Clinical trial NCT02201108
Conditions: Multiple Sclerosis
Sponsor: Genzyme, a Sanofi Company
Start date: 2014-07-16; Completion date: 2024-07-29
Enrollment: 166 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objective:

To assess the effect of teriflunomide in comparison to placebo on disease activity measured by time to first clinical relapse after randomization in children and adolescents 10 to 17 years of age with relapsing forms of multiple sclerosis (MS).

Secondary Objective:

* To assess the effect of teriflunomide in comparison to placebo on disease activity/progression measured by brain magnetic resonance imaging (MRI) and on cognitive function.
* To evaluate the safety and tolerability of teriflunomide in comparison to placebo.
* To evaluate the pharmacokinetics (PK) of teriflunomide.

Detailed description:
The study duration included a screening period up to 4 weeks, a double-blind treatment period of up to 96 weeks, an open-label period which included the remainder of the initial 96 weeks, where applicable, and a 96-week extension, i.e., up to a maximum of 192 weeks after randomization. There was a follow-up period of 4 weeks for participants discontinuing treatment.

Within the 96 weeks double-blind treatment period, the first 4 weeks were PK run-in phase in which PK samples (blood samples) were collected from participants and then 4 weeks of analysis (no samples drawn). The PK run-in phase (total 8 weeks) was intended to provide individual PK parameters to allow the dose adjustment to the 14 milligrams (mg) adult-equivalent dose for the rest of the study.

Participants who experienced a relapse after the PK run-in phase (8 weeks) and confirmed by the Relapse Adjudication Panel and participants who fulfilled MRI criteria (high number of new lesions at weeks 36, 48 or 72 compared to previous images) had the option to continue in an open-label teriflunomide treatment arm up to 192 weeks from randomization.

An optional additional extension period was available for young participants with teriflunomide until the participants are 18 years old and/or able to switch to commercial product, whichever comes first.

Arms: arm 1: Matching placebo tablets arm 2: Teriflunomide oral tablet, three dosages (3.5, 7 or 14 mg) to reach 14 mg adult equivalent
Interventions: intervention 1: Teriflunomide intervention 2: Placebo
Intervention descriptions: intervention 1: Pharmaceutical form:film-coated tablet, Route of administration: oral intervention 2: Pharmaceutical form:tablet, Route of administration: oral

Protocol documents:
Prot_002.pdf: 


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NAMES AND ADDRESSES OF 
COORDINATING 
INVESTIGATOR 
 
Name: 
Address: 
 
 
Tel: 
Fax: 
E-mail: 
 
 
MONITORING TEAM’S 
REPRESENTATIVE 
 
Name: 
Address: 
 
 
 
Tel: 
Fax: 
E-mail: 
 
 
SPONSOR  
Company: 
Address: 
 
 
 
 
Genzyme Corporation 
50 Binney Street 
Cambridge, MA 02142 
USA 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE  
Document history 
Document 
Country-specificity 
if applicable 
Date, version 
Amended protocol 05 
Amended protocol 04 
All 
All 
10-Dec-2020, Version number: 1 (electronic 6.0) 
11-Sep-2019, Version number: 1 (electronic 5.0) 
Amended protocol 03 
All 
02-Aug-2018, Version number: 1 (electronic 4.0) 
Amendment 4 
Russian Federation 
only 
26-Jul-2016, Version number 1 (electronic 1.0) 
Amendment 3 
Russian Federation 
only 
18-Dec-2014, Version number 1 (electronic 1.0) 
Amended protocol 2 
All 
26-Jun 2014, Version number: 1 (electronic 3.0) 
Amendment 2 
All 
11-Jun-2014, Version number: 1 (electronic 1.0) 
Amended protocol 1 
All 
18-Dec-2013, Version number: 1 (electronic 1.0) 
Amendment 1 
All 
18-Dec-2013, Version number: 1 (electronic 1.0) 
Original Protocol 
 
30-May-2013, Version number: 1 (electronic 1.0) 
Amended protocol 05 (10 December 2020) 
This amended protocol 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. 
Overall rationale for the amendment 
The primary drivers for this amended protocol are to implement changes to the conduct 
of the study for patients in the open-label period and optional extension period, to ensure 
continuation of patient treatment, while reducing personal contact with patients.   
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.3/1.4/1.5 
Study flow-chart 
Addition of specifications about weight and ECG during 
remote visits and reference to appendix G (section 
17.7) 
Flexibility for COVID-19 pandemic 
Section 7 Study 
treatments 
Addition of text in case of emergency and reference to 
appendix G (section 17.7) 
Flexibility for COVID-19 pandemic 
Section 7.9 Return 
and/or destruction of 
treatments 
Addition of IMP return specification and reference to 
appendix G (section 17.7) 
Flexibility for COVID-19 pandemic 
Section 8 
Assessment of 
Addition of text in case of emergency and reference to 
appendix G (section 17.7) 
Ease of continuation of study during 
COVID-19 pandemic 
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Section # and 
Name 
Description of Change 
Brief Rationale 
investigational 
medicinal product 
 
Section 8.1 Efficacy 
Addition of text in case of missing assessment and 
reference to Appendix G (section 17.7) 
Flexibility for COVID-19 pandemic 
Section 9 Safety 
endpoints assessed 
in this trial/ Sections 
9.2 Vital signs/9.3 
Physical 
examination/9.4 12-
lead ECG/9.6 
Clinical laboratory 
parameters/9.8.6 Re-
consent process 
Addition of text in case of emergency and reference to 
appendix G (section 17.7), and references to flowcharts. 
Flexibility for COVID-19 pandemic 
Section 10 Study 
procedures 
Addition of text in case of emergency and reference to 
appendix G (section 17.7) 
Flexibility for COVID-19 pandemic 
Section 10.3 
Handling of 
temporary or 
permanent treatment 
discontinuation and 
of patient study 
discontinuation 
Addition of text in case of emergency and reference to 
appendix G (section 17.7) 
Flexibility for COVID-19 pandemic 
Section 10.3.1 
Temporary treatment 
discontinuation with 
IMP 
Addition of cross-references to sections 
For more complete understanding 
Section 10.3.2 
Definitive treatment 
discontinuation with 
IMP 
Addition of text on permanently discontinuation for 
patients close to the end of treatment may be unable to 
continue their final treatment as scheduled (reference to 
appendix G (section 17.7) 
Flexibility for COVID-19 pandemic 
Section 12.3 
Informed consent 
Addition of text in case of emergency (reference to 
appendix G (section 17.7))   
Flexibility for COVID-19 pandemic 
Section 13.3 Source 
document 
requirement 
Addition of monitoring details, techniques, and source 
data verification 
Flexibility for COVID-19 pandemic  
Section 17.7 
Appendix G: 
Contingency 
measures for a 
regional or national 
emergency that is 
declared by a 
government agency  
Addition of appendix in case of emergency 
 
Flexibility for COVID-19 pandemic 
 
Section 17.8 
Appendix H: 
Summaries of 
memos 
Addition of summaries of the 3 memos to detail the 
procedures set up in case of emergency 
Flexibility for COVID-19 pandemic 
 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 17.9 
Appendix I: Protocol 
amendment history  
Inclusion of reason for amended protocol 4 
Amendment history 
Throughout 
Slight rewording  
Clarity or corrections of minor errors 
 
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CLINICAL TRIAL SUMMARY  
COMPOUND: HMR1726      STUDY No: EFC11759      STUDY NAME: TERIKIDS 
TITLE 
A two year, multicenter, randomized, double-blind, placebo-controlled, parallel 
group trial to evaluate efficacy, safety, tolerability, and pharmacokinetics of 
teriflunomide administered orally once daily in pediatric patients with relapsing 
forms of multiple sclerosis followed by an open-label extension 
INVESTIGATOR/TRIAL LOCATION 
Multinational 
PHASE OF DEVELOPMENT 
Phase III 
STUDY OBJECTIVE(S) 
Primary Objective: 
To assess the effect of teriflunomide in comparison to placebo on disease 
activity as measured by time to first clinical relapse after randomization in 
children and adolescents 10 to 17 years of age with relapsing forms of multiple 
sclerosis  
Secondary Objective(s): 
• 
To assess the effect of teriflunomide in comparison to placebo on 
disease activity/progression measured by brain MRI and on cognitive 
function. 
• 
To evaluate the safety and tolerability of teriflunomide in comparison 
to placebo. 
• 
To evaluate the pharmacokinetics (PK) of teriflunomide. 
STUDY DESIGN 
Multicenter, multinational, randomized, double-blind, placebo control, parallel 
group.  
The study will consists of: 
• 
A screening period up to 4 weeks. 
• 
A double-blind treatment period of up to 96 weeks for each patient, 
including a double-blind period and potentially an open label period. 
• 
An open-label period including the remainder of the initial 96 weeks, 
where applicable, and a 96-week extension, ie, up to a maximum of 
192 weeks after randomization.  
• 
An optional additional extension period for young patients with 
teriflunomide until the patients are 18 years old and/or able to switch 
to commercial product, whichever comes first.  
• 
A follow-up period of 4 weeks for patients discontinuing treatment. 
Double-blind treatment period of up to 96 weeks per patient: 
• 
Patients are randomized to either teriflunomide or placebo at 2:1 
ratio (110 patients on teriflunomide vs. 55 patients on placebo).  
• 
Blinded treatment phase begins at randomization and continues to 
Week 96 or when patient experiences a first relapse or high MRI 
activity. 
• 
It includes a blinded PK run-in phase (8 weeks) consisting of 4 
weeks with PK sample collection plus 4 weeks of analysis 
(corresponding to the first 8 weeks after randomization). The PK run-
in (8 weeks) phase is intended to provide individual PK parameters 
to allow the dose adjustment to the 14mg adult-equivalent dose for 
the rest of the study.  
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• 
Patients experiencing a relapse after the PK run-in period (8 weeks) 
and if confirmed by the Relapse Adjudication Panel (RAP) or high 
MRI activity as defined below or completing the 96-week period will 
have the option to continue in the open label period.  
• 
Evaluation of high MRI activity 
1) If 5 or more new/enlarged T2 lesions at Week 24, an additional 
MRI will be performed at Week 36. 
2) Criteria for high MRI activity to qualify for switch to open label 
treatment: 
• 
At least 9 new/enlarged T2 lesions at Week 36  
or  
• 
At least 5 new/enlarged T2 lesions on each of 2 consecutive MRI 
scans at Week 36 and Week 48, or at Week 48 and Week 72. 
(Note: new/enlarged since previous scan) 
Open-label period: 
The open-label period will follow the double-blind period and last until 
192 weeks after randomization. Its duration for a given patient will depend on 
when the patient enters this period. The duration of the open-label period will 
be 96 weeks for patients completing the 96-week double-blind period on 
treatment, and longer for patients switching to open-label during the initial 96 
week double-blind period at the occurrence of a confirmed relapse or in case 
of high MRI activity. 
It includes a blinded PK run-in phase (8 weeks, similarly to the double-blind 
period). 
Optional additional extension period for young patients: 
A treatment extension period with teriflunomide will be proposed to patients too 
young to access commercialized teriflunomide as per authorized indication 
when completing the 192-week treatment period, until they become adult or 
until they are able to switch to commercial product, whichever comes first. 
Follow up period for patients who discontinue: 
Upon discontinuation of the study treatment (either by early termination or not), 
patients who will not be treated with teriflunomide post-study will be required to 
perform an accelerated elimination procedure within a 4 week follow up period. 
Two Clinical Study Reports (CSR) will be issued:  
• 
The first CSR will report the final analysis of the double-blind 
treatment period.The study methods described in this document 
primarily relate to this treatment period and analysis. 
• 
The second CSR will report the analysis of the open-label data at the 
conclusion of the extension period for all included patients.  
The data for the optional additional extension period for young patients will be 
reported separately. 
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STUDY POPULATION  
Main selection criteria 
Inclusion Criteria:  
• 
Patients with diagnosis of  relapsing MS  based on McDonald criteria 
of  2010 and  International Pediatric Multiple Sclerosis Study Group 
criteria for pediatric MS  and have: 
- 
At least one relapse (or attack) in the 12 months preceding 
screening, or, 
- 
At least 2 relapses (or attacks) in the 24 months preceding 
screening.  
• 
<18 years of age and ≥10 years of age at randomization 
Specific for the Russian Federation from 18 December 2014 to 
26 July 2016, ≤17 years of age and ≥13 years of age at 
randomization. 
• 
Signed informed consent/assent obtained from patient and patient’s 
legal representative (parents or guardians) according to local 
regulations. 
Exclusion Criteria: 
• 
EDSS score >5.5 at screening or randomization visits. 
• 
Relapse within 30 days prior to randomization.  
• 
Treated with: 
- 
Glatiramer acetate, interferons, or dimethyl fumarate within 
1 month prior to randomization,  
- 
Fingolimod, or intravenous immunoglobulins within 3 months 
prior to randomization, 
- 
Natalizumab, other immunosuppressant or immunomodulatory 
agents such as cyclophosphamide, azathioprine, cyclosporine, 
methotrexate, mycophenolate, within 6 months prior to 
randomization,  
- 
Cladribine or mitoxantrone within 2 years prior to randomization. 
• 
Treated with alemtuzumab at any time. 
• 
History of HIV infection.  
• 
Contraindication for MRI.  
• 
Pregnant or breast-feeding females or those who plan to become 
pregnant during the study. 
• 
Female patients of child-bearing potential not using highly effective 
contraceptive method (contraception in both female and male is 
required). 
Total expected number of patients 
 
 
 
Expected number of sites: 
165 children and adolescents of either gender <18 years of age and ≥10 years 
of age (including approximately 20% pre-pubertal patients or 10% of patients 
under the age of 13 years at the time of inclusion into the study and at least 
25% male patients): 
• 
55 patients on placebo. 
• 
110 patients on teriflunomide. 
Approximately 100 sites. 
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STUDY TREATMENT(s) 
 
Investigational medicinal product(s) 
Formulation 
Teriflunomide:  
Matching film-coated tablets containing either 
• 
3.5 mg of teriflunomide or, 
• 
7 mg of teriflunomide or,  
• 
14 mg of teriflunomide. 
Placebo: 
Matching placebo tablets 
During the PK run–in period including the 4 weeks analysis (corresponding to 
the first 8 weeks of the study): 7mg adult equivalent, QD: 
• 
For patients 30 ± 10 kg: 
- 
1 teriflunomide tablet (3.5 mg) per day (QD). 
• 
For patients >40 kg: 
- 
1 teriflunomide tablet (7 mg) per day (QD). 
After the end of the PK run-in (8 weeks) phase:14mg adult equivalent, QD: 
If individual predicted PK parameters are equal to or less than the 95th 
percentile of  adult range of predicted PK parameters (repeated doses of 7 
mg): 
• 
For patients 30 kg ± 10 kg 
- 
1 teriflunomide tablet (7 mg) per day (QD). 
• 
For patients >40 kg 
- 
1 teriflunomide tablet (14 mg) per day (QD). 
If individual predicted PK parameters are higher than the 95th percentile of  the 
adult range of predicted PK parameters (repeated doses of 7 mg): 
• 
For patients 30 kg ± 10 kg 
- 
1 teriflunomide tablet (3.5 mg) per day (QD). 
• 
For patients >40 kg 
- 
1 teriflunomide tablet (7 mg) per day (QD). 
Adult range (5th - 95th percentile) of predicted PK parameters: 7 mg dose range 
for Cmax is 8.03 to 49.1 g/mL and for AUC0-24 is 184 to 1160 g.h/mL 
(POH0339) 
Optional additional extension period for young patients: 
1 teriflunomide tablet (14 mg) per day (QD). Based on Investigator’s judgment, 
for patients less than 40 kg, dose could be adjusted to 14 mg every other day. 
Route(s) of administration 
Oral  
Dose regimen 
One per day with or without food preferably at the same time each day. 
Noninvestigational medicinal 
product(s) (if applicable) 
Cholestyramine or Activated charcoal (only for patients undergoing accelerated 
elimination procedure after last dose who will not be treated with teriflunomide 
anymore). 
Route(s) of administration 
Oral  
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ENDPOINT(S) 
Primary Endpoint: 
• 
Time to first clinical relapse after randomization.  
Secondary Endpoints:  
• 
Proportion of relapse free patients at 24, 48, 72 and 96 weeks. 
• 
MRI endpoints: 
- 
Number of new/newly enlarged T2 lesions, 
- 
Number of T1 Gd-enhancing T1 lesions, 
- 
Change in volume of T2 lesions, 
- 
Change in volume of T1 hypointense lesions, 
- 
Number of new T1 hypointense lesions, 
- 
Proportion of patients free of new or enlarged MRI T2-lesions at 
48 weeks and 96 weeks,  
- 
Brain atrophy.  
• 
The number of new/newly enlarged T2 lesions and the number of T1 
Gd-enhancing T1 lesions will be considered the key secondary 
imaging endpoints. 
• 
Cognitive outcome measured by SDMT and a Cognitive Battery Test 
which will include TMT-A and B, SRT, Beery VMI, D-KEFS Fluencies 
(Letter and Category); BVMTR and WASI Vocabulary as available.  
• 
Teriflunomide PK. 
• 
Exploratory endpoint: proportion of disease-free patients. 
ASSESSMENT SCHEDULE 
Efficacy: referring to the 96-week double-blind period 
• 
Clinical relapses.  
• 
EDSS: screening, randomization, after relapse, every 24 weeks and 
at EOT. 
• 
Cognitive battery: randomization and EOT.  
• 
SDMT: randomization, every 24 weeks and at EOT. 
• 
MRI: baseline (a previous MRI performed in the 6 weeks preceding 
randomization could be acceptable if performed according to the 
specifications for this study), 24, 36 (if criteria is met at Week 24), 48, 
72 and 96 weeks. 
Safety and tolerability: referring to the 96-week double-blind period 
• 
AE reporting at each visit. 
• 
Physical examinations: screening, randomization, Weeks 12, 24, and 
every 12 weeks, EOT or early treatment discontinuation and at EOT 
+2W. 
• 
Vital signs: screening, randomization Weeks 4, 8, 12, 24, and every 
12 weeks while on treatment, at EOT or early treatment 
discontinuation, at EOT+2W and at EOT+4W, and after relapse. 
• 
Tanner stage: at baseline, every 24 weeks and EOT (until complete 
sexual maturity defined by Tanner Stage 5). 
• 
Clinical laboratories: screening, randomization, Weeks 4, 8, 12, 16, 
20, 24, then every 6 weeks up to EOT or early treatment 
discontinuation, at EOT + 2W and at EOT + 4W. 
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• 
Serum immunoglobulin (IgG, IgM and IgA) measurements at 
randomization and every 24 weeks. In addition if a patient has a 
vaccination, antibody titers will be assessed before and after 
vaccination (only inactivated vaccines are allowed during study).  
• 
TSH: at randomization and every 24 weeks. 
• 
Peripheral neuropathy: neurological symptoms suggestive of a 
peripheral neuropathy (confirmed with electrophysiological diagnosis 
including nerve conduction). 
• 
ECG: baseline, and at EOT or early treatment discontinuation  
• 
In case of suspected infection, all efforts must be made to determine 
an etiology using the best medical judgment (clinical signs and 
symptoms, laboratory data, imaging findings). 
Pharmacokinetics: 
• 
Blood sample collected to determine teriflunomide  plasma 
concentrations:  
- 
During the 4-week PK run-in (8 weeks) period, at least 3 PK 
samples will be collected (at Weeks 2, 3 and 4). 
• 
Patients entering the open label period will have to re-do the PK run-
in (8 weeks) which requires additional PK samples, if needed 
corresponding to Weeks 2, 3 and 4 of open-label treatment. 
• 
After PK run-in (8 weeks) period in the 96-week double-blind 
treatment phase, PK samples will be taken at Weeks 8, 12, 24, 36 
and EOT.  
• 
A sample will be collected at both follow up visits (EOT+2W and 
EOT+4W) to check if accelerated elimination procedure was 
successful. Both samples will be used to verify that teriflunomide 
plasma concentration is less or equal to 0.02 μg/mL.  Additional 
samples may be required to ensure that teriflunomide plasma 
concentration has reached a level of ≤0.02 μg/mL.   
STATISTICAL CONSIDERATIONS 
Sample size determination: 
In the combined, completed Phase 3 monotherapy adult studies 
(EFC6049/TEMSO and EFC10531/TOWER), 58.7% of placebo patients aged 
≤30 (n=167) experienced at least 1 relapse versus 38.7% in the teriflunomide 
14 mg group (n=163) in a 2-year treatment period. 
For the current study, assuming 60% of placebo patients will experience a 
relapse by 2 years, given a 2:1 teriflunomide to placebo randomization ratio, 
165 patients (110 teriflunomide and 55 placebo) would be needed for 
80% power to detect a hazard ratio (teriflunomide versus placebo) of 0.5 
(2-sided alpha 0.05).  The 2-year rate of relapse in the teriflunomide group 
would be 36.8% and the corresponding hazard rates, assuming the 
time-to-relapse is exponentially distributed with a constant hazard rate, would 
be 0.4581 for placebo and 0.2291 for teriflunomide.   
The sample size and power are calculated using nQuery Advisor 7. The 
sample size is adjusted assuming 20% of patients discontinue the study in 2 
years due to reasons other than relapse. 
Randomization: 
Patients will be randomly assigned to receive either teriflunomide or placebo in 
a 2:1 randomization ratio.  Randomization will be stratified by the country in 
which the patient is being treated and patient’s pubertal status. 
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Analysis dataset: 
The data from the placebo-controlled and the open label teriflunomide 
treatment phases will be the focus of the two respective CSRs. The following 
statistical methods/considerations relate to the analysis of the data from the 
placebo-controlled period. The data from the open label teriflunomide 
treatment arm are non-controlled and supportive in nature; summary statistics 
will be provided for each of the efficacy variables and safety data 
Analysis population: 
The analysis population for efficacy endpoints will be the intent-to-treat (ITT) 
population, defined as all randomized patients who received at least 1 dose of 
study medication. All patients will be analyzed according to the treatment to 
which they are randomized. 
The analysis population for safety endpoints will be the safety population, 
defined as all randomized patients exposed to study medication, regardless of 
the amount of treatment administered.  The safety analyses will be conducted 
according to the treatment patients actually received. 
Analysis of the primary endpoint: 
Time to first confirmed relapse from randomization (including relapses during 
the PK run-in (8 weeks) phase) to last study drug administration will be 
analyzed using a log-rank test with time to first relapse as the dependent 
variable, treatment group as a test variable, and region and pubertal status as 
covariates. Treatment effect as measured by the hazard ratio and its 
associated 95% confidence interval will be estimated using a Cox proportional-
hazards model with adjustment for treatment group, region, pubertal status, 
age, and number of relapses in the year prior to randomization. 
The following sensitivity analyses for the primary endpoint will be performed 
using the similar log-rank test and Cox proportional-hazards model as 
described above. 
• 
Time to first confirmed relapse occurring after the PK run-in (8 
weeks) phase but before the treatment discontinuation. The patients 
who have a relapse during the PK run-in (8 weeks) phase will be 
included in the analysis with the time to first relapse right censored at 
the time of treatment discontinuation.  
• 
Time to first relapse (confirmed or not) after randomization during the 
study treatment.  
• 
Time to first confirmed relapse including relapses during the PK run-
in (8 weeks) phase and relapses reported after the study drug 
discontinuation and up to 96 weeks after randomization. 
• 
Time to first confirmed relapse including high MRI activity (ie, 
meeting criteria for switching into open-label period) as equivalent to 
a confirmed relapse event. 
Analysis of secondary endpoints: 
The proportion of patients relapse-free at Weeks 24, 48, 72 and 96 will be 
estimated based on Kaplan-Meier methods. Interval estimates will be 
calculated using 95% point wise confidence intervals. 
The number of new or enlarged T2-lesions per MRI scan will be analyzed 
using a negative binomial regression model. The model will include the total 
number of new or enlarged T2 lesions as the response variable, with treatment 
group, region, pubertal status and age as covariates. In order to account for 
different numbers of MRI scans performed among patients, the log-
transformed number of scans will be included in the model as an offset 
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variable. The estimated number of lesions per scan and associated 2-sided 
95% confidence interval (CI) will be provided for each treatment group. The 
relative risk, 2-sided 95% CI and p-value will be provided for comparing 
teriflunomide to placebo. The number of T1 Gd-enhancing lesions per MRI 
scan and the number of new T1 hypointense lesions per MRI scan will be 
analyzed using a similar negative binomial regression model as described 
above for T2 lesions.  
To reduce the impact of potential outliers, ordinal logistic regression model 
including treatment group, region, pubertal status and age will also be used to 
analyze these endpoints.  The following categories for the number of lesions, 
0, 1, 2, 3-4 and ≥5 are considered and will be further defined in the SAP. 
Change from baseline in volume of T2 lesions, T1 hypointense lesions and 
brain atrophy will be analyzed using a mixed-effect model with repeated 
measures (MMRM) approach with appropriate transformation if necessary. The 
proportion of patients free of new or enlarged T2 lesions at Weeks 48 and 96 
will be summarized based on all patients having an MRI at these time points.  
The change from baseline in cognitive outcomes will be analyzed descriptively. 
Multiplicity adjustment procedure: 
• 
Statistical significance will be claimed for the primary efficacy 
endpoint if the computed p-value from the primary analysis is ≤0.05.  
No multiplicity adjustment is considered for secondary efficacy 
outcomes for this study.  
Missing data handling:  
Given the time to event analysis methodology, there is no impact on the 
analysis of the primary endpoint for patients experiencing a first relapse and 
moving to open label teriflunomide treatment.  Patients discontinuing double-
blind treatment due to high MRI activity will be censored at discontinuation. 
Patients who prematurely discontinue the study drug will be encouraged to 
continue study follow-up as planned according to the study flowchart.  Missing 
data due to patient’s discontinuation from the study drug, therefore, should be 
greatly reduced.  The main analysis for time to first relapse will include 
relapses during the study treatment.  The relapses reported after the study 
drug discontinuation will be included for supportive analyses. 
Safety analyses: 
The incidence of treatment emergent adverse events (TEAEs), deaths, serious 
adverse events (SAE), AEs leading to treatment discontinuation, and adverse 
event of special interest (AESI), will be summarized by treatment group using 
counts and percentages.  Analyses of laboratory data, vital signs and ECG will 
focus on descriptive statistics and summaries of pediatric potentially clinically 
significant abnormality (PCSA) values.  Patients with peripheral neuropathy 
finding or abdominal findings compatible with pancreatitis will be summarized 
by treatment group using counts and percentages. 
For the optional additional extension period for young patients, the efficacy and 
safety data will be summarized by descriptive statistics. 
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DURATION OF STUDY PERIOD (per 
patient)  
Screening: up to 4 weeks. 
Double-Blind Treatment Period: up to 96 weeks total.  
Open-Label period: after completion/discontinuation of double-blind period for 
the remainder of 192 weeks.  
Optional additional extension period for young patients: after the open-label 
period until the patients are 18 years and/or able to switch to commercial 
product, whichever comes first. It will be implemented in France and possibly 
other countries where local solutions are not possible within a reasonable time 
frame. 
Follow-up period: 4 weeks. Further follow-up may be required to ensure that 
teriflunomide plasma concentration has reached a level of ≤0.02 μg/mL. 
STUDY COMMITTEES 
Data Monitoring Committee: Yes  
A Data Monitoring Committee (DMC), independent from the Sponsor and 
Investigators, will monitor and review all relevant data on a regular basis for 
the assessment of benefit versus risk and provide recommendations about 
further conduct of the trial. 
Adjudication Committee: Yes 
A Relapse Adjudication Panel will review all relapses reported during the 
double-blind period in a blinded fashion in order to confirm whether a subject 
has experienced a protocol-defined relapse.  
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d 
For discontinuing treatment, 2 post drug elimination follow up visits should be scheduled 2 weeks and 4 weeks after study medication discontinuation and initiation of the drug elimination procedure. All 
patients who prematurely and permanently discontinue study medication will be asked to continue until the planned end of double-blind period. 
e 
Re-consent must follow any RAP confirmed MS relapse for continuing in study when occurrence during PK run-in, for switching into open-label period when occurrence after PK run-in. 
f 
To be prescribed at Visit 1 and report checked at Visit 2. MRI scan performed within 6 weeks prior to randomization can be used as the baseline MRI if performed according to the operations manual and 
accepted by the central reader.  
g 
During the adverse event reporting process, specific questions about pulmonary symptoms and peripheral neuropathy symptoms will be asked. (Patients will be instructed to alert the treating physician of 
symptoms suggestive of immunodeficiency). 
h 
Including systolic and diastolic blood pressure, heart rate, body temperature, weight and height (Height only at V2 and EOT); patient standing in bare or stocking feet. Height and weight is to be documented 
in the growth charts –Blood pressure (BP) and heart rate to be measured in both the supine and the standing positions (measures taken 3 minutes after supine and 3 minutes after standing).  
A sphygmomanometer with a blood pressure cuff appropriate to the patient’s arm girth is used. 
i 
Tanner stage to be assessed at baseline, every 24 weeks and at EOT for all patients (until complete sexual maturity).  
j 
Pancreatic ultrasound must be performed if there are clinical or lab abnormalities suggesting pancreatitis or enzymes elevation ≥3 x ULN and must be followed up with a computed tomography (CT) with 
contrast or MRI in case of ultrasound with abnormal pancreatic findings  
k 
The following routine parameters will be measured at screening, randomization, Weeks 4, 12, 24, 36, 48, then every 12 weeks and at EOT: Hematology and differential panel (hemoglobin, hematocrit, red 
blood cell count and red blood cell morphology, mean corpuscular volume, white blood cell count, neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelets); Coagulation panel (prothrombin 
time, and activated partial thromboplastin time); Complete chemistry panel (glucose, creatinine, blood urea nitrogen (BUN), sodium, potassium, chloride, bicarbonate, magnesium, calcium uric acid, 
aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH), total bilirubin, direct/indirect bilirubin, alkaline phosphatase, 
inorganic phosphorus, total protein, albumin, globulin, albumin/globulin ratio, triglycerides, cholesterol and creatine phosphokinase (CPK). Pancreatic enzymes (serum amylase and lipase); Urinalysis (pH, 
ketones, protein, glucose, blood, urobilinogen, bilirubin, microscopic sediment, specific gravity). For pubescent females serum pregnancy test β- Human chorionic gonadotropin; (β-HCG) will be performed 
at screening, randomization and then every 12 weeks  
l 
The following safety laboratory tests will be conducted in between clinical routine lab at  Weeks 8, 16, 20, 30 and then every 12 weeks up to the end of the study (EOT). Study nurse visit at patient’s home 
can be provided (except at Week 8).   In addition at EOT+2 weeks and EOT+4 weeks. The following safety laboratory testing will be conducted: (measuring hematology and differential panel [as above], 
liver function tests [ALT, AST, GGT, total bilirubin, and direct/indirect bilirubin] and pancreatic enzymes [serum amylase and lipase]). In addition, uric acid and inorganic phosphorus will be done at 
EOT+2 weeks and EOT+4 weeks. 
m 
PK samples will be collected at Week 2, 3, and 4 (PK run-in (8 weeks) period); an additional 4th sample may be required in case of inadequate sampling or information/variability from 3 samples.  Study 
nurse visit at patient’s home can be provided when PK sampling is not synchronized with routine lab visit (W2, W3 or in the event the 4th sample is needed).    
n 
Post drug elimination procedure sample to be collected for verification of plasma teriflunomide concentrations ≤0.02 μg/mL 
o 
In addition if a patient has a vaccination, antibody titers will be assessed before and after vaccination (inactivated vaccines only)  
p 
EDSS required also after each clinical relapse, to be performed within 7 days. 
q 
If patient is treated with steroids the MRI should be performed after 14 days discontinuation of the steroids 
r 
ECG should be performed only for patients who had new abnormalities on the EOT ECG 
s 
A tuberculosis test should be performed at screening. An additional test should be performed during the study if deemed clinically indicated. Skin test or blood testing are allowed 
t 
The date of first menarche should be captured if applicable 
u 
Cognitive Battery Tests: TMT-A and B, SRT, Beery visual-motor integration (BVMI), D-KEFS Fluencies (Letter and Category); BVMTR and WASI Vocabulary potentially supplemental. When available 
v 
 IVRS only if treatment is stopped 
Please refer to Section 9.11.4 for details. 
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a 
The open label period starts by the transition visit. It is recommended that there is no time gap between the 2 periods, or as short as possible and if possible less than 2 weeks. In case of start of the open 
label period at the end of the 96 weeks of the double-blind period, the transition visit will generally coincide with the EOT visit of the double-blind period. Recommended windows: The window for obtaining 
biological samples at any given visit will be ±7 days. All other treatment period assessments should be completed within ±7 days of the scheduled visit date relative to the transition visit. Post drug 
elimination follow-up visits should be ±7 days of scheduled visit relative to end of treatment. 
b 
For a regional or national emergency declared by a governmental agency, contingency measures are included in Section 17.7 
c 
End-of-treatment and premature discontinuation visit.  
d 
For patients discontinuing treatment, 2 post drug elimination follow up visits should be scheduled 2 weeks and 4 weeks after study medication discontinuation and initiation of the drug elimination procedure. 
When applicable patients who prematurely and permanently discontinue study medication will be asked to continue until the planned end of double-blind period (ie, 96 weeks after randomization)  
e 
Re-consent before starting open-label period and after confirmed MS relapse and when patients turn adults as per local regulations. 
f 
During the adverse event reporting process, specific questions about pulmonary symptoms and peripheral neuropathy symptoms will be asked. (Patients will be instructed to alert the treating physician of 
symptoms suggestive of immunodeficiency) 
g 
Including systolic and diastolic blood pressure, heart rate, body temperature, weight and height; patient standing in bare or stocking feet. Height and weight is to be documented in the growth charts –Blood 
pressure (BP) and heart rate to be measured in both the supine and the standing positions (measures taken 3 minutes after supine and 3 minutes after standing).  A sphygmomanometer with a blood 
pressure cuff appropriate to the patient’s arm girth is used. Of note, during remote visits, only weight will be collected. 
h 
Tanner stage to be assessed at every 24 weeks and EOT for all patients (until complete sexual maturity).  
i 
Pancreatic ultrasound must be performed if there are clinical or lab abnormalities suggesting pancreatitis or enzymes elevation ≥3 x ULN and must be followed up with a computed tomography (CT) with 
contrast or MRI  
j 
The following routine parameters will be measured at transition visit if previous laboratory assessment was performed more than 4 weeks before, at Weeks 4, 12, 24, 36, 48, then every 12 weeks and at 
EOT: Hematology and differential panel (hemoglobin, hematocrit, red blood cell count and red blood cell morphology, mean corpuscular volume, white blood cell count, neutrophils, lymphocytes, monocytes, 
eosinophils, basophils, platelets); Coagulation panel (prothrombin time, and activated partial thromboplastin time); Complete chemistry panel (glucose, creatinine, blood urea nitrogen (BUN), sodium, 
potassium, chloride, bicarbonate, magnesium, calcium uric acid, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH), 
total bilirubin, direct/indirect bilirubin, alkaline phosphatase, inorganic phosphorus, total protein, albumin, globulin, albumin/globulin ratio, triglycerides, cholesterol and creatine phosphokinase (CPK). 
Pancreatic enzymes (serum amylase and lipase); Urinalysis (pH, ketones, protein, glucose, blood, urobilinogen, bilirubin, microscopic sediment, specific gravity). For pubescent females serum pregnancy 
test β- Human chorionic gonadotropin; (β-HCG) will be performed  every 12 weeks  
k 
The following safety laboratory tests will be conducted in between clinical routine lab at Weeks 8, 16, 20, 30 and then every 12 weeks up to the end of treatment (EOT). Study nurse visit at patient’s home 
can be provided (except at Week 8). In addition at EOT+2 weeks and EOT+4 weeks. The following safety laboratory testing will be conducted: (measuring hematology and differential panel [as above], liver 
function tests [ALT, AST, GGT, total bilirubin, and direct/indirect bilirubin] and pancreatic enzymes [serum amylase and lipase]). In addition, uric acid and inorganic phosphorus will be done at EOT+2 weeks 
and EOT+4 weeks. 
l 
PK samples will be collected at Week 2, 3, and 4 (PK run-in (8 weeks) period); an additional 4th sample may be required in case of inadequate sampling or information/variability from 3 samples.  Study 
nurse visit at patient’s home can be provided when PK sampling is not synchronized with routine lab visit (W2, W3 or in the event the 4th sample is needed.  
m 
Post drug elimination procedure: samples to be collected for verification of plasma teriflunomide concentrations ≤0.02 μg/mL 
n 
In addition if a patient has a vaccination, antibody titers will be assessed before and after vaccination (inactivated vaccines only)  
o 
EDSS required also after each clinical relapse, to be performed within 7 days. 
p 
If patient is treated with steroids the MRI should be performed after 14 days discontinuation of the steroids 
q 
ECG should be performed only for patients who had new abnormalities on the EOT ECG; or when ECG could not be performed at EOT (in exceptional circumstances). 
r 
Cognitive Battery Tests: TMT-A and B, SRT, Beery VMI, BVMTR, D-KEFS Fluencies (Letter and Category);   BVMTR and WASI Vocabulary potentially supplemental. When available 
s 
The number of visits is linked to the time in the previous double blind phase as the maximum period in the study is 192 weeks. The maximum potential duration is therefore 184 weeks 
t 
The date of the menarche should be captured if applicable 
u 
IVRS only if treatment is stopped 
v 
An optional additional extension period with teriflunomide is offered to young patients, to provide them treatment until they are 18 years old and/or can switch to commercial product, whichever comes first. 
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d For patients prematurely discontinuing treatment, 2 post- drug elimination follow-up visits should be scheduled 2 weeks and 4 weeks after study medication discontinuation and initiation of the drug elimination 
procedure. 
e Re-consent before starting optional additional extension period for young patients. 
f 
If patient is treated with steroids the MRI should be performed after 14 days discontinuation of the steroids. No central reading for MRI is planned in the optional additional extension period. 
g During the adverse event reporting process, specific questions about pulmonary symptoms and peripheral neuropathy symptoms will be asked. (Patients will be instructed to alert the treating physician of 
symptoms suggestive of immunodeficiency). 
h Including systolic and diastolic blood pressure, heart rate, body temperature, weight and height; patient standing in bare or stocking feet. Height and weight is to be documented in the growth charts –Blood 
pressure (BP) and heart rate to be measured in both the supine and the standing positions (measures taken 3 minutes after supine and 3 minutes after standing).  A sphygmomanometer with a blood pressure cuff 
appropriate to the patient’s arm girth is used. Of note, during remote visits, only weight will be collected. 
i 
Standard liver function test and hematology tests to be performed every 6 weeks (specific panel to be decided by Investigator). These tests will be performed in local laboratories. Clinical relevant abnormalities 
should be reported as TEAEs (Refer to Section 9.10.2.1). Other data will not be entered in eCRF. 
j 
Post drug elimination procedure: samples to be collected for verification of plasma teriflunomide concentrations ≤0.02 μg/mL. 
 
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TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL NO. 05 ....................................................................................... 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE .................................................................. 3 
1 
FLOW CHARTS ............................................................................................................................. 15 
1.1 
GRAPHICAL STUDY DESIGN ....................................................................................................... 15 
1.2 
STUDY FLOW CHART FOR THE DOUBLE-BLIND TREATMENT PERIOD ............................... 16 
1.3 
FLOW CHART FOR OPEN LABEL EXTENSION PERIOD, FIRST 96 WEEKS ........................... 19 
1.4 
FLOW CHART FOR OPEN LABEL PERIOD, CONTINUED ......................................................... 20 
1.5 
FLOW CHART FOR OPTIONAL ADDITIONAL EXTENSION PERIOD FOR YOUNG 
PATIENTS ...................................................................................................................................... 22 
TABLE OF CONTENTS ................................................................................................................................ 24 
LIST OF TABLES ......................................................................................................................................... 30 
2 
LIST OF ABBREVIATIONS .......................................................................................................... 31 
3 
INTRODUCTION AND RATIONALE ............................................................................................. 33 
3.1 
INTRODUCTION ............................................................................................................................ 33 
3.1.1 
Pediatric Multiple Sclerosis ............................................................................................................ 33 
3.1.2 
Teriflunomide ................................................................................................................................. 34 
3.1.2.1 
Clinical efficacy in adult MS patients .............................................................................................. 34 
3.1.2.2 
Clinical safety in adult MS patients ................................................................................................ 34 
3.1.2.3 
Non-clinical juvenile toxicity program ............................................................................................. 37 
3.1.2.4 
Proposed pediatric study ............................................................................................................... 37 
3.2 
RATIONALE ................................................................................................................................... 38 
3.2.1 
Population rationale ....................................................................................................................... 38 
3.2.2 
Rationale for study design ............................................................................................................. 38 
3.2.3 
Teriflunomide choice of dose and PK run-in (8 weeks) rationale .................................................. 39 
4 
STUDY OBJECTIVES ................................................................................................................... 42 
4.1 
PRIMARY OBJECTIVE .................................................................................................................. 42 
4.2 
SECONDARY OBJECTIVE(S) ...................................................................................................... 42 
5 
STUDY DESIGN ............................................................................................................................ 43 
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5.1 
DESCRIPTION OF THE PROTOCOL ........................................................................................... 43 
5.1.1 
Duration of study participation for each patient ............................................................................. 44 
5.1.2 
Determination of end of clinical trial ............................................................................................... 44 
5.2 
STUDY COMMITTEES .................................................................................................................. 45 
5.2.1 
Data monitoring committee (DMC) ................................................................................................ 45 
5.2.2 
Adjudication Committee (AC) ......................................................................................................... 45 
6 
SELECTION OF PATIENTS .......................................................................................................... 46 
6.1 
NUMBER OF PATIENTS PLANNED ............................................................................................. 46 
6.2 
INCLUSION CRITERIA .................................................................................................................. 46 
6.3 
EXCLUSION CRITERIA ................................................................................................................ 46 
6.3.1 
Exclusion criteria related to study methodology ............................................................................ 46 
6.3.2 
Exclusion criteria related to treatments, which may interfere with the study ................................. 47 
6.3.3 
Exclusion criteria related to study treatment at screening ............................................................. 47 
6.3.4 
Criteria to reduce reproductive risk ................................................................................................ 49 
6.4 
CONCOMITANT MEDICATION ..................................................................................................... 50 
6.4.1 
Standardization of acute therapy for relapses during the study .................................................... 52 
7 
STUDY TREATMENTS ................................................................................................................. 53 
7.1 
INVESTIGATIONAL MEDICINAL PRODUCT ............................................................................... 53 
7.1.1 
HMR1726 (teriflunomide) ............................................................................................................... 53 
7.2 
NON-INVESTIGATIONAL MEDICINAL PRODUCT(S) ................................................................. 54 
7.3 
BLINDING PROCEDURES ............................................................................................................ 54 
7.3.1 
Measures to protect blinding of this trial ........................................................................................ 54 
7.3.2 
Randomization code breaking during the study ............................................................................. 55 
7.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP .............................................. 55 
7.5 
PACKAGING AND LABELING ...................................................................................................... 56 
7.5.1 
Teriflunomide/placebo .................................................................................................................... 56 
7.6 
STORAGE CONDITIONS AND SHELF LIFE ................................................................................ 56 
7.7 
RESPONSIBILITIES ...................................................................................................................... 57 
7.8 
TREATMENT ACCOUNTABILITY AND COMPLIANCE ............................................................... 57 
7.9 
RETURN AND/OR DESTRUCTION OF TREATMENTS .............................................................. 58 
8 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT .............................................. 59 
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8.1 
EFFICACY ..................................................................................................................................... 59 
8.1.1 
Primary efficacy .............................................................................................................................. 60 
8.1.2 
Secondary efficacy ......................................................................................................................... 61 
8.2 
SAFETY ......................................................................................................................................... 61 
8.3 
BIOMARKERS ............................................................................................................................... 62 
9 
SAFETY ENDPOINTS ASSESSED IN THIS TRIAL ..................................................................... 63 
9.1 
SPONTANEOUSLY REPORTED ADVERSE EVENTS ................................................................ 63 
9.2 
VITAL SIGNS ................................................................................................................................. 63 
9.3 
PHYSICAL EXAMINATION ........................................................................................................... 63 
9.4 
12-LEAD ECG ................................................................................................................................ 64 
9.5 
ULTRA SOUND OF THE PANCREAS .......................................................................................... 64 
9.6 
CLINICAL LABORATORY PARAMETERS ................................................................................... 65 
9.6.1 
Routine clinical laboratory parameters........................................................................................... 65 
9.6.2 
Safety clinical laboratory parameters ............................................................................................. 65 
9.6.3 
Additional laboratory parameters ................................................................................................... 66 
9.6.4 
Optional additional extension period for young patients ................................................................ 66 
9.7 
IMMUNOGLOBULINS.................................................................................................................... 66 
9.8 
SAFETY INSTRUCTIONS ............................................................................................................. 66 
9.8.1 
Pre-defined adverse events and laboratory abnormalities for specific reporting (AEPM) ............. 66 
9.8.2 
Laboratory test monitoring ............................................................................................................. 68 
9.8.3 
Monitoring electrocardiogram ........................................................................................................ 68 
9.8.4 
Overdose information ..................................................................................................................... 68 
9.8.5 
General guidance for relapses (refer to Section 10.1.3.5 for detailed instructions) ...................... 68 
9.8.6 
Re-consent process ....................................................................................................................... 69 
9.9 
ACCELERATED ELIMINATION PROCESS .................................................................................. 69 
9.10 
ADVERSE EVENTS MONITORING .............................................................................................. 70 
9.10.1 
Definitions of Adverse Event(s) ...................................................................................................... 70 
9.10.1.1 Adverse Event ................................................................................................................................ 70 
9.10.1.2 Serious Adverse Event .................................................................................................................. 70 
9.10.2 
Obligation of the Investigator regarding safety reporting ............................................................... 71 
9.10.2.1 Adverse events .............................................................................................................................. 71 
9.10.2.2 Serious adverse events ................................................................................................................. 72 
9.10.2.3 Safety observations (follow-up) ...................................................................................................... 72 
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9.10.3 
Obligations of the Sponsor ............................................................................................................. 73 
9.11 
PHARMACOKINETICS (PK) ......................................................................................................... 73 
9.11.1 
Sampling time ................................................................................................................................ 73 
9.11.2 
PK handling procedure .................................................................................................................. 74 
9.11.3 
Bioanalytical method ...................................................................................................................... 74 
9.11.4 
Pharmacokinetic parameters ......................................................................................................... 74 
10 
STUDY PROCEDURES ................................................................................................................ 75 
10.1 
VISIT SCHEDULE .......................................................................................................................... 75 
10.1.1 
Screening (Visit 1, Week-4) ........................................................................................................... 76 
10.1.2 
Randomization Visit (Visit 2) (to be randomly assigned either to teriflunomide or to placebo ....... 77 
10.1.3 
Visits during the double-blind treatment period ............................................................................. 77 
10.1.3.1 Assessments performed for all clinic visits .................................................................................... 77 
10.1.3.2 Assessments performed on the clinic visits specified .................................................................... 77 
10.1.3.3 Safety laboratories performed in between clinic visits ................................................................... 78 
10.1.3.4 Assessments performed on the EOT or premature treatment discontinuation.............................. 78 
10.1.3.5 Assessments performed on the unscheduled relapse visits .......................................................... 79 
10.1.4 
Post drug elimination follow up visits ............................................................................................. 80 
10.1.5 
Open Label Period ......................................................................................................................... 81 
10.1.6 
Optional additional extension period for young patients ................................................................ 81 
10.2 
DEFINITION OF SOURCE DATA .................................................................................................. 81 
10.3 
HANDLING OF TEMPORARY OR PERMANENT TREATMENT DISCONTINUATION AND 
OF PATIENT STUDY DISCONTINUATION .................................................................................. 81 
10.3.1 
Temporary treatment discontinuation with investigational medicinal product(s) ........................... 82 
10.3.2 
Definitive treatment discontinuation with investigational medicinal product(s) .............................. 82 
10.3.2.1 List of criteria for definitive treatment discontinuation .................................................................... 82 
10.3.2.2 Handling of patients after definitive treatment discontinuation ...................................................... 83 
10.3.3 
Procedure for withdrawal of patients from study follow-up schedule ............................................. 83 
11 
STATISTICAL CONSIDERATIONS .............................................................................................. 85 
11.1 
DETERMINATION OF SAMPLE SIZE ........................................................................................... 85 
11.2 
DISPOSITION OF PATIENTS ....................................................................................................... 85 
11.3 
ANALYSIS POPULATIONS ........................................................................................................... 86 
11.3.1 
Efficacy populations ....................................................................................................................... 86 
11.3.1.1 Intent-to-treat (ITT) population ....................................................................................................... 86 
11.3.2 
Safety population ........................................................................................................................... 86 
11.3.3 
Pharmacokinetic population ........................................................................................................... 86 
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11.4 
STATISTICAL METHODS ............................................................................................................. 87 
11.4.1 
Extent of study treatment exposure and compliance ..................................................................... 87 
11.4.2 
Extent of investigational medicinal product exposure .................................................................... 87 
11.4.3 
Compliance .................................................................................................................................... 87 
11.4.4 
Analyses of efficacy endpoints ....................................................................................................... 87 
11.4.4.1 Analysis of primary efficacy endpoint(s) ........................................................................................ 87 
11.4.4.2 Analyses of secondary efficacy endpoints ..................................................................................... 88 
11.4.4.3 Multiplicity considerations .............................................................................................................. 89 
11.4.5 
Analyses of safety data .................................................................................................................. 89 
11.4.6 
Analyses of pharmacokinetic and pharmacodynamic variables .................................................... 92 
11.4.7 
Analyses of quality of life/health economic variables ..................................................................... 92 
11.5 
INTERIM ANALYSIS ...................................................................................................................... 92 
12 
ETHICAL AND REGULATORY STANDARDS ............................................................................. 93 
12.1 
ETHICAL PRINCIPLES ................................................................................................................. 93 
12.2 
LAWS AND REGULATIONS ......................................................................................................... 93 
12.3 
INFORMED CONSENT ................................................................................................................. 93 
12.3.1 
Assent for patients ......................................................................................................................... 94 
12.3.2 
Assent for optional neurofilament assessment .............................................................................. 94 
12.4 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) .............. 95 
13 
STUDY MONITORING................................................................................................................... 96 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) ....................................................................... 96 
13.2 
RESPONSIBILITIES OF THE SPONSOR ..................................................................................... 96 
13.3 
SOURCE DOCUMENT REQUIREMENTS .................................................................................... 97 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST ...................................................................................................................................... 97 
13.5 
USE OF COMPUTERIZED SYSTEMS .......................................................................................... 98 
14 
ADMINISTRATIVE EXPECTATIONS ........................................................................................... 99 
14.1 
CURRICULUM VITAE.................................................................................................................... 99 
14.2 
RECORD RETENTION IN STUDY SITES .................................................................................... 99 
14.3 
CONFIDENTIALITY ....................................................................................................................... 99 
14.4 
PROPERTY RIGHTS ................................................................................................................... 100 
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14.5 
DATA PROTECTION ................................................................................................................... 100 
14.6 
INSURANCE COMPENSATION .................................................................................................. 101 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ............................... 101 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE .......................................................................................................................................... 101 
14.8.1 
Decided by the Sponsor ............................................................................................................... 101 
14.8.2 
Decided by the Investigator ......................................................................................................... 102 
14.9 
CLINICAL TRIAL RESULTS ........................................................................................................ 102 
14.10 
PUBLICATIONS AND COMMUNICATIONS ............................................................................... 102 
15 
CLINICAL TRIAL AMENDMENTS .............................................................................................. 104 
16 
BIBLIOGRAPHIC REFERENCES ............................................................................................... 105 
17 
APPENDICES .............................................................................................................................. 108 
17.1 
APPENDIX A: MCDONALD’S CRITERIA .................................................................................... 108 
17.2 
APPENDIX B: KURTZKE EXPANDED DISABILITY STATUS SCALE AND FUNCTIONAL 
SYSTEM SCORES ...................................................................................................................... 110 
17.3 
APPENDIX C: TANNER PUBERTY STAGE CLASSIFICATION ................................................ 121 
17.4 
APPENDIX D: GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES ........................................................................................................................ 122 
17.5 
APPENDIX E: NEUROFILAMENT LIGHT CHAIN AND NON-GENETIC BIOMARKERS 
PROCESSING ............................................................................................................................. 127 
17.6 
APPENDIX F: COUNTRY SPECIFIC REQUIREMENTS ............................................................ 127 
17.7 
APPENDIX G: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENT AGENCY ...................................... 128 
17.8 
APPENDIX H: SUMMARIES OF MEMOS ON CONTINGENCY MEASURES RELATED 
TO COVID EMERGENCY ........................................................................................................... 129 
17.8.1 
Summary of Memo 18 (21 February 2020) - Specific to China ................................................... 129 
17.8.2 
Summary of Memo 19 (24 March 2020) - Global .............................................................................. 133 
17.8.3 
Summary of Memo 20 (28 April 2020) - Global ................................................................................ 135 
17.9 
APPENDIX I: PROTOCOL AMENDMENT HISTORY ................................................................. 138 
 
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LIST OF TABLES  
Table 1 - Chart for dose adjustment .............................................................................................................. 41 
Table 2 - Washout medications and dosage ................................................................................................. 70 
Table 3 - PK sampling times for teriflunomide concentrations during double-blind treatment period and 
open-label period ........................................................................................................................................... 73 
Table 4 - Pharmacokinetics handling for teriflunomide ................................................................................. 74 
Table 5 – Recommendations on how to handle the visits during coronavirus outbreak ............................. 130 
Table 6 – Overview of study assessments .................................................................................................. 134 
 
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2 
LIST OF ABBREVIATIONS  
 
 
ACTH: 
adrenocorticotrophic hormone 
ADEM: 
acute disseminated encephalomyelitis 
AE: 
adverse event 
AEPM: 
adverse event of pre-specified monitoring 
AESI: 
adverse event of special interest 
ALT: 
alanine aminotransferase 
ARR: 
annualized relapse rate 
BP: 
blood pressure 
BVMI: 
beery visual-motor integration 
BVMTR: 
brief visuospatial memory test revised 
CBT: 
cognitive battery tests 
CI: 
confidence interval 
D-KEFS: 
Delis-Kaplan executive function system 
DMC: 
data monitoring committee 
ECG: 
electrocardiogram 
EDSS: 
expanded disability status scale 
EOT: 
end of treatment 
EPTD: 
early permanent treatment discontinuation 
FS: 
functional system 
GCP: 
Good Clinical Practice 
GMP: 
good manufacturing practice 
HIV: 
human immunodeficiency virus 
HLGT: 
high-level group term  
HLT: 
high level term  
HR: 
heart rate 
ICH: 
International Conference on Harmonization 
IEC: 
Independent Ethics Committee 
IMP: 
investigational medicinal product 
INR: 
international normalized ratio 
IPMSSG: 
international pediatric multiple sclerosis study group 
IRB: 
institutional review board 
ISG: 
independent statistical group 
ITT: 
intent-to-treat 
IVRS/IWRS: 
interactive voice/web response system 
JRA: 
juvenile rheumatoid arthritis 
LLOQ: 
lower limit of quantification 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MRI: 
magnetic resonance imaging or magnetic resonance image 
MS: 
multiple sclerosis 
NSAID: 
non-steroidal anti-inflammatory drugs 
PCSA: 
potentially clinically significant abnormalities 
PK: 
pharmacokinetic 
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PT: 
preferred term  
RAP: 
relapse adjudication panel 
RMS: 
relapsing multiple sclerosis 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SDMT: 
symbol digit modalities test 
SGPT: 
serum glutamate pyruvate transaminase 
SOC: 
system organ class 
SRT: 
selective reminding test 
T2: 
T2-weighted hyperintense lesions 
TEAE: 
treatment emergent adverse event 
TID: 
three times a day 
TMT-A and B: trail-making test A and B 
ULN: 
upper limit of normal 
WASI: 
Wechsler abbreviated scale of intelligence vocabulary 
WBC: 
white blood cell 
WOCBP: 
woman of child bearing potential 
 
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3 
INTRODUCTION AND RATIONALE  
3.1 
INTRODUCTION  
3.1.1 Pediatric Multiple Sclerosis  
Multiple sclerosis (MS) is typically considered to be a disease of young adults.  However, 
pediatric MS, defined as onset of MS before the age of 16, is increasingly recognized and 
accounts for approximately 5 percent of cases (1, 2, 3).  This disorder was previously known as 
early onset MS and juvenile MS. 
Multiple sclerosis in children and differences from the common adult MS form to a large extent 
are understudied.  There is no approved disease modifying therapy indicated for the treatment of 
pediatric MS and the effects of drugs in children have not been formally evaluated in clinical 
trials.  The current treatment and prognosis of pediatric MS are based on that of adult patients, 
because data are limited in pediatric MS and it is assumed that the disease response in children is 
likely to be similar (4, 5, 6, 7). Considering the multiple toxicities that characterize the currently 
used treatment for MS in children, development of an effective and well-tolerated therapy for the 
indication continues to be a major challenge. 
In children, MS needs to be distinguished from other demyelinating disorders of childhood, 
including in particular acute disseminated encephalomyelitis (ADEM).  Consensus definitions for 
pediatric MS have been proposed by multidisciplinary panels (5, 6, 7, 8, 9, 10). 
In general, clinical features are not different from those of the adult form, but some are more 
frequent in comparison with adult MS: 
• Onset with cerebellar and brainstem dysfunction (3, 7). 
• Polysymptomatic presentation, with fever, headache, lethargy, meningism, seizures (acute 
disseminated encephalomyelitis-like onset), especially in very young patients (3). 
• Evolution with a high number of relapses, specially in the first years of the disease, and an 
annualized relapse rate of 1–1.9, which is higher than in adult MS (3, 10, 11, 12). 
• Evolution, with a predominance of the relapsing–remitting course, in more than 90% of 
cases, and the very low frequency of the primary progressive course (3). 
• Development of progression, over a longer interval but a lower age to reach both mild and 
severe disability (11). 
Despite slow accrual of motor disability relatively to adult patients, cognitive impairment has 
been found after 2 years in 70% of children with MS (13). Consequently, a great need exists for 
early and accurate diagnosis of MS in this population, so that effective therapies can be initiated 
promptly. 
Specificities of MS in children also lie in their environment.  The onset of MS in childhood 
typically occurs during the key formative years.  It might restrict school attendance and has the 
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potential to negatively affect the developing neural connections implicated in learning and higher-
order information processing.  Fatigue may also have a great impact on activities and 
development. 
3.1.2 Teriflunomide  
Teriflunomide inhibits dihydroorotate dehydrogenase, the fourth enzyme in the de novo synthesis 
pathway of pyrimidines.  Activated T-lymphocytes utilize both the de novo pyrimidine and 
salvage pathways of pyrimidine ribonucleotide synthesis.  After mitogen stimulation, 
teriflunomide inhibits in vitro T cell proliferation, DNA and RNA synthesis and expression of cell 
surface and nuclear antigens that are directly involved in T cell activation and proliferation.  
Teriflunomide is the primary metabolite of leflunomide (Arava®), which is marketed worldwide 
for the treatment of rheumatoid arthritis. 
Please refer to the current Investigator Brochure for detailed information. 
3.1.2.1 Clinical efficacy in adult MS patients  
The main development program for teriflunomide in adult patients aims at evaluating the benefits 
and risks of teriflunomide, administered orally at 7 mg or 14 mg once a day, as monotherapy in 
the treatment of relapsing forms of MS (RMS). 
The teriflunomide monotherapy program included one Phase 2 study, 2001, and four Phase 3 
studies. 
In the first pivotal Phase 3 study, EFC6049/TEMSO in RMS patients, both doses of teriflunomide 
(7 and 14 mg) significantly reduced annualized relapse rate (ARR; primary study endpoint) by 
31% vs. placebo (p≤0.0005). Teriflunomide 14 mg significantly reduced the risk of disability 
progression (sustained for 12 weeks) by 30% (p=0.03). Teriflunomide was well tolerated at both 
doses. 
In the second confirmatory Phase 3 study, EFC10531/TOWER, the ARR was reduced by 36.3% 
in teriflunomide 14 mg (p=0.0001) dose and by 22.3% (p=0.02) in teriflunomide 7 mg dose 
compared to placebo. Teriflunomide 14 mg significantly reduced the risk of disability progression 
sustained for 12 weeks by 31.5% (p=0.0442). Teriflunomide was well tolerated with a 
manageable safety profile on both doses and no new or unexpected safety signal was identified in 
this study. 
Teriflunomide is approved for adult indication in RMS or RRMS in several countries (including 
the USA and the European Union), and is under review in other countries world-wide. 
3.1.2.2 Clinical safety in adult MS patients  
In the teriflunomide development program, the cumulative exposure to the product in the 
monotherapy trials was over 6200 patient-years. 
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In the Phase 2/3 monotherapy completed placebo-controlled trials, 2430 patients with RMS were 
treated with either teriflunomide 7 mg (838 patients) or 14 mg (786 patients) compared to 
806 patients who were exposed to placebo. The median treatment exposure was approximately 
680 days across treatment groups. 
A total of 2284 patients were exposed to teriflunomide 7 mg and 14 mg with a maximum 
exposure of up to 11.1 years either during the placebo-controlled phase or the extension phase 
with a median duration of 2.1 years. 
Safety data from the ongoing studies were consistent with the findings from the monotherapy 
trials and support the overall safety conclusions. 
Fatal outcome was reported in a total of 13 patients during the entire development program to 
date: 5 deaths occurred in placebo-controlled studies, 8 additional deaths were reported in long 
term extension studies. 
The causes of death were pulmonary infection, and completed suicide in the placebo group, road 
traffic accident, myocardial infarction, death of unknown cause probably due to MS, and sudden 
death of unknown cause in the 7 mg teriflunomide group, and carbon monoxide poisoning 
(completed suicide), septicemia due to Gram-negative organism complicated with disseminated 
intravascular coagulation disorder, sudden cardiac disorder, acute heart failure, pulmonary 
embolism, and 2 completed suicides in the 14 teriflunomide group. 
All of the cases have a plausible explanation. There was no evidence that teriflunomide was a 
causative factor in the events leading to deaths. 
During the placebo-controlled phase, treatment-emergent adverse events (TEAEs) were balanced 
across treatment groups while the percentages of patients with TEAE leading to treatment 
discontinuation were reported with a slightly higher incidence in the teriflunomide groups. The 
most frequently reported TEAEs with an increased incidence with teriflunomide as compared to 
placebo were: alopecia, nausea, diarrhea, and alanine aminotransferase (ALT) increased. Most 
cases of alopecia were reported as hair thinning, decreased hair density, hair loss, associated or 
not with hair texture change with a dose-effect. There was no complete hair loss reported in the 
entire clinical program. Most cases were mild to moderate, reported during the first 6 months, 
lasting for about 4 months, and resolving without corrective therapy, while the patients continued 
the study treatment. 
Events of nausea and diarrhea were reported with a higher frequency in both teriflunomide groups 
than in the placebo with a dose effect. They appeared early after initiation of treatment. They were 
rarely considered as serious and led to treatment discontinuation in only a few patients. 
There was no signal for hepatic toxicity in pre-clinical studies. Mild increases in transaminases, 
ALT below or equal to 3 x upper limit of normal (ULN), were more frequently seen in 
teriflunomide-treated groups as compared to placebo. The frequency of elevations above 3 x ULN 
and higher was balanced across treatment groups. 
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Overall, the clinical trial data does not provide evidence for an increased risk of clinically relevant 
drug induced liver injury with teriflunomide. 
Pancreatic disorders were reported with low incidences, were balanced across treatment groups 
and led to treatment discontinuation in few patients. 
A mean decrease in white blood cell (WBC) counts was observed (mainly neutrophil and 
lymphocyte count decrease) with a small dose response. The mean decrease occurred during the 
first 6 weeks, followed by stabilization over time on-treatment, with a magnitude not exceeding 
15%. The mean decrease was less pronounced in hemoglobin (≤3%) and platelets (<10%) as 
compared to baseline. 
Infections were the most frequently reported TEAEs in placebo-controlled studies. A low and 
similar incidence of serious infections was reported across groups (2.5%, 2.4% and 2.5% in the 
placebo, 7 mg, and 14 mg groups, respectively). The incidence of infections leading to treatment 
discontinuation was similar across all groups. 
The clinical data collected to date do not suggest an increased risk of severe allergic reactions 
with the use of teriflunomide  
In placebo-controlled studies, BP elevations were more frequent on teriflunomide as compared to 
placebo. The analysis of BP measurements over the 2-year treatment period in placebo-controlled 
studies showed a higher mean change from baseline with teriflunomide as compared to placebo 
Patients who developed hypertension on teriflunomide treatment were usually well controlled 
with the introduction of or modification of antihypertensive treatment. This was also true for the 
experience in the long term extension studies. 
There was no clinical evidence for pulmonary toxicity in the available clinical data Events 
potentially related to peripheral neuropathy were reported in all treatment groups A modest 
increase in uric acid elimination, resulting in a 20% to 30% decrease in mean plasma levels of uric 
acid, was observed. The uricosuric effect was considered to be most probably due to an increase 
in renal tubular uric acid elimination. There was no evidence for an increased risk of urolithiasis 
or any other clinically relevant consequence of this effect. 
Non clinical studies conducted with teriflunomide showed embryofetal toxic effects in rats and 
rabbits. 
In clinical studies no structural defects were observed in 30 delivered healthy babies (17 from 
patients and 13 from female partners of male patients treated with teriflunomide). 
Overall, the available safety data suggested that both doses of teriflunomide 7 mg and 14 mg 
administered in clinical studies in patients with RMS were generally well tolerated with a 
manageable safety profile. 
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3.1.2.3 Non-clinical juvenile toxicity program  
Two studies in juvenile animals were performed in juvenile rats to support dosing in children in 
this study: a 2-week range-finding toxicity study in juvenile rats, followed by 7-week toxicity 
study in juvenile rats. When teriflunomide was administered to juvenile rats for 7 weeks, no new 
toxicities were identified that were not previously seen in adult animals. There were no adverse 
effects on growth, physical or neurological development, learning and memory, locomotor 
activity, sexual development, or fertility. Changes in hematology and clinical chemistry included 
minimal effects on erythron parameters, minimal decreases in total protein and globulin 
concentrations, minimal increases in total cholesterol concentrations, and increased triglyceride 
concentrations.  Microscopic changes were observed in the spleen (increased incidence and/or 
severity of hemopoiesis and a very minor reduction of lymphoid hyperplasia), mesenteric and 
mandibular lymph nodes and gut-associated lymphoid tissue (minor reduction in germinal 
follicles).  Marked changes in immune function included failure to mount an appropriate immune 
response after 2 challenges with Keyhole Limpet Hemocyanin (KLH) immunization, greatly 
reduced concentrations of total IgM and IgG, and markedly increased B lymphocyte counts.  At 
the end of the recovery period, all teriflunomide-related findings showed partial or complete 
recovery.  Further details can be found in the current Investigator Brochure.  
3.1.2.4 Proposed pediatric study  
None of the currently approved treatments for adult relapsing MS have been formally studied for 
the treatment of pediatric MS. Once a day tablet of teriflunomide may offer several advantages 
over parenteral medicinal products currently used in treatment for MS in children. Orally 
administered teriflunomide may avoid the stress on children and their caregivers that is associated 
with repeated injections as well as flu-like symptoms following each injection (fever, chills, 
headache, muscle aches and pains) which occur with all interferons, and the injection site 
reactions observed with glatiramer acetate. 
The high number of relapses in the first years of the disease, and the high frequency of patients 
with the relapsing-remitting course suggest that the inflammatory process is more pronounced in 
children with MS compared to adults. This pattern is also suggested by the frequent pleocytosis in 
the cerebrospinal fluid (CSF) (14), and by MRI (15, 4). It seems reasonable to expect that drugs 
targeting the inflammatory process could have a positive beneficial effect in pediatric patients 
with MS similar to adult patients with MS. Further, with profound effects seen on MRI lesions in 
adults, effects on relapses and disease progression are also expected to be similar in a pediatric 
population. 
In summary, the benefit risk profile of teriflunomide has already been shown to be favorable in an 
adult population in the Phase 3 placebo-controlled studies of the monotherapy program. 
Teriflunomide has demonstrated advantages in adult relapsing forms of MS patients in reducing 
frequency of relapse rate, disease progression, and MRI activity. 
The objectives of the proposed clinical pediatric development program are to assess the efficacy, 
safety/tolerability, and pharmacokinetics (PK) of teriflunomide in children and adolescents 10 to 
below 18 years of age with relapsing forms of multiple sclerosis (RMS).  This study will have a 
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double blind placebo control period. Patients who experience a confirmed relapse after 8 weeks in 
the double blind period or high MRI activity as defined in protocol may continue in an open label 
teriflunomide treatment arm. An optional additional extension period with teriflunomide is offered 
to young patients when they complete the study, to provide treatment until they are 18 years old 
and/or can switch to commercial product, whichever comes first. It will be implemented in 
France, and possibly other countries, where local solutions for continued teriflunomide treatment 
are not possible within a reasonable time frame. Details of the study design are described in 
Section 1.1. 
3.2 
RATIONALE  
3.2.1 Population rationale  
In adults, the prevalence of MS is close to 50/100,000 on average. 
The frequency of MS onset before the age of 16 years is estimated at 2-5 % of all cases, and onset 
during infancy and early childhood was observed in 0.2-0.7 % of all cases (3, 10).  Chitnis et al 
(8) recently described the disease characteristics of pediatric MS patients in the United States. 
Physician records of all MS patients seen at the Partners Multiple Sclerosis Center, Brigham and 
Women’s Hospital (Boston, MA), from 2002 to 2008 were recorded in an electronic database and 
included in this study. It was found that 3.06% (135 / 4399) of their patients experienced first 
symptoms before the age of 18. Of those, 10% (ie, 0.3% of all cases) experienced onset between 
10 and 12 years of age (compared with 87% with onset between 13 and 17). 
The last updated survey administered in March 2012 among 76 IPMSSG respondents from 
64 sites in 25 countries identified a minimum prevalence of 4000 cases seen over the past 5 years 
amongst respondents and a minimum incident frequency of 415 new cases seen in 2011 amongst 
respondents (IPMSSG communication July 2012). 
Only 2-5% of patients diagnosed with MS present before age 18 and the majority of these cases 
occur at or after the age of 10. For this reason, neonates and pediatric patients less than 10 years 
of age will not be studied. 
3.2.2 Rationale for study design  
Study design with controlled comparison based on a superiority hypothesis using a clinical 
endpoint has been historically required and/or preferred by most national health authorities in 
order to evaluate a treatment for potential market authorization.  Alternative designs which may 
offer advantages in terms of smaller sample size (superiority on an MRI outcome), or avoidance 
of placebo (eg non-inferiority evaluation versus active comparators) are generally not accepted for 
this purpose, although there can be regional differences in this regard.  However, given the rarity 
of the pediatric population, it is important to design and conduct a trial that will provide globally 
acceptable evidence for evaluation of the benefits and risks of teriflunomide in pediatric MS 
patients.   
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Current consensus is to treat children with MS, although the efficacy of MS therapies has not been 
formally demonstrated in children (4). Therefore, the International Pediatric MS Study Group 
(IPMSSG) has indicated that placebo-controlled trials in children with MS may be acceptable, 
provided there are stringent escape criteria such as offering active treatment in the event of new 
disease activity (4). 
The current design includes such stringent escape criteria and minimizes the potential exposure to 
placebo by specifying time to relapse as the primary endpoint.  In this setting a patient may exit 
the placebo-controlled phase and will be offered active teriflunomide treatment in case of clinical 
relapse occurring after 8 weeks of treatment.  In addition, the protocol includes specific criteria to 
allow for a patient to exit the placebo-controlled phase and be eligible for active treatment in cases 
of a high level of sub-clinical activity (eg, MRI lesions) in absence of a relapse (Verhey et al, 
2013). 
3.2.3 Teriflunomide choice of dose and PK run-in (8 weeks) rationale  
At the beginning of the study, a PK run-in (8 weeks) phase will be conducted with limited PK 
sampling for a duration of 4 weeks, when the concentrations are expected to be at 64% of the 
steady state based on adult data (95% of the steady-state is reached at approximately 12 weeks in 
adults after repeated 7 mg doses).  Then an assessment of the adequacy of dosing will be done 
(4 weeks after the 4-week run in).  Teriflunomide individual predicted steady-state PK parameters 
for each pediatric patient will be compared to the range of individual predicted steady-state PK 
parameters derived from population PK (PopPK) adult model after repeated doses of 7 mg.  The 
dose will be then adjusted if necessary, so the patient has an adult equivalent of 14mg QD. 
In this initial PK run-in (8 weeks) phase, the starting dose (3.5 mg per day for patients with body 
weight of 30 ± 10 kg OR 7 mg per day for patients with body weight >40 kg) is expected to 
correspond to the adult dose of 7 mg QD as per the following rationale. 
• The pharmacodynamic effects in children and adults are expected to be similar. 
• It is predicted that the absorption, distribution, metabolism and excretion of teriflunomide 
will be similar in the children (> 10 years of age) and adults (16, 17, 18, 19, 20, 21, 22), 
(23, 14).  Based on data from juvenile rheumatoid arthritis pediatric (JRA) patients after 
leflunomide administration, the doses in pediatric patients can be extrapolated from the 
adult dose according to body weight.  The body weight correlated strongly with apparent 
distribution volume (V/F) and it correlated weakly with apparent total clearance (CL/F) in 
the pediatric PopPK analysis and, therefore, the doses in pediatric patients were 
extrapolated from the adult dose according to body weight.  This was confirmed as body 
weight was found to be a significant covariate on the V/F in the first PopPK analysis using 
teriflunomide data from adult healthy subjects and MS patients (POH0290).  The V/F was 
increased by ~ 25% in a typical patient of 79.8 kg (75th percentile of patient’s weight) as 
compared to a patient weighing 59.5 kg (25th percentile). 
• The PK run-in (8 weeks) phase is intended to provide exposure in the range of what is 
observed in adult patients receiving 7 mg per day; consequently individual PK parameters 
(Cmax and AUC0-24) will be assessed to allow the dose adjustment at the end of the first 
8 weeks of the core study to the adult-equivalent dose. 
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During the PK run–in period including the 4weeks analysis (corresponding to the first 8 weeks of 
the core study): 7mg adult equivalent, QD: 
• For patients 30 ±10 kg: 
- 
1 teriflunomide tablet (3.5 mg) per day (QD). 
• For patients >40 kg: 
- 
1 teriflunomide tablet (7 mg) per day (QD). 
Individual predicted PK parameters will be assessed at the end of the PK run-in (8 weeks) phase 
(with no interruption of dosing) using a PopPK model adapted to the pediatric population 
(POH0401) and compared to the adult 7 mg PK predicted parameter range derived from the 
second PopPK adult model (POH0339).  Adult range (5th - 95th percentile) of predicted PK 
parameters: 7 mg dose range for Cmax is 8.03 to 49.10 g/mL and for AUC0-24 is 184 to 
1160 g.h/mL. 
After the end of the initial PK run-in (8 weeks) phase (14mg adult equivalent, QD): 
If individual predicted PK parameters are equal to or less than the 95th percentile of adult range of 
predicted PK parameters (repeated doses of 7 mg): 
• For patients 30 kg ± 10 kg 
- 
1 teriflunomide tablet (7 mg) per day (QD). 
• For patients >40 kg 
- 
1 teriflunomide tablet (14 mg) per day (QD). 
If individual predicted PK parameters are higher than the 95th percentile of the adult range of 
predicted PK parameters (repeated doses of 7 mg): 
• For patients 30 kg ± 10 kg 
- 
1 teriflunomide tablet (3.5 mg) per day (QD). 
• For patients >40 kg 
- 
1 teriflunomide tablet (7 mg) per day (QD). 
Dose adjustment will be performed 4 weeks after the end of the 4-week PK run-in (8 weeks) 
phase for the patients based upon PK availability of parameters (see Table 1).  During the rest of 
the study (after the PK run-in (8 weeks)), the dose may be adjusted when patient weight goes from 
≤40 kg to >40kg and vice versa from one visit to the other. 
Optional additional extension period for young patients: 
One teriflunomide tablet (14 mg) per day (QD). Based on Investigator’s judgment, for patients 
less to 40 kg, dose could be adjusted by the Investigator to 14 mg every other day. 
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4 
STUDY OBJECTIVES  
4.1 
PRIMARY OBJECTIVE  
The primary objective of this study is to assess the effect of teriflunomide in comparison to 
placebo on disease activity as measured by time to first clinical relapse after randomization in 
children and adolescents 10 to 17 years of age with relapsing forms of multiple sclerosis 
4.2 
SECONDARY OBJECTIVE(S)  
The secondary objectives of this study are as follows: 
• To assess the effect of teriflunomide in comparison to placebo on disease 
activity/progression measured by brain MRI and on cognitive function. 
• To evaluate the safety and tolerability of teriflunomide in comparison to placebo. 
• To evaluate the pharmacokinetics (PK) of teriflunomide. 
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5 
STUDY DESIGN  
5.1 
DESCRIPTION OF THE PROTOCOL  
EFC11759 is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study.  
It consists of: 
• A screening period up to 4 weeks, designed to evaluate suitability to participate in the trial, 
in terms of MS diagnosis, MS treatment(s), and safety screening evaluations.  No 
investigational medicinal product (IMP) is administered in this period. 
• A double-blind treatment period of up to 96 weeks total duration for each patient 
- 
Patients are randomized to either teriflunomide or placebo at 2:1 ratio (110 patients on 
teriflunomide vs. 55 patients on placebo), 
- 
It includes a blinded PK run-in (8 weeks) phase consisting of 4 weeks of PK sample 
collection plus 4 weeks of analysis (corresponding to the first 8 weeks after 
randomization). The PK run-in (8 weeks) phase is intended to provide individual PK 
parameters to allow the dose adjustment to the 14mg adult-equivalent dose for the rest 
of the study from Week 8, 
- 
Patients experiencing a relapse after the PK run-in (8 weeks) and if confirmed by the 
Relapse Adjudication Panel (RAP) will have the option to continue in an open label 
period. If RAP does not confirm the relapse, the patient can continue in the double-
blind phase or prematurely discontinue the treatment. Similarly, patients with high 
MRI activity (defined in Section 8.1) or completing the 96-week double-blind period 
will have the option to continue in the open label period. 
• An open-label period for the remainder of 192 weeks after randomization 
The open-label period will follow the double-blind period and last until 192 weeks after 
randomization. Its duration for a given patient will depend on when the patient enters this 
period. The duration of the open-label period will be 96 weeks for patients completing the 
96-week double-blind period on treatment, and longer for patients switching to open-label 
during the initial 96 week double-blind period at the occurrence of a confirmed relapse or in 
case of high MRI activity. 
It includes a blinded PK run-in phase (8 weeks, similarly to the double-blind period). 
NOTE: patients, investigators and the study team will remain blinded for the duration of the study. All patients 
entering the open label period from the placebo arm or teriflunomide arm, will repeat a second PK run-in phase one 
sample per week over 4 weeks and 4 weeks of analysis) and will be followed until completion of the planned 
192 weeks from randomization. Placebo patients will start with teriflunomide 7 mg adult equivalent dose QD, while 
teriflunomide patients will continue with the same previous adjusted dose.  
• An optional additional extension period with teriflunomide is offered to young patients 
when they complete the study, to provide treatment until they are 18 years old and/or can 
switch to commercial product, whichever comes first.  
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• Follow up period with accelerated elimination of teriflunomide. 
- 
Patients discontinuing study treatment will have a procedure to accelerate the 
elimination of teriflunomide with either cholestyramine or activated charcoal. 
However, if they will continue to have teriflunomide after the study, this procedure 
will not take place, 
- 
Post drug elimination procedure samples to be collected for verification of clearance of 
plasma teriflunomide concentrations. 
• Two Clinical Study Reports (CSR) will be issued:  
- 
The first CSR will report the final analysis of the 96-week double-blind treatment 
period, including data after treatment discontinuation, as applicable and defined in the 
methods.  The methods described in this document primarily relate to this treatment 
period and analysis, 
- 
The second CSR will report the analysis of the open-label data at the conclusion of the 
extension period for all included patients.  
The data for the optional additional extension period for young patients will be reported 
separately. 
5.1.1 Duration of study participation for each patient  
Each patient will have a screening period up to 4 weeks then a Double-Blind Treatment Period for 
up to 96 weeks (or until a confirmed relapse or high MRI activity as defined in the protocol), and 
an Open-Label Period for the remainder of 192 weeks. The complete treatment duration, from 
randomization to end of open-label extension, will be 192 weeks. The duration of the extension 
will be 96 weeks for patients completing the 96-week double-blind period on treatment, and 
longer for patients switching at a confirmed relapse or in case of high MRI activity. Patients 
discontinuing study treatment will have a post-drug elimination follow-up period of 4 weeks 
which may need to be extended until teriflunomide level is ≤0.02 μg/mL. 
An optional additional extension period with teriflunomide is offered to young patients when they 
complete the study, to provide treatment until they are 18 years old and/or can switch to 
commercial product, whichever comes first. 
Upon completion of the study the Sponsor may evaluate options for further treatment under a 
separate mechanism. 
5.1.2 Determination of end of clinical trial  
The end of the clinical trial occurs on the day of the last visit of the last patient (or last contact 
with the last patient, in the case of no last visit). 
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5.2 
STUDY COMMITTEES  
5.2.1 Data monitoring committee (DMC)  
An independent Data Monitoring Committee (DMC), operating independently from the Sponsor 
and clinical investigators is commissioned for this clinical trial.  This committee is comprised of 
externally-based individuals with expertise in the disease under study.  The primary 
responsibilities of the DMC are to review and evaluate the benefit versus risk and provide 
appropriate recommendations regarding trial continuation to the Sponsor. 
Details of the responsibilities of the DMC will be described in the DMC charter that will be 
provided at study start.  The Sponsor is responsible for promptly reviewing and for taking into 
account in a timely manner the recommendations of the DMC in terms of trial continuation with 
or without alterations or of potential trial termination. 
5.2.2 Adjudication Committee (AC)  
To ensure objectivity in the primary endpoint, a Relapse Adjudication Panel (RAP) will be 
convened to evaluate all relapses reported during the 96-week double-blind period.  The RAP will 
consist of independent neurologists with expertise in MS clinical research. The RAP members 
will be trained on study procedures by the Sponsor (or delegate ie, CRO).  Relapses, as 
adjudicated by the RAP, need to meet strict criteria including the presence of objective signs and 
symptoms that persisted for at least 24 hours. 
RAP assessments will use blinded data and will be performed in real time. Details of the 
responsibilities of the RAP will be described in the RAP charter that will be provided prior to 
study start. 
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6 
SELECTION OF PATIENTS  
6.1 
NUMBER OF PATIENTS PLANNED  
It is planned that a total of approximately 165 children and adolescents of either gender 10 to 
below 18 years of age will be randomized into the core study to receive either teriflunomide (110 
patients) or placebo (55 patients). 
6.2 
INCLUSION CRITERIA  
I 01. Patients with relapsing multiple sclerosis are eligible. Patients should meet the criteria of 
MS based on McDonald criteria 2010 and  International Pediatric Multiple Sclerosis Study 
Group (IPMSSG) criteria for pediatric MS, version of 2012 (5) and have:  
- 
At least one relapse (or attack) in the 12 months preceding screening or,  
- 
At least two relapses (or attack) in the 24 months preceding screening.  
<18 years of age and ≥10 years of age at randomization 
 
Specific for the Russian Federation from 18 December 2014 to 26 July 2016, ≤17 years of age and 
≥13 years of age at randomization (see 17.6).  
Signed informed consent/assent obtained from patient and patient’s legal representative (parents 
or guardians) according to local regulations. 
 
6.3 
EXCLUSION CRITERIA  
Patients who have met all the above inclusion criteria will be screened for the following exclusion 
criteria which are sorted and numbered in the following sub-sections. 
6.3.1 Exclusion criteria related to study methodology  
  Expanded Disability Status Scale score >5.5 at screening or randomization visits. 
  A relapse within 30 days prior to randomization.  
  Body weight <20 kg. 
  Mental condition rendering the patient or parent/guardian unable to understand the nature, 
scope, and possible consequences of the study. 
  Patient or parent/guardian unlikely to comply with the protocol as determined by 
Investigator, eg, uncooperative attitude, inability to return for follow-up visits. 
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  Clinically relevant cardiovascular, hepatic, neurological, endocrine, or other major 
systemic disease making implementation or interpretation of the study results difficult or 
that would put the patient at risk by participating in the study. 
  Persistent significant or severe infection. 
  History of drug or alcohol abuse. 
  Patient or parent/legal guardian is the Investigator or any Sub investigator, research 
assistant, pharmacist, study coordinator, other staff or relative thereof, directly involved in 
the conduct of the study. Any technical/administrative reason that makes it impossible to 
randomize the patient in the study. 
  Contraindication for MRI, ie, presence of pacemaker, metallic implants in high-risk areas 
(ie, artificial heart valves, aneurysm/vessel clips), presence of metallic material 
(ie, shrapnel) in high-risk areas, known history of allergy to any contrast medium 
6.3.2 Exclusion criteria related to treatments, which may interfere with the study  
  Patients must not have used adrenocorticotrophic hormone or systemic corticosteroids for 
2 weeks prior to MRI assessment 
  Treated with : 
• 
Glatiramer acetate, interferons or dimethyl fumarate within 1 month prior to 
randomization.  
• 
Fingolimod or intravenous immunoglobulins within 3 months prior to randomization. 
• 
Natalizumab, other immunosuppressant or immunomodulatory agents such as 
cyclophosphamide, azathioprine, cyclosporine, methotrexate, mycophenolate, within 
6 months prior to randomization. 
• 
Cladribine or mitoxantrone within 2 years prior to randomization. 
  Treated with alemtuzumab at any time. 
  Treated with any investigational drug within 6 months prior to randomization. 
6.3.3 Exclusion criteria related to study treatment at screening  
E 15. Liver function impairment or persisting elevations (confirmed by retest) of alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), or direct bilirubin greater than 
2 x the upper limit of normal range (ULN) based on screening lab values. 
  Active hepatitis or hepatobiliary disease or known history of severe hepatitis. 
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  Pregnant or breast-feeding female patients. 
  Female patients of child-bearing potential or male patient not using highly effective 
(double barrier) contraceptive and /or female patients of childbearing potential who are 
unwilling to or unable to be tested for pregnancy. 
  Patients wishing to parent children (be a partner in the conception of a child) during the 
course of the trial. 
  Patients with significantly impaired bone marrow function or significant anemia, 
leukopenia, or thrombocytopenia: 
• Hemoglobin<10g/dL, 
• Absolute white blood cell count <3000 cells/mm3 (μL) and/or, 
• Platelet count <150 000 cells/mm3 (μL) and/or, 
• Absolute neutrophil ≤1500 cells/mm3 (μL) 
  Persisting elevations (confirmed by retest) of serum amylase or lipase greater than 3-fold 
the upper limit of normal. 
  Active pancreatitis or known history of chronic pancreatic disease.  
  Patients with a congenital or acquired severe immunodeficiency, a history of cancer 
(except for basal or squamous cell skin lesions which have been surgically excised, with no 
evidence of metastasis), lymphoproliferative disease, or any patient who has received 
lymphoid irradiation. 
  History of HIV infection. 
  Positive tuberculin test leading to suspicion of tuberculosis (eg, unless known to have been 
treated for tuberculosis in the past, or interpreted in light of vaccination; if in doubt, chest 
X-ray is recommended). 
  Hypoproteinemia (eg, in case of severe liver disease or nephrotic syndrome) with serum 
albumin <3.0 g/dL. 
  Moderate to severe impairment of renal function, as shown by serum creatinine 
>133 μmol/L (or >1.5 mg/dL). 
  Concomitant use of cholestyramine or prior use within 4 weeks preceding randomization. 
  Known hypersensitivity to teriflunomide, leflunomide or any excipients in the formulation 
of IMP (note: teriflunomide tablets contain lactose therefore investigators should consider 
whether history of lactose intolerance, in particular Lapp lactase deficiency could affect 
treatment tolerability). 
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6.3.4 Criteria to reduce reproductive risk  
The effect of teriflunomide on human fetal development is not known, and may be potentially 
harmful based on results from animal studies. Therefore, all patients must be fully informed as to 
this risk and provide written consent /assent to not become pregnant or father a child during their 
participation in this study. If during the study, a female patient becomes pregnant or decides to 
attempt to become pregnant or if a male patient decides to attempt to father a child, then she or he 
must stop the study medication and undergo the accelerated elimination procedure. 
Female patients must not be breast feeding or pregnant (as confirmed by serum pregnancy test) at 
the time of study entry and must agree to undergo serum pregnancy testing throughout the study at 
each 12-week clinic visit. In addition, pregnancy test should be conducted in case of an 
unexpected delay of menorrhea. 
Definition of “woman not of child bearing potential”: 
• Be sterilized (eg, hysterectomy, bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation). 
A woman of child bearing potential (WOCBP) is any female who has experienced menarche and 
does not meet the criteria for “woman not of child bearing potential”. 
Women of child bearing potential and male subjects must agree that they will take means to 
reduce reproductive risk by agreeing to use a double method of contraception (ie, an acceptable 
method in both female and male) until successful plasma elimination has been confirmed (refer to 
Section 9.9). Acceptable methods of contraception are defined for this protocol as: 
• For male: 
- 
True abstinence: when this is in line with the preferred and usual lifestyle of the 
subject (Periodic abstinence [eg, calendar, ovulation, symptothermal, post ovulation 
methods] and withdrawal are not acceptable methods of contraception), 
- 
Male sterilization (with the appropriate post vasectomy documentation of the absence 
of sperm in the ejaculate), 
- 
Use of condoms throughout the study, in addition to spermicides is recommended.  
• For women of child bearing potential: 
- 
True abstinence: when this is in line with the preferred and usual lifestyle of the 
subject (periodic abstinence [eg, calendar, ovulation, symptothermal, post ovulation 
methods] and withdrawal are not acceptable methods of contraception), 
- 
Highly effective oral contraceptives, such as biphasic and triphasic oral contraceptives 
are considered adequate. Progestogene only pills or “mini pills” which have 
demonstrated high efficacy will be acceptable, 
- 
Injectable hormones (ie, Depo-Provera), hormonal implants, transdermal patches or 
intrauterine device (IUD) or intrauterine systems (IUS) or intravaginal ring 
(NuvaRing) which have demonstrated efficacy comparable to high efficacy oral 
contraceptives are adequate. 
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Therefore: 
For female patients participating to the study: 
If the patient is a “woman not of child bearing potential”, then no method is required. 
If the patient is a WOCBP and meets criteria for “true abstinence” (as defined above) then no 
method is required. These patients must agree that they will use acceptable double methods of 
contraception before becoming sexually active. 
If the patient is a WOCBP and sexually active with a male partner who is sterilized (as defined 
above), then an additional method of contraception is recommended but not required. These 
patients must agree that they will use acceptable double methods of contraception before 
becoming sexually active with another male partner. 
Otherwise both the female patient participating to the study and the male partner must use an 
acceptable method of contraception as defined above. 
For male patients participating to the study: 
If the patient is sterilized (as defined above) then no method is required. 
If the patient meets criteria for “true abstinence” (as defined above) then no method is required. 
These patients must agree that they will use acceptable double methods of contraception before 
becoming sexually active. 
If the patient is sexually active with a female partner who is a “woman not of child bearing 
potential”, then no other method is required. These patients must agree that they will use 
acceptable double methods of contraception before becoming sexually active with another female 
partner. 
Otherwise both the male patient participating to the study and the female partner must use an 
acceptable method of contraception as defined above. 
Local additional requirements are to be followed, eg spermicidal foam / gel / film / cream / 
suppository is to be associated with condoms in UK, as per MHRA rules.  
6.4 
CONCOMITANT MEDICATION  
A concomitant medication is any treatment received by the patient concomitantly to any IMP(s). 
All treatments being taken by the patients on entry to the study or at any time during the study in 
addition to the IMP are regarded as concomitant treatments and must be documented on the Case 
Report Form (CRF).  A history of all prior medications needs to be documented in the eCRF: 
• MS treatments taken within the past 2 years 
• Non MS treatment taken within 4 weeks prior to screening. 
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Concomitant medications should be kept to a minimum during the study. However, if these are 
considered necessary for the patient's welfare and are unlikely to interfere with the IMPs, they 
may be given at the discretion of the Investigator and recorded in the CRF. 
Medications that are permitted during the study may be used as clinically indicated, at the 
physician’s discretion.  However, medication with a low therapeutic index such as digoxin should 
be carefully monitored.  All efforts should be made to adhere to the same dosing regimen during 
conduct of the study.  The combined use of teriflunomide with nonsteroidal anti-inflammatory 
drugs (NSAID) may be associated with an increased incidence of hypertension.  Blood pressure 
(BP) must be monitored carefully before treatment with teriflunomide and at the regular visits 
during study medication administration. 
In adult, repeated doses of teriflunomide had no effect on the pharmacokinetics of S-warfarin. 
However, a 25% decrease in peak international normalized ratio (INR) was observed when 
teriflunomide was coadministered with warfarin as compared with warfarin alone. Therefore, 
when warfarin is coadministered with teriflunomide, close INR follow-up and monitoring is 
recommended. 
In adult, there was an increase in mean repaglinide Cmax and AUC (1.7- and 2.4-fold, 
respectively), following repeated doses of teriflunomide, suggesting that teriflunomide is an 
inhibitor of CYP2C8 in vivo. Therefore, drugs metabolized by CYP2C8, such as repaglinide, 
paclitaxel, pioglitazone or rosiglitazone, should be used with caution during the treatment with 
teriflunomide. 
In adult, there was an increase in mean ethinylestradiol Cmax and AUC0-24 (1.58- and 1.54-fold, 
respectively) and levonorgestrel Cmax and AUC0-24 (1.33- and 1.41-fold, respectively) following 
repeated doses of teriflunomide. While this interaction of teriflunomide is not expected to 
adversely impact the efficacy of oral contraceptives, consideration should be given to the type of 
oral contraceptives used in combination with teriflunomide. 
In adult, there was an increase in mean cefaclor Cmax and AUC (1.43- and 1.54-fold, respectively), 
following repeated doses of teriflunomide, suggesting that teriflunomide is an inhibitor of OAT3. 
Therefore, when teriflunomide is coadministered with substrates of OAT3, such as cefaclor, 
penicillin G, ciprofloxacin, indomethacin, ketoprofen, furosemide, cimetidine, methotrexate, 
zidovudine, caution should be observed. 
In adult, there was an increase in mean rosuvastatin Cmax and AUC (2.65- and 2.51-fold, 
respectively), following repeated doses of teriflunomide. However there was no apparent impact 
of this increase in plasma rosuvastatin exposure on the HMG-CoA reductase activity. If used with 
teriflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. For other substrates 
of BCRP (eg, methotrexate, topotecan, sulfasalazine, daunorubicin, doxorubicin) and the OATP 
family especially HMG-CoA reductase inhibitors (eg, simvastatin, atorvastatin pravastatin, 
methotrexate, nateglinide, repaglinide, rifampin) concomitant administration of teriflunomide 
should also be undertaken with caution. Patients should be monitored closely for signs and 
symptoms of excessive exposure to the drugs and consider reduction of the dose of these drugs. 
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The following concomitant treatments are not permitted due to potential effects on the immune 
system: 
• Cladribine or mitoxantrone. 
• Azathioprine, cyclophosphamide, cyclosporine, methotrexate or mycophenylate. 
• Natalizumab.  
• Leflunomide. 
• Fingolimod. 
• Interferons. 
• Glatiramer acetate. 
• Dimethyl fumarate. 
• Alemtuzumab. 
• Intravenous immunoglobulins. 
• Attenuated live vaccines. 
The following concomitant treatments are not permitted during this study and for a minimum of 
4 weeks prior to randomization: 
• Cholestyramine or activated charcoal, which accelerate elimination of teriflunomide 
(except during the elimination procedure). 
The above therapy exclusions are not exhaustive.  If the Investigator has used or intends to use 
similar drugs not specified above, he/she should contact the local site monitor.  In addition, 
increased side effects may occur in case of recent or concomitant use of hepatotoxic (including 
alcohol), hematotoxic, or immunosuppressive substances in combination with teriflunomide.   
The use of systemic corticosteroids or adrenocorticotrophic hormone (ACTH) within 2 weeks 
prior to MRI assessment is not permitted due to potential interference with MRI assessment. 
Concomitant use of systemic corticosteroids for the treatment of MS relapse is allowed during the 
study (see below). 
6.4.1 
Standardization of acute therapy for relapses during the study  
Relapses may be treated with systemic corticosteroids if clinically necessary and as per 
investigator judgment in doses appropriate for pediatric population.  
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7 
STUDY TREATMENTS  
For a regional or national emergency declared by a governmental agency that results in travel 
restrictions, confinement, or restricted site access, contingency measures are included in Section 
17.7. 
7.1 
INVESTIGATIONAL MEDICINAL PRODUCT  
Both teriflunomide (HMR1726) and placebo are defined as the investigational medicinal products 
(IMP) for this study. 
7.1.1 HMR1726 (teriflunomide)  
Film-coated tablets containing 3.5 mg, 7 mg, and 14 mg teriflunomide will be supplied by the 
Sponsor.  Teriflunomide tablet (s) will be taken orally as a single dose each day of the treatment 
period.  Teriflunomide tablet (s) will be taken with water and may be taken with or without food.  
Patients should be encouraged to take their study medication in the morning at the same time each 
day of the core study period, except on the days in which PK sampling is planned - patients will 
take the study medication at the study site after pre-dose PK sample collection (see 
Section 9.11.1).  
During 4-week PK run-in (8 weeks) phase (7 mg adult equivalent, QD): 
• For patients 30 ± 10 kg: 
- 
1 Teriflunomide tablet (3.5 mg) per day (QD). 
• For patients > 40 kg: 
- 
1 Teriflunomide tablet (7 mg) per day (QD). 
After the end of the PK run-in (8 weeks) phase (Week 8): 
If individual predicted PK parameters are equal to or less than the adult range of predicted PK 
parameters (repeated doses of 7 mg): 
• For patients 30 kg ± 10 kg 
- 
1 Teriflunomide tablet (7 mg) per day (QD). 
• For patients > 40 kg 
- 
1 Teriflunomide tablet (14 mg) per day (QD). 
If individual predicted PK parameters are higher than the 95th percentile of the adult range of 
predicted PK parameters (repeated doses of 7 mg): 
• For patients 30 kg ± 10 kg 
- 
1 Teriflunomide tablet (3.5 mg) per day (QD). 
• For patients > 40 kg 
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- 
1 Teriflunomide tablet (7 mg) per day (QD). 
Adult range (5th - 95th percentile) of predicted PK parameters: 7 mg dose range for Cmax is 8.03 
to 49.10 g/mL and for AUC0-24 is 184 to 1160 g.h/mL. 
Optional additional extension period for young patients: 
One teriflunomide tablet (14 mg) per day (QD). Based on Investigator’s judgment, for patients 
less to 40 kg, dose could be adjusted by the Investigator to 14 mg every other day. 
7.2 
NON-INVESTIGATIONAL MEDICINAL PRODUCT(S)  
Cholestyramine or activated charcoal is used as non IMP in this study during the 4-week post 
elimination period to accelerate teriflunomide elimination process (see Section 9.9).   
7.3 
BLINDING PROCEDURES  
Patients will be randomized to teriflunomide or matching placebo at randomization visit (Visit 2). 
All study medication will be identical film-coated tablets sealed in child resistant-blister packs. 
The study treatment of the double-blind period will be kept blinded to the sites and patients until 
the final database lock. 
7.3.1 Measures to protect blinding of this trial  
Please also refer to Section 7.3.2 randomization code breaking during the study. In the case of an 
SAE, the Investigator may only break the code in exceptional circumstances when knowledge of 
the IMP is essential for treating the patient. The treatment codes will be unblinded by the 
Pharmacovigilance Department for reporting of any unexpected SAE that is reasonably associated 
with the use of IMP. A list of expected events commonly associated (and therefore not 
unexpected) for teriflunomide can be found in the current Investigator Brochure (IB). 
The DMC will review unblinded data. An independent statistical group (ISG), completely 
independent from the Sponsor and Investigators, is responsible for performing the interim data 
analyses and preparing the interim report for the DMC. 
The laboratory responsible for the pharmacokinetic sample bioanalysis will be unblinded as well 
as the pharmacometrician who will calculate the individual predicted PK parameters during the 
PK run-in. They will, however, agree to follow the procedures defined in the Sanofi SOP/Quality 
documents to maintain the blind and not to disclose the randomization schedule or the individual 
unblinded analytical results before the database lock. 
Post accelerated elimination PK samples, collected at the post accelerated elimination follow up 
visits (EOT+2 and EOT+4) to verify plasma teriflunomide concentrations of ≤0.02 μg/mL, could 
potentially unblind the investigational site to a patient’s treatment after study medication 
discontinuation. Site notification is required to inform the Investigator if the accelerated 
elimination procedure needs to be repeated after EOT+4 if the teriflunomide plasma concentration 
at EOT+2 is still above threshold. The risk of unblinding (of discontinued or completed patients) 
is low, since greater than 97% of the patients treated with teriflunomide are expected to have 
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adequately low plasma teriflunomide concentrations following the recommended accelerated 
elimination procedure. 
7.3.2 Randomization code breaking during the study  
In case of a SAE, the code must be broken only in exceptional circumstances when knowledge of 
the IMP is essential for treating the patient. 
Code breaking can be performed at any time by using the proper module of the IVR/IWR 
(Interactive Voice/Web Response) system and/or by calling any other phone number provided by 
the Sponsor for that purpose. If the blind is broken, the Investigator should document the date, 
time of day, and reason for code breaking. 
7.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP  
Patients will be randomly assigned to one of the two groups in a 1:2 ratio and will receive either 
placebo or teriflunomide.  The randomization will be stratified by the country in which the patient 
is being treated and the patient pubertal status.  The randomization code list is generated by the 
interactive web response system and interactive voice response system (IWRS/IVRS) service 
provider. 
Patients filling all inclusion and exclusion criteria at the Visit 1 (Day-28) and Visit 2 (Day 0) are 
qualified for randomization. 
Randomization occurs at Visit 2.  The first dose of randomized IMP (either teriflunomide or 
placebo) will be taken the same day or the following day. 
A patient is considered randomized when allocated to treatment regardless whether the treatment 
kit was used or not. 
The study medication will be administered only to patients included in this study following the 
procedures described in this protocol. 
The randomization treatment kit number list is generated centrally by the sponsor. Investigational 
Products (IMPs) are packaged according to this list. 
The clinical site coordinator will document the medication kit number in the electronic Case 
Report Form (eCRF) and in the patient’s source documents, and the site/patient number on the 
study medication label prior to dispensing to the patient. 
At the randomization visit, at Week 8 (after PK run-in period), Week 12 and then every 12 weeks 
during the course of the study, the investigational site will contact the IWRS/IVRS to allocate a 
new medication kit number to the patient. The IWRS/IVRS will allocate medication kits 
containing the same study medication as the one designated at randomization. A patient will be 
considered randomized once a medication kit number has been assigned by the IWRS/IVRS. 
Therefore, it is important that all inclusion/exclusion criteria are confirmed, and baseline 
procedures are completed prior to the randomization call to the IWRS/IVRS.  
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If a screened patient is not eligible, the Investigator will call IWRS/IVRS to enter the patient as 
screen failure. 
If a patient was deemed a screen failure, he or she may be re-screened for this study after waiting 
at least 4 weeks following the date of screen failure. However, if the screen failure is due to 
non-safety reasons, the patient can be re-screened earlier. If a patient who had previously failed 
screening for any reason is re-screened, the patient must sign a new informed consent form and be 
assigned a new patient number by IWRS/IVRS (the next sequential patient number at the site). 
Patients withdrawn from the study retain their patient number. New patients will always be 
allocated a new patient number. 
7.5 
PACKAGING AND LABELING  
The content of the labeling is in accordance with the GMP requirements and the local regulatory 
specifications and requirements. 
7.5.1 Teriflunomide/placebo  
During the double-blind treatment period and the open-label period for the remainder of 
192 weeks, teriflunomide/placebo will be supplied as 3-Month kit.  A 3-Month kit is a box 
containing 3 child resistant wallets of 35 tablets of 3.5 mg or 7 mg or 14 mg teriflunomide.  Each 
box contains sufficient medication for 12 weeks plus 21 extra-days (=105 tablets).  Each box 
contains 3 wallets of the same strength. 
A 2-panel label is affixed to the box.  At the time of dispensing, the tear-off label of the 2-panel 
label will be removed and adhered to the patient’s treatment log form.  Each wallet has a 1-panel 
label affixed. 
During the optional additional extension period offered to young patients when they complete the 
study, to provide treatment until they are 18 years old and/or can switch to commercial product, 
whichever comes first, two 3-Month kit teriflunomide 14 mg will be supplied in open-labelled 
conditions. It is required that these treatments will not be used after the patient is able to switch to 
commercial product and come back to the last visit with remaining kits, in order to prevent any 
IMP intake once patients have switched to the commercial product. 
7.6 
 STORAGE CONDITIONS AND SHELF LIFE  
Investigators or other authorized persons (eg, pharmacists) will be responsible for storing all 
investigational product supplies in a secure and safe room in accordance with local regulations, 
labeling specifications, policies and procedures. 
Teriflunomide storage conditions are specified on the IMP medication kit boxes and their wallets. 
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7.7 
RESPONSIBILITIES  
The Investigator, the Hospital Pharmacist, or other personnel allowed to store and dispense 
IMP/non IMP will be responsible for ensuring that the IMP/non IMP used in the clinical trial is 
securely maintained as specified by the Sponsor and in accordance with the applicable regulatory 
requirements. 
All IMP/non IMP shall be dispensed in accordance with the Investigator's prescription and it is the 
Investigator's responsibility to ensure that an accurate record of IMP/non NIMP issued and 
returned is maintained. 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc.) should be promptly notified to the 
Sponsor. Some deficiencies may be recorded through a complaint procedure. 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party, allow the IMP to be 
used other than as directed by this Clinical Trial, or dispose of IMP in any other manner. 
7.8 
TREATMENT ACCOUNTABILITY AND COMPLIANCE  
At the end of Visit 2, patient will receive IMP for the following 8 weeks.  
At Visit 4 (W8), a new kit will be then dispensed. 
From V5 (W12), patients will receive subsequent IMP every 12 weeks until the end of the study. 
The patient will receive subsequent IMP every 24 weeks, when participating in the optional 
additional extension period. 
It is the responsibility of the Investigator to check the patients’ compliance to study treatment 
administered. Compliance is tracked by counting dispensed and unused tablets at W8, W12 and 
then from W12 every 12 weeks corresponding to mandatory on site visits until EOT visit. The 
investigator (or authorized delegate) completes the appropriate page of the case report form and 
IMP source document logs by recording the number and dates of doses taken (or not) by the 
patient. 
Temporary study treatment discontinuation should generally not exceed 2 consecutive weeks. 
The monitor in charge of the clinical trial checks the case report form data by comparing the 
recorded data with the retrieved IMP kit and data recorded on the IMP source document logs. 
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7.9 
RETURN AND/OR DESTRUCTION OF TREATMENTS  
Whenever possible all unused investigational product will be destroyed on site according to the 
standard practices of the site. The patient should be reminded to keep all empty boxes and 
remaining study medications and bring them to the next on-site visit ( Section 17.7).  
A detailed treatment log of the destroyed investigational product will be established with the 
Investigator (or the pharmacist) and countersigned by the Investigator and the monitoring team. 
The Investigator will not destroy any investigational product unless the Sponsor provides written 
authorization. When destruction at site cannot be performed, all investigational products will be 
retrieved by the Sponsor. A detailed treatment log of the returned investigational product will be 
established with the Investigator (or the pharmacist) and countersigned by the Investigator and the 
monitoring team). 
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8 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT  
The assessments will be performed according to the schedule presented in the Study Flowchart. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 17.7. 
8.1 
EFFICACY  
In order to assure proper evaluation of the efficacy, at each study center the staff will consist of a 
minimum of 2 neurologists. One neurologist will be the treating neurologist and one will be the 
examining neurologist for a given subject throughout the study. One of the neurologists may be 
the Principal Investigator. This delineation assures that AEs or other health issues for any patient 
do not influence the neurological assessment. In case an assessment (eg, EDSS/FS, MRI) cannot 
be performed during to a regional or national emergency, the patients will be asked to stay at 
home, and study visits that are scheduled during this outbreak may be replaced by phone calls, 
and study assessments that require an on-site visit may be performed at the next scheduled visit or 
as unscheduled evaluation (Section 17.7). 
Treating neurologist 
The treating neurologist will be responsible for subject eligibility evaluation, supervision of study 
medication administration, recording and treating of AEs and assessing relapses, and monitoring 
of safety assessments, including routine laboratory results and concomitant medications. The 
same physician should, as best as possible, maintain the role of treating neurologist for a given 
subject throughout the study. 
Examining neurologist 
The examining neurologist will be responsible for conducting all Functional System (FS) score 
and Expanded Disability Status Scale (EDSS) score assessments. The examining neurologist 
should be certified for EDSS rating prior any involvement in the study. The Investigator can 
delegate the role of examining neurologist to a highly qualified health professional who meets a 
predetermined level of experience in evaluating MS patients including experience in examining 
MS patients and scoring the EDSS/FS. Such a delegation is only allowed when permitted by local 
laws, health authority rules, and ethics committee requirements. Throughout the study, the 
examining neurologist is to remain unaware of the patient’s treatment assignment and the safety 
profile of the patient (AEs, concomitant medications, and laboratory results). All efforts should be 
made to maintain the same person at the role of examining neurologist for a given subject 
throughout the study. All other investigational site staff and the subject must refrain from 
discussing treatment assignment and safety issues with the examining neurologist. 
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All brain scans will be reviewed and interpreted by one or more neuroradiologists at an 
independent, central facility with no access (ie, blinded) to treatment assignment thereby avoiding 
bias.  
An MRI manual explaining the instructions for standard image acquisition requirements, data 
transfer, archiving and shipping, and outlining the phantom data approval process will be 
provided to all centers. 
MRI should not be conducted within 2 weeks of steroid administration due to potential 
interference. 
In case of at least 5 new/enlarged T2 lesions at the MRI of Week 24, an additional MRI will be 
performed at Week 36. 
Then, in case of: 
• At least 9 new/enlarged T2 lesions at Week 36, or,  
• At least 5 new/enlarged T2 lesions on each of the 2 consecutive MRI scans of Week 36 
and Week 48, or, 
• At least 5 new/enlarged T2 lesions on each of the 2 consecutive MRI scans of Week 48 
and Week 72. 
Patients will have the option to continue in an open label teriflunomide treatment arm.  
(Note: new/enlarged refer to previous scan) 
8.1.1 Primary efficacy  
The primary efficacy endpoint for the 96-week double blind treatment period is the time to first 
clinical relapse after randomization 
Subjects/parents/guardians will be instructed to contact their investigator immediately should any 
symptoms suggestive of an MS relapse appear. The subject must be examined as soon as possible, 
within 7 days.  
Relapses are defined as new or recurrent neurological symptoms not associated with fever or 
infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon 
examination by the Examining Neurologist and documented by the Functional System Scores 
(FSS).  The subject must have objective signs on the Examining Neurologist’s examination 
confirming the event and must then be reviewed and confirmed by an independent Relapse 
Adjudication Panel (RAP).  The RAP will assess the relapse in real time. 
New or recurrent symptoms that occur less than 30 days following the onset of a relapse should be 
considered part of the same relapse. 
The investigator can, at his/her discretion, treat the patient with corticosteroids but the switch to 
the open label can only occur if the RAP assesses the event as a relapse. 
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8.1.2 Secondary efficacy  
The secondary efficacy endpoints for the 96-week double-blind treatment period are the 
following: 
• Proportion of relapse free patients at 24, 48, 72 and 96 weeks. 
• MRI endpoints: 
- 
Number of new/newly enlarged T2 lesions,  
- 
Number of T1 Gd-enhancing T1 lesions, 
- 
Change in volume of T2 lesions, 
- 
Change in volume of T1 hypointense lesions, 
- 
Number of new hypointense T1, 
- 
Proportion of patients free of new or enlarged MRI T2-lesions at 48 weeks and 
96 weeks, 
- 
Brain atrophy. 
The number of new/newly enlarged T2 lesions and the number of T1 Gd-enhancing 
T1 lesions will be considered the key secondary imaging endpoints. 
• Cognitive outcome measured by the SDMT and Cognitive Battery Tests (15, 4), when 
available. 
• Teriflunomide PK. 
Exploratory endpoint: proportion of disease-free patients.  
8.2 
SAFETY  
The clinical trial-specific and general safety criteria include: 
• Pre-specified potential risks which will require specific monitoring, management and 
follow-up procedures. 
• Physical examinations: screening, randomization, Weeks 12, 24, and every 12 weeks.  
• Vital signs: screening, randomization, Weeks 4, 8, 12, 24, and every 12 weeks. 
• Laboratory: screening, randomization, every 4 weeks up to 24 weeks and then every 
6 weeks up to the end of treatment (EOT). Patients who enter the open-label period will 
restart the laboratory visit schedule of every 4 weeks up to 24 weeks and then every 
6 weeks up to the EOT.  
• Abdominal ultrasound visits:  for patients with signs or symptoms of pancreatitis. 
• ECG randomization, EOT and after EOT if abnormality. 
• Tuberculosis test (skin test or blood testing are allowed), to be performed at screening. An 
additional test should be performed during the study if deemed clinically indicated. Skin 
test or blood testing are allowed. 
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• AE reporting throughout the duration of the study. A priori, efficacy endpoints as specified 
in the protocol will not be considered as AEs except if, because of the course or severity or 
any other features of such events, the Investigator, according to his/her best medical 
judgment, considers these events as exceptional in this medical condition. Therefore, MS 
relapses will be captured as efficacy events and are excluded from the definition of AE and 
SAE. However, for all associated symptoms or events or if an event that was initially 
considered a possible MS relapse but upon evaluation is found to be any other type of 
event (some example but not limited to: fever, injury, musculoskeletal event, systemic 
illness, mood disorder, etc) the event must be captured as an AE/SAE. 
• In case of suspected infection, tests (eg, appropriate cultures, erythrocyte sedimentation 
rate and/or C reactive protein, chest and/or sinus imaging) must be performed in addition 
to general laboratory testing as clinically indicated. 
• In case of an increase in frequency or severity of infectious illness or due to the nature of 
the infections and suspected immune deficiency, more advanced immunologic testing will 
be required.  The measurements of specific antibody titers in response to intentional 
immunization will be performed as well. 
• Peripheral neuropathy confirmed by nerve conduction study: all neurological symptoms 
suggestive of a peripheral neuropathy will be followed up with nerve conduction studies. 
The Peripheral neuropathies reporting form has to be completed. 
• Avoidance of attenuated live vaccinations during study. 
8.3 
BIOMARKERS  
Neurofilament light chain and other biomarkers may be evaluated from leftover plasma 
PK samples, which were drawn from study patients during the study and after patient/parents 
consent. This process is described in 17.5.  
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9 
SAFETY ENDPOINTS ASSESSED IN THIS TRIAL  
Safety and tolerability will be evaluated using the assessments described below. During the 
optional additional extension period, safety parameters will be evaluated as per investigator’s 
judgement. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 17.7. 
9.1 
SPONTANEOUSLY REPORTED ADVERSE EVENTS  
Collection of adverse events (AEs) spontaneously reported by the patient or observed by the 
investigator extends from the signing of the informed consent form until post drug elimination 
follow up. All patients who prematurely and permanently discontinue double-blind study 
medication will be asked to enter an early permanent treatment discontinuation (EPTD) follow-up 
period, which involves returning to the clinic approximately every 3 months to evaluate adverse 
events until the planned end of the double-blind treatment period (96 weeks). All reported AEs 
will be recorded in the patient’s records and in the case report form at all visits, including the 
unscheduled relapse visit, if necessary. 
Adverse events will be graded by CTCAE version 4.0.  
9.2 
VITAL SIGNS  
Vital signs include systolic and diastolic blood pressure, radial heart rate (HR), and body 
temperature. Vital signs will be obtained at screening, randomization, Weeks 4, 8, 12, 24 and 
every 12 weeks, at EOT, or early treatment discontinuation, and washout period EOT +2W and 
EOT +4W (except height only measured at randomization and EOT), and after relapse. Height 
and weight is to be documented in the growth charts (Section 1.3, Section 1.4, Section 1.5). 
Blood pressure and heart rate are measured after the patient has been supine for 3 minutes.  The 
patient then stands.  Standing blood pressure and heart rate are obtained 3 minutes later.  A 
sphygmomanometer with a blood pressure cuff appropriate to the patient’s arm girth is used. 
9.3 
PHYSICAL EXAMINATION  
Physical examinations are performed at screening, baseline, every 12 weeks thereafter and at 
EOT.  In addition, one examination is also performed at the first post drug elimination follow up 
visit.  Physical examinations should be performed for patients who prematurely discontinued the 
study treatment. 
The Tanner scale (also known as the Tanner stages I-V) is a scale of physical development in 
children, adolescents and adults (Marshall and Tanner, 1969; Marshall and Tanner, 1970). The 
scale defines physical measurements of development based on external primary and secondary sex 
characteristics, such as the size of the breasts, genitalia, and development of pubic hair. 
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Tanner scale is performed either at the study site by the pediatric neurologist or pediatrician or at a 
designated site arranged by the investigator.  Tanner scale is encouraged to be performed at 
scheduled visits.  However, it is acceptable if the assessments are performed shortly after the 
scheduled visits due to logistical reasons. 
The treating neurologist must assess for neurological signs and symptoms suggestive of a 
peripheral neuropathy (defined as bilateral sensory and/or motor involvement with stocking glove 
distribution) at each visit involving a physical examination.  If the treating neurologist suspects a 
peripheral neuropathy then electrophysiological nerve conduction studies must be performed.  If 
the overall assessment of the patient is consistent with a diagnosis of peripheral neuropathy or the 
worsening of a pre-existing peripheral neuropathy, that event will be reported as AE.  If a drug-
related peripheral neuropathy is suspected treatment should be discontinued (Section 1.3, Section 
1.4, Section 1.5). 
9.4 
12-LEAD ECG  
A standard 12-lead ECG will be performed at baseline and at EOT and will be evaluated centrally. 
For ECG, the variables analyzed will be heart rate, PR interval, QRS interval, QT, QTcB 
(QTc interval calculated by Bazett’s method), and QTcF (QTc interval calculated by Fridericia’s 
method). 
In the case of an abnormal ECG (ie, QTcB/QTcF ≥500 msec) transmitted to the centralized ECG 
system and manually interpreted by the cardiologist in the centralized ECG facility, a cardiology 
consultation should be performed, and consideration is should be given to placing the patient 
under supervision in a specialized setting. 
A confirmed prolonged QTc interval (QTcB/QTcF ≥500 msec) should be reported in an expedited 
fashion by the centralized ECG system.  An expedited notification of the finding of QTc interval 
prolongation is communicated to the investigator and to the Sponsor (Section 1.3, Section 1.4, 
Section 1.5). 
9.5 
ULTRA SOUND OF THE PANCREAS  
An ultrasound will be performed for patients with confirmed pancreatic enzymes elevation 
≥3 x ULN and/or symptoms suggestive of pancreatitis. 
The ultrasound examination will be performed according to local standards. A gastroenterologist 
will review the report and provide clinical conclusion. Abnormal findings should be reported as 
AEs. 
All ultrasounds with abnormal pancreatic findings must be followed by a CT scan with contrast or 
MRI of the pancreas and report added to the CRF. 
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9.6 
CLINICAL LABORATORY PARAMETERS  
The Central Laboratory performs clinical laboratory assessments.  This includes two-parts: for 
scheduled study center visits, laboratory samples will be drawn at the site and samples will be 
shipped to the Central Laboratory to be analyzed; for safety laboratory samples collected locally 
in between site visits, blood samples are drawn locally but are shipped to the Central Laboratory 
for analyses. Fasting is not required, but the information on fasting/non fasting conditions will be 
collected.  Local anaesthetic must be offered for blood draws to minimize pain and discomfort. A 
specific written manual regarding the mechanisms and procedures related to the centralized 
laboratory process is provided to each investigator (see Section 1.3, Section 1.4, Section 1.5). 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 17.7. 
9.6.1 Routine clinical laboratory parameters  
The following routine parameters will be measured at screening, randomization, Weeks 4, 12 and 
then every 12 weeks and at EOT:  
• Hematology and differential panel (hemoglobin, hematocrit, red blood cell count and red 
blood cell morphology, mean corpuscular volume, white blood cell count, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelets). 
• Coagulation panel (prothrombin time, and activated partial thromboplastin time).  
• Complete chemistry panel (glucose, creatinine, blood urea nitrogen (BUN), sodium, 
potassium, chloride, bicarbonate, magnesium, uric acid, aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), lactate 
dehydrogenase (LDH), total bilirubin, direct/indirect bilirubin, alkaline phosphatase, 
calcium, inorganic phosphorus, total protein, albumin, globulin, albumin/globulin ratio, 
triglycerides, cholesterol and creatine phosphokinase (CPK).  
• Pancreatic enzymes (serum amylase and lipase). 
• Urinalysis (pH, ketones, protein, glucose, blood, urobilinogen, bilirubin, microscopic 
sediment, specific gravity). 
• For pubescent females serum pregnancy test β- Human chorionic gonadotropin (β-HCG) 
(NOTE:  This test is performed at baseline and every 12 weeks and at EOT or premature 
treatment discontinuation). 
9.6.2 Safety clinical laboratory parameters  
The following safety laboratory testing will be conducted in between clinical routine lab at 
Weeks 8, 16, 20, 30 and then every 12 weeks up to the EOT, measuring hematology and 
differential panel as above 
• Liver function tests [ALT, AST, GGT, total bilirubin, and direct/indirect bilirubin].  
• Pancreatic enzymes [serum amylase and lipase]. 
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At EOT+2 weeks and EOT+4 weeks: 
• Uric acid and inorganic phosphorus will also be performed. 
Note: Any abnormal laboratory value will be immediately rechecked for confirmation before making a 
decision of permanent discontinuation of Investigational Product for the concerned patient. 
Threshold values for laboratory parameters of special concern (ie, liver enzymes, pancreatic 
enzymes and neutrophil counts) are defined for monitoring purposes as AEPMs with expedited 
reporting when thresholds are met; (ie, Neutrophils< 1000/mm3, ALT>3 x ULN and Bilirubin 
>2 x ULN for liver function according to see 17.4), and AEPMs (see Section 9.8.1). 
9.6.3 Additional laboratory parameters  
TSH: at baseline, every 24 weeks and EOT. 
9.6.4 Optional additional extension period for young patients  
After the patient has entered the optional additional extension period, laboratory tests will be 
performed upon investigator discretion based on signs/symptoms of adverse reactions. 
9.7 
IMMUNOGLOBULINS  
Serum immunoglobulins concentration (IgG, IgM and IgA) at randomization and every 24 weeks. 
In addition if a patient has a vaccination, antibody titers will be assessed before and after 
vaccination (only inactivated vaccines are allowed) 
9.8 
SAFETY INSTRUCTIONS  
9.8.1 Pre-defined adverse events and laboratory abnormalities for specific reporting 
(AEPM)  
For the following events, the Investigator should follow the procedures for specific expedited 
reporting in order to assure Sponsor monitoring and DMC review, even if the criteria for 
seriousness are not fulfilled. The Investigator is required to completely document the evaluations 
and treatments and provide them to the Sponsor. For all of these events the “Safety 
complementary form” has to be completed in the eCRF. For some of the listed events specific 
CRF pages have to be completed in addition to that. 
All the following adverse events must be monitored until symptom resolution or until the 
condition stabilizes  
Instructions for reporting and Follow-Up: 
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• Confirmed ALT >2 x ULN by a retest done as soon as possible (in 7 days if ALT 
≤3 x ULN). See 17.4 for guidance of reporting and Follow-Up (note that only ALT is to be 
taken into account in the aminotransferase figure). 
• Any occurrence of ALT >3 x ULN with total bilirubin value >2 x ULN. See 17.4 for 
guidance of reporting and Follow-Up. 
• Any occurrence of ALT >8 x ULN. This should be reported as SAE with the criteria of 
medical importance. See 17.4 for guidance of reporting and Follow-Up. 
• Depressive disorder that is considered clinically important by the investigator; 
• Any occurrence of confirmed (by a retest) neutrophil count of less than 1000 cells/μL. 
See 17.4 for guidance of reporting and Follow-Up. 
• Confirmed serum amylase or lipase >2 x ULN by a retest done as soon as possible (up to 
14 days). 
(Amylase or lipase values greater than 2 x ULN and less than 3 x ULN must be repeated 
within 7 days and weekly thereafter until it is less than 2 x ULN. Amylase or lipase values 
greater than 3 x ULN must be repeated within 48 hours and every 48 hours until it is less 
than 3 x ULN and weekly until it is less than 2 x ULN. Study medication must be 
discontinued if serum amylase or lipase values are greater than 2 x ULN and associated 
with signs or symptoms consistent with pancreatitis. Study medication must also be 
discontinued if serum amylase or lipase values are greater than 5 x ULN, confirmed within 
48 hours, and without signs or symptoms of acute pancreatitis. In this case, a thorough 
evaluation for the basis of these elevations must be performed.) 
• Abdominal CT or MRI scan with findings with pancreatic abnormalities; 
• Pulmonary symptoms such as onset or worsening of cough or dyspnea requiring 
pulmonary evaluation and consistent with a pulmonary toxicity. 
• Peripheral neuropathy confirmed by nerve conduction study. 
All neurological symptoms suggestive of a peripheral neuropathy will be followed up with 
nerve conduction studies.  
• Any sign, symptom, laboratory data suggestive or evocative of renal dysfunction with 
acute renal failure, as defined by a rapid increase in serum creatinine over 150 µmol/L or 
rapid decrease in creatinine clearance below 50ml/min (See 17.4 for guidance of reporting 
and Follow-Up). 
• Severe skin reaction such as toxic epidermal necrolysis or Stevens Johnson syndrome. 
• Sustained increase in blood pressure: SBP ≥160 mmHg, DBP ≥100 mmHg on at least 
2 consecutive visits. 
• Other reasons for expedited reporting: 
- 
Overdose (see Section 9.8.4). An overdose (symptomatic or not) with the IMP is an 
event suspected by the Investigator or spontaneously notified by the patient and 
defined as at least twice the intended dose (ie, 2 tablets) on a given calendar day. The 
circumstances (ie, accidental or intentional) should be clearly specified in the verbatim 
and symptoms, if any, entered on separate AE form, 
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- 
Any pregnancy diagnosed in a female subject or in the female partner of a male subject 
during treatment with the IMP must be reported to the Sponsor immediately. The 
treatment should be withdrawn and the accelerated elimination procedure performed. 
Information related to the pregnancy must be provided to the Sponsor. Information 
related to the birth of a child of an exposed patient must be provided to the Sponsor. 
The “Drug exposure via parent” form must be completed. 
9.8.2 Laboratory test monitoring  
In the case of elevated aminotransferases, neutropenia, thrombocytopenia, acute renal failure, or 
suspicion of rhabodomyolysis, the specific follow-up actions for this abnormality should be 
initiated according to the appended decision chart (17.4 – General guidance for the follow-up of 
laboratory abnormalities).  
9.8.3 Monitoring electrocardiogram  
The ECG of any clinical trial patient with a clearly prolonged QTc interval (QTcB/QTcF 
≥500 msec) will be reported in an expedited fashion by the centralized ECG system to the 
investigator and to the Sponsor. 
Appropriate medical diligence by the investigator, in such an instance, includes an investigation 
of the cause of the QTc interval prolongation.  This investigation includes clinical laboratories to 
determine serum potassium, calcium, and magnesium levels, as well as to obtain a PK sample at 
the time of discovery of the QTc interval prolongation. 
9.8.4 Overdose information  
An overdose with the IMP is an event suspected by the investigator or spontaneously notified by 
the patient (not based on systematic pill count) and defined as any dose above the recommended 
maximal dose administered within the Clinical Trial: 
• Overdose is defined as 2 or more tablets of IMP in one day (a 24-hour period)  
NOTE:  The circumstance (ie, accidental or intentional), amount, and time period should be 
clearly specified in the verbatim terminology. 
9.8.5 General guidance for relapses (refer to Section 10.1.3.5 for detailed instructions)  
Subjects/parents/guardians will be instructed to contact their investigator immediately should any 
neurological symptom appear. The subject must be examined as soon as possible, but within 
7 days of contact as follows: 
Patient should have a physical exam and a complete neurological examination with FSS/EDSS by 
the blinded rater. 
The relevant information will be sent to the RAP for confirmation of relapse. 
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The RAP will determine whether a subject has experienced a protocol-defined relapse.  The RAP 
will review, in an expedited fashion, the records of all subjects who develop new or worsening 
neurological symptoms.  All reviews will be done based on subject examination records from the 
Treating Neurologist and Examining Neurologist, but without knowledge of the subject’s 
treatment assignment.   
9.8.6 Re-consent process  
Patients/parents/guardian may decide to discontinue study treatment or to discontinue from 
participation in the trial at any time.  In addition, to continue study participation, patients must 
undergo a repeat informed consent process when they enter the open label period or when they 
enter the optional additional extension period for young patients. They must also re-consent each 
time they have a RAP-confirmed relapse in the PK run-in, and each time they have a confirmed 
relapse in the open-label period. 
The re-consent/assent process must include discussion with the patient/parents/guardians about 
the alternative approaches to therapy, such as all approved therapies, that are available to him or 
her. 
Additional re-consents may be needed as per local regulations, eg, when patients turn 18.  
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 17.7. 
9.9 
ACCELERATED ELIMINATION PROCESS  
Oral intake of cholestyramine or activated charcoal significantly accelerates the elimination of 
teriflunomide.  The preferred washout medication is cholestyramine.  Without using the 
accelerated elimination procedure, it may take years for teriflunomide plasma concentrations to 
reach acceptable low levels (≤0.02 μg/mL) due to the long elimination half-life.  All patients who 
complete or discontinue the study drug must undergo one of the accelerated elimination 
procedures described below. These procedures must be carried out at the study site by the 
Investigator. For patients who will continue to the commercially available drug, no accelerated 
elimination procedure is required. 
Accelerated elimination procedure 
The accelerated elimination procedure must be initiated in all patients who have definitively 
discontinued the study medication and will not continue teriflunomide treatment after completion 
of the study. The recommended procedure is cholestyramine with a dose adjusted for children’s 
weight (240 mg/kg/day (80 mg TID)). Alternatively, 50 g oral activated charcoal powder 
administered every 12 hours for 11 days may be used. 
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Table 2 - Washout medications and dosage  
 
Cholestyramine 
Activated Charcoal 
Washout (11 days) 
240mg/kg/day TID 
2 x 50 g =  100 g daily 
After treatment with either cholestyramine or activated charcoal taken for 11 days, the 
teriflunomide plasma concentration has to be verified as <0.02 μg/mL prior to withdrawal 
from/completion of the study. A post-washout PK sample will be collected immediately following 
administration of washout medication and at both post-drug elimination follow up visits 
(EOT+2W and EOT+4W). The PK samples after washout will be labeled separately from the 
regular pharmacokinetic samples (using labels and tubes provided in the Washout lab kit) and will 
be analyzed using a more sensitive bioanalytical assay (see Section 9.11.3). Feed-back on plasma 
levels above 0.02 μg/mL will be provided only when requested by the Investigator, eg, in case of 
desired pregnancy. This is applicable for women or men wishing to parent a child, or in specific 
situations, including planned prescription of fingolimod, natalizumab or mitoxantrone. If the 
sample collected at EOT+2 weeks has blood plasma levels of teriflunomide >0.02 μg/mL, the site 
will be notified at EOT+4 weeks and the cholestyramine/charcoal treatment should be repeated. 
The level should continue to be followed every two weeks until it is equal or below 0.02 μg/mL.  
Both cholestyramine and activated charcoal may influence the absorption of estrogens and 
progestogens and reduce the effectiveness of oral contraceptives; therefore, the use of alternative 
contraceptive methods for women is recommended during the accelerated elimination procedure. 
9.10 
ADVERSE EVENTS MONITORING  
All events will be managed and reported in compliance with all applicable regulations, and 
included in the final clinical study report. 
9.10.1 Definitions of Adverse Event(s)  
9.10.1.1 Adverse Event  
An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. 
9.10.1.2 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 
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 it were more severe. 
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• 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 patient or may require 
intervention (ie, specific measures or corrective treatment) to prevent one of the other outcomes 
listed in the definition above. 
Note: The following medically important events intend to serve as a guideline for determining 
which condition has to be considered as a medically important event. It is not intended to be 
exhaustive: 
• Intensive treatment in an emergency room or at home for: 
- 
Allergic bronchospasm,  
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia…),  
- 
Convulsions (seizures, epilepsy, epileptic fit, absence…) 
- 
Development of drug dependency or drug abuse, 
- 
ALT >3 x ULN + total bilirubin >2 x ULN or asymptomatic ALT increase  
>10 x ULN, 
- 
Suicide attempt or any event suggestive of suicidality, 
- 
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling), 
- 
Bullous cutaneous eruptions, 
- 
Cancers diagnosed during the study or aggravated during the study, 
- 
Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the study 
(only if judged as unusual/significant by the Investigators in studies assessing 
specifically the effect of a study drug on these diseases). 
9.10.2 Obligation of the Investigator regarding safety reporting  
9.10.2.1 Adverse events  
All AEs regardless of seriousness or relationship to IMP, spanning from the signature of the 
Informed Consent Form, until the end of the clinical trial as are recorded on the corresponding 
page(s) included in the case report form. 
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Whenever possible, a diagnosis or single syndrome is reported instead of symptoms.  The 
investigator specifies the date of onset, intensity, action taken with respect to IMP, corrective 
treatment/therapy given, additional investigations performed, outcome, and his/her opinion as to 
whether there is a reasonable possibility that the AE was caused by the IMP. Intensity will be 
graded based on CTCAE Version 4.0.  
Laboratory, vital signs, or ECG abnormalities are recorded as AEs only if they are clinically 
significant or defined as AEPM (see Section 9.8.1): 
• Symptomatic, or, 
• Requiring either corrective treatment or consultation, or, 
• Leading to IMP discontinuation or modification of dosing, or, 
• Fulfilling a seriousness criterion. 
A priori, efficacy endpoints as specified in the protocol will not be considered as AEs except if, 
because of the course or severity or any other features of such events, the Investigator, according 
to his/her best medical judgment, considers these events as exceptional in this medical condition. 
9.10.2.2 Serious adverse events  
In the case of occurrence of an SAE, the investigator must immediately: 
• ENTER (within 24 hours) the information related to the SAE in the appropriate pages 
screens of the electronic case report form; the system automatically sends the notification 
to the Monitoring Team after approval of the investigator within the electronic case report 
form or after a standard delay. 
• SEND (preferably by fax or email) the photocopy of all examinations carried out and the 
dates on which these examinations were performed, to the representative of the 
Monitoring Team.  Care is taken to ensure that the patient's identity is protected and the 
patient'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 with the report. 
• PROVIDE all further data updates that should be reported in the electronic case report 
form. Further documentation as well as additional information (for lab data, concomitant 
medication, patient status) is sent (by fax or email) to the Monitoring Team within 
1 working day of knowledge.  In addition, every effort should be made to further 
document each SAE that is fatal or life threatening within the week (7 days) following 
initial notification. 
• UTILIZE a back-up plan (using paper flow) when the electronic case report form system 
does not work. 
9.10.2.3 Safety observations (follow-up)  
• The investigator should take all appropriate measures to ensure the safety of the patients, 
notably he/she should follow up the outcome of SAE and AEs of special interest until 
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clinical recovery is complete and laboratory results have returned to normal or until 
progression has been stabilized or until death.  In all cases, this may imply that 
observations will continue beyond the last planned visit of the patient, and that additional 
investigations may be requested by the Monitoring Team. 
• When treatment is prematurely discontinued, the patient’s observations will continue until 
the end of the study (except for patients discontinuing during the optional additional 
treatment extension period). 
• At any time after the end of the study for the patient, if a SAE/AEPM is brought to the 
attention of the investigator and considered by him/her to be caused by the IMP with a 
reasonable possibility, the investigator should report the event with immediate notification 
to the Monitoring Team. 
9.10.3 Obligations of the Sponsor  
During the course of the study, the Sponsor will report in an expedited manner all SAEs that are 
both unexpected and at least reasonably related to the IMP (SUSAR), to the Health Authorities, 
Institutional Review Boards (IRBs), Independent Ethics Committees (IEC) as appropriate and to 
the investigators. 
9.11 
PHARMACOKINETICS (PK)  
9.11.1 Sampling time   
Blood samples will be collected at the following times for the evaluation of teriflunomide PK in 
pediatric patients. Local anaesthetic must be offered for blood draws to minimize pain and 
discomfort. 
Table 3 - PK sampling times for teriflunomide concentrations during double-blind treatment period 
and open-label period  
Visit 
 
Dosing 
status 
Sampling Time 
Week 2, 3, 4, 8, 12, 24, 36 and 
EOT and overdose 
 
Pre-dose 
One PK sample:  approximately 5 minutes before IMP intake 
Time and date of the PK sample collection and time of last IMP intake 
recorded  
Post drug elimination (both visits) 
 
No dosing 
One PK sample is taken per visit to verify that plasma teriflunomide 
concentration is less or equal to 0.02 μg/mL. 
Date and time of the PK sample collection will be recorded 
EOT: End of treatment; IMP = investigational medicinal product; PK = pharmacokinetics. 
PK samples will be collected at Week 2, 3, and 4 (PK run-in [8 weeks] period); an additional 4th 
sample may be required in case of inadequate sampling or information/variability from 3 samples.  
Study nurse visit at patient’s home can be provided when PK sampling is not synchronized with 
routine or safety lab visit (W2, W3 or in the event the 4th sample is needed). 
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9.11.2 PK handling procedure  
Special procedures for collection, storage, and shipping of teriflunomide PK samples are 
described in the operational manual for handling samples to be sent by the Central Laboratory. An 
overview of PK handling procedures for teriflunomide PK samples is provided in Table 4. 
Table 4 - Pharmacokinetics handling for teriflunomide  
Sample type  
Teriflunomide 
Blood sample volume 
2 mL 
Anticoagulant 
Sodium heparin 
Blood handling procedures 
Keep whole blood on ice until harvest (must be within 30 minutes of sampling time) 
by centrifugation at approximately 1500-2000 g for approximately 10 minutes.  
Separate the plasma into a storage tube. 
Plasma storage conditions 
In 5 mL Sarstedt polypropylene, screw cap, flat base tube (Product Code 
No. 60.558 PP) (www.sarstedt.com) at -20°C. 
9.11.3 Bioanalytical method  
Teriflunomide PK samples will be assayed using a validated liquid chromatography method 
coupled with tandem mass spectrometry (LC-MS/MS) with a lower limit of quantification of 
0.01 µg/mL under the responsibility of Covance Bioanalytical Services, LLC, Indianapolis, IN, 
USA. 
9.11.4 Pharmacokinetic parameters  
An assessment of the adequacy of dosing will be done at the end of the PK run-in (8 weeks) 
phase. For each pediatric patient, teriflunomide Ctrough from Weeks 4, 8 and 12 will be used to 
calculate individual post hoc steady-state predicted PK parameters (Cmax and AUC0-24) using the 
PopPK model adapted to the pediatric population (POH0401). These predicted parameters will 
then be compared to the range (5th - 95th percentile) of the individual predicted PK parameters in 
adult patients after repeated doses of 7 mg. Adult range (5th - 95th percentile) of predicted 
PK parameters: 7 mg dose range for Cmax is 8.03 to 49.10 g/mL and for AUC0-24 is 184 to 
1160 g.h/mL. (POH0339; including data from studies TDR10892, 2001 EFC6049/TEMSO, 
EFC10891/TENERE and EFC10531/TOWER). 
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10 
STUDY PROCEDURES  
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 17.7. 
10.1 
VISIT SCHEDULE  
It is preferred that all study visits take place in the morning.  Visits can be performed on 
2 consecutive days when convenient. If a patient is prematurely discontinued from the study 
treatment, all EOT visit procedures should be performed.    
The visit schedule consists of the following visits: 
• Screening (Visit 1/Week -4) up to 4 weeks prior to the randomization visit (Visit 2). 
- 
No IMP is administered in this period. 
• Double-Blind Treatment period 
- 
Randomization (to either teriflunomide or placebo) at randomization (Visit 2), 
- 
Patients will be on the treatment period of the study for 96 weeks unless prematurely 
discontinued or switching to the open-label extension period, 
- 
Patients experiencing a relapse after the PK run-in period (8 weeks) and if confirmed 
by the Relapse Adjudication Panel (RAP) will have the option to continue in an open 
label teriflunomide treatment arm. If RAP does not confirm the relapse, the patient 
may continue in the double-blind treatment period or prematurely discontinue 
treatment, 
- 
Visit 3 (W4) to Visit 20 (W96/EOT), 
- 
For patients prematurely discontinued from treatment, Visit 20 (W96/EOT) procedures 
should be performed, 
- 
Clinical laboratories are performed in both routine study site visits and safety 
laboratory visits that are performed locally (see Section 1.2; two separate lines in the 
flowchart to indicate the different schedules), 
- 
In case of at least 5 new/enlarged T2 lesions at the MRI of Week 24, an additional 
MRI will be performed at Week 36. Then, in case of at least 9 new/enlarged T2 
lesions at Week 36 or at least 5 new/enlarged T2 lesions on each of the 2 consecutive 
MRI scans of Week 36 and Week 48, or at least 5 new/enlarged T2 lesions on each of 
the 2 consecutive MRI scans of Week 48 and Week 72, patients will have the option to 
continue in the open label period.  
• Post drug elimination follow up period (4 weeks)  
- 
No IMP is administered in this period, 
- 
Patients who complete the treatment period as well as patients who discontinue 
prematurely should be scheduled for 2 follow-up visits (Visit 21 and Visit 22), 
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- 
Patients will be taking non-IMP (either cholestyramine or activated charcoal) to 
accelerate the drug elimination process, starting immediately after IMP discontinuation 
(ie, the same day or the day after). 
10.1.1 Screening (Visit 1, Week-4)  
This visit is to be conducted up to 4 weeks prior to randomization (Visit 2). 
The following items will be checked/performed and recorded: 
• Informed consent/assent to be signed prior to all screening assessments 
- 
Patient must sign the assent form, 
- 
Patient’s legal guardian must sign the informed consent. 
• Eligibility by review of Inclusion/Exclusion criteria. 
• Demographic data. 
• Medical and surgical history, including: 
- 
Concurrent illnesses, 
- 
Detailed neurological history, 
- 
Detailed vaccination history. 
• Prior medications. 
• EDSS assessment. 
• Adverse event reporting. 
• Vital signs (BP, HR, body temperature and weight). 
• Physical examination. 
• Clinical laboratories 
- 
Hematology and differential panel, 
- 
Coagulation group panel, 
- 
Liver function panel, 
- 
Chemistry panel, 
- 
Pancreatic enzyme tests, 
- 
Urinalysis panel, 
- 
Pregnancy testing (β-HCG), 
- 
Tuberculosis test. 
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10.1.2 Randomization Visit (Visit 2) (to be randomly assigned either to teriflunomide or to 
placebo  
The following items will be checked/performed and recorded and then patients are randomized to 
either teriflunomide or placebo group: 
• Verification of eligibility by review of Inclusion/Exclusion criteria. 
• Prior medications. 
• Randomization via IVRS.  
• EDSS. 
• Symbol Digit Modalities Test (SDMT) and Cognitive battery test. 
• Brain MRI (can be performed anytime between Visit 1 and Visit 2) A previous MRI 
performed in the 6 weeks preceding randomization could be acceptable if performed 
according to the specifications for this study.  
• Adverse event reporting. 
• Vital signs (BP, HR, body temperature, height and weight). 
• Physical examination, including Tanner assessment.  
NOTE: Tanner can be performed either at the study site or by pediatricians independent of the study clinic.  This 
examination can be done at Visit 2 or shortly after Visit 2 and it is independent of criteria for randomization. 
• 12-lead ECG. 
• Pregnancy testing (β-HCG). 
• Clinical laboratories (including immunoglobulins and TSH). 
• Concomitant medications. 
• Dispensing study medication. 
10.1.3 Visits during the double-blind treatment period  
10.1.3.1 Assessments performed for all clinic visits  
• Adverse event reporting. 
• Concomitant medications. 
• Vital signs (BP, HR, body temperature and weight); height only at the Visit 2 and EOT 
visit. 
• Accountability/compliance. 
10.1.3.2 Assessments performed on the clinic visits specified  
• Dispense study medication: Week 8, 12 and every 12 weeks.  
• EDSS: Every 24 weeks.  
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• SDMT: Every 24 weeks.  
• Laboratory routine parameters at Weeks 4, 12, 24, 36, 48 then every 12 weeks. 
• Β-HCG every 12 weeks. 
• Immunoglobulins and TSH every 24 weeks. 
• Physical examinations: Week 12, then every 12 weeks. 
• Tanner Staging at Week 24, 48, 72 (until complete sexual maturity defined by Tanner 
Stage 5). 
• Pre- and post- dose plasma PK sampling: Weeks 2, 3, 4, 8, 12, 24, 36.  
• Brain MRI: Weeks 24, 48, 72 and 36 if necessary. 
• 12-lead ECG:  Baseline and at EOT or premature treatment discontinuation. 
10.1.3.3 Safety laboratories performed in between clinic visits  
Safety laboratory visits will be scheduled in between clinic visits. At Weeks 8, 16, 20, 30 and then 
every 12 weeks until the end of the treatment (EOT), the following safety laboratory testing will 
be conducted: 
• Measuring hematology and differential panel (as above). 
• Liver function tests (ALT, AST, GGT, total bilirubin, and direct/indirect bilirubin). 
• Pancreatic enzymes (serum amylase and lipase). 
Study nurse visit at patient’s home can be provided (except at Week 8).  
Safety laboratory visits, with prior documented study site approval, may be collected at a qualified 
blood testing center more convenient to the patient’s travel needs.  The samples will be sent by the 
test center to the Central laboratory.  Safety blood samples may only be analyzed at the test center 
(ie, local laboratory) in exceptional cases where a patient requires emergency treatment involving 
the need of immediate laboratory results or where centralized analysis is not possible. 
10.1.3.4 Assessments performed on the EOT or premature treatment discontinuation  
Patients who complete the treatment period or who prematurely discontinue should complete EOT 
procedures including both safety and efficacy assessments. This visit does not need to be 
performed when the patient switches to the open label period after a confirmed relapse or high 
MRI activity (as per protocol criteria).  Prematurely discontinued patients are encouraged to 
participate in an early permanent treatment discontinuation (EPTD): they will be followed for 
safety until they complete 96 weeks from randomization. This includes discontinuation from the 
open label period, when it occurs within 96 weeks of randomization. 
• EDSS. 
• SDMT. 
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• Cognitive Battery Test. 
• Brain MRI. 
• Adverse event reporting. 
• Vital signs. 
• Physical examination. 
• ECG 12-leads. 
• Tanner staging. 
• Clinical routine laboratories (including immunoglobulins and TSH). 
• Concomitant medication. 
• Accountability / compliance. 
• Teriflunomide PK sampling. 
Post drug elimination process (ie, prescribing Cholestyramine or Activated charcoal and 
scheduling for two follow up visits) should be initiated. 
10.1.3.5 Assessments performed on the unscheduled relapse visits  
At each evaluation of a potential relapse, the following procedures will be performed. The 
procedures should be performed in the order in which they appear: 
1.  Patients or parents/guardians must call the study site within 48 hours of symptom onset to 
report any symptoms that suggest a possible relapse and present for evaluation. All calls to 
the site reporting a possible relapse should be recorded in a call log maintained at the site as 
part of source documentation.  
2.  Patient should be evaluated at the site within 7 days of onset of neurological symptoms.  
3.  Blinded rater performs examination to document the Functional System Scores (FSS) and 
EDSS, with no reference to previous scores. Conversation between the rater and patient 
should elicit only the minimum historical information needed to complete these tasks.  
4.  Treating Neurologist or designee obtains vital signs, and takes a history of recent symptoms. 
A blinded rater may NOT serve as designee for the Treating Neurologist.  
5.  Supportive laboratory testing, as indicated, is performed. 
6.  Treating Neurologist completes Clinical Event source documents. Treating Neurologist also 
determines whether there is a fever or other disqualifying event.  
7.  If the Treating Neurologist determines treatment for relapse or other clinical event is 
warranted, treatment can be initiated after the blinded rater’s assessment is complete, 
regardless of whether the event is RAP-confirmed.  
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Information on all suspected relapses occurring during the double-blind period will be also 
assessed by a Relapse Adjudication Panel (RAP) in real time.  
Treating neurologists do not need to wait for RAP-confirmation to initiate treatment that he or she 
deems necessary, including corticosteroid treatment for suspected relapses.  
The following will also be checked/ performed and recorded: 
• Adverse events. 
• Concomitant medications. 
• Vital signs (BP, HR, body temperature and weight). 
• Time and date of last dose prior to the visit.  
• If the patient has had a RAP confirmed relapse: signing the informed consent/assent form 
in order to continue in the study. 
• The appointment for the next scheduled clinic visit and safety laboratory visit, if 
appropriate, will be confirmed. 
10.1.4 Post drug elimination follow up visits  
Two post-washout follow up visits should be scheduled 2 weeks and 4 weeks after study 
medication discontinuation and initiation of the washout procedure. These visits are not required 
in case the patient receives commercial product immediately after the study end. 
The following items will be checked/performed and recorded at Visit 21 (EOT+2W) and Visit 22 
(EOT+4W): 
• Adverse events reporting. 
• Concomitant medications. 
• Vital signs (BP, HR, body temperature and weight). 
• Physical examination at EOT + 2 Weeks only. 
• ECG should be performed only for patients who had new abnormalities on the EOT ECG. 
• Clinical safety laboratories 
- 
Hematology and differential panel, 
- 
Liver function panel, 
- 
Pancreatic enzyme tests, 
- 
Uric acid and inorganic phosphorus. 
• Post-washout PK sampling (note that the EOT+4W PK sample should be taken even if the 
EOT+2W PK sample is under 0.02 µg/mL, to document stability level as per EU SmPC). 
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In case of adverse events AE/abnormal laboratory values, or teriflunomide level > 0.02 µg/mL 
after the elimination treatment, follow up until resolution should be planned. 
10.1.5 Open Label Period  
Procedures are described in the specific flow chart Section 1.3, Section 1.4, Section 1.5, and in 
Section 17.7. 
10.1.6  Optional additional extension period for young patients   
During the optional additional extension period for young patients, the study visits will be 
performed every 24 weeks and will include the followings: 
• AE reporting. 
• Concomitant medications. 
• Brain MRI (every year). No central reading for MRI is planned in the optional additional 
extension period. 
• Routine neurological exams, vital signs, and physical examinations as per local practice. 
• Clinical laboratories: standard liver function tests and hematology tests to be performed 
every 6 weeks (specific panel to be decided by Investigator).  These tests will be 
performed in local laboratories. Clinically relevant abnormalities should be reported as 
TEAEs (see Section 9.10.2.1). Other data will not be entered in CRFs. 
In addition, all centralized activities will be suspended. Laboratory tests will no longer be 
performed except at the end of treatment visit (EOT). Safety laboratory test may be performed at 
any time during the study based on signs and symptoms. These tests will be performed at a local 
facility. Potential additional local requirements for laboratory monitoring should be taken into 
account.  
10.2 
DEFINITION OF SOURCE DATA  
Source documents are defined as original documents, data, and records.  This includes, but is not 
limited to the following: hospital records, clinic and office charts, study-specific source document 
worksheets including Neurostatus-EDSS worksheets, phone logs, memoranda, evaluation 
checklists, laboratory requisitions and reports, abdominal ultrasound reports and images, 
abdominal CT scans and/or MRI, local lab reports (if applicable), medication dispensing records, 
patient questionnaires, computer printouts, electronic data/information sources including 
IVR/IWR notifications, and any other documentation regarding the patient. 
10.3 
HANDLING OF TEMPORARY OR PERMANENT TREATMENT DISCONTINUATION 
AND OF PATIENT STUDY DISCONTINUATION  
The IMP should be continued whenever possible. In case the IMP is stopped, it should be 
determined if it could be temporarily or permanent. 
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Temporary IMP discontinuation may be considered by the Investigator because of suspected AEs 
or disruption of the clinical trial due to a regional or national emergency declared by a 
governmental agency (Section 17.7). For all temporary intervention discontinuations, duration 
should be recorded by the Investigator in the appropriate pages of the CRF or eCRF.  
10.3.1 Temporary treatment discontinuation with investigational medicinal product(s)  
Re-initiation of treatment with the IMP will be done under close and appropriate clinical/and or 
laboratory monitoring once the Investigator will have considered according to his/her best medical 
judgment that the responsibility of the IMP in the occurrence of the concerned event was unlikely 
and if the selection criteria for the study are still met (see Section 6.2 and Section 6.3). 
All temporary treatment discontinuation and date of treatment re-initiation should be recorded by 
the Investigator in the appropriate pages when considered as confirmed. 
10.3.2 Definitive treatment discontinuation with investigational medicinal product(s)  
All patients who prematurely and permanently discontinue study medication will be asked to 
continue until the planned end of the double-blind treatment period EPTD.  After completion of 
the premature discontinuation visit (EOT) and the post drug elimination follow-up visits, the 
patients continue to have study visits approximately every 12 weeks for clinical follow-up 
including EDSS, relapse reporting, AE reporting and Concomitant Medications recording. 
In a specific emergency, participants who are close to the end of treatment may be unable to 
continue their final treatment as scheduled. These patients would be considered to have 
permanently discontinued their treatment (Section 17.7). 
10.3.2.1 List of criteria for definitive treatment discontinuation  
The patients discontinue from study treatment if the patients/parents/guardians decide to do so, at 
any time and irrespective of the reason or the investigator may decide that it is best for the patient 
to stop treatment. 
Study medication will be discontinued and the washout procedure will be performed after any of 
the following events: 
Safety 
• If acute, potentially life-threatening cytopenias develop.   
• If severe bullous skin reactions develop.  As soon as skin or mucosal reactions are 
observed which raise the suspicion of such severe reactions. 
• A SGPT/ALT >3-fold ULN must be repeated within 48 hours.  In the event of a confirmed 
value of >3- fold ULN, study medication should be discontinued and subject monitored 
until the value normalizes. 
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• A SGPT/ALT between 2 and 3-fold ULN associated with any of the following signs and 
symptoms including fever, rash, abdominal pain, dark urine, light stools. 
• A serum amylase and/or lipase >2-fold ULN associated with symptoms consistent with 
pancreatitis (eg, abdominal pain, back pain, nausea and vomiting, fever, sweating) or 
serum amylase and/or lipase >5-fold ULN with or without associated symptoms. 
• Abdominal CT scan or MRI findings consistent with chronic pancreatitis.  A washout 
procedure will be initiated following discontinuation. 
• If a drug-related peripheral neuropathy is diagnosed. 
• If pulmonary toxicity is diagnosed. 
• If a patient is found to be HIV positive. 
Other 
• If a female patient becomes pregnant or wishes to become pregnant during the study (if a 
female patient confirms plans to continue the pregnancy). 
• If a male patient wishes to father a child during the study. 
10.3.2.2 Handling of patients after definitive treatment discontinuation  
Patients will be followed up according to the study procedures up to the scheduled date of study 
completion (96 weeks from randomization), or up to recovery or stabilization of a followed-up 
AE, whichever comes last. 
If possible, all patients who prematurely and permanently discontinue study medication will be 
asked to perform EOT visit procedures and will be scheduled for post drug elimination visits.  
Wash-out medications should be prescribed (Cholestyramine or Activated charcoal, see 
Section 9.9). All definitive treatment discontinuation should be recorded by the Investigator in the 
appropriate eCRF pages when considered as confirmed. 
10.3.3 Procedure for withdrawal of patients from study follow-up schedule  
The patients may withdraw from the study if they decide to do so, at any time and irrespective of 
the reason. 
All study withdrawals should be recorded by the Investigator in the appropriate eCRF pages when 
considered as confirmed; 
For patients who fail to return to the site, the Investigator should make the best effort to re-contact 
the patient (eg, contacting patient’s family or private physician, review available registries or 
health care database), and to determine his/her health status, including at least his/her vital status. 
Attempts to contact such patients must be documented in the patient’s records (eg, times and dates 
of attempted telephone contact, receipt for sending a registered letter).  
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Patients who did not complete the study and for whom no end-of-treatment data are available will 
be considered as lost to follow-up. 
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11 
STATISTICAL CONSIDERATIONS  
The data from the placebo-controlled and the open label teriflunomide treatment phases will be 
the focus of the CSR of their respective phase. The following statistical methods/considerations 
relate to the analysis of the data from the placebo-controlled period. The data from the open label 
teriflunomide treatment arm are non-controlled and supportive in nature; summary statistics will 
be provided for each of the efficacy variables and safety data. For the optional additional 
extension period for young patients, the efficacy and safety data will be summarized by 
descriptive statistics and reported separately. 
11.1 
DETERMINATION OF SAMPLE SIZE  
The sample size calculation is based on the primary efficacy endpoint, time to first confirmed 
relapse after randomization.  Assuming 60% of placebo patients will experience a relapse by 
2 years, 165 children aged 10 to <18 years (110 teriflunomide and 55 placebo; including 
approximately 20% pre-pubertal patients or 10% of patients under the age of 13 years at time of 
inclusion into the study and at least 25% male patients) are needed for 80% power to detect a 
hazard ratio (teriflunomide versus placebo) of 0.5 (2-sided alpha 0.05).  The 2-year rate of relapse 
in the teriflunomide group would be 36.8% and the corresponding hazard rates, assuming the 
time-to-relapse is exponentially distributed with a constant hazard rate, would be 0.4581 for 
placebo and 0.2291 for teriflunomide.  The sample size is adjusted assuming 20% of patients 
discontinue the study in 2 years due to reasons other than relapse.  Calculations are performed 
using nQuery Advisor 7. 
The assumption for the percentage of placebo patients with relapse at 2 years is based on the 
combined data from the completed Phase III monotherapy adult studies (EFC6049/TEMSO and 
EFC10531/TOWER), where 58.7% of placebo patients aged ≤30 (n=167) experienced at least 
1 relapse in a 2-year treatment period.  Of note, the corresponding percentage was 38.7% in the 
163 patients aged ≤30 treated with teriflunomide 14 mg. 
11.2 
DISPOSITION OF PATIENTS  
Screened patients are defined as any patient who met the inclusion criteria and where signed 
informed consent/assent was obtained from the patient and patient’s legal representative (parents 
or guardians) according to local regulations. 
Randomized patients consist of all patients, who have been allocated a treatment kit through the 
study randomization process, ie, with a treatment kit number allocated and recorded in the 
IVRS/IWRS database, regardless of whether the treatment kit was used or not. 
Patients treated without being randomized will not be considered as randomized and will not be 
included in any efficacy population. Their safety experience will be reported separately, and these 
patients will not be in the safety population. 
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For any patient randomized more than once, only the data associated with the first randomization 
will be used in any analysis population. The safety experience associated with any later 
randomization will be assessed separately. 
11.3 
ANALYSIS POPULATIONS  
The randomized population includes any patient who has been allocated to a randomized 
treatment regardless of whether the treatment kit was used or not.  
11.3.1 Efficacy populations  
11.3.1.1 Intent-to-treat (ITT) population  
The analysis population for efficacy endpoints will be the ITT population, defined as all 
randomized patients who receive at least 1 dose of study medication, analyzed according to the 
treatment allocated by randomization.  
11.3.2 Safety population  
The analysis population for safety endpoints will be the safety population, defined as all 
randomized patients exposed to study medication, regardless of the amount of treatment 
administered. The safety analyses will be conducted according to the treatment patients actually 
received. 
In addition: 
• Nonrandomized but treated patients will not be part of the safety population, but their 
safety data will be presented separately. 
• Randomized patients for whom it is unclear whether they took the study medication will 
be included in the safety population as randomized. 
• For patients receiving both study medications during the trial, the treatment group 
allocation for as-treated analysis will be teriflunomide treatment. 
11.3.3 Pharmacokinetic population  
The PK population is a subset of the safety population containing patients who have at least one 
PK sample taken. Patients will be analyzed in the treatment group corresponding to the treatment 
actually received as defined for the safety population. 
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11.4 
STATISTICAL METHODS  
11.4.1 Extent of study treatment exposure and compliance  
The extent of study treatment exposure and compliance will be assessed and summarized by 
actual treatment received within the safety population. 
11.4.2 Extent of investigational medicinal product exposure  
Duration of IMP exposure is defined as:  last dose date – first dose date + 1 day, regardless of 
unplanned intermittent discontinuations. The distribution of treatment duration will be 
summarized by treatment group using descriptive statistics. 
11.4.3 Compliance  
A given administration will be considered noncompliant if the patient did not take the planned 
dose of treatment as required by the protocol. No imputation will be made for patients with 
missing or incomplete data. 
Treatment compliance, above-planned and under-planned dosing percentages will be summarized 
descriptively (N, Mean, SD, Median, Min, and Max). The percentage of patients with compliance 
<80% will be summarized. In addition, the number and percentage of patients with at least 
1 above-planned dosing administration will be given, as well as the number and percentage of 
patients with 0, (0, 20%], and >20% under-planned dosing administrations. 
11.4.4 Analyses of efficacy endpoints  
11.4.4.1 Analysis of primary efficacy endpoint(s)  
Main statistical model and adjustment for covariates: 
Time to first relapse will be analyzed using a log-rank test with time to first relapse as the 
dependent variable, treatment group as a test variable, and region and pubertal status as covariates. 
The first RAP confirmed relapse, occurring from randomization (including relapses during the PK 
run-in (8 weeks) phase) to the end of the randomized, placebo-controlled study treatment period, 
will be included for analysis. Treatment effect as measured by the hazard ratio and its associated 
95% confidence interval will be estimated using a Cox proportional-hazards model with factors 
for treatment group, region, pubertal status, age, and number of relapses in the year prior to 
randomization.  Statistical significance will be claimed for the primary endpoint if the p-value for 
the 2-sided log-rank test is ≤0.05. 
Handling of dropouts: 
Given the time to event analysis methodology, there is no impact on the analysis of the primary 
endpoint for patients experiencing a first relapse and moving to the open label teriflunomide 
treatment.  Patients discontinuing double-blind treatment due to high MRI activity will be 
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censored at discontinuation. Patients who prematurely discontinue the study drug will be 
encouraged to continue study follow-up as planned according to the study flowchart.  The main 
analysis for time to first relapse will include relapses during the placebo-controlled study 
treatment period.  Relapses reported after study drug discontinuation (for non-relapse reason) will 
be included in a supportive analysis. 
Sensitivity analysis: 
The following sensitivity analyses for the primary endpoint will be performed using the similar 
log-rank test and Cox proportional-hazards model as described above. 
• Time to first confirmed relapse occurring after the PK run-in (8 weeks) phase but before 
the treatment discontinuation. The patients who have a relapse during the PK run-in 
(8 weeks) phase will be included in the analysis with the time to first relapse right 
censored at the time of treatment discontinuation.  
• Time to first relapse (confirmed or not) after randomization during the study treatment.  
• Time to first confirmed relapse including relapses during the PK run-in (8 weeks) phase 
and relapses reported after the study drug discontinuation and up to 96 weeks after 
randomization. 
• Time to first confirmed relapse including high MRI activity meeting criteria for switching 
into open-label period as an equivalent to confirmed relapse event. 
Subgroup analysis: 
Subgroup analyses will be performed for the primary efficacy endpoint. The results will be 
presented for demographic (eg, pubertal status, age, sex, race) and other (eg, MS history, region) 
subgroups. One of these analyses will include patients with relapsing-remitting form of MS versus 
other forms. The detailed information will be provided in the Statistical Analysis Plan (SAP). 
11.4.4.2 Analyses of secondary efficacy endpoints  
The proportion of patients relapse-free at Weeks 24, 48, 72 and 96 will be estimated based on 
Kaplan-Meier methods. Interval estimates will be calculated using 95% point wise confidence 
intervals. 
The number of new or enlarged T2-lesions per MRI scan will be analyzed using a negative 
binomial regression model. The model will include the total number of new or enlarged 
T2-lesions as the response variable, with treatment group, region, pubertal status and age as 
covariates. In order to account for different numbers of MRI scans performed among patients, the 
log-transformed number of scans will be included in the model as an offset variable. The 
estimated number of lesions per scan and associated 2-sided 95% CI will be provided for each 
treatment group. The relative risk, 2-sided 95% confidence interval (CI) and p-value will be 
provided for comparing teriflunomide to placebo. 
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The number of T1 Gd-enhancing lesions per MRI scan and the number of new T1 hypointense 
lesions per MRI scan will be analyzed using a similar negative binomial regression model as 
described above for T2 lesions. 
To reduce the impact of potential outliers, an ordinal logistic regression model including treatment 
group, region, pubertal status and age will also be used to analyze these endpoints.  The following 
categories for the number of lesions, 0, 1, 2, 3-4 and ≥5, are considered and will be further defined 
in the SAP. 
A Poisson regression model with a robust error variance will be used in sensitivity analyses. 
Change from baseline in volume of T2 lesions, T1 hypointense lesions and brain atrophy will be 
analyzed using a mixed-effect model with repeated measures (MMRM) approach with appropriate 
transformation if necessary. The proportion of patients free of new or enlarged T2-lesions at 
Weeks 48 and 96 will be summarized based on all patients having an MRI at these time points.   
More details will be provided in the SAP. 
The change from baseline in cognitive outcomes at each visit will be analyzed descriptively. 
11.4.4.3 Multiplicity considerations  
Statistical significance will be claimed for the primary efficacy endpoint if the computed p-value 
from the primary analysis is ≤0.05.  No multiplicity adjustment is considered for secondary 
efficacy outcomes for this study. 
11.4.5 Analyses of safety data  
The summary of safety results will be presented by treatment group.  Analysis of safety will be 
performed using the safety population. Safety data in patients who do not belong to the safety 
population (eg, exposed but not randomized) will be listed separately, as appropriate. 
The safety analysis will be based on the reported AEs and other safety information including 
clinical laboratory data, vital signs and ECG data. The baseline value is defined as the last 
available value before the first intake of IMP. 
The observation periods for safety during the 96-week double-blind period will be as follows: 
• Screening Period is from informed consent to first dose of IMP. 
• Treatment-emergent adverse event (TEAE) period is defined as from first dose of IMP up 
to 4 weeks (28 days) after last dose of IMP or up to inclusion in open label treatment 
phase, whichever occurs first. The TEAE period can be divided into 2 distinct periods: 
- 
Treatment Period from first dose of IMP to last dose of IMP,  
- 
Accelerated elimination period from 1 day after treatment period up to 4 weeks 
(28 days) after last dose of IMP or up to inclusion in open label treatment phase, 
whichever occurs first. 
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• The post-treatment period is from the day after the TEAE period to the end of the 96-week 
double-blind period, where applicable. 
All safety analyses will adhere to sanofi “Guideline for the Analysis and Reporting of Safety Data 
from Clinical Trials”. 
Adverse events: 
Pre-treatment, treatment-emergent, and post-treatment AEs are defined as AEs that developed or 
worsened during the screening, TEAE, and post-treatment observation periods.  TEAEs will be 
further differentiated as "TEAEs during treatment period" and "TEAEs during accelerated 
elimination period". 
The analysis will focus on TEAEs. TEAEs during treatment period and TEAEs during accelerated 
elimination period will be analyzed separately and combined, as applicable. Proportion of patients 
with at least one TEAE, treatment emergent SAE, TEAE leading to discontinuation, and 
treatment-emergent AEs of special interest will be tabulated by treatment group. In addition 
TEAEs will be described according to maximum intensity and relation to the study medication. 
Non treatment emergent serious AE will be summarized separately. 
Adverse event incidence tables will present by system organ class (SOC) (sorted by 
internationally agreed order), high-level group term (HLGT), high level term (HLT) and preferred 
term (PT) sorted in alphabetical order for each treatment group, the number (n) and percentage 
(%) of patients experiencing an AE. Multiple occurrences of the same event in the same patient 
will be counted only once in the tables within a treatment phase. The denominator for 
computation of percentages is the safety population within each treatment group. 
Patient data listings will be provided for all AEs, TEAEs, SAEs, deaths (if any) and AEs leading 
to treatment discontinuation. 
Clinical laboratory evaluation: 
The analysis of laboratory data will focus on descriptive statistics and summaries of potentially 
clinically significant abnormalities (PCSA) and Common Terminology Criteria for Adverse Event 
(CTCAE) abnormalities based on data from the treatment emergent period. For each parameter, 
results and changes from baseline will be summarized by treatment group for baseline and each 
post baseline time point, endpoint, minimum and maximum value. Summary statistics will include 
number of patients, mean, standard deviation, median, Q1, Q3, minimum and maximum. The 
proportion of patients who had at least one incidence of PCSA/CTCAE at any time during the 
TEAE period, treatment period, and accelerated elimination period will be summarized by 
treatment group. Listings will be provided with flags indicating clinically out-of range values, as 
well as PCSA values. 
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Drug-Induced Liver Injury: 
The liver function tests, namely, ALT, AST, alkaline phosphatase and total bilirubin are used to 
assess possible drug induced liver toxicity. The proportion of patients with PCSA/CTCAE values 
at any post-baseline visit by baseline status will be displayed by treatment group for each 
parameter. The proportion of patients with PCSA values at any post baseline visit will also be 
displayed by duration of exposure for each treatment group. 
Time to onset of the initial ALT and AST elevation (>3 x ULN) and total bilirubin elevation 
(>2 x ULN) will be analyzed for each parameter using Kaplan-Meier estimates, presented by 
treatment group. A graph of distribution of peak values of ALT versus peak values of total 
bilirubin will also be presented. Note that the ALT and total bilirubin values are presented on a 
logarithmic scale. The graph will be divided into 4 quadrants with a vertical line corresponding to 
3 x ULN for ALT and a horizontal line corresponding to 2 x ULN for total bilirubin. 
The normalization (to ≤1 ULN) of elevated liver function tests will be summarized by categories 
of elevation (3 x, 5 x, 10 x, 20 x ULN for ALT and AST, 1.5 x ULN for alkaline phosphatase, and 
1.5 x and 2 x ULN for total bilirubin), with the following categories of normalization: never 
normalized, normalized before permanent discontinuation of study drug, and normalized after 
permanent discontinuation of study drug. Note that a patient will be counted only under the 
maximum elevation category. 
The incidence of liver related TEAEs will be summarized by treatment group. The selection of 
preferred terms will be based on standardized MedDRA query (SMQ) Drug related hepatic 
disorders – comprehensive search (narrow). 
Vital signs and ECG: 
The analysis of vital signs and ECG will focus on descriptive statistics and summaries of PCSA 
and outliers based on data from the treatment emergent period. For each parameter, results and 
changes from baseline will be summarized by treatment group for baseline and each post baseline 
time point, endpoint, minimum and maximum value. Summary statistics will include number of 
patients, mean, standard deviation, median, Q1, Q3, minimum and maximum. 
The proportion of patients who had at least one incidence of PCSA/outlier at any time during the 
TEAE period, treatment period, and accelerated elimination period will be summarized by 
treatment group. Listings will be provided with flags indicating clinically out-of range values, as 
well as PCSA values. 
Other safety variables: 
Patients with peripheral neuropathy finding or abdominal ultrasound findings during the treatment 
emergent period will be summarized by treatment group using counts and percents. 
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11.4.6 Analyses of pharmacokinetic and pharmacodynamic variables  
Teriflunomide plasma concentrations will be summarized by mean, SD, geometric mean, 
coefficient of variation, median, minimum, and maximum at each visit where a PK sample is 
taken for teriflunomide-treated patients.  
If date and/or time of the drug intake and/or sampling are missing then the concentration will not 
be taken into account. Where concentration values are below the lower limit of quantification 
(LLOQ), one-half of the LLOQ will be used. 
Teriflunomide individual post hoc predicted PK parameters (Cmax and AUC0-24) will be 
summarized by mean, SD, geometric mean, coefficient of variation, median, minimum, and 
maximum at each visit of the PK run-in (8 weeks) phase(s) for teriflunomide-treated patients.  
Values will be expressed in the tables with no more than three significant figures. 
11.4.7 Analyses of quality of life/health economic variables  
Not applicable. 
11.5 
INTERIM ANALYSIS  
No formal interim efficacy analysis of the double-blind treatment period is planned. A Data 
Monitoring Committee (DMC), independent from the Sponsor and Investigators, will monitor and 
review all relevant data on a regular basis for the assessment of benefit versus risk and provide 
recommendations about further continuation of the trial. 
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12 
ETHICAL AND REGULATORY STANDARDS  
12.1 
ETHICAL PRINCIPLES  
This Clinical Trial will be conducted in accordance with the principles laid down by the 18th 
World Medical Assembly (Helsinki, 1964) and all applicable amendments laid down by the 
World Medical Assemblies, and the ICH guidelines for Good Clinical Practice (GCP). 
In compliance with sanofi public disclosure commitments, this clinical trial will be recorded in the 
public registry website clinicaltrials.gov before the enrollment of the first patient. The registry 
will contain basic information about the trial sufficient to inform interested patients (and their 
healthcare practitioners) how to enroll in the trial. 
12.2 
LAWS AND REGULATIONS  
This Clinical Trial will be conducted in compliance with all international guidelines, and national 
laws and regulations of the country(ies) in which the Clinical Trial is performed, as well as any 
applicable guidelines (Section 13). 
12.3 
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 (and the 
parent[s] or guardian[s]) of all pertinent aspects of the Clinical Trial including the written 
information giving approval/favorable opinion by the Ethics Committee (IRB/IEC). 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 written Informed Consent Form should 
be signed, name filled in and personally dated by the patient or by the patient’s legally acceptable 
representative, and by the person who conducted the informed consent discussion. Local law must 
be observed in deciding whether one or both parents/guardians consent is required. If only one 
parent or guardian signs the consent form, the Investigator must document the reason for only one 
parent or guardian’s signature. A specific Informed Consent Form will be obtained before 
entering into the optional additional extension period for young patients. 
A copy of the signed and dated written Informed Consent Form will be provided to the patient.  
If informed consent is obtained under special circumstances (emergency, from a guardian, minor, 
etc.), the method should be specified following the ICH requirements. The first part of the section 
should be adapted, keeping the point as appropriate. 
The Informed Consent Form and the Assent Form 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/IEC) for approval/favorable opinion. 
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The Investigator (according to applicable regulatory requirements), or a person designated by the 
Investigator, should fully inform the patient (and the parent[s] or guardian[s]) of all pertinent 
aspects of the clinical trial including the written information given approval / favorable opinion by 
the Ethics Committee (IRB/IEC). All participants should be informed to the fullest extent possible 
about the study in language and terms they are able to understand. 
In addition, participants will assent as detailed below or will follow the Ethics Committee 
(IRB/IEC) approved standard practice for pediatric participants at each participating center (age of 
assent to be determined by the IRB’s/IEC’s or be consistent with the local requirements): 
Participants who can read the Assent Form will do so before writing their name and dating or 
signing and dating the form. 
Participants who can write but cannot read will have the assent form read to them before writing 
their name on the form. 
Participants who can understand but who can neither write nor read will have the assent form read 
to them in presence of an impartial witness, who will sign and date the Assent form to confirm 
that assent was given. 
The Informed Consent Form and the Assent Form 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/IEC) for approval / favorable opinion. 
In relation with the population of patients exposed in the trial ie, pediatric/minor patients, the 
IRB/IEC should ensure proper advice from specialist with pediatrics expertise (competent in the 
area of clinical, ethical and psychosocial problems in the field of pediatrics) according to national 
regulations. This should be documented. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 17.7. 
12.3.1 Assent for patients  
An assent is to be signed by children and adolescents 10-below 18 years of age, also for the 
optional additional extension period.  The language for assent is age appropriate for participants to 
understand the clinical trial. 
12.3.2 Assent for optional neurofilament assessment  
A dedicated informed consent form (ICF) will be prepared for the use of leftover mandatory PK 
samples for optional exploratory research and will be submitted to the appropriate Ethics 
Committee (IRB/IEC) for approval/favorable opinion.  The Investigator or authorized designee 
will explain to each participant/parents the objectives and conditions of the exploratory research. 
Participants will be told that they are free to refuse to participate (without impact on study 
participation) and may withdraw their consent at any time and for any reason during the storage 
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period. A separate signature will be required to document a participant's agreement to allow any 
remaining specimens to be used for exploratory research.  
12.4 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC)  
As required by local regulation, the Investigator or the Sponsor must submit this Clinical Trial  to 
the appropriate Ethics Committee (IRB/IEC), 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 
Ethics Committee (IRB/IEC) composition. 
The Clinical Trial (study number, Clinical Trial  title and version number), the documents 
reviewed (Clinical Trial , Informed Consent Form, Investigator’s Brochure, Investigator’s 
curriculum vitae [CV], etc.) and the date of the review should be clearly stated on the written 
(IRB/IEC) approval/favorable opinion. 
IMP will not be released at the study site and 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 should be 
submitted to the Ethics Committee (IRB/IEC) before implementation, unless the change is 
necessary to eliminate an immediate hazard to the patients, in which case the IRB/IEC should be 
informed as soon as possible. It 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 Ethics Committee (IRB/IEC). 
A progress report is sent to the Ethics Committee (IRB/IEC) at least annually and a summary of 
the Clinical Trial’s outcome at the end of the Clinical Trial. 
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13 
STUDY MONITORING  
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S)  
The Investigator(s) and delegated Investigator staff undertake(s) to perform the Clinical Trial in 
accordance with this Clinical Trial, ICH guidelines for Good Clinical Practice and the applicable 
regulatory requirements. 
The Investigator is required to ensure compliance with all procedures required by the Clinical 
Trial 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 
(with the help of the CRF, Discrepancy Resolution Form [DRF] or other appropriate instrument) 
in an accurate and legible manner according to the instructions provided and to ensure direct 
access to source documents by 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 Sub-
Investigators to assist in the conduct of the Clinical Trial in accordance with the Clinical Trial. All 
Sub-Investigators shall be appointed and listed in a timely manner. The Sub- Investigators will be 
supervised by and work under the responsibility of the Investigator. The Investigator will provide 
them with a copy of the Clinical Trial and all necessary information. 
13.2 
RESPONSIBILITIES OF THE SPONSOR  
The Sponsor of this Clinical Trial is responsible to Health Authorities for taking all reasonable 
steps to ensure the proper conduct of the Clinical Trial as regards ethics, Clinical Trial 
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 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, AEPM 
documentation and reporting, AE documentation, IMP allocation, patient compliance with the 
IMP regimen, IMP accountability, concomitant therapy use and quality of data. 
 
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13.3 
SOURCE DOCUMENT REQUIREMENTS  
According to the ICH guidelines for Good Clinical Practice, the Monitoring Team must check the 
CRF entries against the source documents, except for the pre-identified source data directly 
recorded in the CRF. The Informed Consent Form will include a statement by which the patient 
allows the Sponsor’s duly authorized personnel, the Ethics Committee (IRB/IEC), 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 maintain the confidentiality of all personal 
identity or personal medical information (according to confidentiality and personal data protection 
rules). 
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality such as 
Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), methods, 
responsibilities and requirements, including handling of noncompliance issues and monitoring 
techniques (central, remote, or on-site monitoring) are provided in separate study documents. 
Study monitors will perform ongoing source data verification to confirm that data entered into the 
eCRF by authorized site personnel are accurate, complete, and verifiable from source documents; 
that the safety and rights of participants are being protected; and that the study is being conducted 
in accordance with the currently approved protocol and any other study agreements, ICH GCP, 
and all applicable regulatory requirements. 
13.4 
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 information to be modified must not be overwritten. The 
corrected information will be transcribed by the authorized person next to the previous value, 
initialed and dated. 
Should a correction be made, the corrected information will be entered in the e-CRF overwriting 
the initial information. An audit trail allows identifying the modification.  
Description of the collection of the e-CRF (visit by visit or other). 
Data are available within the system to the Sponsor as soon as they are entered in the e-CRF. 
The computerized handling of the data by the Sponsor after review of the e-CRFs may generate 
additional requests (DRF) to which the Investigator is obliged to respond by confirming or 
modifying the data questioned. The requests with their responses will be appended to the CRFs 
held by the Investigator and the Sponsor. 
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The computerized handling of the data by the Sponsor when available in the eCRF may generate 
additional requests (DRF) 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 
e-CRF. 
13.5 
USE OF COMPUTERIZED SYSTEMS  
Computerized systems used during the different steps of the study are: 
• For data management activities, described in operational manual. 
• For pharmacokinetic activities, NONMEM® computer program. 
• For statistical activities, SAS. 
• For pharmacovigilance activities, AEGIS. 
• For monitoring activities, IMPACT 14. 
• For medical writing activities, VEEVA VAULT RIM. 
External data loading is planned for this clinical trial. 
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14 
ADMINISTRATIVE EXPECTATIONS  
14.1 
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. 
14.2 
RECORD RETENTION IN STUDY SITES  
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. 
14.3 
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, 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 and other necessary documentation to the Ethics 
committee (IRB/IEC) is expressly permitted, the IRB/IEC 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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Furthermore, the Investigator and the Sponsor agree to adhere to the principles of personal data 
confidentiality in relation to the patients, Investigator and its collaborators involved in the study. 
14.4 
PROPERTY RIGHTS  
All information, documents and IMP provided by the Sponsor or its designee are and remain the 
sole property of the Sponsor. 
The Investigator shall not 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. 
14.5 
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. 
Subject race or ethnicity will be collected in this study because these data are required by several 
health authorities (eg, on afro American population for FDA, on Asian population for the PMDA 
in Japan or S-FDA in China).  
The data collected in this study will only be used for the purpose(s) of the study and to document 
the evaluation of the benefit/ risk ratio, efficacy and safety of the product(s). They may be further 
processed if they have been anonymized. 
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14.6 
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 
maintaining their own liability insurance policy. An insurance certificate will be provided to the 
Ethics Committees (IECs/IRBs) or health authorities in countries requiring this document. 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES  
For the purpose of ensuring compliance with the clinical trial, Good Clinical Practice 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. 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE  
14.8.1 Decided by the Sponsor  
Decided by the Sponsor in the following cases 
• If the information on the product leads to doubt as to the benefit/risk ratio. 
• If the Investigator has received from the Sponsor all IMP, means and information 
necessary to perform the clinical trial and has not included any patient after a reasonable 
period of time mutually agreed upon. 
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• In the event of breach by the Investigator of a fundamental obligation under this 
agreement, including but not limited to breach of the clinical trial, breach of the applicable 
laws and regulations or breach of the ICH guidelines on Good Clinical Practice. 
• If the total number of patients are included earlier than expected. 
• Conduct of the study is no longer feasible due to changes in therapeutic landscape or 
ability to recruit or complete the study as designed.  
In any case the Sponsor will notify the Investigator of its decision by written notice. 
14.8.2 Decided by the Investigator  
The Investigator must notify (30 days' prior notice) the Sponsor of his/her decision and give the 
reason in writing. 
In all cases (decided by the Sponsor or by the Investigator), the appropriate Ethics Committee(s) 
(IRB/IEC) and Health Authorities should be informed according to applicable regulatory 
requirements. 
14.9 
CLINICAL TRIAL RESULTS  
The Sponsor will be responsible for preparing clinical study reports and providing summary of 
study results to the Investigator. 
14.10 PUBLICATIONS AND COMMUNICATIONS  
A publication committee may be established to take the responsibility for the first international 
publication. Authorship will include members of the steering committee, employees of the 
Sponsor, and the principal Investigators at up to 3 top enrolling sites. The committee chairman 
will be appointed by the Sponsor who will serve as the principle Investigator for the study and 
lead author on the first international publication.   
NOTE: If a data monitoring committee is used in the clinical trial, Sanofi is free to publish, and to 
communicate the recommendations made by the data monitoring committee, using all existing or 
future means of communication with an agreement between both parties. 
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. 
As the study is being conducted at multiple sites, the Sponsor agrees that, consistent with 
scientific standards, first presentation or publication of the results of the study shall be made only 
as part of a publication of the results obtained by all sites performing the study. However, if no 
multicenter publication has occurred within twelve (12) months of the completion of this study at 
all sites, the Investigator shall have the right to publish or present independently the results of this 
study to the review procedure set forth herein.   The Investigator shall provide the Sponsor with a 
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copy of any such presentation or publication derived from the study for review and comment at 
least 30 days in advance of any presentation or submission for publication.  In addition, if 
requested by the Sponsor, any presentation or submission for publication shall be delayed for a 
limited time, not to exceed 90 days, to allow for filing of a patent application or such other 
measures as the Sponsor deems appropriate to establish and preserve its proprietary rights.  
The Investigator shall not use the name(s) of the Sponsor and/or 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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15 
CLINICAL TRIAL AMENDMENTS  
All appendices attached hereto and referred to herein are made part of this clinical trial. 
The Investigator should not implement any deviation from, or changes of the clinical trial without 
agreement by the Sponsor and prior review and documented approval/favorable opinion from the 
IRB/IEC 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. 
Any amendment to the clinical trial requires written approval/favorable opinion by the Ethics 
Committee (IRB/IEC) prior to its implementation, unless there are overriding safety reasons. 
In some instances, an amendment may require a change to the informed consent form. The 
Investigator must receive an IRB/IEC approval/favorable opinion concerning the revised informed 
consent form prior to implementation of the change and patient signature should be re-collected if 
necessary.  
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16 
BIBLIOGRAPHIC REFERENCES  
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features of children and adolescents with multiple sclerosis. Neurology. 2007;68(Suppl 
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clinical diagnosis, therapeutic strategies, and future directions. Lancet Neurol. 2007;6:887-
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4. Chitnis T, Tardieu M, Amato MP, Banwell B, Bar-Or A, Ghezzi A, et al. International 
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6. Krupp LB, Banwell B, Tenembaum S. Consensus definitions proposed for pediatric multiple 
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9. Gorman MP, Healy BC; Polgar-Turcsanyi M, Chitnis T. Increased Relapse Rate in Pediatric-
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early onset multiple sclerosis: Comparison of data from Moscow and Vancouver. Clin Neurol 
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13. Amato MP, Goretti B, Ghezzi A, Lori S, Zipoli V, Moiola L, et al. Cognitive and psychosocial 
features in childhood and juvenile MS: two year follow up. Neurology.2010 Sep 
28;75(13):1134-40. 
14. Shi J, Kovacs SJ, Wang Y, Ludden TM, Bhargava VO. Population pharmacokinectics of the 
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Digit Modalities Test: implications for multiple sclerosis clinical trials. Multiple Sclerosis. 
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16. Pohl D, Rostasy K, Reiber H, Hanefeld F. CSF characteristics in early-onset multiplesclerosis. 
Neurology. 2004;63;1966-7. 
17. Waubant E, Chabas D, Okuda D, Glenn O, Mowry E, Henry RG, et al. Difference in disease 
burden and activity in pediatric patients on brain magnetic resonance imaging at time of 
multiple sclerosis onset vs adults. Arch Neurol. 2009;66:967-71. 
18. Chabas D, Castillo-Trivino T, Mowry EM, Strober JB, Glenn OA, Waubant E. Vanishing MS 
T2-bright lesions before puberty: a distinct MRI phenotype. Neurology. 2008;71:1090–3. 
19. Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. 
Development pharmacology drug disposition, action, and therapy in infants and children. N 
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21. Anderson GD, Lynn AM. Optimizing pediatric dosing: a developmental pharmacologic 
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22. Sanofi-aventis. Report HWA 486/1037 Phase IB Trial of Leflunomide in Pediatric Subjects 
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23. Sanofi-aventis. Report HWA 486/3503 Efficacy and safety of leflunomide versus 
methotrexate in the treatment of pediatric patients with juvenile rheumatoid arthritis. 02 
December 2004. Clinical study report available upon request. 
24. Kuhle J., Kropshofer H., Haering DA, Kundu U, Meinert R, Barro C, et al. Blood 
neurofilament light chain as a biomarker of MS disease activity and treatment response. 
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25. Gaetani L, Blennow K, Calabresi P, Di Filippo M, Parnetti L, Zetterberg H. Neurofilament 
light chain as a biomarker in neurological disorders. J Neurol Neurosurg Psychiatry. 
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26. Reinert M.C., Barro C. Neurofilament light chain is a useful biomarker in paediatric multiple 
sclerosis. Abstract[Online]. [cited 2019 Sept 11]. Available from:URL: 
https://onlinelibrary.ectrims-congress.eu/ectrims/2018/ectrims-
2018/228510/jutta.grtner.neurofilament.light.chain.is.a.useful.biomarker.in.paediatric.html. 
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17 
APPENDICES  
17.1 
APPENDIX A: MCDONALD’S CRITERIA  
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17.2 
APPENDIX B: KURTZKE EXPANDED DISABILITY STATUS SCALE AND 
FUNCTIONAL SYSTEM SCORES  
The Kurtzke Expanded Disability Status Scale and Functional Systems are reproduced in this 
appendix. 
 
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17.3 
APPENDIX C: TANNER PUBERTY STAGE CLASSIFICATION  
 
Tanner puberty stage classification 
 
Classification of sex maturity stages in girls 
 
Stage 
Pubic hair 
Stage 
Breasts 
P1 Preadolescent 
B1 Preadolescent 
P2 Sparse, lightly pigmented, straight, 
medial border of labia 
B2 Breast and papilla elevated as small 
mound; areolar diameter increased 
P3 Darker, beginning to curl, increased 
amount 
B3 Breast and areola enlarged, no contour 
separation 
P4 Coarse, curly, abundant but amount 
less than in adult 
B4 Areola and papilla form secondary mound 
P5 Adult feminine triangle, spread to 
medial surface of thighs 
B5 Mature; nipple projects, areola part of 
general breast contour 
 
Classification of sex maturity stages in boys 
 
Stage 
Pubic hair 
Stage 
Testes 
P1 None 
T1 
Preadolescent 
P2 Scanty, long, slightly pigmented 
T2 
Enlarged scrotum, pink texture altered 
P3 Darker, starts to curl, small amount 
T3 
Larger 
P4 Resembles adult type, but less in 
quantity; coarse, curly 
T4 
Larger, scrotum dark 
P5 Adult distribution, spread to medial 
surface of thighs 
T5 
Adult size 
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17.4 
APPENDIX D: GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES  
 
 
Neutrophils < 1000/mm3
Repeat immediately a full blood count if value close 
to 1000/mm3
Neutrophils < 1000/mm3 confirmed 
with signs of infection
1. DISCONTINUE 
Investigational Product, 
hospitalization should be 
considered
2. PERFORM biological 
investigations for infection
3. INFORM the local monitor
4. INVESTIGATE previous treatments, particularly long -term, 
even a long time ago, exposure to toxic agents, e.g., benzene, 
X-rays, etc.
5. PERFORM and collect the following investigations (results):
• RBC and platelet counts
• Serology: EBV, (HIV), mumps, measles, rubella
6. DECISION for bone marrow aspiration: to be taken in 
specialized unit
7. FREEZE serum (5 mL x 2) on Day 1 (cessation of 
Investigational Product) and Day 5 (For further investigations)
8. MONITOR the leukocyte count 3 times per week for at least 
one week, then twice a month until it returns to normal
Neutrophils < 1000/mm3 confirmed 
with no signs of infection
1. DISCONTINUE 
Investigational Product
2. INVESTIGATE for infection
in both situations
NEUTROPENIA
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17.5 
APPENDIX E: NEUROFILAMENT LIGHT CHAIN AND NON-GENETIC BIOMARKERS 
PROCESSING  
 
1. Participation in the exploration of the effect of teriflunomide on biomarkers in plasma 
such as Neurofilament light (NfL) chain and potentially other non-genetic biomarkers 
related to MS disease is optional and does not involve genetic testing. No additional blood 
samples will be required to be drawn from study patients for this exploratory research. The 
Investigator or authorized designee will explain to each participant/parents the objectives 
of the exploratory research, and participants/parents will have to provide a separate 
consent to participate in this exploratory analysis if they agree to participate. It will be 
made clear their refusal will not impact their participation in the study 
2. NfL and other non-genetic biomarkers will be assessed from leftover plasma PK samples 
(when available) collected during the study, for all the patients who consented, at the 
following time points: W2, W12, W24, W36 and W96 for the double-blind period. 
3. Additional time points of the double-blind and the open-label may be potentially included. 
4. A highly sensitive single molecule array (SIMOA) immunoassay which has recently been 
developed to measure NfL in plasma/serum will be used. 
5. For the patients consenting to this research, samples will be stored in accordance with 
local regulations at a facility selected by the Sponsor to enable further analysis of 
biomarker responses to teriflunomide.  
6. Results of these exploratory biomarker analyses will be summarized in an ad hoc report 
separate from the main CSRs of the double-blind and open-label periods.  
17.6 
APPENDIX F: COUNTRY SPECIFIC REQUIREMENTS  
Amendments for the Russian Federation 
• As per Amendment 3 dated 18 December 2014, at the request of the Ministry of Health 
of the Russian Federation, the age range was restricted, for the Russian Federation only, to 
include patients aged from 13 to 17 rather than 10 to 17 years old.  
- 
Section clinical trial summary  - Study population – Main selection criteria – Inclusion 
criteria: 
≤17 years of age and ≥13 years of age at randomization 
- 
Section 6.2 – Inclusion criteria  
≤17 years of age and ≥13 years of age at randomization 
• As per Amendment 4 dated 26 July 2016, the previous age range for the recruitment in 
the Russian Federation that was restricted to patients aged 13 to ≤17, rather than 10 to ≤17, 
was amended again to allow the recruitment of children 10 to ≤12 years of age, based on 
the availability of blinded safety data from the global study that show no age specific 
safety concerns. Therefore, this amendment harmonized the study entry criteria in the 
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Russian Federation related to the age of the patients at enrollment with the age range in the 
global protocol. 
- 
Section clinical trial summary - Study population – Main selection criteria – Inclusion 
criteria: 
≤17 years of age and ≥10 years of age at randomization 
- 
Section 6.2 – Inclusion criteria  
≤17 years of age and ≥10 years of age at randomization 
17.7 
APPENDIX G: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENT AGENCY  
During the coronavirus outbreak of the first quarter of 2020, emergency actions were taken 
through Memos 18, 19, and 20 sent to the Investigators, dated 21 February 2020, 24 March 2020 
and 28 April 2020, respectively (memo summaries in Section 17.8).    
Study treatment 
The following contingencies may be implemented for the duration of the emergency to make 
clinical supplies available to the participant for the duration of the emergency:  the Direct-to-
Patient (DTP) supply of teriflunomide (HMR1726) or cholestyramine or activated charcoal can be 
delivered from the PI/site where allowed by local regulations and agreed upon by the patient (see 
Section 17.8.2).  
Assessment of investigational medicinal product – Study procedures 
Attempts should be made to perform all assessments in accordance with the approved protocol to 
the extent possible. In case this is not possible due to a temporary disruption caused by an 
emergency, focus should be given to assessments necessary to ensure the safety of participants 
and those important to preserving the main scientific value of the study. 
In exceptional cases, under regional or national emergencies (epidemic disease), onsite visits may 
be replaced with telephone/remote visits. The patient interviews could be performed by phone, 
local safety labs and some efficacy assessments could be performed off-site if agreed by the 
patient and permissible per local regulations. 
Procedures to be considered in the event of a regional or national emergency declared by a 
governmental agency: 
• If onsite visits are not possible, remote visits may be planned for the collection of possible 
safety and/or efficacy data; the Investigator or delegate will perform a phone-call at each 
onsite planned visit to collect safety data, concomitant treatment and date and time of IMP 
intake after DTP. Changes to the visit schedule, details regarding contact with patients 
outside study visits, and all data collected remotely (eg, adverse events, concomitant 
medication, …) will be properly documented in the subject’s medical record and the study 
eCRF. 
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• If onsite visits are not possible visit windows may be extended for assessment of safety 
and/or efficacy data that cannot be done remotely as unscheduled assessment;  
• If onsite visit and home visit are not possible, a temporary treatment discontinuation may 
be considered. The Investigator or delegate will perform a phone-call visit at each onsite 
planned visit to collect safety data and concomitant treatment. 
• Use of local clinic or laboratory locations are allowed.  
Contingency procedures are suggested below and in Section 1.3, Section 1.5, Section 7, Section 
7.9, Section 8, Section 9, Section 9.11.4, Section 12.3, Section 13.3) for an emergency that 
prevents access to the study site, to ensure the safety of the participants, to consider continuity of 
the clinical study conduct, protect trial integrity, and assist in maintaining compliance with Good 
Clinical Practice in Conduct of Clinical Trials Guidance. Sponsor agreement MUST be obtained 
prior to the implementation of these procedures for the duration of the emergency (Section 
17.8.2). 
During the emergency, if the site will be unable to adequately follow protocol mandated 
procedures, alternative treatment outside the clinical trial should be proposed, and administration 
of study intervention may be temporarily delayed/halted. 
Informed consent, assent for patients, and assent for optional neurofilament assessment  
For a regional or national emergency declared by a governmental agency, contingency procedures 
may be implemented for the duration of the emergency. The participant or their legally authorized 
representative should be verbally informed prior to initiating any changes that are to be 
implemented for the duration of the emergency (eg, study visit delays/treatment extension, use of 
local labs) (see Section 17.8.3).  
Statistical analysis 
The impact of the regional or national emergency declared by a governmental agency on study 
conduct will be summarized (eg, study discontinuation or discontinuation/delay/omission of the 
intervention due to the emergency). Any additional analyses and methods required to evaluate the 
impact on efficacy (eg, missing data due to the emergency) and safety will be detailed in the SAP. 
17.8 
APPENDIX H: SUMMARIES OF MEMOS ON CONTINGENCY MEASURES RELATED 
TO COVID EMERGENCY  
17.8.1 Summary of Memo 18 (21 February 2020) - Specific to China   
Impact of Coronavirus outbreak on study conduct in the concerned sites and study team 
recommendations for patients follow up and Direct to Patient (DTP) in emergency IMP 
delivery at patient’s location because of novel Coronavirus (nCOV19) outbreak in China 
 
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Under this DTP, only the oral medications teriflunomide tablet (7 or 14 mg) per day will be 
provided. The investigator takes the full responsibility to decide whether the patient would be 
considered eligible for DTP or not, based on the medical history. 
In patients receiving teriflunomide tablet (7 or 14 mg) through DTP, the investigator is expected: 
• to contact the patients via regular phone calls (every two weeks or more frequently if 
needed) to oversee the tolerability of study treatment and consult patients; 
• to ensure that patients can reach out to investigator in case of an emergency, that requires 
urgent medical intervention; 
• to guarantee that patients receiving teriflunomide tablet (7 or 14 mg) are managed at study 
site / other hospital setting in case of adverse events that require hospitalization. 
All above steps should be well documented in the patient’s health records at study site. Also, local 
guidelines release for clinical trials should be referred and followed. 
The different steps regarding the Direct to Patient access are described below: 
• The process starts with the proposal of DTP by the site staff and agreement by the patient. 
• To deal with this emergency situation, we propose Investigators or delegates to request the 
activation of DTP delivery to the CRA by email by specifying at least : patient number, 
date of DTP delivery and site contact (site number, phone number, location, email address) 
as soon as DTP option is identified; 
• The CRA then completes the Coronavirus template Project Responsibility Agreement 
PRA with all specific information (study specificities, site address, phone contact at site 
and mail, Patient ID and visit, quantities to be sent) and send it to the Investigational 
Product Manager (IPM) for validation by email; 
• The IPM checks and signs the PRA and send it directly to Marken team at 
Sanofi.DTP@marken.com; 
• Marken DTP Team contacts the study staff (by mail and/or phone) in order to get the filled 
Booking Form (appendix 1) based on PRA information and to arrange with the site the 
IMP collection date at site and the delivery date at patient’s location according to the 
GDPR regulation (appendix 2). Marken will support the sites in case of questions. The 
Sponsor does not have access to the patient’s personal information according to the 
GDPR; 
• Marken will then send shipping box and additional materials if necessary, to the 
investigator site in order to make the shipment secure; 
• The day of IMP collection, as for an usual visit, the investigator or delegate have to 
perform the IRT call to get the treatment number allocated to the patient. Patient is then 
contacted by the investigator or delegate (phone contact to investigate for any new or 
worsening AE, change in concomitant medication, any other relevant information; 
• The investigator or delegate will have to fill in the shipping box with the allocated kits and 
the patient contact card with the treatment kit information. A sharp container could also be 
provided if needed; 
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• The day of IMP collection, Marken comes at site to close and takes away the parcel with 
the kits and the patient card to the patient’s location; 
• Marken then calls the patient to define a slot of delivery; 
• Patient receives the delivery and signs the Acknowledgement of Receipt; 
• Marken sends back the AoR to the site. The form is to be archived at the Site source 
documents file. 
Patient must be reminded to contact the site without delay in case he/she have any issues (AEs, 
IMP compliance, IMP damaged etc.). 
All questions related to the implementation of DTP in your site for patients treated under 
EFC11759 study should be addressed to the Sanofi monitoring team (CRA). 
17.8.2 Summary of Memo 19 (24 March 2020) - Global   
Impact of Coronavirus disease (Covid-19) outbreak on study conduct in the concerned sites 
and recommendations for patients follow up and option of IMP delivery at patient’s location 
Following the Covid-19 outbreak, many countries have implemented measures for quarantine 
or for ‘social distancing’ to try to control the number of new infections. In addition, the 
increasing number of patients and healthcare demand puts increasing pressure on global 
healthcare system. Sanofi greatly respects everybody working in healthcare who is helping 
patients and their families through the Covid-19 pandemic. 
Covid-19 also impacts the conduct of clinical studies. Sanofi would like to implement changes 
to the conduct of the study to ensure continuation of patient treatment, while reducing 
personal contact with patients, especially as MS patients are at increased risk for 
complications of coronavirus infection. 
With this memo, Sanofi is providing you detailed instructions regarding these new measures. 
In short, they impact the following: 
• Study visits and assessments: In order to reduce potential exposure to the virus, patients 
will be asked to stay at home, and study visits that are scheduled during this outbreak may 
be replaced by phone calls, and study assessments that require an on-site visit may be 
performed at the next scheduled visit or as unscheduled evaluation (Table 6). 
• Direct to Patient (DTP): In order to avoid treatment discontinuation for patients enrolled 
in EFC11759 clinical trial, Sanofi offers Direct to Patient’s study drug (teriflunomide) 
delivery from clinical sites directly to patient’s home. This is applicable for the countries in 
which the implementation of the DTP process was approved. The investigator liaised with 
your monitor for confirmation. 
• Documentation in CRF: We would like to ask you to clearly document changes to the 
visit schedule as well as details regarding contact with patients outside study visits, and 
any information about the adverse events and concomitant medication in the source 
document and then in the eCRF. 
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▪ For sending by courier, the site staff should inform them that they will 
receive by mail 3 original copies for parent consent and patient assent. 
▪ For sending via e-mail, the site staff should confirm that the patient is using 
a private secured network. 
▪ Current post address or e-mail address should be checked with the patient’s 
parents and the patient. 
- 
If the patient cannot attend this first call, a second appointment should be made to 
explain to the patient the reason for the new assent. 
• Copies of consent/assent should be sent by e-mail or courier. 
• Once consent/assent received, a phone call with delegated site staff should be scheduled to 
re- explain the aim of the reconsenting and to answer any questions from patient’s parents 
and the patient. When the “e-mail” option is used, the patient’s parents and the patient 
should be reminded that the originals have to be retained and given to the investigator 
when the patient and/or patient’s parents will be able to return to the site/hospital. 
• If the patient and his/her parents agree to provide their consent, they should sign consent 
and assent and: 
- 
When “courier” option is used, the Principal Investigator, sub-investigator or other site 
staff member authorized to handle the ICF process sends back the consent/assent by 
courier. They should sign all original copies of consent and assent. One original copy 
of the consent and assent is to be kept by the patient’s parents and the patient. All other 
original copies (2 original copies of the parents’ consent and 2 original copies of the 
patient’s assent) should be sent back to the site by courier. 
- 
When “e-mail” option is used, the Principal Investigator, sub-investigator or other site 
staff member authorized to handle the ICF process emails back the scan of the 
consent/assent, or takes a picture of the consent/assent on mobile phone and sends it to 
the delegated site staff (this is not preferred option). 
• Once the site receives the original copies of the parent’s consent and patient’s assent: 
- 
Sent by courier, the Principal Investigator, sub-investigator or other site staff member 
authorized to handle the ICF process should sign all original copies received. One of 
these fully signed original copies should be kept at site (1 original copy of the parents’ 
consent and 1 original copy of the patient’s assent) and the remaining ones should be 
sent back to the patient’s parents and the patient. 
- 
Sent by e-mail, the Principal Investigator, sub-investigator or other site staff member 
authorized to handle the ICF process should print-out parent’s consent and patient’s 
assent, sign them and send a scan copy of the fully signed parent’s consent and 
patient’s assent back to the patient’s parents and patient. Original copies should be 
kept at site. 
Before the implementation of this process regardless the option used, IRB/IECs have to be 
notified. Of course, the process cannot be implemented if refused by IRB/IEC. 
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We also recommend checking the Guidance on the management of clinical trials during the 
Covid-19 pandemic issued by the different local Health Authorities and if there is any local 
guidance issued by IRB/EC by the concerned country with recommendations on reconsenting. 
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17.9 
APPENDIX I: PROTOCOL AMENDMENT HISTORY  
REASON FOR AMENDMENT 1 AND AMENDED PROTOCOL 1 (18 December 2013): 
One MRI is added, at Week 24, in addition to the scans at baseline, Week 48 and Week 96, in 
order to strengthen MRI data which are important in the study. It will provide information on 
early effect of teriflunomide on MRI endpoints, and increase the power on these endpoints, by 
being included in statistical modeling. This higher frequency is commonly used in clinical 
practice. In addition, an MRI will be performed in case of confirmed relapse after PK run-in, to 
provide additional data before switching to open-label treatment, in particular if the relapse occurs 
before the Week 24 MRI.  
In addition, it is specified that in case of at least 5 new/enlarged T2 lesions at the MRI of 
Week 24, an additional MRI will be performed at Week 36. Then, in case of -at least 
9 new/enlarged T2 lesions at Week 36 (new since Week 24), or -at least 5 new/enlarged T2 
lesions at both Week 36 and Week 48 (10 total on these 2 MRIs, new since Week 24), patients 
will have the option to continue in an open label teriflunomide treatment arm.  It is expected that 
the number of patients meeting these stringent criteria will be low. It is considered that in case of 
a high number of new/enlarged MRI lesions, investigators will generally be willing to end the 
study treatment which potentially is a placebo, and that standardization of rules is appropriate 
under these circumstances.  
In the initial protocol, only the two main MRI endpoints are listed, ie, number of new/enlarged T2 
lesions and number of Gd-enhancing T1 lesions. The following have been added: change in 
volume of T2 lesions, change in volume of T1 hypointense lesions, number of new T1 
hypointense lesions and brain atrophy. The MRI endpoints have been grouped together.  
Immunoglobulin (IgG, IgM and IgA) measurements have been added at baseline and every 
24 weeks, in the aim of providing additional information on a potential, although not expected, 
effect of teriflunomide on the immune system in this age group.  
The Poisson regression model with a robust error variance is changed to a negative binomial 
model for the analysis of the number of new or enlarged T2-lesions per MRI scan and the number 
of T1 Gd-enhancing lesions per MRI scan MRI. While the Poisson regression model with robust 
error variance accommodates the overdispersed MRI lesion count data, simulations generally 
show the negative binomial provides a better fit.  Furthermore, the negative binomial model is 
commonly used for analysis of this type of count data in clinical trials. To reduce the impact of 
potential outliers, ordinal logistic regression model including treatment group, region, pubertal 
status and age will also be used to analyze these endpoints.  The following categories for the 
number of lesions, 0, 1, 2, 3-4 and ≥5, are considered and will be further defined in the Statistical 
Analysis Plan. The Poisson regression model with a robust error variance will be used in 
sensitivity analyses. 
In addition, numerous clarifications and text corrections are made throughout the protocol. These 
include corrections of the level of title, as the description of assessments appeared inappropriately 
as subsections of the Section 7 Study Treatment. All subsequent numbering is modified. 
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REASON FOR AMENDMENT 2 (11 June 2014) AND AMENDED PROTOCOL 2 
(26 June 2014): 
Extension of open-label period 
The open-label period is extended up to 192 weeks after randomization, instead of 96 weeks 
previously. This change provides patients with the option to enter open-label period for patients 
completing the 96-week double-blind period.  
The duration of the open-label period for a given patient will depend on when he/she enters this 
period. The duration of the open-label period will be 96 weeks for patients completing the 
96-week double-blind period on treatment, and longer for patients switching to open-label during 
the initial 96 week double-blind period at the occurrence of a confirmed relapse or in case of high 
MRI activity.  
The flow-chart of the open-label period is prolonged and adjusted to extend up to 192 weeks 
(maximum).  
Addition of one MRI timepoint 
One MRI is added, at Week 72, in addition to the scans at baseline, Week 24, Week 48 and 
Week 96, in order to strengthen MRI data which are important in the study. The frequency of 
MRI will thus be one MRI every 24 weeks.  
In addition, a criterion for switch into open-label period taking this additional MRI scan into 
account is added as follows: at least 5 new/enlarged T2 lesions on each of the 2 consecutive MRI 
scans of Week 48 and Week 72. 
Exclusion criteria 
The required minimum washout period duration for previous MS treatment is modified. It is 
broken down into the following categories:  
• 1 month prior to randomization: glatiramer acetate, interferons, dimethyl fumarate.  
• 3 months prior to randomization: fingolimod, or intravenous immunoglobulins.  
• 6 months prior to randomization: natalizumab, or other immunosuppressant or 
immunomodulatory agents such as cyclophosphamide, azathioprine, cyclosporine, 
methotrexate, mycophenolate.  
• 2 years prior to randomization: cladribine or mitoxantrone.  
Previous treatment with alemtuzumab is added to the list of exclusion criteria.  
A note is added that teriflunomide tablets contain lactose and that therefore, investigators should 
consider whether history of lactose intolerance, in particular Lapp lactase deficiency could affect 
treatment tolerability.  
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Regarding contraception, a note is added that local additional requirements are to be followed, 
eg, spermicidal foam / gel / film / cream / suppository is to be associated with condoms in UK, as 
per MHRA rules. 
Endpoints 
Proportion of patients free of new or enlarged MRI T2-lesions at 48 weeks and 96 weeks is added 
as an additional endpoint. It is specified that the main MRI endpoints will be the number of 
new/newly enlarged T2 lesions and the number of T1 Gd-enhancing T1 lesions.  Proportion of 
disease-free patients is added as an exploratory endpoint.  
Miscellaneous 
Added text to the introduction on rationale for placebo-controlled design (Section 3.2.2 Rationale 
for study design).  
Added endocrine function evaluation consisting of measurement of TSH every 24 weeks and at 
EOT.  
Added text that local anaesthetic must be offered for blood draws to minimize pain and 
discomfort. 
Corrected text in Section 9.8.1Pre-defined adverse events and laboratory abnormalities for 
specific reporting (AEPM) to restore the instructions that were included in the initial protocol but 
had been inadvertently taken out in amended protocol 1.  
In addition, numerous minor clarifications and text corrections are made throughout the protocol. 
REASON FOR AMENDED PROTOCOL 3 (02 August 2018): 
The efficacy and safety of teriflunomide are evaluated in children with pediatric multiple sclerosis 
(MS) in Study EFC11759/Terikids, which is ongoing. The enrolment in the study is completed. 
Teriflunomide is currently approved in countries participating in this study for the treatment of 
adult patients with relapsing remitting multiple sclerosis (RRMS). At the end of their participation 
in the study, some patients will be too young to access commercial teriflunomide as per 
authorized indication. This open-label optional additional extension period may be considered for 
such patients. The optional additional extension period will assess the continued safety and 
efficacy of teriflunomide in patients until they are 18 years old and/or are able to switch to 
commercial teriflunomide in their country, whichever comes first. It will be implemented in 
France, and possibly other countries, where local solutions for continued teriflunomide treatment 
are not possible within a reasonable time frame.  
The optional additional extension period will be performed in conditions approaching clinical 
practice. In this perspective, the dose will be decided by the Investigator without knowledge of the 
dose in the study. This is necessary to ensure blinding and integrity of the core study, and it is 
similar to what is done for young patients who receive marketed Aubagio at the end of the study 
in the context of local country specific solutions. The recommended dose will be teriflunomide 14 
mg for patients >40 kg, in continuation to the open-label period of the study, in which the 
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maintenance dose is 14 mg adult equivalent and is expected to be usually 14 mg. This is supported 
by the good safety of teriflunomide in the study up to now. If the investigator considers that a 
lower dose would be more appropriate, in particular for patients <40 kg (which is expected to be 
infrequent, as patients’ age will be ≥14 years old), it is possible to administer teriflunomide 14 mg 
with a lower frequency, eg, every other day for an equivalent of 7 mg. 
The safety of teriflunomide is being continuously monitored in the Study EFC11759/Terikids. 
Regular safety reviews have been performed by an independent external Data Monitoring 
Committee (DMC). No major safety issues have been identified since the beginning of the study. 
Teriflunomide Clinical Investigators’ Brochure and SmPC/USPI should be taken into account for 
patients entering the optional additional extension period. 
In addition, Sanofi uses this opportunity to edit other sections of the protocol as listed below, to 
correct some minor discrepancies and to clarify some sentences. 
Inconsistencies, typographical, and spelling errors throughout the document were also corrected. 
REASON FOR AMENDED PROTOCOL 4 (11 September 2019): 
This amended protocol is considered to be nonsubstantial 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 neither significantly impacts the safety or physical/mental integrity of participants nor 
the scientific value of the study. 
Overall rationale for the amendment 
The protocol is being amended to add an Additional Research of the effect of teriflunomide on 
biomarkers in plasma, such as the neurofilament light chain (NfL) and potentially other 
biomarkers (not yet identified) related to MS disease. The biomarkers will be measured from 
leftover plasma PK samples (when available) collected during the study. No additional blood 
samples will be required to be drawn from study patients for this exploratory research. 
Neurofilament light chain has been shown to be a biomarker of the disease activity and tissue 
damage in relapsing remitting multiple sclerosis in the adult (24, 25). There is little literature in 
pediatric MS (26). Of note, this research will not involve genetic testing.  
NfL could potentially be a marker of ongoing axonal damage. It can be measured in the blood and 
may be earlier and more sensitive than MRI scan measures such as brain volume. Development of 
NfL in pediatric MS may contribute to optimize future MS therapies in children. NfL levels will 
also be analyzed in relation to clinical parameters.  
Participation will be optional. The Investigator or authorized designee will explain to each 
participant/parents the objectives of the exploratory research, and participants/parents will provide 
a separate consent to participate in this exploratory analysis if they agree to participate. It will be 
made clear their refusal will not impact their participation in the study. 
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For the patients consenting to this additional research, samples will be stored in accordance to 
local regulations following the last participant’s last visit for the study at a facility selected by the 
Sponsor to enable further analysis of biomarker responses to teriflunomide.  
With Amendment 4, leftover plasma PK samples may be used for research to develop methods, 
assays, prognostics and/or companion diagnostics related to the disease process, pathways 
associated with the disease state. 
The time points considered include W2, W12, W24, W36 and W96 from the double-blind period. 
The selection of time points may be adjusted, with potential additions from the double-blind and 
the open-label periods. It is anticipated to use a highly sensitive single molecule array (SIMOA) 
immunoassay which has recently been developed to measure NfL in plasma/serum.  
Results of these exploratory biomarker analyses will be summarized in an ad hoc report separate 
from the main clinical study reports (CSR) of the double-blind and open-label periods.  
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................................................... 5 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................ 6 
1.1 
STUDY DESIGN AND RANDOMIZATION ...................................................................................... 6 
1.2 
OBJECTIVES ................................................................................................................................... 6 
1.2.1 
Primary objectives ............................................................................................................................ 6 
1.2.2 
Secondary objectives ....................................................................................................................... 7 
1.3 
DETERMINATION OF SAMPLE SIZE ............................................................................................. 7 
1.4 
STUDY PLAN ................................................................................................................................... 8 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL .................................. 9 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN ....................... 9 
2 
STATISTICAL AND ANALYTICAL PROCEDURES .................................................................... 11 
2.1 
ANALYSIS ENDPOINTS ............................................................................................................... 11 
2.1.1 
Demographic and baseline characteristics .................................................................................... 11 
2.1.2 
Prior or concomitant medications ................................................................................................... 12 
2.1.3 
Efficacy endpoints .......................................................................................................................... 12 
2.1.3.1 
Primary efficacy endpoint(s) .......................................................................................................... 13 
2.1.3.2 
Secondary efficacy endpoint(s) ...................................................................................................... 13 
2.1.3.3 
Additional efficacy endpoints ......................................................................................................... 14 
2.1.4 
Safety endpoints ............................................................................................................................ 14 
2.1.4.1 
Adverse events variables ............................................................................................................... 14 
2.1.4.2 
Deaths ............................................................................................................................................ 15 
2.1.4.3 
Laboratory safety variables ............................................................................................................ 16 
2.1.4.4 
Vital signs variables ....................................................................................................................... 17 
2.1.4.5 
Electrocardiogram variables .......................................................................................................... 17 
2.1.4.6 
Tanner scales ................................................................................................................................. 17 
2.1.5 
Pharmacokinetic variables ............................................................................................................. 17 
2.1.6 
Immunoglobulins ............................................................................................................................ 18 
2.2 
DISPOSITION OF PATIENTS ....................................................................................................... 18 
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2.3 
ANALYSIS POPULATIONS ........................................................................................................... 19 
2.3.1 
Enrolled population ........................................................................................................................ 19 
2.3.2 
Efficacy population ......................................................................................................................... 19 
2.3.3 
Safety population ........................................................................................................................... 19 
2.3.4 
Pharmacokinetic population ........................................................................................................... 20 
2.4 
STATISTICAL METHODS ............................................................................................................. 20 
2.4.1 
Demographics and baseline characteristics .................................................................................. 20 
2.4.2 
Prior or concomitant medications ................................................................................................... 21 
2.4.3 
Extent of investigational medicinal product exposure and compliance ......................................... 21 
2.4.3.1 
Extent of investigational medicinal product exposure .................................................................... 21 
2.4.3.2 
Compliance .................................................................................................................................... 22 
2.4.4 
Analyses of efficacy endpoints ....................................................................................................... 23 
2.4.4.1 
Analysis of primary efficacy endpoint............................................................................................. 23 
2.4.4.2 
Analyses of secondary efficacy endpoints ..................................................................................... 24 
2.4.4.3 
Analysis of additional efficacy endpoint ......................................................................................... 27 
2.4.4.4 
Multiplicity issues ........................................................................................................................... 29 
2.4.5 
Analyses of safety data .................................................................................................................. 30 
2.4.5.1 
Analyses of adverse events ........................................................................................................... 31 
2.4.5.2 
Deaths ............................................................................................................................................ 34 
2.4.5.3 
Analyses of laboratory variables .................................................................................................... 35 
2.4.5.4 
Analyses of vital sign variables ...................................................................................................... 36 
2.4.5.5 
Analyses of electrocardiogram variables ....................................................................................... 37 
2.4.5.6 
Analysis of Tanner scales .............................................................................................................. 37 
2.4.6 
Analyses of pharmacokinetic variables .......................................................................................... 37 
2.4.7 
Analyses of immunogenicity variables ........................................................................................... 38 
2.5 
DATA HANDLING CONVENTIONS .............................................................................................. 38 
2.5.1 
General conventions ...................................................................................................................... 38 
2.5.2 
Missing data ................................................................................................................................... 38 
2.5.3 
Windows for time points ................................................................................................................. 41 
2.5.4 
Unscheduled visits ......................................................................................................................... 44 
2.5.5 
Pooling of centers for statistical analyses ...................................................................................... 45 
2.5.6 
Statistical technical issues ............................................................................................................. 45 
3 
INTERIM ANALYSIS ..................................................................................................................... 46 
4 
DATABASE LOCK ........................................................................................................................ 47 
5 
SOFTWARE DOCUMENTATION ................................................................................................. 48 
6 
REFERENCES ............................................................................................................................... 49 
7 
LIST OF APPENDICES ................................................................................................................. 50 
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APPENDIX A 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA ...................... 51 
APPENDIX B 
SUMMARY OF STATISTICAL ANALYSES ........................................................................ 67 
APPENDIX C 
FLOW CHART FOR OPEN LABEL EXTENSION PERIOD ................................................ 69 
APPENDIX D 
LIST OF SEARCH TERMS FOR COVID-19 (MEDDRA V24.0) ......................................... 73 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
 
ADEM: 
acute disseminated encephalomyelitis  
AE: 
adverse event 
ALT: 
alanine aminotransferase 
ARR: 
annualized relapse rate 
AST: 
aspartate aminotransferase 
ATC: 
Anatomic Therapeutic Chemical 
BMI: 
body mass index 
BUN: 
blood urea nitrogen 
CI: 
confidence interval 
CNS: 
central nervous system 
CRF: 
case report form 
CSR: 
clinical study report 
DBL: 
database lock 
ECG: 
electrocardiogram 
EDSS: 
expanded disability status scale 
EOT: 
end of treatment 
FSS: 
functional system scores  
GGT: 
gamma glutamyl transferase 
HLGT: 
high level group term 
HLT: 
high level term 
HR: 
heart rate 
ILD: 
interstitial lung disease  
IMP: 
investigational medicinal product 
IVRS: 
interactive voice response system  
LDH: 
lactate dehydrogenase 
LLOQ: 
lower limit of quantification 
LLT: 
lower-level term 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MRI: 
magnetic resonance imaging 
MS: 
multiple sclerosis 
PK: 
pharmacokinetic(s) 
PT: 
preferred term 
SDMT: 
symbol digit modalities test 
SOC: 
system organ class 
TEAE: 
treatment emergent adverse event 
TSH: 
thyroid stimulating hormone 
WHO-DD: 
World Health Organization Drug Dictionary 
β-HCG: 
serum β-human chorionic gonadotropin 
 
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1 
OVERVIEW AND INVESTIGATIONAL PLAN  
1.1 
STUDY DESIGN AND RANDOMIZATION  
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study followed 
by an open-label extension period in children and adolescents 10 to 17 years of age with relapsing 
forms of multiple sclerosis. It consists of: 
• A screening period up to 4 weeks 
• A double-blind period of up to 96 weeks treatment for each patient 
• An open-label period including the remainder of the initial 96 weeks treatment, where 
applicable, and a 96-week extension, ie, up to a maximum of 192 weeks after 
randomization 
• An optional additional extension period for young patients with teriflunomide until the 
patients are 18 years old and/or able to switch to commercial product, whichever comes 
first 
• A follow-up period of 4 weeks for patients discontinuing treatment. 
After a screening, eligible patients will be randomly assigned to receive either teriflunomide or 
placebo in a 2:1 randomization ratio (110 teriflunomide and 55 placebo) via Interactive Voice 
Response System (IVRS). Randomization will be stratified by the country and patient’s pubertal 
status. 
The unblinding of this Phase 3 study will be taken place after the core database lock (DBL), 
which is expected to be done approximately 28 days after the last patient last visit (LPLV) in the 
double-blind period/core part of the study. An interim clinical study report (CSR) of the open-
label period of this study will be planned upon the core DBL. 
The data from the placebo-controlled and the open label teriflunomide treatment periods will be 
the focus of the CSR of their respective phase. Relevant statistical methods/considerations that 
mainly relate to the analysis of the data from the placebo-controlled period are employed for data 
analysis of the open-label period. The data from the open label teriflunomide treatment arm are 
non-controlled and supportive in nature; summary statistics will be provided for efficacy variables 
and safety data. More details on interim analysis for the interim CSR of the open-label period are 
provided in Section 3 Interim Analysis. 
1.2 
OBJECTIVES  
1.2.1 Primary objectives  
The primary objective of this study is to assess the effect of teriflunomide in comparison to 
placebo on disease activity as measured by time to first clinical relapse after randomization in 
children and adolescents 10 to 17 years of age with relapsing forms of multiple sclerosis. 
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1.2.2 Secondary objectives  
The secondary objectives of this study are as follows: 
• To assess the effect of teriflunomide in comparison to placebo on disease 
activity/progression measured by brain MRI and on cognitive function 
• To evaluate the safety and tolerability of teriflunomide in comparison to placebo 
• To evaluate the pharmacokinetics (PK) of teriflunomide. 
1.3 
DETERMINATION OF SAMPLE SIZE  
The sample size calculation is based on the primary efficacy endpoint, time to first confirmed 
clinical relapse after randomization. Assuming 60% of placebo patients will experience a relapse 
by 2 years, 165 children aged 10 to 17 years (110 teriflunomide and 55 placebo; with at least 
22 and 11, pre-pubertal, respectively) are needed for 80% power to detect a hazard ratio 
(teriflunomide versus placebo) of 0.5 (2-sided alpha 0.05). The 2-year rate of relapse in the 
teriflunomide group would be 36.8% and the corresponding hazard rates, assuming the time-to-
relapse is exponentially distributed with a constant hazard rate, would be 0.4581 for placebo and 
0.2291 for teriflunomide. The sample size is adjusted assuming 20% of patients discontinue the 
study in 2 years due to reasons other than relapse. Calculations are performed using nQuery 
Advisor 7. 
The assumption for the percentage of placebo patients with relapse at 2 years is based on the 
combined data from the completed Phase III monotherapy adult studies (EFC6049/TEMSO and 
EFC10531/TOWER), where 58.7% of placebo patients aged ≤30 (n=167) experienced at least 
1 relapse in a 2-year treatment period. Of note, the corresponding percentage was 38.7% in the 
163 patients aged ≤30 treated with teriflunomide 14 mg. 
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1.4 
STUDY PLAN  
The study design is briefly described in the following graphical presentation: 
 
Note: An optional additional extension period with teriflunomide is offered to young patients when they complete the study, to provide treatment 
until they are 18 years old and/or can switch to commercial product, whichever comes first. 
Table 1 - Study schedule for the double-blind period  
Variable 
Visit 
Brain MRI 
Screening, Weeks 24, 48, 72 and Week 96/end of treatment (EOT)a visit, Week 36 if necessary 
EDSS 
Screening, randomization, Weeks 24, 48, 72, Week 96/EOTa visit, and unscheduled relapse 
visits 
SDMT 
Randomization, Weeks 24, 48, 72, and Week 96/EOTa visit, 
Cognitive Battery Test 
Randomization and EOTa visit 
Clinical Laboratory 
Screening, randomization, every 4 weeks up to 24 weeks and then every 6 weeks up to the 
Week 96/EOTa  
Vital signs 
Screening, randomization, Weeks 4, 8, 12, 24, and every 12 weeks up to Week 96/EOTa visit 
ECG 
randomization, Week 96/EOTa and after EOTa if abnormality 
Immunoglobulins and TSH 
Randomization, Weeks 24, 48, 72 and Week 96/EOTa visit 
PK 
Weeks 2, 3, 4, 8, 12, 24, 36 and Week 96/EOTa visit 
Physical examinations 
Screening, randomization, Weeks 12, 24, and every 12 weeks up to Week 96/EOTa visit 
Tanner assessment 
Randomization, at Week 24, 48, 72, and at Week 96/EOTa for all patients (until complete sexual 
maturity). 
a Patients who complete the double-blind treatment period or who prematurely discontinue, should complete EOT visit. 
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Table 2 - Study schedule for the open-label period  
Variable 
Visit 
Brain MRI 
Weeks 48, 96,144 and Week 192/end of treatment (EOT)0 visit 
EDSS 
Weeks 24, 48, 72, 96, 120, 144, 168, Week 192/EOT0 visit, and unscheduled 
relapse visits 
SDMT 
Weeks 24, 48, 72, 96, 120, 144, 168, Week 192/EOT0 visit 
Cognitive Battery Test 
Week 96 and Week 192/EOT0 visit 
Clinical Laboratory 
Transition, Weeks 4, 12, and then every 12 weeks up to the Week 192/EOT0  
Vital signs b 
Transition, Weeks 4, 8, 12, and then every 12 weeks up to the Week 192/EOT0 
ECG  
Week 192/EOT0 and after EOT0 if abnormality on EOT or ECG could not be 
performed at EOT (in exceptional circumstances). 
Immunoglobulins and TSH 
Week 96 and Week 192/EOT0 visit 
PK 
Weeks 2, 3, 4, 8, 12, 24, 36 and Week 192/EOT0 visit 
Physical examinations 
Weeks 12, 24, and then every 24 weeks up to the Week 192/EOT0 
Tanner assessment 
Every 24 weeks up to the Week 192/EOT0 for all patients (until complete sexual 
maturity). 
Note: For a regional or national emergency declared by a governmental agency, contingency measures are included in the protocol 
section 17.7. Remote visits and unscheduled visits may be planned for the collection of possible safety and/or efficacy data. 
a Patients who complete the open-label treatment period or who prematurely discontinue, should complete EOT visit 
b During remote visits, only weight should be collected. 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
This statistical analysis plan (SAP) is specified for efficacy and safety analyses with all data 
collected in the open-label period for the open label CSR. 
This section summarizes major changes to the protocol statistical section with emphasis on 
changes after study start (after the first patient was enrolled). 
The statistical section of the protocol for open label period was never changed in an amendment. 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN  
In this section summarize major changes in statistical analysis features made in approved SAP 
versions, with emphasis on changes after study start (after the first patient was enrolled).  
Statistical analysis for open-label period was not addressed in previous version of SAP or in 
amended protocol. The statistical analysis plan history table below gives the timing, rationale, and 
key details for major changes to the statistical analysis features in the statistical analysis plan. 
Changes also incorporated in a protocol amendment are cross-referenced to Table 3. 
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Table 3 - Statistical analysis plan statistical changes  
SAP 
version 
number 
Date 
approved 
Rationale 
Description of statistical changes 
1 
05-May-2019 
Many of the patients will be studied 
during the period of age-expected 
brain volume increase, thus brain 
atrophy is not appropriate 
Replace “brain atrophy” to “percentage change 
of brain volume”. 
1 
05-May-2019 
To explore long-term treatment effect 
in teriflunomide/teriflunomide and 
placebo/teriflunomide group 
Add annualized relapse rate (ARR) and time to 
sustained disability progression as additional 
endpoint in section 2.1.3.3 and 2.4.4.3. 
2 
 
To fulfill requirement from health 
authorities  
Added ethnicity in the demographic section 
2 
 
To investigate Covid-19 impact on 
study conduct and assessment of 
safety and efficacy of teriflunomide  
1) Added Covid-19 related disposition summary 
2) Added extent of exposure and compliance 
summary for Covid-19 impact. 
3) Added Covid-19 related adverse event 
analysis.  
3) Modified censoring rule for time-to-event 
endpoint and OL EOT analysis visit window for 
potential Covid-19 delay. 
2 
 
To correct typo  
Added 1 day for each of the target day and 
analysis visit windows in section 2.5.3  
 
 
 
 
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2 
STATISTICAL AND ANALYTICAL PROCEDURES  
The data from the double-blind and the open label teriflunomide treatment periods will be the 
focus of the CSR of their respective period. The following statistical methods/considerations in 
this SAP relate to the analysis of the data from the open label period. The analysis of the data 
from the double-blind period was addressed in a separate SAP. The optional additional extension 
period will be reported separately.  
2.1 
ANALYSIS ENDPOINTS  
2.1.1 Demographic and baseline characteristics  
The baseline value is defined as the last available value before the first intake of IMP in the 
double-blind period, unless otherwise specified. 
All baseline safety and efficacy parameters (apart from those listed below) are presented along 
with the on-treatment summary statistics in the efficacy and safety sections (see Section 2.4.4 and 
Section 2.4.5). 
Demographic characteristics 
Demographic variables are gender (Male, Female), race (Caucasian/white, Black, Asian/Oriental, 
other), ethnicity (Hispanic or Latino, Not Hispanic or Latino), region (definition of the regions are 
provided in Section 2.5.5), age in years at study consent of the double-blind period (quantitative 
and qualitative variable: <13, and ≥13 years), pubertal status, Tanner staging. 
Medical or surgical history 
Medical (or surgical) history includes concurrent illnesses, detailed neurological history and 
detailed vaccination history.  
This information will be coded using the version of Medical Dictionary for Regulatory Activities 
(MedDRA) currently in effect at Sanofi at the time of database lock. 
Disease characteristics at baseline  
Specific disease history includes the following: 
• Time since first diagnosis of Multiple sclerosis (MS) relative to randomization (in years)  
• Time since first symptoms of MS relative to randomization (in years)  
• Time since most recent relapse onset relative to randomization (in months)  
• MS type (relapsing remitting, progressive relapsing) 
• Number of relapses experienced within past 1 year (quantitative variable and qualitative 
variable: 0, 1, 2 and ≥3) 
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• Number of relapses experienced within past 2 years (quantitative variable and qualitative 
variable: 0, 1, 2, 3 and ≥4) 
• Number of relapses experienced overall (quantitative variable and qualitative variable: 
0, 1, 2, 3 and ≥4) 
• With previous MS medication in the last 2 years (Yes, No) 
• Total number of any events since onset of MS (0, 1, 2-5 and >5) and the subtype (Non 
encephalopathic Central nervous system (CNS) clinical events, Acute Disseminated 
Encephalomyelitis (ADEM), other event). 
Vital signs  
Vital signs at baseline as well as extension baseline (defined as the last available value before the 
first intake of IMP in the open-label extension period) are weight in kilograms (quantitative 
variable and qualitative variable: ≤40, >40), height in cm, Body Mass Index (BMI) in kg/m2. 
Other 
Alcohol habits within the last 12 months and smoking habits will also be summarized.  
Any technical details related to computation, dates, and imputation for missing dates are described 
in Section 2.5.  
2.1.2 Prior or concomitant medications  
All medications taken during the open-label period are to be reported in the case report form 
(CRF) pages. 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
using the version currently in effect at Sanofi at the time of database lock. 
• Prior medications are those the patient used prior to first investigational medicinal product 
(IMP) intake in the double-blind period. Prior medications can be discontinued before 
first IMP administration or can be ongoing during treatment period.  
• Concomitant medications are any treatments received by the patient concomitantly to the 
IMP, from the day of first IMP intake in the double-blind period to the day of last IMP 
intake in the open-label period 
• Follow-up medications are those the patient took running from the day after the last IMP 
intake in the open-label period up to the end of the open-label period 
Any technical details related to computation, dates, imputation for missing dates are described in 
Section 2.5. 
2.1.3 Efficacy endpoints  
Evaluation schedule for efficacy variables is presented in Table 1 and Table 2. 
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Note that all efficacy evaluations up to closeout measurement will be included for analysis unless 
otherwise specified. Baseline for efficacy variable is defined as the last non-missing value on or 
before the date of randomization in the double-blind period. For patients who have no value on or 
before randomization date, the last non-missing value on (at pre-dosing) or before the date of 
first dose intake in the double-blind period will be used as baseline. 
2.1.3.1 Primary efficacy endpoint(s)  
The primary efficacy endpoint is the time to first clinical relapse after randomization up to end of 
double-blind treatment period, which is not directly applicable for the open-label treatment period 
since Relapse Adjudication Panel (RAP) of the double-blind period was not continued into the 
open-label period. Refer to the SAP for the double-blind period of the study. 
However, time to first clinical relapse after randomization in double-blind period up to the end of 
the open-label treatment period will be performed on relapses with objective signs on the 
Examining Neurologist’s examination (which is the basis for RAP confirming relapses) as 
a primary efficacy endpoint for analysis period from randomization to the end of the open-label 
period. 
2.1.3.2 Secondary efficacy endpoint(s)  
The secondary efficacy endpoints pertaining to the open-label period are the following: 
• Time to first clinical relapse since enrollment into the open-label period up to the exit of 
the open-label treatment period  
• Proportion of clinical relapse free patients at 24, 48, 72, 96, 120, 144, 168 and 192 weeks 
• MRI endpoints at 48, 96, 144 and 192 weeks: 
- 
Number of new/newly enlarged T2 lesions 
- 
Number of Gd-enhancing T1 lesions 
- 
Change in volume of T2 lesions 
- 
Change in volume of T1 hypointense lesions 
- 
Number of new hypointense T1 lesions 
- 
Proportion of patients free of new or enlarged MRI T2 lesions  
- 
Percentage change of brain volume  
The number of new/newly enlarged T2 lesions and the number of Gd-enhancing T1 
lesions will be considered the key secondary imaging endpoints. 
• Cognitive outcome measured by the SDMT and Cognitive Battery Tests  
• Teriflunomide PK 
• Exploratory endpoint: proportion of disease-free patients. 
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2.1.3.3 Additional efficacy endpoints  
The following endpoints, which have not been planned in the protocol for the double-blind period, 
are added as relevant for efficacy analysis of the open-label period.  
• Annualized relapse rate (ARR) since the enrollment into the open-label period up to the 
exit of the open-label treatment period. 
• Time to sustained disability progression (using EDSS) since randomization in 
double-blind period up to the end of open-label treatment period. 
2.1.4 Safety endpoints  
The safety analysis will be based on the reported adverse events and other safety information, 
such as clinical laboratory data, vital signs, ECG, etc. 
Observation period 
The observation period of the open-label period will be divided into 3 epochs: 
• The treatment epoch is defined as the time from the first administration of the IMP in the 
open-label period to the last administration of the IMP in the open-label period. 
• The accelerated elimination epoch is defined as the time from 1 day after the open-label 
treatment epoch up to 4 weeks (28 days) after the last administration of the IMP in the 
open-label period or up to the first administration in optional additional extension period, 
whichever occurs first. 
The treatment-emergent adverse event (TEAE) period will include both treatment and accelerated 
elimination epochs. 
• The posttreatment epoch is defined as the period of time starting from the day after the 
end of the treatment-emergent adverse event period up to the end of the open-label period 
(defined as the first dose of optional additional extension IMP for patients enter optional 
additional extension period, or the last protocol-planned visit, EOT +4W, in the open-label 
period or the resolution/stabilization of a followed-up AE for patients do not enter). 
The on-study observation period is defined as the combination of TEAE period and posttreatment 
epoch. 
2.1.4.1 Adverse events variables  
Adverse event observation period 
• Treatment-emergent adverse events are adverse events that developed or worsened or 
became serious during the treatment-emergent adverse event period in the open-label 
period of the study. 
• Posttreatment adverse events are adverse events that developed or worsened or became 
serious during the posttreatment period in the open-label period of the study. 
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All adverse events, including serious adverse events (SAEs) and adverse events of special interest 
(AESI) will be coded to a lower-level term (LLT), preferred term (PT), high-level term (HLT), 
high-level group term (HLGT), and associated primary system organ class (SOC) using the 
version of Medical Dictionary for Regulatory Activities (MedDRA) currently in effect at Sanofi at 
the time of database lock.  
Record the occurrence of adverse events (including serious adverse events and AESI) from the 
time of signed informed consent until the end of the study. 
AESIs include the following terms: 
• Gastrointestinal disorders (Nausea and diarrhea) 
• Hepatic disorders 
• Pancreatic disorders 
• Bone marrow disorders 
• Infections and Infestations 
- 
A specific analysis of Covid-19 related adverse events will be performed, using the 
search terms described in Appendix D 
• Hypersensitivity 
• Severe skin reaction 
• Malignancy 
• Hypertension 
• Cardiac Arrhythmias 
• Pulmonary disorders (ILD) 
• Embolic and Thrombotic 
• Hemorrhage  
• Peripheral neuropathy 
• Convulsions  
• Alopecia 
• Psychiatric disorders  
Additional AESIs may be identified through the ongoing studies. The complete list of AESIs and 
details of the grouping algorithm will be finalized prior to the Database Lock (DBL).  
2.1.4.2 Deaths  
The deaths observation periods are per the observation periods defined above.  
• Death on-study: deaths occurring during the on-study observation period 
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• Death on-treatment: deaths occurring during the treatment-emergent adverse event period 
• Death post-study: deaths occurring after the end of the study (ie, the end of open-label 
period) 
2.1.4.3 Laboratory safety variables  
Clinical laboratory data consists of blood analysis, including hematology, clinical chemistry, and 
urinalysis. Clinical laboratory values after conversion will be analyzed into standard international 
units and international units will be used in all listings and tables. 
Blood samples for routine clinical laboratories will be taken at Screening, randomization, 
Weeks 4, 12 and then every 12 weeks up to the EOT (Week 96, premature treatment 
discontinuation visit and the time when patient switches to the open label period after a clinical 
confirmed relapse or high MRI activity whichever comes first) in the double-blind period, and 
then at transition, Weeks 4, 12 and then every 12 weeks up to the EOT (Week 192 or premature 
treatment discontinuation visit whichever comes first) in the open-label period. The laboratory 
parameters will be classified as follows:  
• Hematology 
- 
Red blood cells and platelets and coagulation: hemoglobin, hematocrit, mean 
corpuscular hemoglobin, red blood cell count, platelet count, prothrombin time, 
activated partial thromboplastin time 
- 
White blood cells: white blood cell count, neutrophils, lymphocytes, monocytes, 
basophils, eosinophils 
• Clinical chemistry 
- 
Metabolism: glucose, cholesterol, triglycerides, total protein, albumin, globulin, 
albumin/globulin ratio, creatine phosphokinase(CPK), serum amylase and lipase 
- 
Electrolytes: sodium, potassium, chloride, calcium, inorganic phosphorus, 
bicarbonate, magnesium  
- 
Renal function: creatinine, creatinine clearance, blood urea nitrogen (BUN), uric acid 
- 
Liver function: alanine aminotransferase(ALT), aspartate aminotransferase(AST), 
alkaline phosphatase, Gamma Glutamyl Transferase(GGT), lactate dehydrogenase 
(LDH), total bilirubin, direct/indirect bilirubin 
- 
Pregnancy test: Serum β-human chorionic gonadotropin (β-HCG) for pubescent 
females (NOTE: This test is performed at screening, randomization and then every 
12 weeks and EOT in the double-blind period, and then every 12 weeks and EOT in 
the open-label period)  
• Urinalysis - quantitative analyses: pH, ketones, protein, glucose, blood, urobilinogen, 
bilirubin, microscopic sediment and specific gravity  
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The following safety laboratory testing will be conducted in between clinical routine lab at 
Weeks 8, 16, 20, 30 and then every 12 weeks up to the EOT in the double-blind period, and then 
at Weeks 8, 16, 20, 30 and then every 12 weeks up to EOT in the open-label period measuring 
• Hematology (as above) 
• Liver function tests (ALT, AST, GGT, total bilirubin, and direct/indirect bilirubin) 
• Pancreatic enzymes (serum amylase and lipase). 
At EOT +2 weeks and EOT +4 weeks:  
• Uric acid and inorganic phosphorus will also be performed. 
Laboratory assessment for TSH will also be performed at randomization, every 24 weeks and 
EOT in the double-blind period, and then at Week 96 and EOT in the open-label period. 
Technical formulas are described in Section 2.5.1. 
2.1.4.4 Vital signs variables  
Vital signs include: radial heart rate,) systolic and diastolic blood pressure (standing and supine) 
and body temperature. Weight and height will be documented in the growth charts. 
2.1.4.5 Electrocardiogram variables  
A standard 12-lead ECG will be performed at randomization, EOT in the double-blind period and 
EOT in the open-label period and will be evaluated centrally. 
ECG parameters include heart rate, PR interval, QRS interval, QT, and corrected QTc (QTc 
interval calculated by Bazett’s method) and QTcF (QTc interval calculated by Fridericia’s 
method). 
2.1.4.6 Tanner scales  
The Tanner scale (also known as the Tanner Stages I-V) will be used to define physical 
measurements of growth and development ((including sexual development and endocrine 
function), based on external primary and secondary sex characteristics, such as the size of the 
breasts, genitalia, and development of pubic hair. 
Tanner stage will be performed at baseline, every 24 weeks and EOT (until the patient completes 
sexual maturity (defined by Tanner Stage 5).  
2.1.5 Pharmacokinetic variables  
Blood samples will be collected at Week 2, 3 and 4 (PK run-in [8 weeks] period), 12, 24, 36 and 
EOT visit or in case of overdose in the double-blind and open-label period. An additional sample 
may be required during the PK run-in period in case of inadequate sampling or 
information/variability. 
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2.1.6 Immunoglobulins  
Serum immunoglobulins concentration (IgG, IgM and IgA) will be performed at randomization 
and every 24 weeks up to Week 96/EOT in the double-blind period, and then at Week 96 and 
Week 192/EOT in the open-label period. 
In addition if a patient has a vaccination, antibody titers will be assessed before and after 
vaccination (only inactivated vaccines are allowed). 
2.2 
DISPOSITION OF PATIENTS  
This section describes patient disposition for both patient study status and the patient analysis 
populations. 
All the tables in this section will be presented by the treatment groups the patients were allocated 
to in the double-blind and open-label period (placebo/teriflunomide versus 
teriflunomide/teriflunomide) as well as the overall treatment group.  
Enrolled patients are defined as any patient who entered the open-label period and where signed 
informed consent/assent was re-obtained from the patient and patient’s legal representative 
(parents or guardians) according to local regulations when they enter the open-label period of the 
study. 
For patient study status, the total number of patients in each of the following categories will be 
presented in the clinical study report using a flowchart diagram or summary table: 
• Patients who were randomized and treated in the double-blind period 
• Patients who completed the double-blind period 
• Patients who discontinued from the double-blind period 
• Enrolled patients in the open-label period 
• Patients who enrolled but were not treated in the open-label period 
• Patients who completed the open-label treatment period 
• Patients who discontinued open-label treatment period 
• Patients who discontinued open-label treatment by main reason for permanent treatment 
discontinuation in the open-label period 
• Patient’s decision to permanently discontinue the treatment in the open-label period. 
For all categories of patients, percentages will be calculated using the number of enrolled patients 
as the denominator. Reasons for treatment discontinuation will be supplied in tables giving 
numbers and percentages by treatment group. 
The Covid-19 related disposition information will be summarized separately including number of 
patients were impacted by the Covid-19, Covid-19 related reasons for permanent treatment 
discontinuation. The summary of disposition by visit impacted by the Covid-19 will be 
summarized if applicable.  
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Patients who did not complete the study and for whom no end-of-treatment data are available will 
be considered as lost to follow-up.  
All critical or major deviations potentially impacting efficacy analyses, drug-dispensing 
irregularities, and other major or critical deviations will be summarized in tables giving numbers 
and percentages of deviations by treatment group. The critical or major deviations that related to 
the Covid-19, regardless of deviation categories, will be summarized by treatment group 
separately. 
Kaplan-Meier estimates of the cumulative incidence of permanent IMP discontinuation for any 
reason will be provided for open-label period. Time to withdrawal will be defined as the number 
of days from the first open-label IMP intake date until the last IMP intake date for the open-label 
period. Patients who complete the open-label period will be censored at the date of end of the 
open-label period. A listing of patients, along with reasons for treatment discontinuation, will be 
provided with their relationship with Covid-19. 
Additionally, the analysis populations for safety, efficacy, and pharmacokinetics (See Section 2.3) 
will be summarized in a table by number of patients on the enrolled population.  
• Efficacy population  
• Safety population 
• Pharmacokinetics population. 
2.3 
ANALYSIS POPULATIONS  
2.3.1 Enrolled population  
The enrolled population is defined as patients who were randomized in the double-blind period 
and enrolled in open-label period analyzed according to the treatment group allocated by 
randomization in double-blind period (ie, placebo/teriflunomide versus 
teriflunomide/teriflunomide).  
2.3.2 Efficacy population  
The efficacy population is defined as all patients enrolled and were treated with at least 1 dose of 
teriflunomide in the open-label treatment period analyzed according to the treatment group 
allocated by randomization in the double-blind period (ie, placebo/teriflunomide versus 
teriflunomide/teriflunomide).  
2.3.3 Safety population  
The safety population is defined as all patients enrolled in the open-label treatment period and 
received any dose of teriflunomide in the open-label period. It will be used for the safety analyses 
in the open-label period. 
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The safety analyses will be conducted according to the treatment patients actually received in the 
double-blind and open-label period (placebo/teriflunomide versus teriflunomide/teriflunomide) as 
well as the overall treatment group. 
2.3.4 Pharmacokinetic population  
The PK population is a subset of the safety population containing patients who have at least 
one PK sample taken in the open-label period. Patients will be analyzed in the treatment group 
corresponding to the treatment actually received as defined for the safety population. 
2.4 
STATISTICAL METHODS  
2.4.1 Demographics and baseline characteristics  
All demographics and baseline characteristics parameters will be summarized on the enrolled 
population analyzed in the treatment group to which they were allocated to in the double-blind 
and open-label period (placebo/teriflunomide versus teriflunomide/teriflunomide) as well as the 
overall treatment group. Analyses for the safety population will be included in the appendices if 
the size of the safety population is different (>10%) from the size of that in the efficacy 
population for any treatment group. 
Continuous data will be summarized using the number of available data, mean, standard 
deviation (SD), median, minimum, and maximum for any treatment group. Categorical and 
ordinal data will be summarized using the number and percentage of patients with non-missing 
data (unless otherwise noted) in any treatment group.  
Parameters described in Section 2.1.1 will be summarized by treatment group and overall 
treatment groups using descriptive statistics. P-values or statistics tests on demographic and 
baseline characteristic data will not be calculated. 
Medical and surgical history 
Medical and surgical history will be summarized by primary SOC and HLT for each treatment 
group. The table will be sorted by SOC internationally agreed order and decreasing frequency of 
HLT based on the overall incidence in the overall treatment group. 
No specific description of the safety parameters will be provided at baseline. If relevant, the 
baseline values will be described along with each safety analysis. 
No specific description of the efficacy parameters will be provided at baseline. If relevant, the 
baseline values will be described along with each efficacy analysis. 
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2.4.2 Prior or concomitant medications  
The prior or concomitant medications will be presented for the enrolled population. Analyses for 
the safety population will be included in the appendices if the size of the safety population is 
different (>10%) from the size of that in the efficacy population for any treatment group. 
Medications will be summarized by placebo/teriflunomide, teriflunomide/teriflunomide and 
overall treatment groups according to the WHO-DD dictionary, considering the first digit of the 
Anatomic Therapeutic Chemical (ATC) class (anatomic category) and the first 3 digits of the 
ATC class (therapeutic category). All ATC codes corresponding to a medication will be 
summarized, and patients will be counted once in each ATC category (anatomic or therapeutic) 
linked to the medication. Therefore patients may be counted several times for the same 
medication.  
The table for prior medications will be sorted by decreasing frequency of ATC followed by all 
other therapeutic classes based on the incidence in the overall treatment groups. In case of equal 
frequency regarding ATCs (anatomic or therapeutic categories), alphabetical order will be used. 
The tables for concomitant and follow-up medications will be sorted by decreasing frequency of 
ATC followed by all other therapeutic classes based on the incidence in the overall treatment 
group. In case of equal frequency regarding ATCs, alphabetical order will be used.  
In addition, prior MS medication, the inducers and systemic corticosteroid treatment for MS 
relapse will be analyzed by number and percentage of confirmed relapse requiring steroid 
treatment. 
2.4.3 Extent of investigational medicinal product exposure and compliance  
The extent of IMP exposure and compliance in the open-label period will be assessed and 
summarized by actual treatment (placebo/teriflunomide, teriflunomide/teriflunomide and overall 
treatment group) within the safety population (Section 2.3.3). 
2.4.3.1 Extent of investigational medicinal product exposure  
The extent of IMP exposure will be assessed by the duration of IMP exposure in the open-label 
period of the study. 
Duration of open-label IMP exposure is defined as last dose date of teriflunomide - first dose date 
of teriflunomide +1 day in the open-label period, regardless of unplanned intermittent 
discontinuations (see Section 2.5.2 for calculation in case of missing or incomplete data). 
Duration of open-label IMP exposure will be summarized descriptively as a quantitative variable 
(number, mean, SD, median, minimum, and maximum). In addition, duration of treatment 
exposure will also be summarized categorically by numbers and percentages for each of the 
following categories and cumulatively according to these categories: >0 to ≤4 weeks, >4 to 
≤12 weeks, >12 to ≤24 weeks, >24 to ≤48 weeks, >48 to ≤72 weeks, >72 to ≤96 weeks, >96 to 
≤120 weeks, >120 to ≤144 weeks, >144 to ≤168 weeks, >168 to <192 weeks and ≥192 weeks. 
The number and percentage of patients by final open-label IMP dose and by dose at the end of PK 
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run-in of the open-label period will also be presented by each treatment group. A list of the 
patients who changed dose after the end of the PK run-in of the open-label period will be 
provided. The number and percentage of patients with each open-label IMP dose level by visit and 
with dose increase/decrease/unchanged by visit will also be presented by each treatment group if 
necessary. Cumulative exposure of the IMP taken in the double-blind and open-label treatment 
periods will be summarized with descriptive statistics from the first dose of IMP in the double-
blind period to the last dose of IMP in the open-label period for each treatment group. 
2.4.3.2 Compliance  
A given administration will be considered noncompliant if the patient did not take the planned 
dose of treatment as required by the protocol. No imputation will be made for patients with 
missing or incomplete data.  
Percentage of compliance for a patient will be defined as the number of administrations that the 
patient was compliant divided by the total number of administrations that the patient was planned 
to take during the treatment epoch defined in Section 2.1.4. 
Above-planned dosing percentage for a patient will be defined as the number of administrations 
that the patient took a higher dose than planned divided by the total number of administrations 
that the patient was planned to take during the treatment epoch.  
Under-planned dosing percentage for a patient will be defined as the number of administrations 
that the patient took a lower dose than planned divided by the total number of administrations that 
the patient was planned to take during the treatment epoch. 
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Treatment compliance, above-planned, and under-planned dosing percentages will be summarized 
descriptively as quantitative variables (number, mean, SD, median, minimum, and maximum). 
The percentage of patients whose compliance is <80% will be summarized. In addition, numbers 
and percentages of patients with at least 1 above-planned dose administration will also be 
provided, as well as numbers and percentages of patients with 0, (0, 20%], and >20% under-
planned dose administrations.  
In order to address impact of the Covid-19 pandemic, Covid-19 impacted compliance summary 
will be provided based on safety population including but not limit to the below items. 
• 
Number of patients who used Direct-to-patient (DTP) 
• 
Number of patients who did not compliant to the protocol IMP administration due to the Covid-19 
(e.g. dose interruption, dose prolongation, etc.) 
• 
Number of patients who had dose interruption due to the Covid-19  
• 
Duration of non-compliant period due to the Covid-19 
• 
Duration of dose interruption period due to the Covid-19. 
Treatment compliance will also be summarized by group (3.5 mg, 7 mg, and 14 mg teriflunomide 
at the end of PK run-in phase of the open-label period) and baseline body weight (≤40, >40 kgs). 
2.4.4 Analyses of efficacy endpoints  
All the following efficacy analysis will be conducted on efficacy population, according to the 
treatment group allocated by randomization in the double-blind period (ie, placebo/teriflunomide 
versus teriflunomide/teriflunomide). Baseline values of the double-blind period will be used as the 
baseline in the efficacy analysis for the open-label CSR, unless otherwise noted.  
Analyses of efficacy endpoints of the open-period period are of exploratory intent in principle. 
Long-term treatment effects and the 95% confidence intervals, where applicable, will be assessed 
since the randomization date in the double-blind period throughout the last visit of the open-label 
period of the study; unless otherwise noted. P-values will be provided if applicable. No 
confirmative conclusion should be drawn based on p-value because of exploratory nature of open-
label period analysis. 
2.4.4.1 Analysis of primary efficacy endpoint  
Clinical relapses are defined as new or recurrent neurological symptoms not associated with fever 
or infection, lasting at least 24 hours, and accompanied by new objective neurological findings 
upon examination by the Examining Neurologist and documented by the Functional System 
Scores (FSS).New or recurrent symptoms that occur less than 30 days following the onset of 
a relapse are considered part of the same relapse.  
Note that the process of confirmation of clinical relapse is different between the double-blind 
period and the open-label period. Confirmation in the double-blind period involves the Relapse 
Adjudication Panel (RAP), whereas confirmation in the open-label period is done by the 
investigative center. However, some analyses will combine confirmed relapses from both 
treatment periods, as the criteria used in the two processes are similar.  
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The first clinical confirmed relapse occurring from randomization in the double-blind period 
(including relapses during the PK run-in (8 weeks) phase) to the end of the open-label period will 
be included for analysis. Treatment effect as measured by the hazard ratio and its associated 
95% confidence interval will be estimated using a Cox proportional-hazards model with robust 
variance estimation (1). Cox model will include factors for treatment group, region, pubertal 
status, age, and number of relapses in the year prior to randomization. The duration of time to the 
event will be included in the modeling to offset the lengths of individual observations. Kaplan-
Meier estimates of probability of clinical relapse at Week 24, 48, 72, 96, 120, 144, 168 and 
192 will be estimated. The complementary log-log transformation will be used to construct 
95% confidence intervals. A Kaplan-Meier survival curve from randomization in double-blind 
period to the end of open-label period will be presented. A stratified log-rank test with time to 
first clinical relapse as the dependent variable, treatment group as a test variable, region 
(definition of the regions are provided in Section 2.5.5), and pubertal status as covariates will be 
provided as supportive.  
Censoring rule 
If a patient has no clinical relapse after randomization in double-blind period and before treatment 
discontinuation/completion in the open-label period, the patient will be considered as free of 
relapse till the date of last IMP administration reported on the EOT page. If this date is missing, 
last dose date on the IMP administration page will be used.  
Given that confirmation of relapse in the open-label period is based on objective neurological 
examinations, it is possible that a patient remained on treatment but did not perform any objective 
neurological examinations due to Covid-19 pandemic. If a patient reported suspected MS relapse 
and had no objective neurological examinations assessed afterwards due to the pandemic, the 
censor date will be the date of the last EDSS or FSS assessment. 
2.4.4.2 Analyses of secondary efficacy endpoints  
2.4.4.2.1 Time to first clinical relapse after enrollment of open-label period up to the end of 
open-label period  
The first clinical relapse occurring from enrollment of open-label period to the end of the open-
label period will be included for analysis. Hazard ratio with associated 95% confidence interval, 
Kaplan-Meier estimates and its 95% confidence interval will be presented using the same method 
as described in Section 2.4.4.1. A stratified log-rank test with time to first clinical relapse as the 
dependent variable, treatment group as a test variable, region (definition of the regions are 
provided in Section 2.5.5), and pubertal status as covariates will be provided. 
Censoring rule 
If a patient has no clinical relapse after enrollment in open-label period and before treatment 
discontinuation/completion in the open-label period, the patient will be considered as free of 
relapse till the date of last IMP administration reported on the EOT page. If this date is missing, 
last dose date on the IMP administration page will be used. 
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Given that confirmation of relapse in the open-label period is based on objective neurological 
examinations, it is possible that a patient remained on treatment but did not perform any objective 
neurological examinations due to Covid-19 pandemic. If a patient reported suspected MS relapse 
and had no objective neurological examinations assessed afterwards due to the pandemic, the 
censor date will be the date of the last EDSS or FSS assessment. 
2.4.4.2.2 The proportion of clinical relapse-free patients  
The proportion of patients with clinical relapse-free at Weeks 24, 48, 72, 96, 120, 144, 168 and 
192 will be estimated based on Kaplan-Meier methods. The complementary log-log 
transformation will be used to construct 95% confidence intervals. A Kaplan-Meier graph 
summarizing the event probability over time will be presented. 
2.4.4.2.3 Magnetic resonance imaging (MRI) variables  
General rules for MRI variables 
The protocol requires that the MRI should not be performed until after a minimum of 14 days 
following completion of corticosteroid therapy. Thus, MRI values obtained within 14 days of 
systemic corticosteroid therapy will be excluded from the analysis. 
Baseline for MRI variables is defined as the last non-missing, valid MRI value that was measured 
before or on the day of first administration of IMP in the double-blind period. A previous MRI 
performed in the 6 weeks preceding randomization could be used as the baseline if performed 
according to the specifications for this study. For valid MRI values in subsequent post baseline 
visits, time windows (see Table 4 and Table 5 in Section 2.5.3) between visits will be used to 
capture MRI measurements. For multiple records within a visit window, the one closest to the 
targeted visit date will be used. 
Number of lesions 
The number of new or enlarged T2 lesions per MRI scan will be analyzed using a negative 
binomial regression model with robust variance estimation. The model will include the total 
number of new or enlarged T2 lesions as the response variable, with treatment group, region, 
pubertal status and age as covariates. In order to account for different numbers of MRI scans 
performed among patients, the log-transformed number of scans will be included in the model as 
an offset variable. The robust error variances can be estimated by specifying the patient identifier 
in the repeated statement using SAS PROC GENMOD. The estimated number of lesions per scan 
and associated 2-sided 95% confidence interval (CI) will be provided for each treatment group.  
The number of T1 Gd-enhancing lesions per MRI scan and the number of new T1 hypointense 
lesions per MRI scan will be analyzed using a similar negative binomial regression model as 
described above for T2 lesions. 
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Volume of lesions and brain 
Descriptive statistics of the change from baseline in volume of T2 lesions, T1 hypointense lesions 
and the percentage change of brain volume in the original scale will be summarized at each visit 
by treatment group. 
The proportion of patients free of new or enlarged T2 lesions 
The proportion of patients free of new or enlarged T2 lesions at Weeks 48, 96, 144 and 192 will 
be summarized based on all patients having an MRI at these time points. Kaplan-Meier methods 
will be used for estimation. 
Censoring rule 
If a patient has no new or enlarged T2 lesions detected by MRI scan before treatment 
discontinuation/completion in the open-label treatment period, the patient will be considered as 
free of new or enlarged T2 lesions till the date of last during-treatment MRI assessment. The last 
during-treatment MRI assessment is defined as last MRI assessment before treatment 
discontinuation/completion in the treatment period. In rare cases, if a patient had a delayed MRI 
scheduled during the open-label period but performed after the open-label EOT visit due to the 
Covid-19 pandemic, then the delayed MRI result will be considered in the open-label analysis. 
This MRI assessment is considered as during-treatment assessment. 
2.4.4.2.4 EDSS  
EDSS score and the change from baseline in EDSS score in the double-blind period will be 
summarized with descriptive statistics at each visit by treatment group. 
2.4.4.2.5 Cognitive outcome  
The change from baseline in Cognitive Battery Tests and SDMT will be summarized 
descriptively. Box plot will be provided as well. 
2.4.4.2.6 Disease free patient  
Disease-free patients were defined as patients with  
• No confirmed clinical relapse. 
• No 24-week sustained disability progression (≥0.5-point EDSS score increase if baseline 
EDSS score >5.5 or ≥1-point EDSS score increase from baseline if baseline EDSS score 
≤5.5, persisting for ≥24 weeks). 
• Free of MRI activity: No Gd-enhancing T1 lesions and no new/enlarging T2 lesions. 
Alternative definitions of disease-free status, eg, using cognitive information may be additionally 
explored.  
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The proportion of disease-free patient at Weeks 48, 96, 144 and 192 will be summarized based on 
all patients having an MRI at these time points. Kaplan-Meier methods will be used for 
estimation. 
2.4.4.3 Analysis of additional efficacy endpoint  
2.4.4.3.1 Annualized relapse rate  
The annualized relapse rate (ARR) is defined as the number of confirmed clinical relapses occurred 
during the study per patient-year. It will be analyzed in open-label period only. A confirmed 
clinical relapse is defined as the appearance of a new clinical sign/symptom or clinical worsening 
of a previous sign/symptom (one that had been stable for at least 30 days) that persists for 
a minimum of 24 hours in the absence of fever. Each episode of relapse must be confirmed by the 
treating neurologist, based on the objective assessments by an independent evaluator (the 
examining neurologist) by documenting either of the following: 
A) A 1-point increase in at least two FS functions, or a 2-point increase in at least one FS 
function (excluding bowel/bladder and cerebral) from the previous clinically stable 
assessment, or; 
B) An increase of at least 0.5 point in EDSS score (unless EDSS=0, then an increase of at least 
1.0 point is required) from the previous clinically stable assessment. 
Relapses are collected on CRF page “MS relapse”. The objective confirmation, based on the 
protocol-defined criteria, is reported (Yes/No) in the CRF. Only confirmed clinical relapses will 
be used in the analysis. 
A gross estimate of annualize d relapse rate for a treatment group would be the total number of 
relapses for patients in the treatment group divided by the sum of standardized study durations for 
patients in the treatment group. Total number of confirmed clinical relapses and standardized study 
duration will be calculated for each patient. 
• Total number of confirmed clinical relapses is defined as the number of confirmed clinical 
relapses with onset between enrollment date of the open-label period and treatment 
discontinuation/completion date (same as last dose IMP intake date). 
• Standardized study duration (in year) will be calculated by (last dose IMP intake date - 
enrollment date of the open-label period + 1) / 365.25. 
Adjusted ARR will be performed using a Poisson regression model with robust error variance 
that would accommodate the potential over-dispersed data appropriately. The model will 
include the total number of clinical relapses as the response variable, treatment group as the test 
variable, pubertal status, and region as covariates. In order to account for different treatment 
durations among subjects, the log-transformed standardized treatment duration will be included 
in the model as an “offset” variable for appropriate computation of relapse rate. The robust error 
variances can be estimated by specifying the patient identifier in the repeated statement using 
SAS PROC GENMOD, and this is equivalent to the Generalized Estimating Equation (GEE) 
model. In comparison to the regular Poisson model, the GEE estimator is robust against 
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violation of the correlation structure and the distributional assumptions. The treatment-by-strata 
and treatment-by-region interactions will be evaluated separately at the 5% level of significance 
by adding the corresponding interaction term to the model. If a statistically significant 
interaction is detected at p <0.05, further investigations will be performed for the possibility of 
qualitative interaction. 
The estimated relapse rates and 2-sided 95% confidence intervals will be provided for each 
treatment group. Nelson-Aalen mean cumulative function plot will be provided for descriptive 
purposes. 
2.4.4.3.2 Time to sustained disability progression (using EDSS)  
The time to sustained disability progression will be assessed by EDSS during the study. The first 
disability progression (ie, confirmed disability worsening) is defined as a sustained increase of at 
least 1.0 point (0.5 for subjects with baseline EDSS >5.5) persisting for at least 24 weeks from 
baseline EDSS in the double-blind period of the study.  
The minimum EDSS increase used to define disability progression is referred to as “minimum 
increase” in the following text. The initial EDSS increase that meets this “minimum increase” 
criterion is referred to as “the onset”. An EDSS measurement at or after 24 weeks following the 
onset is necessary to confirm the initial increase and is referred to as “24-week EDSS 
confirmation”. All EDSS measurements (with or without relapse) will be used to determine the 
onset of a disability progression. However, for the purpose of confirmation, only EDSS 
measured more than 30 days after the onset of a confirmed relapse will be used to avoid 
a confirmation caused by a temporary relapse. In order to confirm that the EDSS increase is 
persistent for at least 24 weeks, the following conditions have to be satisfied: (1) The 24-week 
EDSS confirmation needs to maintain at least the minimum increase; (2) all EDSS measurements 
between the onset and the 24-week EDSS confirmation need to maintain at least the minimum 
increase. Once a disability progression is confirmed, time to disability progression is defined as 
“date of onset - date of randomization (in the double-blind period) + 1”. If a patient has no 
disability progression on or before last during treatment EDSS evaluation, then the patient is 
considered as disability progression free until the date of last during treatment EDSS evaluation. 
The last during treatment EDSS evaluation is defined as last measurement during treatment period 
(measurement at last scheduled visit for patients who complete the treatment, or measurement at 
the close-out visit for patients who discontinue the treatment). 
If a patient dies for any reason without a 24-week EDSS confirmation, the disability progression 
will be considered as confirmed with the date of the onset as the date of progression unless any 
EDSS measured within the 24 weeks did not maintain the minimum increase. Death due to MS 
(EDSS=10) will be counted as confirmed progression. The progression date is the date of death 
if there is no prior qualifying EDSS increase and it is the date of the first qualifying EDSS 
increase if there is such an EDSS increase prior to the death. All the derivation will be based on 
the exact EDSS evaluation date. Since the actual visit may have been +/-7 days from the 
scheduled visit, a -7 days window will be used to define the period of 24 weeks. 
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Censoring rules 
• If a patient has no EDSS increase that meets the criteria for progression before treatment 
discontinuation/completion, then the patient will be considered as free of progression till 
the date of last during-treatment EDSS evaluation. 
• If a patient has an EDSS increase that meets the criteria for progression before treatment 
discontinuation, all available EDSS assessments obtained during the follow-up visits will 
be used to serve the purpose of progression confirmation. The patient will be considered as 
having disability progression if the first increase during treatment period is confirmed for at 
least 24 weeks during the follow-up visits. If the EDSS from the follow-up visit(s) does 
not confirm a sustained increase or despite all possible attempts, no confirmatory EDSS 
assessment is obtained after withdrawal, the patient will be considered as free of disability 
progression until the date of last during treatment EDSS evaluation. 
• If a patient has an EDSS increase that meets the criteria for progression and completes the 
treatment period before the progression can be confirmed, then the patient will be 
considered as free of progression till the date of last during-treatment EDSS evaluation. 
• In rare cases, if a patient had a delayed EDSS scheduled during the open-label period but 
performed during the optional extension period due to the Covid-19 pandemic, then this 
assessment will still be considered as during-treatment EDSS evaluation. The delayed 
EDSS result will be considered in the sustained disability progression determination 
process in the open-label analysis.  
• In rare cases, if a patient had a delayed EDSS scheduled during the open-label period but 
performed after treatment discontinuation due to the Covid-19 pandemic, then the delayed 
EDSS result will be used for progression confirmation purpose only. 
The hazard ratio and 95%CI for teriflunomide/teriflunomide versus placebo/teriflunomide will be 
estimated using Cox regression model with treatment group, region and baseline pubertal status as 
covariates, offset by the lengths of individual observations. 
The Kaplan-Meier method will be used to estimate median time (if possible) to disability 
progression sustained for at least 24 weeks and cumulative disability progression rates specific to 
each treatment group. Kaplan-Meier graphs will be generated; quartiles and point probabilities 
will be calculated. Interval estimates will be calculated using 95% point wise confidence 
intervals. 
2.4.4.4 Multiplicity issues  
Statistical significance will be claimed for the primary efficacy endpoint (time to first clinical 
relapse after randomization) of the double-blind period only, if the computed p-value from this 
primary analysis with a 2-sided log-rank test is <0.05.  
Efficacy analyses performed for primary and secondary endpoints of the open-label period are of 
exploratory intent in principle to better understand treatment effects of teriflunomide monotherapy 
beyond the double-blind period in the pediatric population. The step-down testing procedure for 
controlling multiplicity will not be applied to these exploratory analyses in the open-label period. 
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2.4.5 Analyses of safety data  
The summary of safety results will be presented by treatment patients actually received in the 
double-blind and open-label period (placebo/teriflunomide and teriflunomide/teriflunomide) and 
overall treatment group. Baseline values of the double-blind period will be used as the baseline in 
the safety analysis for the open-label CSR, unless otherwise noted.  
General common rules 
All safety analyses will be performed on the safety population as defined in Section 2.3.3, unless 
otherwise specified, using the following common rules: 
• Safety data in patients who do not belong to the safety population will be listed separately. 
• The baseline value is defined as the last available value before the first intake of IMP in 
the double-blind period. 
• The potentially clinically significant abnormality (PCSA) values are defined as abnormal 
values considered medically important by the Sponsor according to predefined 
criteria/thresholds based on literature review and defined by the Sponsor for clinical 
laboratory tests, vital signs, and ECG (PCSA version dated May 2014 [Appendix A]). 
• PCSA criteria will determine which patients had at least 1 PCSA during the treatment-
emergent adverse event period, taking into account all evaluations performed during the 
treatment-emergent adverse event period, including nonscheduled or repeated evaluations. 
The number of all such patients will be the numerator for the on-treatment PCSA 
percentage. 
• The treatment-emergent PCSA denominator by group for a given parameter will be based 
on the number of patients assessed for that given parameter in the treatment-emergent 
adverse event period by treatment group on the safety population. 
• For quantitative safety parameters based on central laboratory/reading measurements, 
descriptive statistics will be used to summarize results and change from baseline values of 
the double-blind period by visit and treatment group. Summaries will include the endpoint 
value and/or the minimum and maximum value. The endpoint value is commonly defined 
as the value collected at the same day/time of the last administration of IMP in the open-
label period. If this value is missing, this endpoint value will be the closest value prior to 
the last dose intake.  
• All the values including unscheduled measurements will be assigned to the appropriate 
safety analysis visit window. In the presence of multiple measurements of the same test in 
the same window (see Table 6 and Table 7 in Section 2.5.3), the one closest to the targeted 
visit date will be used for the by-visit summaries. 
• The analysis of the safety variables will be essentially descriptive and no systematic 
testing is planned. 
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2.4.5.1 Analyses of adverse events  
Generalities 
The primary focus of adverse event reporting will be on treatment-emergent adverse events 
(TEAEs) in the open-label period. Posttreatment adverse events will be described separately.  
TEAEs will be further differentiated as "TEAEs during treatment epoch" and "TEAEs during 
accelerated elimination epoch". TEAEs during treatment epoch and TEAEs during accelerated 
elimination epoch will be analyzed separately and combined, as applicable.  
If an adverse event date/time of onset (occurrence, worsening, or becoming serious) is incomplete, 
an imputation algorithm will be used to classify the adverse event as treatment-emergent, or 
posttreatment. The algorithm for imputing date/time of onset will be conservative and will classify 
an adverse event as treatment emergent unless there is definitive information to determine it is 
posttreatment. Details on classification of adverse events with missing or partial onset dates are 
provided in Section 2.5.2. 
Adverse event incidence tables will present by SOC, HLGT, HLT, and PT, sorted in alphabetical 
order for each treatment group, the number (n) and percentage (%) of patients experiencing 
an adverse event. Multiple occurrences of the same event in the same patient will be counted only 
once in the tables within a treatment period. The denominator for computation of percentages is 
the safety population within each treatment group. 
Sorting within tables ensures the same presentation for the set of all adverse events within the 
observation period (treatment-emergent, and posttreatment). For that purpose, the table of all 
treatment-emergent adverse events presented by SOC and PT sorted by the internationally agreed 
SOC order and decreasing frequency of PTs within SOCs will define the presentation order for all 
other tables unless otherwise specified. Sorting will be based on results for the overall treatment 
group. 
Analysis of all treatment-emergent adverse events 
The following treatment-emergent adverse event summaries will be generated for the safety 
population. 
• Overview of treatment-emergent adverse events, summarizing number (%) of patients 
with any 
- 
Treatment-emergent adverse event 
- 
Serious treatment-emergent adverse event 
- 
Treatment-emergent adverse event leading to death 
- 
Treatment-emergent adverse event leading to permanent treatment discontinuation 
• All treatment-emergent adverse event by primary SOC, HLGT, HLT, and PT, showing 
number (%) of patients with at least 1 treatment-emergent adverse event sorted by the 
SOC internationally agreed order. The other levels (HLGT, HLT, PT) will be presented in 
alphabetical order. 
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• All treatment-emergent adverse events by primary SOC and PT, showing the number (%) 
of patients with at least 1 treatment-emergent adverse event, sorted by the internationally 
agreed SOC order and by decreasing incidence of PTs within each SOC. This sorting order 
will be applied to all other tables, unless otherwise specified. 
• Common TEAEs (incidence ≥2% in any treatment group for PT) by primary SOC, HLGT, 
HLT, and PT, showing number (%) of patients with at least one common TEAE, sorted by 
the internationally agreed SOC order. The other levels (HLGT, HLT, and PT) will be 
presented in alphabetical order. 
• All treatment-emergent adverse events regardless of relationship and related by primary 
SOC, HLGT, HLT and PT, showing the number (%) of patients with at least 1 treatment-
emergent adverse event, sorted by the internationally agreed SOC order. The other levels 
(HLGT, HLT, PT) will be presented in alphabetical order. 
• All treatment-emergent adverse events by maximal severity, presented by primary SOC 
and PT, showing the number (%) of patients with at least 1 treatment-emergent adverse 
event by severity (ie, mild, moderate, or severe), sorted by the sorting order defined above. 
• Number (%) of patients experiencing treatment-emergent adverse event(s) presented by 
primary and secondary SOC, HLGT, HLT, and PT sorted by the internationally agreed 
SOC order. The other levels (HLGT, HLT, PT) will be presented in alphabetical order 
• Number (%) of patients experiencing TEAE(s) presented by PT, sorted by decreasing 
incidence of PT. 
• By patient listing of TEAE(s) occurred within 2 months after first dose increase for 
teriflunomide treated patients showing treatment group, patient identified, age, gender, 
race, primary SOC decode, PT decode, verbatim (diagnosis), onset date and study day, 
date of death (if relevant), recovery date/time, event duration, outcome, intensity/grade, 
relationship to study treatment, action taken with study treatment and corrective 
treatment/therapy, AE serious criteria, flag for AE status, and Covid-19 related flag. 
Analysis of all treatment emergent serious adverse event(s) 
• All treatment-emergent serious adverse events by primary SOC, HLGT, HLT, and PT, 
showing the number (%) of patients with at least 1 serious treatment-emergent adverse 
event, sorted by the internationally agreed SOC order. The other levels (HLGT, HLT, PT) 
will be presented in alphabetical order. 
• All treatment-emergent serious adverse events by primary SOC and PT, showing the 
number (%) of patients with at least 1 serious treatment-emergent adverse event, sorted by 
the internationally agreed SOC order and by decreasing incidence of PTs within each 
SOC. 
• All treatment-emergent serious adverse events regardless of relationship and related to 
IMP, by primary SOC, HLGT, HLT, and PT, showing the number (%) of patients with at 
least 1 treatment-emergent serious adverse event, sorted by the internationally agreed SOC 
order. The other levels (HLGT, HLT, PT) will be presented in alphabetical order. 
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• Number (%) of patients with at least one treatment-emergent serious adverse events by 
seriousness criteria. 
• By-patient listing of treatment-emergent SAEs showing treatment group, patient 
identified, age, gender, race, primary SOC decode, PT decode, verbatim (diagnosis), onset 
date and study day, date of death (if relevant), recovery date/time, event duration, 
outcome, intensity/grade, relationship to study treatment, action taken with study treatment 
and corrective treatment/therapy, AE serious criteria, flag for AE status, and Covid-19 
related flag. 
Analysis of all treatment-emergent adverse event(s) leading to treatment discontinuation 
• All treatment-emergent adverse events leading to treatment discontinuation, by primary 
SOC, HLGT, HLT, and PT, showing the number (%) of patients sorted by the 
internationally agreed SOC order. The other levels (HLGT, HLT, PT) will be presented in 
alphabetical order. 
• All treatment-emergent adverse events leading to treatment discontinuation, by primary 
SOC and PT, showing the number (%) of patients sorted by the internationally agreed 
SOC order and by decreasing incidence of PTs within each SOC.  
• By-patient listing of TEAEs leading to treatment discontinuation showing treatment group, 
patient identified, age, gender, race, primary SOC decode, PT decode, verbatim 
(diagnosis), onset date and study day, date of death (if relevant), recovery date/time, event 
duration, outcome, intensity/grade, relationship to study treatment, action taken with study 
treatment and corrective treatment/therapy, AE serious criteria, flag for AE status, flag for 
seriousness, and Covid-19 related flag. 
AESIs summaries 
• All treatment emergent adverse events of special interest, by primary SOC, HLGT, HLT, 
and PT, showing number (%) of patients with at least one TEAE sorted by SOC 
internationally agreed order. The other level (HLGT, HLT, PT) will be presented in 
an alphabetic order. 
In addition, the following exposure adjusted analyses will be performed for treatment emergent 
adverse events with pre-specified monitoring adverse events. 
The frequency of TEAEs across pre-defined time intervals will be provided for the treatment 
emergent AESIs, where the time intervals will be defined as: >0-≤1 week, >1-≤4 week, 
>4-≤12 weeks, >12-≤24 weeks, >24-≤36 weeks, >36-≤48 weeks, >48-≤60 weeks, >60-≤72 weeks, 
>72-≤84 weeks, >84-≤96 weeks, >96-≤108 weeks, >108-≤120 weeks, >120-≤132 weeks, 
>132-≤144 weeks, >144-≤156 weeks, >156-≤168 weeks, >168-≤180 weeks, >180-≤192 weeks 
and >192 weeks for open-label period. In each time interval, the denominator for calculation of 
percentage will be the number of patients exposed at the beginning of the time interval who did 
not report the given TEAE in the preceding intervals and the numerator will be the number of 
patients with at least one TEAE occurring in this time interval. Only the first event will be 
counted and all recurrent events will not be included. 
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Analysis of posttreatment adverse events 
• All posttreatment adverse events by primary SOC and PT, showing the number (%) of 
patients with at least 1 posttreatment adverse event, sorted by the internationally agreed 
SOC order and decreasing incidence of PTs within each SOC. 
• All posttreatment serious adverse events by primary SOC and PT, showing the number 
(%) of patients with at least 1 posttreatment serious adverse event, sorted by the 
internationally agreed SOC order and decreasing incidence of PTs within each SOC. 
Long-term Safety Analysis 
Long-term safety of teriflunomide exposure will also be analyzed by including all teriflunomide 
exposure, ie, from randomization in the double-blind period in the teriflunomide group and from 
start in the open-label period in the placebo group, for the complete study population analyzed in 
one overall group. Key safety analyses on TEAEs, SAEs, TEAEs leading to treatment 
discontinuation and AESIs. 
Safety Subgroup Analysis 
Safety subgroup analyses will be performed for key tables of TEAEs/SAEs/AESIs and TEAEs 
leading to treatment discontinuation during the treatment-emergent adverse event period in the 
open-label period by: 
• Intrinsic factors 
- 
Age group at study consent of the double-blind period (<13, ≥13 years) 
- 
Gender 
- 
Race 
- 
Pubertal status (at study consent, and at disease onset)  
- 
Baseline weight group in the double-blind period (≤40, >40 kgs) 
- 
MS subtypes (relapsing-remitting MS, other forms)  
- 
High disease activity at baseline (defined as 2 or more relapses in the past year of 
screening, and 1 or more Gadolinium enhancing lesions on baseline MRI of the 
double-blind period) (Yes, No) 
• Extrinsic factors 
- 
Region (as defined in Section 2.5.5). 
2.4.5.2 Deaths  
The following summaries of deaths will be generated for the safety population. 
• Number (%) of patients who died by study period (on-study, on-treatment, poststudy). 
• Treatment-emergent adverse events leading to death (death as an outcome on the adverse 
event case report form page as reported by the Investigator) by primary SOC, HLGT, 
HLT, and PT showing number (%) of patients sorted by internationally agreed SOC order, 
with HLGT, HLT, and PT presented in alphabetical order within each SOC. 
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• By-patient listing of deaths showing treatment group, patient identified, age, gender, race, 
duration of exposure, date of death, primary reason of death. 
2.4.5.3 Analyses of laboratory variables  
The summary statistics (including number, mean, median, Q1, Q3, standard deviation, minimum 
and maximum) of all laboratory variables (central laboratory values and changes from baseline) 
will be calculated for each visit or study assessment (baseline, each postbaseline time point, last 
on-treatment and/or minimum and maximum value during the treatment-emergent adverse event 
period) by treatment group. Mean changes from baseline with the corresponding standard error 
will be plotted over time (at same time points) in each treatment group for laboratory parameters 
of primary interest. This section will be organized by biological function. 
PCSA will be assessed based on age group at each visit. After subjects turn to be adult, the adult 
criteria will be applied. The incidence of PCSAs (list provided in Appendix A) at any time during 
the treatment-emergent adverse event period will be summarized by biological function and 
treatment group whatever the baseline level and/or according to the following baseline status 
categories:  
• Normal/missing. 
• Abnormal according to PCSA criterion or criteria. 
The proportion of patients with key PCSA values at any time during the treatment-emergent 
adverse event period will also be displayed by duration of exposure for each treatment group.  
For parameters for which no PCSA criteria are defined, similar table(s) using the normal range 
will be provided. 
A listing of patients with at least one post-baseline PCSA will be provided and will display the 
whole profile over time at any time of all parameters of the corresponding biological function. In 
this listing, baseline, endpoint value and individual values will be flagged when lower or higher 
than the lower or upper laboratory limits and/or when reaching the absolute limit of abnormality 
criteria. 
Drug-induced liver injury 
The liver function tests, namely AST, ALT, alkaline phosphatase, and total bilirubin, are used to 
assess possible drug-induced liver toxicity. The proportion of patients with PCSA values at any 
postbaseline visit by baseline status will be displayed by treatment group for each parameter. The 
proportion of patients with PCSA values at any postbaseline visit will also be displayed by 
duration of exposure for each treatment group.  
Time to onset of the initial ALT and AST elevation (>3 x upper limit of normal range [ULN]) and 
total bilirubin elevation (>2 x ULN) (time to first observation of ALT >3 x ULN or total bilirubin 
>2 x ULN, whichever comes first) will be analyzed using Kaplan-Meier estimates, presented by 
treatment group. Consideration should be given to the impact of the spacing of scheduled tests. 
A graph of distribution of peak values of ALT versus peak values of total bilirubin will also be 
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presented. Note that the ALT and total bilirubin values are presented on a logarithmic scale. The 
graph will be divided into 4 quadrants with a vertical line corresponding to 3 x ULN for ALT and 
a horizontal line corresponding to 2 x ULN for total bilirubin. 
Listing of possible Hy’s law cases identified by treatment group (eg, patients with any elevated 
ALT>3 x ULN, and associated with an increase in bilirubin ≥2 x ULN), presented with ALT, 
AST, alkaline phosphatase, total bilirubin, and the following complementary parameters: 
conjugated bilirubin and prothrombin time/international normalized ratio, creatine phosphokinase 
and serum creatinine.  
Summarize the normalization by parameter (to ≤1 x ULN or return to baseline) of elevated liver 
function tests by categories of elevation (3 x, 5 x, 10 x, 20 x ULN for ALT and AST, 1.5 x ULN 
for alkaline phosphatase, and 1.5 x and 2 x ULN for total bilirubin), with the following categories 
of normalization: never normalized, normalized despite treatment continuation of IMP, or 
normalized after IMP discontinuation. Note that a patient will be counted only under the 
maximum elevation category. 
Proportion of patients with ALT >1 x ULN and ALT >2 x ULN at post-baseline visits will be 
presented by treatment group. 
Summarize the incidence of liver-related adverse events by treatment group. The selection of 
preferred terms will be based on the hepatic disorder SMQ. 
TSH 
TSH will also be summarized for each study assessment by treatment group.  
2.4.5.4 Analyses of vital sign variables  
The summary statistics (including number, mean, median, Q1, Q3, standard deviation, minimum 
and maximum) of all vital signs variables (raw data and changes from baseline) will be calculated 
for each visit or study assessment (baseline, each postbaseline time point, last on-treatment and/or 
minimum and maximum value during the treatment-emergent adverse event period) by treatment 
group. For blood pressure, height and weight, mean changes from baseline with the corresponding 
standard error will be plotted over time (at same time points) in each treatment group. 
PCSA will be assessed based on age group at each visit. After subjects turn to be adult, the adult 
criteria will be applied. The incidence of PCSAs at any time during the treatment-emergent 
adverse event period will be summarized by treatment group irrespective of the baseline level 
and/or according to the following baseline status categories:  
• Normal/missing. 
• Abnormal according to PCSA criterion or criteria. 
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2.4.5.5 Analyses of electrocardiogram variables  
The summary statistics (including number, mean, median, Q1, Q3, standard deviation, minimum 
and maximum) of all ECG variables (central reading and changes from baseline) will be 
calculated for each visit or study assessment (baseline, each postbaseline time point, last 
on-treatment and/or minimum and maximum value during the treatment-emergent adverse event 
period) by treatment group. Mean changes from baseline with the corresponding standard error 
will be plotted over time (at the same time points) in each treatment group.  
PCSA will be assessed based on age group at each visit. After subjects turn to be adult, the adult 
criteria will be applied. The incidence of PCSAs at any time during the treatment-emergent 
adverse event period will be summarized by treatment group irrespective of the baseline level 
and/or according to the following baseline status categories:  
• Normal/missing. 
• Abnormal according to PCSA criterion or criteria. 
2.4.5.6 Analysis of Tanner scales  
Summary of raw value and change of Tanner scales (including number, mean, median, standard 
deviation, minimum and maximum) from baseline will be presented for each location (pubic hair 
and breasts in girls, pubic hair and testes in boys) for each visit by gender and treatment groups. 
The distribution of number of days to the first Tanner stage increase by 1 point, 2 points, and 3 or 
more points in each location will be estimated by gender and treatment group using the Kaplan–
Meier product limit estimator. The Kaplan-Meier for patients first achieving Tanner Stage 5 in 
either location during the open-label blind period plot also will be provided by treatment group for 
each gender.  
Shift table for Tanner scales shifted from pre-treatment scales at study consent to post-treatment 
scales at Week 192/EOT will be summarized by gender and location in each treatment group.  
2.4.6 Analyses of pharmacokinetic variables  
The summary statistics (including number, mean, standard deviation, geometric mean, coefficient 
of variation, median, minimum and maximum) of teriflunomide plasma concentrations will be 
calculated for each visit or study assessment for teriflunomide-treated patients. 
If date and/or time of the drug intake and/or sampling are missing, then the concentration will not 
be taken into account. Where concentration values are below the lower limit of quantification 
(LLOQ), one-half of the LLOQ will be used at given study visits.  
Population pharmacokinetic analysis will be conducted per a separate analysis plan and reported 
separately. 
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2.4.7 Analyses of immunogenicity variables  
The summary statistics (including number, mean, standard deviation, geometric mean, coefficient 
of variation, median, minimum and maximum) of serum immunoglobulins concentration (IgG, 
IgM and IgA) will be provided for each visit or study assessment by treatment group. 
Listing will be provided for patients with concomitant vaccine administration.  
2.5 
DATA HANDLING CONVENTIONS  
2.5.1 General conventions  
The following formulas will be used for computation of parameters. 
Demographic formulas 
Age = integer part of (date of consent in the double-blind period– date of birth) / 365.25 
BMI (in kg/m²) = weight in kg / (height [in m] x height [in m]) 
Renal function formulas  
Creatinine clearance (CrCl) value for children up to 18 years old will be derived from body 
length and plasma creatinine (Scr) using the updated Schwartz (Bedside Schwartz) equation: 
For children/adolescents: CrCl (mL/min/1.73m2) = 0.413 x (height [cm] / Scr [µmol/L]), 
where eGFR (estimated glomerular filtration rate) = mL/min/1.73 m2 
Creatinine clearance value for adults will be derived using the equation of Cockcroft and Gault: 
For males: 𝒄𝒓𝒄𝒍(𝒎𝑳/𝒎𝒊𝒏) =
(𝟏𝟒𝟎−𝒂𝒈𝒆)×𝒘𝒆𝒊𝒈𝒉𝒕 (𝒌𝒈)
𝟎.𝟖𝟏𝟒×𝒄𝒓𝒆𝒂𝒕𝒊𝒏𝒊𝒏𝒆 (𝝁𝒎𝒐𝒍/𝑳)  
For females: 𝒄𝒓𝒄𝒍(𝒎𝑳/𝒎𝒊𝒏) =
(𝟏𝟒𝟎−𝒂𝒈𝒆)×𝒘𝒆𝒊𝒈𝒉𝒕 (𝒌𝒈)
𝟎.𝟖𝟏𝟒×𝒄𝒓𝒆𝒂𝒕𝒊𝒏𝒊𝒏𝒆 (𝝁𝒎𝒐𝒍/𝑳) × 𝟎. 𝟖𝟓 
The last height or weight measurement on or before the visit of the creatinine measurement will 
be used. The age collected at the visit will be used. 
2.5.2 Missing data  
For data listings, the character date will always be used to present the date collected in the CRF. 
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Handling of computation of treatment duration if investigational medicinal product end of 
treatment date is missing  
For the calculation of the treatment duration, the date of the last dose of IMP is equal to the date 
of last administration reported on the end-of-treatment case report form page. If this date is 
missing, the exposure duration should be left as missing.  
The last dose intake should be clearly identified in the case report form and should not be 
approximated by the last returned package date. 
Handling of multiple sclerosis medical history missing/partial dates 
If the date of first MS diagnosis, first symptoms of MS or most recent relapse onset is incomplete, 
earliest possible day will be imputed for calculation, ie, unknown day will be set in 1st day of the 
month, and unknown month will be set in January. Unknown year will not be imputed.  
Handling of medication missing/partial dates 
For the purpose of determination whether the medication is prior or concomitantly, no imputation 
of medication start/end dates or times will be performed. If a medication date or time is missing or 
partially missing and it cannot be determined whether it was taken prior or concomitantly, it will 
be considered a prior, concomitant, and posttreatment medication.  
For concomitant systemic corticosteroid used to identify invalid MRI scans (MRI should be done 
after a minimum of 14 days following the completion of a course of corticosteroid). 
Below is the imputation rule: 
If start day is missing, and start month and year are not missing: 
Impute the start day using the first day of the month. Imputation flag is “D”. 
If start month is missing, and start year is not missing: 
If end date is not missing/partial date, and the start year are the same as end date -5, then impute 
the start date using end date -5; if the year are earlier than end date -5, then impute the month and 
day using December 31. Imputation flag is “M”. If the end date is also missing/partial date, this 
record will not be imputed and will not be used to identify invalid MRI scans. 
If start year is missing: 
If end date is not missing/partial date, impute the start date using end date -5. Imputation flag is 
“Y”. If the end date is also missing/partial date, this record will not be imputed and will not be 
used to identify invalid MRI scans. 
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If end day is missing and end month and year are not missing: 
If the end month and year are the same as start date +5, then impute the end date using start date 
+5; If the month and year are earlier than start date +5, then impute the day using the last day of 
the month; If the month and year are later than start date +5, then impute the day using the 
first day of the month. If this leads to a date after end of study follow up date, use the end of 
follow up date instead. Imputation flag is “D”. 
If end month is missing and year is not missing: 
If the end year are the same as start date +5, then impute the end date using start date +5; If the 
year are earlier than start date +5, then impute the month and day using December 31; If the year 
are later than start date +5, then impute the month and day using January 01. If this leads to a date 
after end of study follow up date, use the end of follow up date instead. Imputation flag is “M”. 
If end year is missing: 
Impute the end date using start date +5. If this leads to a date after end of study follow up date, 
use the end of follow up date instead. Imputation flag is “Y”. 
A special note, if the systemic corticosteroid start day is missing and month and year are not 
missing, the rule of 5 days after the start would not apply for the initial imputation. Thus for these 
cases, after imputation of start date, the end date will be re-imputed by repeating the above rules. 
If the start month and/or year are missing, the end date will not be imputed and this record will not 
be used to identify invalid MRI scans. 
The above data imputations will only be used to identify invalid MRI scans. 
Handling of adverse events with missing or partial date/time of onset 
Missing or partial adverse event onset dates and times will be imputed so that if the partial 
adverse event onset date/time information does not indicate that the adverse event started prior to 
treatment or after the treatment-emergent adverse event period, the adverse event will be 
classified as treatment-emergent. No imputation of adverse event end dates/times will be 
performed. These data imputations are for categorization purpose only and will not be used in 
listings. No imputation is planned for date/time of adverse event resolution. 
Handling of adverse events when date and time of first investigational medicinal product 
administration is missing 
When the date of the first IMP administration is missing, all adverse events that occurred on or 
after the day of randomization should be considered as treatment-emergent adverse events. The 
exposure duration should be kept as missing. 
The last dose intake should be clearly identified in the case report form and should not be 
approximated by the last returned package date. 
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Handling of missing assessment of relationship of adverse events to investigational medicinal 
product 
If the assessment of the relationship to IMP is missing, then the relationship to IMP has to be 
assumed and the adverse event considered as such in the frequency tables of possibly related 
adverse events, but no imputation should be done at the data level. 
Handling of missing severity of adverse events 
If the severity is missing for 1 of the treatment-emergent occurrences of an adverse event, the 
maximal severity on the remaining occurrences will be considered. If the severity is missing for 
all the occurrences, a “missing” category will be added in the summary table. 
Handling of potentially clinically significant abnormalities  
If a patient has a missing baseline he will be grouped in the category “normal/missing at 
baseline.” 
For PCSAs with 2 conditions, one based on a change from baseline value of the double-blind 
period or a normal range and the other on a threshold value, with the first condition being missing, 
the PCSA will be based only on the second condition. 
For a PCSA defined on a threshold and/or a normal range, this PCSA will be derived using this 
threshold if the normal range is missing; eg, for eosinophils the PCSA is >0.5 GIGA/L or >ULN 
if ULN ≥0.5 GIGA/L. When ULN is missing, the value 0.5 should be used. 
Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSA values.  
2.5.3 Windows for time points  
Time window for MRI measurements and SDMT will be used to capture data collected between 
visits. It is defined in Table 4 and Table 5. Baseline values will be the baseline defined in the 
double-blind period of the study. All days in the visit window tables for double-blind period 
(Table 4 and Table 6) and the open-label period (Table 5 and Table 7) are relative to the first dose 
date in each period respectively. 
Table 4 - Visit window for MRI variables and SDMT in the double-blind period  
Week  
Visit 
Target day 
Schedule Aa 
Schedule Bb 
0 
Baseline 
1 
Up to 1st dose date 
Up to 1st dose date 
24 
Visit 8 
169 
after 1st dose date - 252 
after 1st dose date -210 
36 
Visit 10 
253 
Not applicable 
211 - 294 
48 
Visit 12 
337 
253 - 420 
295 - 420 
72 
Visit 16 
505 
421 - 588 
421 - 588 
96 
Visit 20 
673 
589 - Last double-blind dose date + 
60 days and before 1st open label dose 
589 - Last double-blind dose date + 
60 days and before 1st open label dose 
a SDMT and MRI variables for patients without MRI assessment for Week 36  
b MRI variables for patients with MRI assessment for Week 36 
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Table 5 - Visit window for MRI variables and SDMT in the open-label period  
Week 
Visit 
Target day 
SDMT 
MRI variables 
0 
OL transition 
visit 
1 
Up to the first dose in OL period 
Up to the first dose in OL period 
24 
OL Visit 7 
169 
after 1st open-label dose date - 252 
Not applicable 
48 
OL Visit 11 
337 
252 - 420 
after 1st open-label dose date – 504 
72 
OL Visit 15 
505 
421 – 588 
Not applicable 
96 
OL Visit 19 
673 
589 – 756 
505 – 840 
120 
OL Visit 23 
841 
757 – 924 
Not applicable 
144 
OL Visit 27 
1009 
925 – 1092 
841 – 1176 
168 
OL Visit 31 
1177 
1093 – 1260 
Not applicable 
192 
OL Visit 35 
1345 
1261 - Later of the Last open-label 
visit date or the 1st dose date in 
optional additional extension period 
1177 - Later of the Last open-label visit 
date or before 1st dose date in optional 
additional extension period 
For multiple records within a visit window, the one closest to the targeted visit date will be used. 
Selected safety variables will be summarized by the analysis window defined in Table 6 and 
Table 7 of Section 2.5.3 for the by visit descriptive analysis. All available values obtained 
between 2 visits including unscheduled measurements will be pooled according to the visit 
window. In the event of multiple measurements of the same test in the same window, the 
one closest to the targeted visit date will be used for the by-visit summary. 
Table 6 - Visit window for safety variables in the double-blind period  
Week 
Visit 
Schedule Aa 
Schedule Bb 
Vital signs 
0 
Baseline 
Up to 1st double-blind 
dose date 
Up to 1st double-blind 
dose date 
Up to 1st double-blind 
dose date 
4 
Visit 3 
after 1st double-blind 
dose date - 56 
after 1st double-blind 
dose date - 42 
after 1st double-blind 
dose date - 42 
8 
Visit 4 
Not applicable 
43 - 70 
43 - 70 
12 
Visit 5 
57 - 126 
71 - 98 
71 - 126 
16 
Visit 6 
Not applicable 
99 - 126 
Not applicable 
20 
Visit 7 
Not applicable 
127 - 154 
Not applicable 
24 
Visit 8 
127 - 210 
155 -189 
127 - 210 
30 
Visit 9 
Not applicable 
190 - 231 
Not applicable 
36 
Visit 10 
211 - 294 
232 - 273 
211 - 294 
42 
Visit 11 
Not applicable 
274 - 315 
Not applicable 
48 
Visit 12 
295 - 378 
316 - 357 
295 - 378 
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Week 
Visit 
Schedule Aa 
Schedule Bb 
Vital signs 
54 
Visit 13 
Not applicable 
358 -399 
Not applicable 
60 
Visit 14 
379 - 462 
400 - 441 
379 - 462 
66 
Visit 15 
Not applicable 
442 - 483 
Not applicable 
72 
Visit 16 
463 - 546 
484 - 525 
463 - 546 
78 
Visit 17 
Not applicable 
526 - 567 
Not applicable 
84 
Visit 18 
547 - 630 
568 - 609 
547 - 630 
90 
Visit 19 
Not applicable 
610 - 651 
Not applicable 
96 
Visit 20 
631 - end of double-
blind periodc 
652- end of double-
blind periodc 
631 - end of double-blind 
periodc 
a Schedule A includes: Coagulation panel (prothrombin time, and activated partial thromboplastin time); Complete chemistry panel 
(glucose, creatinine, BUN, sodium, potassium, chloride, bicarbonate, magnesium, calcium uric acid, LDH, alkaline phosphatase, inorganic 
phosphorus, total protein, albumin, globulin, albumin/globulin ratio, triglycerides, cholesterol and CPK. Urinalysis (pH, ketones, protein, 
glucose, blood, urobilinogen, bilirubin, microscopic sediment, specific gravity). 
b Schedule B includes: Hematology and differential panel (hemoglobin, hematocrit, red blood cell count, mean corpuscular hemoglobin, 
white blood cell count, neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelets); liver function tests [ALT, AST, GGT, total 
bilirubin, and direct/indirect bilirubin] and pancreatic enzymes [serum amylase and lipase]). 
c End of double-blind period is defined as last double-blind dose date + 28 days and before 1st open label dose, whichever comes first. 
Table 7 - Visit window for safety variables in the open-label period  
Week 
Visit 
Schedule Aa 
Schedule Bb 
Vital signsd 
0 
OL transition visit 
Up to the first dose in OL 
period 
Up to the first dose in OL 
period 
Up to the first dose in OL 
period 
4 
OL Visit 2 
after 1st open-label dose 
date - 56 
after 1st open-label dose 
date - 42 
after 1st open-label dose 
date - 42 
8 
OL Visit 3 
Not applicable 
43 - 70 
43 - 70 
12 
OL Visit 4 
57 - 126 
71 - 98 
71 - 126 
16 
OL Visit 5 
Not applicable 
99 - 126 
Not applicable 
20 
OL Visit 6 
Not applicable 
127 - 154 
Not applicable 
24 
OL Visit 7 
127 - 210 
155 -189 
127 - 210 
30 
OL Visit 8 
Not applicable 
190 - 231 
Not applicable 
36 
OL Visit 9 
211 - 294 
232 - 273 
211 - 294 
42 
OL Visit 10 
Not applicable 
274 - 315 
Not applicable 
48 
OL Visit 11 
295 - 378 
316 - 357 
295 - 378 
54 
OL Visit 12 
Not applicable 
358 -399 
Not applicable 
60 
OL Visit 13 
379 – 462 
400 - 441 
379 - 462 
66 
OL Visit 14 
Not applicable 
442 - 483 
Not applicable 
72 
OL Visit 15 
463 - 546 
484 - 525 
463 - 546 
78 
OL Visit 16 
Not applicable 
526 - 567 
Not applicable 
84 
OL Visit 17 
547 - 630 
568 - 609 
547 - 630 
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Week 
Visit 
Schedule Aa 
Schedule Bb 
Vital signsd 
90 
OL Visit 18 
Not applicable 
610 - 651 
Not applicable 
96 
OL Visit 19 
631 - 714 
652 - 693 
631 - 714 
102 
OL Visit 20 
Not applicable 
694 - 735 
Not applicable 
108 
OL Visit 21 
715 - 798 
736 - 777 
715 - 798 
114 
OL Visit 22 
Not applicable 
778 - 819 
Not applicable 
120 
OL Visit 23 
799 - 882 
820 - 861 
799 - 882 
126 
OL Visit 24 
Not applicable 
862 - 903 
Not applicable 
132 
OL Visit 25 
883 - 966 
904 - 945 
883 - 964 
138 
OL Visit 26 
Not applicable 
946 - 987 
Not applicable 
144 
OL Visit 27 
967 - 1050 
988 - 1029 
967 - 1050 
150 
OL Visit 28 
Not applicable 
1030 - 1071 
Not applicable 
156 
OL Visit 29 
1051 - 1134 
1072 - 1113 
1051 - 1134 
162 
OL Visit 30 
Not applicable 
1114 - 1155 
Not applicable 
168 
OL Visit 31 
1135 - 1218 
1156 - 1197 
1135 - 1218 
174 
OL Visit 32 
Not applicable 
1198 - 1239 
Not applicable 
180 
OL Visit 33 
1219 - 1302 
1240 - 1281 
1219 - 1302 
186 
OL Visit 34 
Not applicable 
1282 - 1323 
Not applicable 
192 
OL Visit 35 
1303 - end of open-label 
periodc 
1324 - end of open-label 
periodc 
1303 - end of open-label 
periodc 
a Schedule A includes: Coagulation panel (prothrombin time, and activated partial thromboplastin time); Complete chemistry panel 
(glucose, creatinine, BUN, sodium, potassium, chloride, bicarbonate, magnesium, calcium uric acid, LDH, alkaline phosphatase, inorganic 
phosphorus, total protein, albumin, globulin, albumin/globulin ratio, triglycerides, cholesterol and CPK. Urinalysis (pH, ketones, protein, 
glucose, blood, urobilinogen, bilirubin, microscopic sediment, specific gravity). 
b Schedule B includes: Hematology and differential panel (hemoglobin, hematocrit, red blood cell count, mean corpuscular hemoglobin, 
white blood cell count, neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelets); liver function tests [ALT, AST, GGT, total 
bilirubin, and direct/indirect bilirubin] and pancreatic enzymes [serum amylase and lipase]). 
c End of open-label period is defined as later of the last open-label visit date or before 1st dose date in the optional additional extension 
period. 
d If remote visits, only weight will be collected for vital signs. Assessment date should be collected separately for weight and other 
assessments. 
2.5.4 Unscheduled visits  
Unscheduled MRI scans and SDMT will be assigned to the appropriate analysis window (defined 
in Table 4 and Table 5, Section 2.5.3). Otherwise, only scheduled visit efficacy measurements 
will be used for by visit analysis to exclude the temporary fluctuations in the clinical status that 
may occur with a relapse. 
Laboratory and vital sign data from unscheduled visits will be used in PCSA analysis. The 
unscheduled visits will also be assigned to the appropriate analysis time window (defined in  
Table 6 and Table 7, Section 2.5.3) for the summary of change from baseline by visit. The 
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one closest to the targeted visit date will be used in the presence of multiple measurements within 
the same time window. 
2.5.5 Pooling of centers for statistical analyses  
Study centers will be pooled into geographical regions for statistical analysis. Final adjustment to 
the region list will be made before the database lock. 
• Europe: Belgium, Bulgaria, Estonia, France, Greece, Lithuania, Netherlands, Portugal, 
Russian federation, Serbia, Spain, Ukraine, United Kingdom 
• North America: Canada, United States 
• Asia: China 
• Middle East: Turkey, Israel, Lebanon 
• North Africa: Tunisia, Morocco. 
2.5.6 Statistical technical issues  
Not Applicable. 
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3 
INTERIM ANALYSIS  
An interim analysis for open label CSR is planned at core DBL (ie, approximately 28 days after 
last patient last visit in the double-blind period of this study). 
Only data collected up to the date of core DBL will be used for this interim analysis. Analysis 
results will be summarized in an interim CSR for this open-label period. 
Summary of patient disposition, demographics and key baseline characteristics, concomitant 
medications, extent of IMP exposure and compliance will be provided, as described in  
Section 2.2, Section 2.4.1, Section 2.4.2, and Section 2.4.3, respectively, in the interim analysis 
report.  
For efficacy endpoints, the interim analysis will be performed for the following efficacy endpoints 
in which details are provided in Section 2.4.4.  
• Time to first clinical relapse after randomization up to the end the open-label treatment 
period 
• Time to first clinical relapse after enrollment of open-label period up to the end of open-
label period 
• Proportion of clinical relapse-free patients 
• Magnetic resonance imaging (MRI) variables 
- 
Number of new/newly enlarged T2 lesions 
- 
Number of Gd-enhancing T1 lesions 
- 
Change in volume of T2 lesions 
- 
Change in volume of T1 hypointense lesions 
- 
Number of new hypointense T1 lesions 
- 
Proportion of patients free of new or enlarged MRI T2 lesions at 48, 96, 144 and 
192 weeks 
- 
Percentage change in brain volume 
• Cognitive outcome measured by the SDMT and Cognitive Battery Tests 
• Annualized relapse rate 
• Sustained disability progression (using EDSS). 
Summary of teriflunomide PK levels at each visit will also be provided with descriptive statistics. 
For safety endpoints, key safety results including TEAE, SAE, AESI, death, AEs leading to 
treatment discontinuation along with related laboratory values, vital signs, and Tanner scales, in 
which details are provided in Section 2.4.4.4 will be provided in the interim analysis report. Long-
term safety data reported in the double-blind and the open-label treatment period s will also be 
performed for this interim CSR. 
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4 
DATABASE LOCK  
The interim database is planned to be locked approximately 28 days after last patient last visit in 
the double-blind period. The final database is planned to be locked approximately 28 days after 
last patient last visit in the open-label period of the study. This final database lock will not include 
patient data collected in the optional additional extension period beyond the final DBL of the 
study. 
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5 
SOFTWARE DOCUMENTATION  
All summaries and statistical analyses will be generated using SAS Version 9.2 or higher. 
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6 
REFERENCES  
1. Lin DY, Wei LJ. The robust inference for the Cox proportional hazards model. J Am Stat 
Assoc.1989;84(408):1074-8. 
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7 
LIST OF APPENDICES  
 
Appendix A:
Potentially clinically significant abnormalities (PCSA) criteria 
Appendix B: 
Summary of statistical analyses 
Appendix C: 
Flow chart for open label extension period 
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Appendix A 
Potentially clinically significant abnormalities criteria  
 
Criteria for potentially clinically significant abnormalities 
For studies in children 
(Version 3.0 May 2014) 
Parameter 
Age range 
PCSA 
Comments 
ECG parameters 
Ref. : Rijnbeek P.R. et al., Eur Heart J 2001; 
Davignon A. et al., Ped Cardiol 1979/1980; Semizel 
E.et al., Cardiol Young 2008; Mulberg AE et al. 
Pediatric Drug Development Concepts and 
applications. John Wiley & sons, Inc. 2009 
HR 
Birth/0 to 27 days old (Neonates) 
90 bpm and decrease from baseline 20 bpm 
190 bpm and increase from baseline 20 bpm 
 
28 days/1 month to 23 months old (Infants) 
80 bpm and decrease from baseline 20 bpm 
175 bpm and increase from baseline 20 bpm 
24 months/2 years to <6 years old (Children) 
75 bpm and decrease from baseline 20 bpm 
140 bpm and increase from baseline 20 bpm 
6 to <12 years old (Children) 
50 bpm and decrease from baseline 20 bpm 
120 bpm and increase from baseline 20 bpm 
12 to 16/18 years old (Adolescents) 
50 bpm and decrease from baseline 20 bpm 
120 bpm and increase from baseline 20 bpm 
PR 
Birth/0 to 27 days old (Neonates) 
120 ms 
 
28 days/1 month to 23 months old (Infants) 
140 ms 
24 months/2 years to <6 years old (Children) 
160 ms 
6 to <12 years old (Children) 
170 ms 
12 to 16/18 years old (Adolescents) 
180 ms 
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Criteria for potentially clinically significant abnormalities 
For studies in children 
(Version 3.0 May 2014) 
Parameter 
Age range 
PCSA 
Comments 
QRS 
Birth/0 to 27 days old (Neonates) 
85 ms 
 
28 days/1 month to 23 months old (Infants) 
85 ms 
2 to <6 years old (Children) 
95 ms 
6 to <12 years old (Children) 
100 ms 
12 to 16/18 years old (Adolescents) 
110 ms 
QTc  
Birth/0 to <12 years old  
(Neonates, Infants, Children) 
Absolute values (ms)  
Borderline: 431-450 ms  
Prolonged*: >450 ms  
Additional: ≥500 ms 
AND 
Increase from baseline  
Borderline: Increase from baseline 30-60 ms 
Prolonged*: Increase from baseline >60 ms 
To be applied to QTcF 
*QTc prolonged and QTc >60 ms are the PCSA to 
be identified in individual subjects/patients listings. 
 
12 to 16/18 years old (Adolescents) 
Borderline: 431-450 ms (Boys); 451-470 ms (Girls) 
Prolonged*: >450 ms (Boys); >470 ms (Girls) 
Additional: ≥500 ms 
AND 
Increase from baseline  
Borderline: Increase from baseline 30-60 ms 
Prolonged*: Increase from baseline >60 ms  
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Criteria for potentially clinically significant abnormalities 
For studies in children 
(Version 3.0 May 2014) 
Parameter 
Age range 
PCSA 
Comments 
Vital Signs 
Ref. : Kidney Disease Outcomes Quality Initiatives 
(KDOQI) Guideline 13; 1996; The fourth report on 
the diagnosis, evaluation, and treatment of high 
blood pressure in children and adolescents, 
Pediatrics 2004; Bowman E & Fraser S Neonatal 
Handbook 2012; Mulberg AE et al. Pediatric Drug 
Development Concepts and applications. John 
Wiley & sons, Inc. 2009; Pediatric respiratory rates 
http://www.health.ny.gov/ 
SBP  
Birth/0 to 27 days old (Neonates) 
60 mmHg and decrease from baseline 20 mmHg  
85 mmHg and increase from baseline 20 mmHg 
Based on definition of Hypertension as average 
SBP or DBP ≥95th percentile for gender, age, and 
height on ≥3 occasions 
28 days/1 month to 23 months old (Infants) 
70 mmHg and decrease from baseline 20 mmHg  
98 mmHg and increase from baseline 20 mmHg 
24 months/2 years to <6 years old (Children) 
70 mmHg and decrease from baseline 20 mmHg  
101 mmHg and increase from baseline 20 mmHg 
6 to <12 years old (Children) 
80 mmHg and decrease from baseline 20 mmHg  
108 mmHg and increase from baseline 20 mmHg 
12 to 16/18 years old (Adolescents) 
90 mmHg and decrease from baseline 20 mmHg  
119 mmHg and increase from baseline 20 mmHg 
DBP 
Birth/0 to 27 days old (Neonates) 
34 mmHg and decrease from baseline 10 mmHg  
50 mmHg and increase from baseline 10 mmHg 
 
28 days/1 month to 23 months old (Infants) 
34 mmHg and decrease from baseline 10 mmHg  
54 mmHg and increase from baseline 10 mmHg 
24 months/2 years to <6 years old (Children) 
34 mmHg and decrease from baseline 10 mmHg  
59 mmHg and increase from baseline 10 mmHg  
6 to <12 years old (Children) 
48 mmHg and decrease from baseline 10 mmHg  
72 mmHg and increase from baseline 10 mmHg  
12 to 16/18 years old (Adolescents) 
54 mmHg and decrease from baseline 10 mmHg  
78 mmHg and increase from baseline 10 mmHg  
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Statistical Analysis Plan 
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Page 54 
Criteria for potentially clinically significant abnormalities 
For studies in children 
(Version 3.0 May 2014) 
Parameter 
Age range 
PCSA 
Comments 
Orthostatic 
hypotension 
All age ranges 
SBP: St - Su ≤-20 mmHg  
DBP: St - Su ≤-10 mmHg  
 
Temperature 
All age ranges 
Rectal, ear or temporal artery: >100.4°F/38.0°C 
Oral or pacifier: >99.5°F/37.5°C 
Axillary or skin infrared: >99°F/37.2°C 
Ear temperature not accurate below 6 months of 
age 
Respiratory rate 
Birth/0 to 27 days old (Neonates) 
<30 per minutes  
>60 per minutes 
Based on normal range 
 
28 days/1 month to 23 months old (Infants) 
<24 per minutes  
>40 per minutes 
24 months/2 years to <6 years old (Children) 
<22 per minutes  
>34 per minutes 
6 to <12 years old (Children) 
<18 per minutes  
>30 per minutes 
12 to 16/18 years old (Adolescents) 
<12 per minutes  
>20 per minutes 
Sa02 
All age ranges 
<95% 
 
Weight 
All ranges 
>5% weight loss from baseline 
Based on identification of trends in the child’s 
growth with a series of visits 
WHO Multicentre Reference Study Group, 2006; 
Center for Disease Control. Growth chart 2007 
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Statistical Analysis Plan 
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Page 55 
Criteria for potentially clinically significant abnormalities 
For studies in children 
(Version 3.0 May 2014) 
Parameter 
Age range 
PCSA 
Comments 
Clinical Chemistry  
Ref Molleston JP et al. JPGN 2011; Moritz et al., 
Pediatrics 1999; Moritz et al., Pediatr Nephrol 2005 ; 
Sedlacek et al., Seminars in Dialysis 2006) Gong G 
et al. Clinical Biochemistry 2009; Masilamani et al. 
Arch Dis Children 2012; Mulberg AE et al. Pediatric 
Drug Development Concepts and applications. John 
Wiley & sons, Inc. 2009 
ALT/SGPT 
All age ranges 
>3 ULN 
By distribution analysis: 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Based on normal ranges: 6 to 50 U/L (0-5 days), 5 
to 45 U/L (1-19 years)  
AST/SGOT 
All age ranges 
>3 ULN 
By distribution analysis: 
>3 ULN 
>5 ULN  
>10 ULN  
>20 ULN 
Based on normal ranges: 35 to 140 U/L (0-5 days), 
15 to 55 U/L (1-9 years), 5 to 45 U/L (10-19 years) 
Alkaline 
Phosphatase 
All age ranges 
≥1.5 ULN 
Based on normal ranges: 145 to 420 U/L (1-9 
years), 130 to 560 U/L (10-11 years), 200 to 495 U/L 
(Boys 12-13 years), 105 to 420 U/L (Girls 12-13 
years), 130 to 525 U/L (Boys 14-15 years), 70 to 
130 U/L (Girls 14-15 years), 65 to 260 U/L (Boys 
16-19 years), 50 to 130 U/L (Girls 16-19 years) 
Total Bilirubin 
All age ranges 
≥1.3 ULN 
CF = mg x 1.7 = µmol 
Based on normal ranges: <6 mg/dL (Term 0-1 day), 
<8 mg/dL (Term 1-2 days), <12 mg/dL 
(Term 3-5 days), <1 mg/dL (Term >5 days) 
Conjugated Bilirubin 
All age ranges 
>35% Total Bilirubin and TBILI≥1.3 ULN 
CF = mg x 1.7 = µmol 
Based on normal range: 0 to 0.4 mg/dL  
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Statistical Analysis Plan 
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Page 56 
Criteria for potentially clinically significant abnormalities 
For studies in children 
(Version 3.0 May 2014) 
Parameter 
Age range 
PCSA 
Comments 
ALT and Total 
Bilirubin 
All age ranges  
ALT ≥3 ULN and Total Bilirubin ≥2 ULN 
 
CPK 
All age ranges 
≥3 ULN 
 
Creatinine 
Birth/0 to <6 years old (Neonates, Infants, 
Children) 
>53 µmol/L or 0.6 mg/dL  
CF = mg x 8.8 = µmol 
Based on normal ranges: <0.6 mg/dL (0-1 year), 
0.5 to 1.5 mg/dL (1 to 16/18 years) 
6 years to <12 years old (Children) 
>90 µmol/L or 1.1mg/dL 
12 years to 16/18 years old ( Adolescents) 
>132 µmol/L or 1.5mg/dL 
Creatinine Clearance 
All age ranges 
50 % of normal  
<60 mL/min/1.73m2 (After 1 year old) 
Based on GFR Bedside Schwartz Formula 
Based on normal ranges: 20 to 50 (<8 days), 25 to 
80 (8 days to 1 month), 30 to 90 (1-6 months), 40 to 
115 (6-12 months), 60 to 190 (12-23 months), 90 to 
165 (2-12 years), 80-120 (After 12 years)  
Uric Acid  
All age ranges 
<2.0 mg/dL or 119 µmol/L 
>8.0 mg/dL or 476 µmol/L  
CF = mg x 5.95 = µmol 
Based on normal ranges: 2.4 to 6.4 mg/dL  
Blood Urea Nitrogen 
(BUN) 
Birth/0 to 27 days old (Neonates) 
≥4.3 mmol/L or 12 mg/dL 
CF = g x 16.66 = mmol 
Based on normal ranges: 3 to 12 mg/dL (NN; 5 to 
18 mg/dL (other classes of age) 
28 days/1 month to 16/18 years old (Infants, 
Children, Adolescents) 
≥6.4 mmol/L or 18 mg/dL 
Chloride 
All age ranges 
≤80 mmol/L or 80 mEq/L 
≥115 mmol/L or 115 mEq/L 
CF = 1 
Based on normal range: 98 to 106 
Sodium 
All age ranges 
≤129 mmol/L or 129 mEq/L 
≥150 mmol/L or 150 mEq/L 
CF = 1 
Based on normal range : 134 to 146 
Potassium 
Birth/0 to 27 days old (Neonates) 
≤3.0 mmol/L or 3.0 mEq/L 
≥7.0 mmol/L or 7.0 mEq/L 
CF = 1 
Based on normal ranges: 3.0 to 7.0 (NN); 3.5 to 
6.0 (Infants); 3.5 to 5.0 (>Infants) 
28 days/1 month to 23 months old (Infants) 
≤3.5 mmol/L or 3.5 mEq/L 
≥6.0 mmol/L or 6.0 mEq/L 
24 months/2 years to 16/18 years old (Children, 
Adolescents) 
≤3.5 mmol/L or 3.5 mEq/L 
≥5.5 mmol/L or 5.5 mEq/L 
Bicarbonate 
All age ranges 
≤16 mmol/L or 16 mEq/L 
≥30 mmol/L or 30 mEq/L 
CF = 1 
Based on normal range: 18 to 26 
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Statistical Analysis Plan 
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Page 57 
Criteria for potentially clinically significant abnormalities 
For studies in children 
(Version 3.0 May 2014) 
Parameter 
Age range 
PCSA 
Comments 
Calcium total 
All age ranges 
≤2.0 mmol/L or 8.0 mg/dL 
≥2.9 mmol/L or 11.6 mg/dL 
CF = mg x 0.025 = mmol 
Based on normal range: 8.4 to 10.9 mg/dL 
Calcium ionized 
All age ranges 
≤1.0 mmol/L or 4.0 mg/dL 
≥1.4 mmol/L or 5.6 mg/dL 
CF = mg x 0.025 = mmol 
Based on normal range: 4.0 to 5.1 mg/dL 
Total Cholesterol 
All age ranges  
>6.20 mmol/L or 240 mg/dL 
CF = g x 2.58 = mmol 
Based on normal ranges: 45 to 182 mg/dL 
(1-3 years), 109 to 189 mg/dL (4-6 years), 126 to 
191 mg/dL (Boys 6-9 years), 122 to 209 mg/dL 
(Girls 6-9 years), 130 to 204 mg/dL 
(Boys 10-14 years), 124-217 mg/dL (Girls 
10-14 years), 114 to 198 mg/dL (Boys 15-19 years), 
125 to 212 mg/dL (Girls 14-19 years) 
Triglycerides 
All age ranges 
>4.0 mmol/L or 350 mg/dL 
After >12 hours of fast) 
CF = g x 1.14 = mmol 
Based on normal ranges: 30 to 86 mg/dL (Boys 
0-5 years), 32 to 99 mg/dL (Girls 0-5 years), 
31-108 mg/dL (Boys 6-11 years), 35 to 114 mg/dL 
(Girls 6-11 years), 36 to 138 mg/dL (Boys 
12-15 years), 43 to 138 mg/dL (Girls 12-15 years), 
40 to 163 mg/dL (Boys 16-19 years), 40-128 mg/dL 
(Girls 16-19 years) 
Lipasemia 
All age ranges 
>2 ULN 
Based on normal ranges: 3 to32 U/L (1-18 years) 
Amylasemia 
All age ranges 
>2 ULN 
Based on normal ranges: 10 to 30 U/L (NN), 10 to 
45 U/L (1-18 years) 
Glucose 
All age ranges 
Hypoglycaemia <2.7 mmol/L or 50 mg/dL 
Hyperglycaemia >7 mmol/L or 120 mg/dL (fasted after 
>12 hours of fast); >10.0 mmol/L or 180 mg/dL (unfasted) 
CF = g x 5.55 = mmol 
Based on normal ranges: 50 to 90 mg/dL (NN), 60 
to 100 mg/dL (Child) 
CRP 
All age ranges 
>2 ULN or 
>10 mg/L (if ULN not provided) 
Based on normal ranges: <6 mg/L 
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Statistical Analysis Plan 
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Page 58 
Criteria for potentially clinically significant abnormalities 
For studies in children 
(Version 3.0 May 2014) 
Parameter 
Age range 
PCSA 
Comments 
Hematology 
Common Terminology Criteria for Adverse Events 
v3.0 (CTCAE), 2006 ; Division of Microbiology and 
Infectious Diseases Pediatric Toxicity Tables, 2007 ; 
Division of AIDS Table for Grading the Severity of 
Adult and Pediatric Adverse Events, 2004; Mulberg 
AE et al. Pediatric Drug Development Concepts and 
applications. John Wiley & sons, Inc. 2009; Family 
Practice Notebook, LLC, 2012; Tietz NW et al. 
Clinical Guide to Laboratory Testing, 3rd edition 
1995 
WBC 
Birth/0 to 27 days old (Neonates) 
<4.0 GIGA/L or 4000/mm3 
>25.0 GIGA/L or 25 000/mm3 
To be used if no differential count available 
Based on normal ranges: 9000 to 30 000/mm3 
(birth), 9400 to 38 000/mm3 (0-1 day), 5000 to 
21 000/mm3 (1 day-1 month), 6000 to 17 500/mm3 
(1 month-2 years), 5000 to 17 000/mm3 (2-6 years), 
4500 to 15 500/mm3 (6-11 years), 4500 to 
13 500/mm3 (11-18 years) 
28 days/1 month to 23 months old (Infants) 
<4.0 GIGA/L or 4000/mm3 
>20.0 GIGA/L or 20 000/mm3 
24 months/2 years to <6 years old (Children) 
<3.0 GIGA/L or 3000/mm3 
>16.0 GIGA/L or 16 000 /mm3 
6 to <12 years old (Children) 
<5.0 GIGA/L or 5000/mm3 
>17.0 GIGA/L or 17 000 /mm3 
12 to 16/18 years old (Adolescents) 
<4,5 GIGA/L or 5000/mm3 
>13.5 GIGA/L or 17 000/mm3 
Lymphocytes (ALC) 
Birth/0 to 27 days old (Neonates) 
<1.2 GIGA/L or 1200/mm3 
>17.0 GIGA/L or 17 000/mm3 
Based on normal ranges: 2000 to 11 500/mm3 
(0-1 days), 2000 to 17 000/mm3 (2 days-1 month), 
3000 to 13 500/mm3 (1 month-2 years), 1500 to 
9 500/mm3 (2-6 years), 1500 to 8000/mm3 
(6-10 years), 1200 to 5200/mm3 (10-18 years) 
28 days/1 month to 23 months old (Infants) 
<2.0 GIGA/L or 2000/mm3 
>13.5 GIGA/L or 13 500/mm3 
24 months/2 years to <6 years old (Children) 
<1.0 GIGA/L or 1000/mm3 
>9.5 GIGA/L or 9500/mm3 
6 to <12 years old (Children) 
<1.0 GIGA/L or 1000/mm3 
>8.0 GIGA/L or 8000/mm3 
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Statistical Analysis Plan 
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Page 59 
Criteria for potentially clinically significant abnormalities 
For studies in children 
(Version 3.0 May 2014) 
Parameter 
Age range 
PCSA 
Comments 
12 to 16/18 years old (Adolescents) 
<0.6 GIGA/L or 600 /mm3 
>6.0 GIGA/L or 6000/mm3 
Absolute Neutrophil 
Count (ANC) 
Birth/0 to 27 days old (Neonates) 
<4.0 GIGA/L or 4000/mm3 (1 day old) 
<1.5 GIGA/L or 1500/mm3 (2-7 days old) 
<1.25 GIGA/L or 1250/mm3 (>7 day-1 month old) 
>1 ULN 
Based on normal ranges: 5000 to 28 000/mm3 
(0-1 day), 1000 to 10 000 (1 day-1 month), 1000 to 
8500 (1-12 months), 1500 to 8500 (1 to 6 years), 
1500 to 8000 (6 to 10 years), 1800 to 8000 (10 to 
18 years)  
28 days/1 month to 23 months old (Infants) 
<1.0 GIGA/L or 1000/mm3 (1-3 months) 
<1.2 GIGA/L or 1200/mm3 (3-24 months) 
>1 ULN 
24 months/2 years to <6 years old (Children) 
<1.2 GIGA/L or 1200/mm3 
>1 ULN 
6 to <12 years old (Children) 
<1.2 GIGA/L or 1200/mm3 
>1 ULN 
12 to 16/18 years old (Adolescents)  
<1.2 GIGA/L or 1200/mm3 
>1 ULN 
Eosinophils 
All age ranges 
>0.5 GIGA/L or 500/mm3  
Or >ULN if ULN >0.5 GIGA/L or 500/mm3 
Based on normal ranges: 0 to 500/mm3 (0-1 month), 
0 to 300/mm3 (1 month-18 years) 
Hemoglobin 
Birth/0 to 27 days old (Neonates) 
< 86 mmol/L or 12.0 g/dL or any decrease >0.31 mmol/L 
or 2 g/dL 
CF = g x 1.55 = mmol 
Based on normal ranges: 15 to 20 g/dL (0-3 days), 
12.5 to 18.5 g/dL (1-2 weeks), 10.0 to 13.0 g/dL 
(1-6 months), 10.5 to 13.0 g/dL (7 months-2 years), 
11.5 to 13.0 g/dL (2-5 years), 11.5 to 
14.5 (5-8 years), 12.0 to 15.2 g/dL (13-18 years)  
28 days/1 month to 23 months old (Infants) 
<1.40 mmol/L or 9.0 g/dL or any decrease >0.31 mmol/L 
or 2 g/dL 
24 months/2 years to <16/18 years old (Children, 
Adolescents) 
<1.55 mmol/L or10.0 g/dL or any decrease >0.31 mmol/L 
or 2 g/dL 
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Statistical Analysis Plan 
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Page 60 
Criteria for potentially clinically significant abnormalities 
For studies in children 
(Version 3.0 May 2014) 
Parameter 
Age range 
PCSA 
Comments 
Hematocrit 
Birth/0 to 27 days old (Neonates) 
<0.39 l/l or 40% 
>0.61 l/l or 47% 
CF = % x 0.01 = l/l 
Based on normal ranges: 45% to 61% (0-3 days), 
39% to 57% (1-2 weeks), 29% to 42 % (1-6 
months), 33% to 38% (7 months-2 years), 34% to 
39 % (2-5 years), 35% to 42% (5-8 years); 36% to 
47% (13-18 years) 
28 days/1 month to 23 months old (Infants) 
<0.29 l/l or 29% 
>0.42 l/l or 42% 
24 months/2 years to <16/18 years old 
(Adolescents) 
<0.32 l/l or 32% 
>0.47 l/l or 47% 
Platelets 
All age ranges 
<100 GIGA/L or 100 000/mm3 
>700 GIGA/L or 700 000/mm3 
Based on normal ranges: 250 000 to 450 000/mm3 
(NN); 300 000 to 700 000/mm3 (1-6 months), 
250 000 to 600 000/mm3 (7 months-2 years), 
250 000 to 550 000/mm3 (2-12 years), 150 000 to 
450 000/mm3 (13-18 years) 
Urinalysis 
Patel HP, Pediatr Clin N Am, 2006 
Ketonuria 
All age ranges 
Presence 
Semi-quantitative methods 
Glycosuria 
All age ranges 
Presence 
Semi-quantitative methods 
Hematuria 
All age ranges 
>1+ 
Semi-quantitative methods 
Proteinuria 
All age ranges 
>1+ 
Semi-quantitative methods 
 
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Statistical Analysis Plan 
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Page 61 
Criteria for potentially clinically significant abnormalities 
for Phase 2/3 studies (oncology excepted) 
(Version 3.0 May 2014) 
Parameter 
PCSA 
Comments 
Clinical Chemistry 
ALT 
By distribution analysis : 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be expressed in ULN, not in IU/L.  
Concept paper on DILI - FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning zero can be 
deleted. 
AST 
By distribution analysis : 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be expressed in ULN, not in IU/L.  
Concept paper on DILI - FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning zero can be 
deleted. 
Alkaline Phosphatase 
>1.5 ULN 
Enzymes activities must be expressed in ULN, not in IU/L. 
Concept paper on DILI - FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Total Bilirubin 
>1.5 ULN 
>2 ULN 
Must be expressed in ULN, not in µmol/L or mg/L. Categories are 
cumulative. 
Concept paper on DILI - FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Conjugated Bilirubin 
>35% Total Bilirubin and TBILI>1.5 ULN 
Conjugated bilirubin dosed on a case-by-case basis. 
ALT and Total Bilirubin 
ALT>3 ULN and TBILI>2 ULN 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
To be counted within a same treatment phase, whatever the interval 
between measurements. 
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Statistical Analysis Plan 
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Page 62 
Criteria for potentially clinically significant abnormalities 
for Phase 2/3 studies (oncology excepted) 
(Version 3.0 May 2014) 
Parameter 
PCSA 
Comments 
CPK 
>3 ULN 
>10 ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning zero can be 
deleted. 
CrCl (mL/min) 
(Estimated creatinine clearance based on the Cockcroft-
Gault equation)  
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - <60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥ 90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with impaired renal function-study design, 
data analysis, and impact on dosing and labeling 
eGFR (mL/min/1.73m2) 
(Estimate of GFR based on an MDRD equation)  
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - <60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with impaired renal function-study design, 
data analysis, and impact on dosing and labeling 
Creatinine 
≥150 μmol/L (Adults) 
≥30% change from baseline 
≥100% change from baseline 
Benichou C., 1994. 
Uric Acid 
Hyperuricemia  
Hypouricemia  
 
>408 μmol/L 
<120 μmol/L  
Harrison- Principles of internal Medicine 17th Ed., 2008. 
Blood Urea Nitrogen 
≥17 mmol/L 
 
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Statistical Analysis Plan 
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Page 63 
Criteria for potentially clinically significant abnormalities 
for Phase 2/3 studies (oncology excepted) 
(Version 3.0 May 2014) 
Parameter 
PCSA 
Comments 
Chloride 
<80 mmol/L 
>115 mmol/L 
 
Sodium 
≤129 mmol/L 
≥160 mmol/L 
 
Potassium 
<3 mmol/L 
≥5.5 mmol/L 
FDA Feb 2005. 
Total Cholesterol 
≥7.74 mmol/L  
Threshold for therapeutic intervention. 
Triglycerides 
≥4.6 mmol/L 
Threshold for therapeutic intervention. 
Lipasemia 
≥3 ULN 
 
Amylasemia 
≥3 ULN 
 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
≤3.9 mmol/L and <LLN 
≥11.1 mmol/L (unfasted); ≥7 mmol/L (fasted) 
 
ADA May 2005. 
ADA Jan 2008. 
HbA1c 
>8% 
 
Albumin 
≤25 g/L 
 
CRP 
>2 ULN or >10 mg/L (if ULN not provided) 
 FDA Sept 2005. 
Hematology 
WBC 
<3.0 GIGA/L (Non-Black); <2.0 GIGA/L (Black) 
≥16.0 GIGA/L 
Increase in WBC: not relevant. 
To be interpreted only if no differential count available. 
Lymphocytes 
>4.0 GIGA/L 
 
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Statistical Analysis Plan 
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Page 64 
Criteria for potentially clinically significant abnormalities 
for Phase 2/3 studies (oncology excepted) 
(Version 3.0 May 2014) 
Parameter 
PCSA 
Comments 
Neutrophils 
<1.5 GIGA/L (Non-Black);<1.0 GIGA/L (Black) 
International Consensus meeting on drug-induced blood cytopenias, 
1991. 
FDA criteria. 
Monocytes 
>0.7 GIGA/L 
 
Basophils 
>0.1 GIGA/L 
 
Eosinophils 
>0.5 GIGA/L or >ULN (if ULN≥0.5 GIGA/L) 
Harrison- Principles of internal Medicine 17th Ed., 2008. 
Hemoglobin 
≤115 g/L (Male); ≤95 g/L (Female) 
≥185 g/L (Male); ≥165 g/L (Female) 
Decrease from Baseline ≥20 g/L 
Criteria based upon decrease from baseline are more relevant than 
based on absolute value. Other categories for decrease from baseline 
can be used (≥30 g/L, ≥40 g/L, ≥50 g/L). 
Hematocrit 
≤0.37 v/v (Male) ; ≤0.32 v/v (Female) 
≥0.55 v/v (Male) ; ≥0.5 v/v (Female) 
 
RBC 
≥6 Tera/L 
Unless specifically required for particular drug development, the analysis 
is redundant with that of Hb. 
Otherwise, consider FDA criteria. 
Platelets 
<100 GIGA/L 
≥700 GIGA/L 
International Consensus meeting on drug-induced blood cytopenias, 
1991. 
Urinalysis 
pH 
≤4.6 
≥8 
 
Vital signs 
HR 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline≥20 bpm 
To be applied for all positions (including missing) except STANDING. 
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Statistical Analysis Plan 
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Page 65 
Criteria for potentially clinically significant abnormalities 
for Phase 2/3 studies (oncology excepted) 
(Version 3.0 May 2014) 
Parameter 
PCSA 
Comments 
SBP 
≤95 mmHg and decrease from baseline ≥20mmHg 
≥160 mmHg and increase from baseline ≥20 mmHg 
To be applied for all positions (including missing) except STANDING. 
DBP 
≤45 mmHg and decrease from baseline ≥10 mmHg 
≥110 mmHg and increase from baseline ≥10 mmHg 
To be applied for all positions (including missing) except STANDING. 
Orthostatic Hypotension 
Orthostatic SDB 
Orthostatic DBP 
 
 
≤-20 mmHg 
≤-10 mmHg 
 
Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
FDA Feb 2007. 
ECG 
Ref.: ICH E14 guidance (2005) and E14 Q&A (2012), and Cardiac 
Safety Research Consortium White Paper on PR and QRS (Nada et al. 
Am Heart J. 2013; 165(4) : 489-500) 
HR 
<50 bpm 
<50 bpm and decrease from baseline ≥20 bpm 
<40 bpm 
<40 bpm and decrease from baseline ≥20 bpm 
<30 bpm 
<30 bpm and decrease from baseline ≥20 bpm 
>90 bpm 
>90 bpm and increase from baseline ≥20bpm 
>100 bpm  
>100 bpm and increase from baseline ≥20bpm 
>120 bpm  
>120 bpm and increase from baseline ≥20 bpm 
Categories are cumulative 
 
 
 
 
 
 
Categories are cumulative 
 
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Statistical Analysis Plan 
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Page 66 
Criteria for potentially clinically significant abnormalities 
for Phase 2/3 studies (oncology excepted) 
(Version 3.0 May 2014) 
Parameter 
PCSA 
Comments 
PR 
>200 ms 
>200 ms and increase from baseline ≥25% 
> 220 ms 
>220 ms and increase from baseline ≥25% 
> 240 ms 
> 240 ms and increase from baseline ≥25% 
Categories are cumulative 
QRS 
>110 ms 
>110 ms and increase from baseline ≥25% 
>120 ms 
>120 ms and increase from baseline ≥25% 
Categories are cumulative 
QT 
>500 ms 
 
QTc 
Absolute values (ms) 
 
>450 ms 
>480 ms 
>500 ms 
 
Increase from baseline 
Increase from baseline ]30-60] ms 
Increase from baseline >60 ms 
To be applied to any kind of QT correction formula.  
Absolute values categories are cumulative 
 
QTc >480 ms and QTc>60 ms are the 2 PCSA categories to be 
identified in individual subjects/patients listings. 
 
VV-CLIN-0475390 2.0


Statistical Analysis Plan 
28-Jun-2021 
HMR1726-EFC11759 - teriflunomide 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 67 
Appendix B 
Summary of statistical analyses  
EFFICACY ANALYSIS IN THE OPEN-LABEL PERIOD 
Endpoint 
Analysis population 
Primary analysis 
Supportive analysis 
Subgroup analysis 
Other analyses 
Primary endpoint 
Time to first clinical relapse 
after randomization in 
double-blind period up to 
the end the open-label 
treatment period 
Efficacy 
Cox proportional hazard model  
Kaplan-Meier methods, 
log-rank test 
No 
No 
Secondary endpoints 
Time to first clinical relapse 
since enrollment into the 
open-label period up to the 
exit of the open-label 
treatment period  
Efficacy 
Cox proportional hazard model  
Kaplan-Meier methods. 
Log-rank test 
No 
No 
The proportion of clinical 
relapse-free patients at 
Weeks 24, 48, 72 and 96,  
Efficacy 
Kaplan-Meier methods 
No 
No 
No 
The number of new or 
enlarged T2 lesions, T1 
Gd-enhancing lesions and 
new T1 hypointense lesions  
Efficacy 
Negative binomial regression model  
No 
No 
No 
Change from baseline in 
volume of T2 lesions, T1 
hypointense lesions, the 
percentage change of brain 
volume;  
Efficacy 
Descriptive summary 
No 
No 
No 
The proportion of patients 
free of new or enlarged T2 
lesions at Weeks 48 and 96 
Efficacy 
Kaplan-Meier methods 
No 
No 
No 
VV-CLIN-0475390 2.0


Statistical Analysis Plan 
28-Jun-2021 
HMR1726-EFC11759 - teriflunomide 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 68 
Endpoint 
Analysis population 
Primary analysis 
Supportive analysis 
Subgroup analysis 
Other analyses 
Cognitive outcomes and 
EDSS 
Efficacy 
Descriptive summary 
No 
No 
No 
Disease free patient 
Efficacy 
Kaplan-Meier methods 
No 
No 
No 
Additional efficacy endpoints 
Annualized relapse rate 
Efficacy 
Poisson regression model 
No 
No 
No 
Time to sustained disability 
progression 
Efficacy 
Cox proportional hazard model  
Kaplan-Meier methods  
No 
No 
 
SAFETY ANALYSES IN THE OPEN-LABEL PERIOD 
Endpoint 
Analysis population 
Primary analysis 
Supportive 
analysis 
Subgroup analysis 
Other analyses 
Adverse events 
Safety 
Descriptive summary 
No 
Yes, Subgroups: demographic (eg, age, sex, 
race, pubertal status, weight), other (eg, MS 
subtypes, high disease activity based on MRI, 
region)  
No 
Lab/vital signs/ECG 
Safety 
Descriptive summary 
No 
No 
No 
Tanner scales 
Safety 
Descriptive summary 
Kaplan-Meier methods 
No 
No 
VV-CLIN-0475390 2.0








Statistical Analysis Plan 
28-Jun-2021 
HMR1726-EFC11759 - teriflunomide 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 72 
i 
The following routine parameters will be measured at transition visit if previous laboratory assessment was performed more than 4 weeks before, at Weeks 4, 12, 24, 36, 48, then every 12 weeks and at EOT: 
Hematology and differential panel (hemoglobin, hematocrit, red blood cell count and red blood cell morphology, mean corpuscular volume, white blood cell count, neutrophils, lymphocytes, monocytes, eosinophils, 
basophils, platelets); Coagulation panel (prothrombin time, and activated partial thromboplastin time); Complete chemistry panel (glucose, creatinine, blood urea nitrogen (BUN), sodium, potassium, chloride, 
bicarbonate, magnesium, calcium uric acid, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH), total bilirubin, direct/indirect 
bilirubin, alkaline phosphatase, inorganic phosphorus, total protein, albumin, globulin, albumin/globulin ratio, triglycerides, cholesterol and creatine phosphokinase (CPK). Pancreatic enzymes (serum amylase and 
lipase); Urinalysis (pH, ketones, protein, glucose, blood, urobilinogen, bilirubin, microscopic sediment, specific gravity). For pubescent females serum pregnancy test β- Human chorionic gonadotropin; (β-HCG) will 
be performed every 12 weeks. 
j 
The following safety laboratory tests will be conducted in between clinical routine lab at Weeks 8, 16, 20, 30 and then every 12 weeks up to the end of treatment (EOT). Study nurse visit at patient’s home can be 
provided (except at Week 8). In addition at EOT+2 weeks and EOT+4 weeks. The following safety laboratory testing will be conducted: (measuring hematology and differential panel [as above], liver function tests 
[ALT, AST, GGT, total bilirubin, and direct/indirect bilirubin] and pancreatic enzymes [serum amylase and lipase]). In addition, uric acid and inorganic phosphorus will be done at EOT+2 weeks and EOT+4 weeks. 
k PK samples will be collected at Week 2, 3, and 4 (PK run-in (8 weeks) period); an additional 4th sample may be required in case of inadequate sampling or information/variability from 3 samples. Study nurse visit 
at patient’s home can be provided when PK sampling is not synchronized with routine lab visit (W2, W3 or in the event the 4th sample is needed.  
l 
Post drug elimination procedure: samples to be collected for verification of plasma teriflunomide concentrations ≤0.02 μg/mL. 
m In addition if a patient has a vaccination, antibody titers will be assessed before and after vaccination (inactivated vaccines only)  
n EDSS required also after each clinical relapse, to be performed within 7 days. 
o If patient is treated with steroids the MRI should be performed after 14 days discontinuation of the steroids. 
p ECG should be performed only for patients who had new abnormalities on the EOT ECG. 
q Cognitive Battery Tests: TMT-A and B, SRT, Beery VMI, BVMTR, D-KEFS Fluencies (Letter and Category); BVMTR and WASI Vocabulary potentially supplemental. When available. 
r 
The number of visits is linked to the time in the previous double blind phase as the maximum period in the study is 192 weeks. The maximum potential duration is therefore 184 weeks. 
s The date of the menarche should be captured if applicable. 
t 
IVRS only if treatment is stopped. 
u An optional additional extension period with teriflunomide is offered to young patients, to provide them treatment until they are 18 years old and/or can switch to commercial product, whichever comes first. 
 
 
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