summary of 
the study results to the Investigator. 
16.10 PUBLICATIONS AND COMMUNICATIONS 
The Investigator undertakes not to make any publication or release pertaining to the study and/or 
results of the study prior to the Sponsor’s written consent, being understood that the Sponsor will 
not unreasonably withhold its approval. 
The Investigator shall not use the name(s) of the Sponsor and/or of its employees in advertising or 
promotional material or publication without the prior written consent of the Sponsor. The Sponsor 
shall not use the name(s) of the Investigator and/or the collaborators in advertising or promotional 
material or publication without having received his/her and/or their prior written consent(s). 
The Sponsor has the right at any time to publish the results of the study. 
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CLINICAL TRIAL PROTOCOL AMENDMENTS 
All appendices attached hereto and referred to herein are made part of this clinical trial protocol. 
The Investigator should not implement any deviation from, or changes of the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB of an amendment, except where necessary to eliminate an immediate hazard(s) to 
clinical trial patients, or when the change(s) involves only logistical or administrative aspects of 
the trial. Any change agreed upon will be recorded in writing, the written amendment will be 
signed by the Investigator and by the Sponsor and the signed amendment will be filed with this 
clinical trial protocol. 
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
IRB prior to its implementation, unless there are overriding safety reasons. 
In some instances, an amendment may require a change to the ICF. The Investigator must receive 
an IRB written approval/favorable opinion concerning the revised ICF prior to implementation of 
the change and patient signature should be re-collected if necessary. 
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18 
BIBLIOGRAPHIC REFERENCES 
1. National Multiple Sclerosis Society. Multiple sclerosis: Just the facts [Online]. 2011 [cited 
2011 Oct 27]; Available from: URL:http://www.nationalmssociety.org/about-multiple-
sclerosis/index.aspx 
2. Moreau T, Coles A, Wing M, Thorpe J, Miller D, Moseley I, et al. CAMPATH-IH in multiple 
sclerosis. Mult Scler. 1996;1(6):357-65. 
 
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19 
APPENDICES 
Not applicable. 
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