Efficacy, Safety and Pharmacokinetics of Teriflunomide in Pediatric Patients With Relapsing Forms of Multiple Sclerosis (TERIKIDS)

• ClinicalTrials.gov Identifier: NCT02201108
• Recruitment Status: Active, not recruiting
• First Posted: July 25, 2014
• Results First Posted: November 30, 2020
• Last Update Posted: November 30, 2020
• Sponsor: Genzyme, a Sanofi Company
• Information provided by (Responsible Party): Sanofi ( Genzyme, a Sanofi Company )

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Multiple Sclerosis
• Interventions: Drug: Teriflunomide; Drug: Placebo
• Enrollment: 166

Participant Flow

Recruitment Details	Study was conducted at 57 active centers in 21 countries. A total of 185 participants were screened between 16 July 2014 and 27 December 2017, of which 166 participants were enrolled and randomized. A total of 19 participants failed screening mainly due to meeting exclusion criteria.
Pre-assignment Details	Participants were randomly assigned to receive either teriflunomide or placebo in a 2:1 ratio (109 teriflunomide and 57 placebo) via Interactive Voice Response System. Randomization was stratified by the country and participant's pubertal status. Data reported based on the primary completion date of 25 October 2019.

Arm/Group Title	Placebo	Teriflunomide
Arm/Group Description	Participants received Placebo matching to teriflunomide tablet orally once daily (QD) for 96 weeks.	Participants received 1 Teriflunomide tablet, 3.5 milligram (mg) (in case of body weight [BW] up to 40 kilogram [kg]) or 7 mg (in case of BW greater than[>] 40 kg) orally QD for 8 weeks. After 8 weeks, based on participant's predicted pharmacokinetic (PK) parameters, teriflunomide was administered in following manner up to 96 weeks:if predicted PK parameters less than or equal to (<=) 95th percentile of adult range after 7 mg QD:1 tablet of 7 mg daily (for BW up to 40 kg) or 1 tablet of 14 mg daily (for BW>40 kg); or if predicted PK parameters>95th percentile of adult range:1 tablet of 3.5 mg daily (for BW up to 40 kg) or 1 tablet of 7 mg daily (for BW>40 kg). The adult range (5th-95th percentile) of predicted steady state PK parameters for 7 mg dose was defined as maximum concentration observed (Cmax) ranging from 8.03 to 49.10 microgram per milliliter (mcg/mL) and area under the curve from time 0 hour to 24 hours (AUC0-24) ranging from 184 to 1160 microgram*hour per milliliter (mcg*h/mL).
Period Title: Overall Study
Started [1]	57	109
On-going Participants	0	58
Completed	53	102
Not Completed	4	7
Reason Not Completed
Adverse Event	0	6
Lack of Efficacy	2	1
Withdrawal by Subject	2	0
[1] Randomized and treated participants.

Baseline Characteristics

Arm/Group Title		Placebo	Teriflunomide	Total
Arm/Group Description		Participants received Placebo matching to teriflunomide tablet orally QD for 96 weeks.	Participants received 1 Teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) orally QD for 8 weeks. After 8 weeks, based on participant's predicted PK parameters, teriflunomide was administered in following manner up to 96 weeks: if predicted PK parameters <= 95th percentile of adult range after 7 mg QD: 1 tablet of 7 mg daily (for BW up to 40 kg) or 1 tablet of 14 mg daily (for BW >40 kg); or if predicted PK parameters >95th percentile of adult range: 1 tablet of 3.5 mg daily (for BW up to 40 kg) or 1 tablet of 7 mg daily (for BW >40 kg). The adult range (5th - 95th percentile) of predicted steady state PK parameters for a 7 mg dose was defined as Cmax ranging from 8.03 to 49.10 mcg/mL and AUC0-24 ranging from 184 to 1160 mcg*h/mL.	Total of all reporting groups
Overall Number of Baseline Participants		57	109	166
Baseline Analysis Population Description		Analysis was performed on all randomized participants.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	57 participants	109 participants	166 participants
		14.7 (2.1)	14.6 (2.0)	14.6 (2.0)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	57 participants	109 participants	166 participants
	Female	39 68.4%	72 66.1%	111 66.9%
	Male	18 31.6%	37 33.9%	55 33.1%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants
Race	Number Analyzed	57 participants	109 participants	166 participants
	Caucasian/White	42 73.7%	75 68.8%	117 70.5%
	Black	1 1.8%	4 3.7%	5 3.0%
	Asian/Oriental	12 21.1%	25 22.9%	37 22.3%
	Other	2 3.5%	5 4.6%	7 4.2%

Outcome Measures

1. Primary Outcome

Title	Time to First Confirmed Clinical Relapse
Description	Time to first clinical relapse was defined as the duration (in weeks) between randomization and first confirmed clinical relapse. Clinical relapses were 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 neurological examination and documented by a standardized, quantified functional system score (FSSs) which included 8 items and items were rated on different scales: brain stem, cerebellar and cerebral functions rated on a scale of 0 to 5; visual, pyramidal, sensory and bowel/bladder rated on a scale of 0 to 6 and ambulation on a scale of 0 to 12, where higher score in each scale indicated worsened neurological function. Confirmed clinical relapse were reviewed and confirmed by an independent Relapse Adjudication Panel (RAP). A participant without confirmed clinical relapse, was considered as clinical relapse free until the end of Week 96.
Time Frame	Baseline up to Week 96

Outcome Measure Data

Analysis Population Description

Analysis was performed on Intent-to-treat (ITT) population, which consisted of all randomized participants analyzed according to the treatment allocated by randomization.

Arm/Group Title	Placebo	Teriflunomide
Arm/Group Description:	Participants received Placebo matching to teriflunomide tablet orally QD for 96 weeks.	Participants received 1 Teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) orally QD for 8 weeks. After 8 weeks, based on participant's predicted PK parameters, teriflunomide was administered in following manner up to 96 weeks: if predicted PK parameters <= 95th percentile of adult range after 7 mg QD: 1 tablet of 7 mg daily (for BW up to 40 kg) or 1 tablet of 14 mg daily (for BW >40 kg); or if predicted PK parameters >95th percentile of adult range: 1 tablet of 3.5 mg daily (for BW up to 40 kg) or 1 tablet of 7 mg daily (for BW >40 kg). The adult range (5th - 95th percentile) of predicted steady state PK parameters for a 7 mg dose was defined as Cmax ranging from 8.03 to 49.10 mcg/mL and AUC0-24 ranging from 184 to 1160 mcg*h/mL.
Overall Number of Participants Analyzed	57	109
Median (Full Range); Unit of Measure: weeks
	39.14; (0.1 to 98.0)	75.29; (0.1 to 98.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Teriflunomide
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2949
	Comments	Threshold for significance was < 0.05.
	Method	Stratified Log-Rank test
	Comments	Derived from log-rank test with stratification of region and pubertal status.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.657
	Confidence Interval	(2-Sided) 95%; 0.388 to 1.113
	Estimation Comments	Hazard ratio was 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 as covariates and with robust variance estimation.

2. Secondary Outcome

Title	Probability of Participants Who Were Clinical Relapse Free at Weeks 24, 48, 72 and 96
Description	Participant was considered as free of clinical relapse if participant had no confirmed clinical relapse before treatment discontinuation/completion in 96 weeks treatment period. Clinical relapses:defined as new/recurrent neurological symptoms not associated with fever/infection, lasted at least 24 hours, and accompanied by new objective neurological findings upon neurological examination and documented by standardized, quantified FSSs which included 8 items;items were rated on different scales:brain stem, cerebellar and cerebral functions rated on scale of 0 to 5;visual, pyramidal, sensory and bowel/bladder rated on scale of 0 to 6 and ambulation on scale of 0 to 12, where higher score in each scale indicated worsened neurological function. New/recurrent symptoms that occurred less than 30 days following onset of relapse were considered part of same relapse. Probability of participants who were clinical relapse free at specified weeks was estimated by Kaplan-Meier method and reported.
Time Frame	Weeks 24, 48, 72 and 96

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population.

Arm/Group Title	Placebo	Teriflunomide
Arm/Group Description:	Participants received Placebo matching to teriflunomide tablet orally QD for 96 weeks.	Participants received 1 Teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) orally QD for 8 weeks. After 8 weeks, based on participant's predicted PK parameters, teriflunomide was administered in following manner up to 96 weeks: if predicted PK parameters <= 95th percentile of adult range after 7 mg QD: 1 tablet of 7 mg daily (for BW up to 40 kg) or 1 tablet of 14 mg daily (for BW >40 kg); or if predicted PK parameters >95th percentile of adult range: 1 tablet of 3.5 mg daily (for BW up to 40 kg) or 1 tablet of 7 mg daily (for BW >40 kg). The adult range (5th - 95th percentile) of predicted steady state PK parameters for a 7 mg dose was defined as Cmax ranging from 8.03 to 49.10 mcg/mL and AUC0-24 ranging from 184 to 1160 mcg*h/mL.
Overall Number of Participants Analyzed	57	109
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: probability of relapse free participants
Week 24	0.750; (0.615 to 0.844)	0.807; (0.720 to 0.870)
Week 48	0.590; (0.444 to 0.710)	0.684; (0.587 to 0.763)
Week 72	0.531; (0.379 to 0.662)	0.619; (0.517 to 0.705)
Week 96	0.455; (0.293 to 0.603)	0.594; (0.491 to 0.683)

3. Secondary Outcome

Title	Magnetic Resonance Imaging (MRI) Assessment: Number of New or Enlarged T2 Lesions Per MRI Scan
Description	Number of new or enlarged T2 lesions per scan was defined as the total number of new or enlarged T2 lesion that occurred during the 96 weeks treatment period divided by the total number of scans performed during 96 weeks. To account for the different numbers of scans performed among the participants, a negative binomial regression model with robust variance estimation was used. The model included the total number of new or enlarged T2-lesions as the response variable, with treatment group, region, pubertal status and age as covariates and log-transformed number of scans as an offset variable.
Time Frame	Baseline up to Week 96

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population.

Arm/Group Title	Placebo	Teriflunomide
Arm/Group Description:	Participants received Placebo matching to teriflunomide tablet orally QD for 96 weeks.	Participants received 1 Teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) orally QD for 8 weeks. After 8 weeks, based on participant's predicted PK parameters, teriflunomide was administered in following manner up to 96 weeks: if predicted PK parameters <= 95th percentile of adult range after 7 mg QD: 1 tablet of 7 mg daily (for BW up to 40 kg) or 1 tablet of 14 mg daily (for BW >40 kg); or if predicted PK parameters >95th percentile of adult range: 1 tablet of 3.5 mg daily (for BW up to 40 kg) or 1 tablet of 7 mg daily (for BW >40 kg). The adult range (5th - 95th percentile) of predicted steady state PK parameters for a 7 mg dose was defined as Cmax ranging from 8.03 to 49.10 mcg/mL and AUC0-24 ranging from 184 to 1160 mcg*h/mL.
Overall Number of Participants Analyzed	57	109
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: lesions per scan
	10.515; (4.705 to 23.500)	4.735; (2.122 to 10.567)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Teriflunomide
	Comments	A hierarchical testing method was used to control Type-I error. Testing was then performed sequentially in the order the outcome measures are reported. The hierarchical testing sequence continued only when previous outcome measure was statistically significant at 5%.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0006
	Comments	Negative binomial regression model with robust variance estimation: total number of new/enlarged T2-lesions as response variable;treatment group, region, baseline pubertal status & age as covariates;log-transformed number of scans as offset variable.
	Method	Negative binomial regression model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Relative risk ratio
	Estimated Value	0.450
	Confidence Interval	(2-Sided) 95%; 0.285 to 0.711
	Estimation Comments	Negative binomial regression model with robust variance estimation: total number of new/enlarged T2-lesions as response variable;treatment group, region, baseline pubertal status & age as covariates;log-transformed number of scans as offset variable.

4. Secondary Outcome

Title	Magnetic Resonance Imaging Assessment: Number of T1 Gadolinium (Gd)-Enhancing T1 Lesions Per MRI Scan
Description	The number of T1 Gd-Enhancing lesions per scan was defined as the total number of lesions that occurred during the 96 weeks treatment period divided by the total number of scans performed during 96 weeks. To account for the different number of scans performed among the participants, a negative binomial regression model with robust variance estimation was used. The model included the total number of T1-lesions as the response variable, with treatment group, region, pubertal status and age as covariates and log-transformed number of scans as an offset variable.
Time Frame	Baseline up to Week 96

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population.

Arm/Group Title	Placebo	Teriflunomide
Arm/Group Description:	Participants received Placebo matching to teriflunomide tablet orally QD for 96 weeks.	Participants received 1 Teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) orally QD for 8 weeks. After 8 weeks, based on participant's predicted PK parameters, teriflunomide was administered in following manner up to 96 weeks: if predicted PK parameters <= 95th percentile of adult range after 7 mg QD: 1 tablet of 7 mg daily (for BW up to 40 kg) or 1 tablet of 14 mg daily (for BW >40 kg); or if predicted PK parameters >95th percentile of adult range: 1 tablet of 3.5 mg daily (for BW up to 40 kg) or 1 tablet of 7 mg daily (for BW >40 kg). The adult range (5th - 95th percentile) of predicted steady state PK parameters for a 7 mg dose was defined as Cmax ranging from 8.03 to 49.10 mcg/mL and AUC0-24 ranging from 184 to 1160 mcg*h/mL.
Overall Number of Participants Analyzed	57	109
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: lesions per scan
	7.505; (2.482 to 22.695)	1.897; (0.656 to 5.489)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Teriflunomide
	Comments	Testing according to the hierarchical testing procedure (hypothesis formally tested only if the preceding outcome measure was significant at 5%).
	Type of Statistical Test	Superiority
	Comments	P-value and relative risk ratio was calculated by negative binomial regression model with robust variance estimation: total number of T1 Gd-enhancing T1 lesions as response variable, treatment group, region, baseline T1 Gd-enhancing T1 lesion count, pubertal status at baseline and age as covariates and log-transformed number of scans as offset variable.
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Negative binomial regression model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Relative risk ratio
	Estimated Value	0.253
	Confidence Interval	(2-Sided) 95%; 0.126 to 0.505
	Estimation Comments	[Not Specified]

5. Secondary Outcome

Title	Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T2 Lesions at Weeks 24, 48, 72 and 96
Description	Volume of T2 lesions was measured by MRI scan.
Time Frame	Baseline, Weeks 24, 48, 72 and 96

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population. Here, 'number analyzed' represent the number of participants analyzed for each category.

Arm/Group Title		Placebo	Teriflunomide
Arm/Group Description:		Participants received Placebo matching to teriflunomide tablet orally QD for 96 weeks.	Participants received 1 Teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) orally QD for 8 weeks. After 8 weeks, based on participant's predicted PK parameters, teriflunomide was administered in following manner up to 96 weeks: if predicted PK parameters <= 95th percentile of adult range after 7 mg QD: 1 tablet of 7 mg daily (for BW up to 40 kg) or 1 tablet of 14 mg daily (for BW >40 kg); or if predicted PK parameters >95th percentile of adult range: 1 tablet of 3.5 mg daily (for BW up to 40 kg) or 1 tablet of 7 mg daily (for BW >40 kg). The adult range (5th - 95th percentile) of predicted steady state PK parameters for a 7 mg dose was defined as Cmax ranging from 8.03 to 49.10 mcg/mL and AUC0-24 ranging from 184 to 1160 mcg*h/mL.
Overall Number of Participants Analyzed		57	109
Least Squares Mean (Standard Error); Unit of Measure: milliliters
Week 24	Number Analyzed	44 participants	96 participants
		0.148 (0.047)	0.075 (0.042)
Week 48	Number Analyzed	24 participants	72 participants
		0.135 (0.051)	0.060 (0.044)
Week 72	Number Analyzed	18 participants	64 participants
		0.204 (0.054)	0.065 (0.045)
Week 96	Number Analyzed	16 participants	54 participants
		0.201 (0.054)	0.073 (0.045)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Teriflunomide
	Comments	Week 24: Analysis performed using a Mixed-effect model with repeated measures (MMRM) adjusted for pubertal status, region, visit, treatment-by-visit interaction and cubic root transformed baseline volume.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0462
	Comments	[Not Specified]
	Method	MMRM
	Comments	MMRM analysis adjusted for pubertal status at baseline, region, visit, treatment-by-visit interaction and cubic root transformed baseline volume.
Method of Estimation	Estimation Parameter	LS Mean difference
	Estimated Value	-0.073
	Confidence Interval	(2-Sided) 95%; -0.144 to -0.001
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.036
	Estimation Comments	MMRM analysis adjusted for pubertal status at baseline, region, visit, treatment-by-visit interaction and cubic root transformed baseline volume.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Teriflunomide
	Comments	Week 48: Analysis performed using a MMRM adjusted for pubertal status, region, visit, treatment-by-visit interaction and cubic root transformed baseline volume.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0917
	Comments	[Not Specified]
	Method	MMRM
	Comments	MMRM analysis adjusted for pubertal status at baseline, region, visit, treatment-by-visit interaction and cubic root transformed baseline volume.
Method of Estimation	Estimation Parameter	LS Mean difference
	Estimated Value	-0.074
	Confidence Interval	(2-Sided) 95%; -0.161 to 0.012
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.044
	Estimation Comments	MMRM analysis adjusted for pubertal status at baseline, region, visit, treatment-by-visit interaction and cubic root transformed baseline volume.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Teriflunomide
	Comments	Week 72: Analysis performed using a MMRM adjusted for pubertal status, region, visit, treatment-by-visit interaction and cubic root transformed baseline volume.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0052
	Comments	[Not Specified]
	Method	MMRM
	Comments	MMRM analysis adjusted for pubertal status at baseline, region, visit, treatment-by-visit interaction and cubic root transformed baseline volume.
Method of Estimation	Estimation Parameter	LS Mean difference
	Estimated Value	-0.139
	Confidence Interval	(2-Sided) 95%; -0.235 to -0.043
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.048
	Estimation Comments	MMRM analysis adjusted for pubertal status at baseline, region, visit, treatment-by-visit interaction and cubic root transformed baseline volume.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Teriflunomide
	Comments	Week 96: Analysis performed using a MMRM adjusted for pubertal status, region, visit, treatment-by-visit interaction and cubic root transformed baseline volume.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0100
	Comments	[Not Specified]
	Method	MMRM
	Comments	MMRM analysis adjusted for pubertal status at baseline, region, visit, treatment-by-visit interaction and cubic root transformed baseline volume.
Method of Estimation	Estimation Parameter	LS Mean difference
	Estimated Value	-0.128
	Confidence Interval	(2-Sided) 95%; -0.225 to -0.031
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.049
	Estimation Comments	MMRM analysis adjusted for pubertal status at baseline, region, visit, treatment-by-visit interaction and cubic root transformed baseline volume.

6. Secondary Outcome

Title	Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T1 Hypointense Lesions
Description	Volume of T1 hypointense lesions was measured by MRI scan.
Time Frame	Baseline, Weeks 24, 48, 72 and 96

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population. Here, 'number analyzed' represent the number of participants analyzed for each category.

Arm/Group Title		Placebo	Teriflunomide
Arm/Group Description:		Participants received Placebo matching to teriflunomide tablet orally QD for 96 weeks.	Participants received 1 Teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) orally QD for 8 weeks. After 8 weeks, based on participant's predicted PK parameters, teriflunomide was administered in following manner up to 96 weeks: if predicted PK parameters <= 95th percentile of adult range after 7 mg QD: 1 tablet of 7 mg daily (for BW up to 40 kg) or 1 tablet of 14 mg daily (for BW >40 kg); or if predicted PK parameters >95th percentile of adult range: 1 tablet of 3.5 mg daily (for BW up to 40 kg) or 1 tablet of 7 mg daily (for BW >40 kg). The adult range (5th - 95th percentile) of predicted steady state PK parameters for a 7 mg dose was defined as Cmax ranging from 8.03 to 49.10 mcg/mL and AUC0-24 ranging from 184 to 1160 mcg*h/mL.
Overall Number of Participants Analyzed		57	109
Mean (Standard Deviation); Unit of Measure: milliliters
Week 24	Number Analyzed	44 participants	96 participants
		0.4 (1.3)	0.0 (0.7)
Week 48	Number Analyzed	23 participants	72 participants
		0.2 (0.6)	0.3 (2.8)
Week 72	Number Analyzed	18 participants	63 participants
		0.1 (0.7)	0.1 (0.6)
Week 96	Number Analyzed	16 participants	53 participants
		0.1 (0.5)	0.1 (0.7)

7. Secondary Outcome

Title	Magnetic Resonance Imaging Assessment: Number of New T1 Hypointense Lesions Per MRI Scan
Description	The number of new T1 hypointense lesions were obtained from MRI scans.
Time Frame	Baseline up to Week 96

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population.

Arm/Group Title	Placebo	Teriflunomide
Arm/Group Description:	Participants received Placebo matching to teriflunomide tablet orally QD for 96 weeks.	Participants received 1 Teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) orally QD for 8 weeks. After 8 weeks, based on participant's predicted PK parameters, teriflunomide was administered in following manner up to 96 weeks: if predicted PK parameters <= 95th percentile of adult range after 7 mg QD: 1 tablet of 7 mg daily (for BW up to 40 kg) or 1 tablet of 14 mg daily (for BW >40 kg); or if predicted PK parameters >95th percentile of adult range: 1 tablet of 3.5 mg daily (for BW up to 40 kg) or 1 tablet of 7 mg daily (for BW >40 kg). The adult range (5th - 95th percentile) of predicted steady state PK parameters for a 7 mg dose was defined as Cmax ranging from 8.03 to 49.10 mcg/mL and AUC0-24 ranging from 184 to 1160 mcg*h/mL.
Overall Number of Participants Analyzed	57	109
Measure Type: Number; Unit of Measure: lesions
	714	848

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Teriflunomide
	Comments	Negative binomial regression model with robust variance estimation, with total number of new hypointense T1 lesions as response variable, with treatment group, region, baseline pubertal status and age as covariates and log-transformed number of scans as an offset variable.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0236
	Comments	Negative binomial regression model with robust variance estimation:total number of new T1 hypointense lesions as response variable;treatment group, region, baseline pubertal status & age covariates;log-transformed number of scans as offset variable.
	Method	Negative binomial regression model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Relative risk ratio
	Estimated Value	0.507
	Confidence Interval	(2-Sided) 95%; 0.281 to 0.913
	Estimation Comments	Negative binomial regression model with robust variance estimation:total number of new T1 hypointense lesions as response variable;treatment group, region, baseline pubertal status & age covariates;log-transformed number of scans as offset variable.

8. Secondary Outcome

Title	Magnetic Resonance Imaging Assessment: Percentage of Participants Free of New or Enlarged MRI T2-Lesions
Description	Percentage of participants who were free of new or enlarged T2 lesions at Weeks 48 and 96 were reported.
Time Frame	Weeks 48 and 96

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population.

Arm/Group Title	Placebo	Teriflunomide
Arm/Group Description:	Participants received Placebo matching to teriflunomide tablet orally QD for 96 weeks.	Participants received 1 Teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) orally QD for 8 weeks. After 8 weeks, based on participant's predicted PK parameters, teriflunomide was administered in following manner up to 96 weeks: if predicted PK parameters <= 95th percentile of adult range after 7 mg QD: 1 tablet of 7 mg daily (for BW up to 40 kg) or 1 tablet of 14 mg daily (for BW >40 kg); or if predicted PK parameters >95th percentile of adult range: 1 tablet of 3.5 mg daily (for BW up to 40 kg) or 1 tablet of 7 mg daily (for BW >40 kg). The adult range (5th - 95th percentile) of predicted steady state PK parameters for a 7 mg dose was defined as Cmax ranging from 8.03 to 49.10 mcg/mL and AUC0-24 ranging from 184 to 1160 mcg*h/mL.
Overall Number of Participants Analyzed	57	109
Measure Type: Number; Unit of Measure: percentage of participants
Week 48	10.5	17.4
Week 96	3.5	10.1

9. Secondary Outcome

Title	Magnetic Resonance Imaging Assessment: Percent Change From Baseline in Brain Volume at Weeks 24, 48, 72 and 96
Description	Percent change from baseline in brain volume (assessed using MRI scans of the Brain) at weeks 24, 48, 72 and 96 was reported.
Time Frame	Baseline, Weeks 24, 48, 72 and 96

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population. Here, 'number analyzed' represent the number of participants analyzed for each category.

Arm/Group Title		Placebo	Teriflunomide
Arm/Group Description:		Participants received Placebo matching to teriflunomide tablet orally QD for 96 weeks.	Participants received 1 Teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) orally QD for 8 weeks. After 8 weeks, based on participant's predicted PK parameters, teriflunomide was administered in following manner up to 96 weeks: if predicted PK parameters <= 95th percentile of adult range after 7 mg QD: 1 tablet of 7 mg daily (for BW up to 40 kg) or 1 tablet of 14 mg daily (for BW >40 kg); or if predicted PK parameters >95th percentile of adult range: 1 tablet of 3.5 mg daily (for BW up to 40 kg) or 1 tablet of 7 mg daily (for BW >40 kg). The adult range (5th - 95th percentile) of predicted steady state PK parameters for a 7 mg dose was defined as Cmax ranging from 8.03 to 49.10 mcg/mL and AUC0-24 ranging from 184 to 1160 mcg*h/mL.
Overall Number of Participants Analyzed		57	109
Mean (Standard Deviation); Unit of Measure: percent change
Week 24	Number Analyzed	42 participants	90 participants
		-0.3 (0.7)	-0.2 (0.8)
Week 48	Number Analyzed	23 participants	68 participants
		-0.5 (1.0)	-0.5 (0.9)
Week 72	Number Analyzed	18 participants	58 participants
		-0.8 (1.2)	-0.7 (1.1)
Week 96	Number Analyzed	15 participants	50 participants
		-0.9 (1.2)	-0.8 (1.1)

10. Secondary Outcome

Title	Cognitive Assessment: Change From Baseline in Total Number of Correct Substitutions Measured by Symbol Digit Modalities Test (SDMT) at Weeks 24, 48, 72 and 96
Description	SDMT measures the time to pair abstract symbols with specific numbers. It is a simple substitution task that gives the examinee 90 seconds to pair specific numbers with given geometric figures as a measure for screening cognitive impairment. The score is the number of correct substitution and ranged from 0 (worst outcome) to 110 (best outcome), where higher score indicated better cognitive function.
Time Frame	Baseline, Weeks 24, 48, 72 and 96

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population. Here, 'number analyzed' represent the number of participants analyzed for each category.

Arm/Group Title		Placebo	Teriflunomide
Arm/Group Description:		Participants received Placebo matching to teriflunomide tablet orally QD for 96 weeks.	Participants received 1 Teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) orally QD for 8 weeks. After 8 weeks, based on participant's predicted PK parameters, teriflunomide was administered in following manner up to 96 weeks: if predicted PK parameters <= 95th percentile of adult range after 7 mg QD: 1 tablet of 7 mg daily (for BW up to 40 kg) or 1 tablet of 14 mg daily (for BW >40 kg); or if predicted PK parameters >95th percentile of adult range: 1 tablet of 3.5 mg daily (for BW up to 40 kg) or 1 tablet of 7 mg daily (for BW >40 kg). The adult range (5th - 95th percentile) of predicted steady state PK parameters for a 7 mg dose was defined as Cmax ranging from 8.03 to 49.10 mcg/mL and AUC0-24 ranging from 184 to 1160 mcg*h/mL.
Overall Number of Participants Analyzed		57	109
Mean (Standard Deviation); Unit of Measure: score on a scale
Week 24	Number Analyzed	44 participants	94 participants
		4.6 (11.6)	4.8 (9.2)
Week 48	Number Analyzed	24 participants	69 participants
		6.2 (13.5)	6.1 (10.3)
Week 72	Number Analyzed	19 participants	63 participants
		7.0 (12.7)	6.0 (11.2)
Week 96	Number Analyzed	16 participants	53 participants
		9.1 (10.9)	8.3 (11.1)

11. Secondary Outcome

Title	Cognitive Assessment: Change From Baseline in Number of Completed Items Measured by Symbol Digit Modalities Test at Weeks 24, 48, 72 and 96
Description	SDMT measures the time to pair abstract symbols with specific numbers. It is a simple substitution task that gives the examinee 90 seconds to pair specific numbers with given geometric figures as a measure for screening cognitive impairment. The score is the number of completed items and ranged from 0 (worst outcome) to 110 (best outcome), where higher score indicated better cognitive function.
Time Frame	Baseline, Weeks 24, 48, 72 and 96

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population. Here, 'number analyzed' represent the number of participants analyzed for each category.

Arm/Group Title		Placebo	Teriflunomide
Arm/Group Description:		Participants received Placebo matching to teriflunomide tablet orally QD for 96 weeks.	Participants received 1 Teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) orally QD for 8 weeks. After 8 weeks, based on participant's predicted PK parameters, teriflunomide was administered in following manner up to 96 weeks: if predicted PK parameters <= 95th percentile of adult range after 7 mg QD: 1 tablet of 7 mg daily (for BW up to 40 kg) or 1 tablet of 14 mg daily (for BW >40 kg); or if predicted PK parameters >95th percentile of adult range: 1 tablet of 3.5 mg daily (for BW up to 40 kg) or 1 tablet of 7 mg daily (for BW >40 kg). The adult range (5th - 95th percentile) of predicted steady state PK parameters for a 7 mg dose was defined as Cmax ranging from 8.03 to 49.10 mcg/mL and AUC0-24 ranging from 184 to 1160 mcg*h/mL.
Overall Number of Participants Analyzed		57	109
Mean (Standard Deviation); Unit of Measure: score on a scale
Week 24	Number Analyzed	44 participants	94 participants
		3.4 (11.3)	3.8 (9.0)
Week 48	Number Analyzed	24 participants	69 participants
		5.4 (13.3)	5.0 (10.1)
Week 72	Number Analyzed	19 participants	63 participants
		5.6 (13.0)	4.8 (11.0)
Week 96	Number Analyzed	16 participants	53 participants
		7.6 (11.0)	7.1 (11.1)

12. Secondary Outcome

Title	Cognitive Assessment: Change From Baseline in Brief Visuospatial Memory Test-Revised (BVMT-R) Scores at Week 96
Description	The BVMT consists of three trials in which participants must recall shapes by drawing figures on a blank page (response booklet) after being given the opportunity to memorize the figures (given in BMVT-R form) for 10 seconds. BMVT-R form consists of six figures. Points are awarded based on the accuracy of the drawn figure and by correct placement on the blank page. A minimum of 0 to 12 points/scores are awarded per trial, so a participant can score between 0 and 36 points for all three trials (by adding the points/score from each trial), where higher score indicates better outcome.
Time Frame	Baseline, Week 96

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure.

Arm/Group Title	Placebo	Teriflunomide
Arm/Group Description:	Participants received Placebo matching to teriflunomide tablet orally QD for 96 weeks.	Participants received 1 Teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) orally QD for 8 weeks. After 8 weeks, based on participant's predicted PK parameters, teriflunomide was administered in following manner up to 96 weeks: if predicted PK parameters <= 95th percentile of adult range after 7 mg QD: 1 tablet of 7 mg daily (for BW up to 40 kg) or 1 tablet of 14 mg daily (for BW >40 kg); or if predicted PK parameters >95th percentile of adult range: 1 tablet of 3.5 mg daily (for BW up to 40 kg) or 1 tablet of 7 mg daily (for BW >40 kg). The adult range (5th - 95th percentile) of predicted steady state PK parameters for a 7 mg dose was defined as Cmax ranging from 8.03 to 49.10 mcg/mL and AUC0-24 ranging from 184 to 1160 mcg*h/mL.
Overall Number of Participants Analyzed	7	36
Mean (Standard Deviation); Unit of Measure: score on a scale
	1.9 (10.7)	0.8 (6.0)

13. Secondary Outcome

Title	Cognitive Assessment: Change From Baseline in Trail Making Test- Part A (TMT-A) Test Scores (in Seconds) at Week 96
Description	'Trail Making Test Part A' is a neuropsychological test of visual attention and task switching. The task requires a participant to 'connect-the-dots' of 25 consecutive numbers (1,2, 3,etc.) in sequential order on a sheet of paper or computer screen. The goal of the participant is to finish the test as quickly as possible, and the time taken to complete the test used as the primary performance metric (in seconds). This is a timed test and the number of seconds to complete the task is recorded. Maximum time allowed is 300 seconds. A lower score indicates better cognitive function.
Time Frame	Baseline, Week 96

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure.

Arm/Group Title	Placebo	Teriflunomide
Arm/Group Description:	Participants received Placebo matching to teriflunomide tablet orally QD for 96 weeks.	Participants received 1 Teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) orally QD for 8 weeks. After 8 weeks, based on participant's predicted PK parameters, teriflunomide was administered in following manner up to 96 weeks: if predicted PK parameters <= 95th percentile of adult range after 7 mg QD: 1 tablet of 7 mg daily (for BW up to 40 kg) or 1 tablet of 14 mg daily (for BW >40 kg); or if predicted PK parameters >95th percentile of adult range: 1 tablet of 3.5 mg daily (for BW up to 40 kg) or 1 tablet of 7 mg daily (for BW >40 kg). The adult range (5th - 95th percentile) of predicted steady state PK parameters for a 7 mg dose was defined as Cmax ranging from 8.03 to 49.10 mcg/mL and AUC0-24 ranging from 184 to 1160 mcg*h/mL.
Overall Number of Participants Analyzed	4	13
Mean (Standard Deviation); Unit of Measure: seconds
	3.8 (11.8)	-3.1 (19.5)

14. Secondary Outcome

Title	Cognitive Assessment: Change From Baseline in Trail Making Test B (TMT-B) Test Scores (in Seconds) at Week 96
Description	TMT-B is a cognitive test that gives a measure of various aspects of cognitive performance. It is used to measure cognitive fatigue. The test consists of 25 circles containing 13 sequential numbers (1-13) and 12 sequential letters (A-L) positioned. The test evaluates the time (in seconds) to correctly order letters and numbers in alternate order (1, A, 2, B etc.). Maximum time allowed is 300 seconds, where less time/lower score indicates better cognitive function/performance.
Time Frame	Baseline, Week 96

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure.

Arm/Group Title	Placebo	Teriflunomide
Arm/Group Description:	Participants received Placebo matching to teriflunomide tablet orally QD for 96 weeks.	Participants received 1 Teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) orally QD for 8 weeks. After 8 weeks, based on participant's predicted PK parameters, teriflunomide was administered in following manner up to 96 weeks: if predicted PK parameters <= 95th percentile of adult range after 7 mg QD: 1 tablet of 7 mg daily (for BW up to 40 kg) or 1 tablet of 14 mg daily (for BW >40 kg); or if predicted PK parameters >95th percentile of adult range: 1 tablet of 3.5 mg daily (for BW up to 40 kg) or 1 tablet of 7 mg daily (for BW >40 kg). The adult range (5th - 95th percentile) of predicted steady state PK parameters for a 7 mg dose was defined as Cmax ranging from 8.03 to 49.10 mcg/mL and AUC0-24 ranging from 184 to 1160 mcg*h/mL.
Overall Number of Participants Analyzed	4	13
Mean (Standard Deviation); Unit of Measure: seconds
	-14.4 (29.6)	-29.5 (56.6)

15. Secondary Outcome

Title	Cognitive Assessment: Change From Baseline in Beery Visual-motor Integration (BVMI) Scores at Week 96
Description	The Beery VMI is a non-verbal assessment that assessed the extent to which individuals can integrate their visual and motor abilities. The participants were provided with geometric designs ranging from simple line drawings to more complex figures and were asked to copy the designs. The test consisted of 24 figures. One point was scored for each successful copy of drawings and no scoring was given when the participant failed to copy the drawings properly. Each successful copying of drawings was summed up and the total was scored on a scale ranged from 0 to 24, where higher score indicated better visual construction skills/better visual and motor abilities and lower score indicated poor visual construction skills/poor visual and motor abilities.
Time Frame	Baseline, Week 96

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure.

Arm/Group Title	Placebo	Teriflunomide
Arm/Group Description:	Participants received Placebo matching to teriflunomide tablet orally QD for 96 weeks.	Participants received 1 Teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) orally QD for 8 weeks. After 8 weeks, based on participant's predicted PK parameters, teriflunomide was administered in following manner up to 96 weeks: if predicted PK parameters <= 95th percentile of adult range after 7 mg QD: 1 tablet of 7 mg daily (for BW up to 40 kg) or 1 tablet of 14 mg daily (for BW >40 kg); or if predicted PK parameters >95th percentile of adult range: 1 tablet of 3.5 mg daily (for BW up to 40 kg) or 1 tablet of 7 mg daily (for BW >40 kg). The adult range (5th - 95th percentile) of predicted steady state PK parameters for a 7 mg dose was defined as Cmax ranging from 8.03 to 49.10 mcg/mL and AUC0-24 ranging from 184 to 1160 mcg*h/mL.
Overall Number of Participants Analyzed	12	47
Mean (Standard Deviation); Unit of Measure: score on a scale
	0.6 (2.2)	-0.3 (4.8)

16. Secondary Outcome

Title	Cognitive Assessment: Change From Baseline in Wechsler Abbreviated Scale of Intelligence-II (WASI-II) Vocabulary Total Raw Scores at Week 96
Description	The WASI-II: Vocabulary test is a quick estimate of an individual's level of intellectual functioning which comprised of 31 total items that require the participant to orally define 3 images and 28 words presented both orally and visually. Items 1 to 3 rated on a score of 0 or 1, items 4 and 5 rated on a score of 0 or 2, items 6 to 31 rated on a scale of 0 to 2. Each item score was summed up to derive the total score which was ranged from 0 (minimum score) to 59 (maximum score), where higher score indicated better level of intellectual functioning/higher level of intelligence.
Time Frame	Baseline, Week 96

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population. Here, "Overall Number of Participants Analyzed" = participants with available data for this outcome measure.

Arm/Group Title	Placebo	Teriflunomide
Arm/Group Description:	Participants received Placebo matching to teriflunomide tablet orally QD for 96 weeks.	Participants received 1 Teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) orally QD for 8 weeks. After 8 weeks, based on participant's predicted PK parameters, teriflunomide was administered in following manner up to 96 weeks: if predicted PK parameters <= 95th percentile of adult range after 7 mg QD: 1 tablet of 7 mg daily (for BW up to 40 kg) or 1 tablet of 14 mg daily (for BW >40 kg); or if predicted PK parameters >95th percentile of adult range: 1 tablet of 3.5 mg daily (for BW up to 40 kg) or 1 tablet of 7 mg daily (for BW >40 kg). The adult range (5th - 95th percentile) of predicted steady state PK parameters for a 7 mg dose was defined as Cmax ranging from 8.03 to 49.10 mcg/mL and AUC0-24 ranging from 184 to 1160 mcg*h/mL.
Overall Number of Participants Analyzed	1	1
Mean (Standard Deviation); Unit of Measure: score on a scale
	5.0	4.0

17. Secondary Outcome

Title	Cognitive Assessment: Change From Baseline in Delis-Kaplan Executive Function System (D-KEFS) Letter Fluency Total Correct Raw Score at Week 96
Description	Letter Fluency is a condition measured in the Delis-Kaplan Executive Function System (D-KEFS). Participants are asked to name as many words as they can, starting with a specified letter for 60 seconds. The words cannot be names, places, numbers or grammatical variants of previous answers. Repeated answers are not scored as a correct response. There are 3 trials, with 3 different letters. The total number of correct responses is totaled for all 3 trials and a Letter Fluency Score is given. A higher score is considered better. There is no set range as the score depends on how many correct words the participant relays in the given time period.
Time Frame	Baseline, Week 96

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population. Here, "Overall Number of Participants Analyzed" = participants with available data for this outcome measure.

Arm/Group Title	Placebo	Teriflunomide
Arm/Group Description:	Participants received Placebo matching to teriflunomide tablet orally QD for 96 weeks.	Participants received 1 Teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) orally QD for 8 weeks. After 8 weeks, based on participant's predicted PK parameters, teriflunomide was administered in following manner up to 96 weeks: if predicted PK parameters <= 95th percentile of adult range after 7 mg QD: 1 tablet of 7 mg daily (for BW up to 40 kg) or 1 tablet of 14 mg daily (for BW >40 kg); or if predicted PK parameters >95th percentile of adult range: 1 tablet of 3.5 mg daily (for BW up to 40 kg) or 1 tablet of 7 mg daily (for BW >40 kg). The adult range (5th - 95th percentile) of predicted steady state PK parameters for a 7 mg dose was defined as Cmax ranging from 8.03 to 49.10 mcg/mL and AUC0-24 ranging from 184 to 1160 mcg*h/mL.
Overall Number of Participants Analyzed	1	2
Mean (Standard Deviation); Unit of Measure: score on a scale
	-3.0	4.0 (9.9)

18. Secondary Outcome

Title	Cognitive Assessment: Change From Baseline in Delis-Kaplan Executive Function System Category Fluency Total Correct Raw Score at Week 96
Description	Category Fluency is a condition measured in the D-KEFS. It measures participant's ability to generate words from three different categories (e.g., fruits, vegetables and animals), within a minute for each category. Total score is number of correct words for each category with no points for repetitions or non-words. Score range 0 to unlimited, where 0 = low score, higher score indicates better performance.
Time Frame	Baseline, Week 96

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population. Here, "Overall Number of Participants Analyzed" = participants with available data for this outcome measure.

Arm/Group Title	Placebo	Teriflunomide
Arm/Group Description:	Participants received Placebo matching to teriflunomide tablet orally QD for 96 weeks.	Participants received 1 Teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) orally QD for 8 weeks. After 8 weeks, based on participant's predicted PK parameters, teriflunomide was administered in following manner up to 96 weeks: if predicted PK parameters <= 95th percentile of adult range after 7 mg QD: 1 tablet of 7 mg daily (for BW up to 40 kg) or 1 tablet of 14 mg daily (for BW >40 kg); or if predicted PK parameters >95th percentile of adult range: 1 tablet of 3.5 mg daily (for BW up to 40 kg) or 1 tablet of 7 mg daily (for BW >40 kg). The adult range (5th - 95th percentile) of predicted steady state PK parameters for a 7 mg dose was defined as Cmax ranging from 8.03 to 49.10 mcg/mL and AUC0-24 ranging from 184 to 1160 mcg*h/mL.
Overall Number of Participants Analyzed	1	2
Mean (Standard Deviation); Unit of Measure: score on a scale
	6.0	5.0 (5.7)

19. Secondary Outcome

Title	Cognitive Assessment - Selective Reminding Test (SRT): Change From Baseline in Total Number of Words on Delayed Recall at Week 96
Description	SRT is a test to assess verbal learning and memory. During the administration of the SRT only the examiner and the participant should be in the testing room. A list of twelve words is read aloud by the examiner at a rate of one word per two seconds. The participant is asked to recall all twelve words after a 30 minute delay. Only the words that are missed on the preceding trial are given in the consecutive trial. The total score represents a sum score of total 6 trials, therefore the range is from 0-72. The lower the value the worse the outcome, higher value indicates better recall.
Time Frame	Baseline, Week 96

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population. Here, "Overall Number of Participants Analyzed" = participants with available data for this outcome measure.

Arm/Group Title	Placebo	Teriflunomide
Arm/Group Description:	Participants received Placebo matching to teriflunomide tablet orally QD for 96 weeks.	Participants received 1 Teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) orally QD for 8 weeks. After 8 weeks, based on participant's predicted PK parameters, teriflunomide was administered in following manner up to 96 weeks: if predicted PK parameters <= 95th percentile of adult range after 7 mg QD: 1 tablet of 7 mg daily (for BW up to 40 kg) or 1 tablet of 14 mg daily (for BW >40 kg); or if predicted PK parameters >95th percentile of adult range: 1 tablet of 3.5 mg daily (for BW up to 40 kg) or 1 tablet of 7 mg daily (for BW >40 kg). The adult range (5th - 95th percentile) of predicted steady state PK parameters for a 7 mg dose was defined as Cmax ranging from 8.03 to 49.10 mcg/mL and AUC0-24 ranging from 184 to 1160 mcg*h/mL.
Overall Number of Participants Analyzed	1	2
Mean (Standard Deviation); Unit of Measure: score on a scale
	1.0	-0.5 (2.1)

20. Secondary Outcome

Title	Pharmacokinetics: Steady-state Trough Concentration (Ctrough) of Teriflunomide
Description	Ctrough was defined as the concentration reached by the drug before the next dose is administered. Data for this outcome measure was planned to be collected and analyzed separately for each dose of Teriflunomide.
Time Frame	Predose on Week 36

Outcome Measure Data

Analysis Population Description

Analysis was performed on PK population which included all randomized participants exposed to double-blind study medication and had at least 1 PK sample taken. Here, 'overall number of participants analyzed' = participants evaluable for this outcome measure and "0'' signifies that none of the participant was evaluable for Teriflunomide 3.5 mg arm.

Arm/Group Title	Teriflunomide 3.5 mg	Teriflunomide 7 mg	Teriflunomide 14 mg
Arm/Group Description:	Participants with BW up to 40 kg received 1 Teriflunomide tablet, 3.5 mg orally QD for 8 weeks. After 8 weeks, based on participant's predicted PK parameters, teriflunomide was administered in following manner up to 96 weeks: if predicted PK parameters <= 95th percentile of adult range: 1 tablet of 7 mg daily (for BW up to 40 kg) or 1 tablet of 14 mg daily (for BW >40 kg); or if predicted PK parameters >95th percentile of adult range: 1 tablet of 3.5 mg daily (for BW up to 40 kg) or 1 tablet of 7 mg daily (for BW >40 kg).	Participants with BW >40 kg received 1 Teriflunomide tablet, 7 mg orally QD for 8 weeks. After 8 weeks, based on participant's predicted PK parameters, teriflunomide was administered in following manner up to 96 weeks: if predicted PK parameters <= 95th percentile of adult range after 7 mg QD: 1 tablet of 7 mg daily (for BW up to 40 kg) or 1 tablet of 14 mg daily (for BW >40 kg); or if predicted PK parameters >95th percentile of adult range: 1 tablet of 3.5 mg daily (for BW up to 40 kg) or 1 tablet of 7 mg daily (for BW >40 kg).	After 8 weeks, based on participant's predicted PK parameters, teriflunomide was administered in following manner up to 96 weeks: if predicted PK parameters <= 95th percentile of adult range after 7 mg QD: 1 tablet of 7 mg daily (for BW up to 40 kg) or 1 tablet of 14 mg daily (for BW >40 kg); or if predicted PK parameters >95th percentile of adult range: 1 tablet of 3.5 mg daily (for BW up to 40 kg) or 1 tablet of 7 mg daily (for BW >40 kg).
Overall Number of Participants Analyzed	0	10	66
Mean (Standard Deviation); Unit of Measure: micrograms per milliliter
		53.1 (25.3)	67.8 (41.7)

Adverse Events

Time Frame	Adverse events (AEs) were collected from signature of the Informed Consent Form up to 96 weeks.
Adverse Event Reporting Description	All reported AEs were treatment-emergent AEs (TEAEs), which developed/worsened during TEAE period (defined as time from 1st intake of investigational medicinal product (IMP) to last intake of IMP in 96-weeks double-blind treatment period). Safety population included all randomized participants exposed to double-blind study medication, regardless of the amount of treatment administered.
Arm/Group Title	Placebo		Teriflunomide
Arm/Group Description	Participants received Placebo matching to teriflunomide tablet orally QD for 96 weeks.		Participants received 1 Teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) orally QD for 8 weeks. After 8 weeks, based on participant's predicted PK parameters, teriflunomide was administered in following manner up to 96 weeks: if predicted PK parameters <= 95th percentile of adult range after 7 mg QD: 1 tablet of 7 mg daily (for BW up to 40 kg) or 1 tablet of 14 mg daily (for BW >40 kg); or if predicted PK parameters >95th percentile of adult range: 1 tablet of 3.5 mg daily (for BW up to 40 kg) or 1 tablet of 7 mg daily (for BW >40 kg). The adult range (5th - 95th percentile) of predicted steady state PK parameters for a 7 mg dose was defined as Cmax ranging from 8.03 to 49.10 mcg/mL and AUC0-24 ranging from 184 to 1160 mcg*h/mL.
All-Cause Mortality
	Placebo		Teriflunomide
	Affected / at Risk (%)		Affected / at Risk (%)
Total	0/57 (0.00%)		0/109 (0.00%)
Serious Adverse Events
	Placebo		Teriflunomide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/57 (10.53%)		12/109 (11.01%)
Blood and lymphatic system disorders
Neutropenia † 1	0/57 (0.00%)	0	1/109 (0.92%)	1
Cardiac disorders
Cardiomyopathy † 1	0/57 (0.00%)	0	1/109 (0.92%)	1
Congenital, familial and genetic disorders
Familial Mediterranean Fever † 1	1/57 (1.75%)	1	0/109 (0.00%)	0
Eye disorders
Diplopia † 1	0/57 (0.00%)	0	1/109 (0.92%)	1
Gastrointestinal disorders
Anal Fissure † 1	1/57 (1.75%)	1	0/109 (0.00%)	0
Anal Fistula † 1	0/57 (0.00%)	0	1/109 (0.92%)	1
Pancreatitis Acute † 1	0/57 (0.00%)	0	1/109 (0.92%)	1
Infections and infestations
Appendicitis † 1	1/57 (1.75%)	1	0/109 (0.00%)	0
Pulmonary Tuberculosis † 1	0/57 (0.00%)	0	1/109 (0.92%)	1
Upper Respiratory Tract Infection † 1	0/57 (0.00%)	0	1/109 (0.92%)	1
Injury, poisoning and procedural complications
Joint Dislocation † 1	1/57 (1.75%)	1	0/109 (0.00%)	0
Lumbar Vertebral Fracture † 1	0/57 (0.00%)	0	1/109 (0.92%)	1
Peripheral Nerve Injury † 1	0/57 (0.00%)	0	1/109 (0.92%)	1
Investigations
Alanine Aminotransferase Increased † 1	0/57 (0.00%)	0	1/109 (0.92%)	1
Blood Creatine Phosphokinase Increased † 1	0/57 (0.00%)	0	2/109 (1.83%)	2
Transaminases Increased † 1	0/57 (0.00%)	0	1/109 (0.92%)	1
Nervous system disorders
Epilepsy † 1	1/57 (1.75%)	1	1/109 (0.92%)	2
Syncope † 1	1/57 (1.75%)	1	2/109 (1.83%)	3
Respiratory, thoracic and mediastinal disorders
Asthma † 1	1/57 (1.75%)	1	0/109 (0.00%)	0
1 Term from vocabulary, MedDRA 22.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	2%
	Placebo		Teriflunomide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	40/57 (70.18%)		85/109 (77.98%)
Blood and lymphatic system disorders
Anaemia † 1	1/57 (1.75%)	1	3/109 (2.75%)	3
Neutropenia † 1	0/57 (0.00%)	0	3/109 (2.75%)	5
Cardiac disorders
Palpitations † 1	0/57 (0.00%)	0	3/109 (2.75%)	3
Ear and labyrinth disorders
Ear Pain † 1	2/57 (3.51%)	2	3/109 (2.75%)	3
Tinnitus † 1	1/57 (1.75%)	1	3/109 (2.75%)	3
Endocrine disorders
Autoimmune Thyroiditis † 1	2/57 (3.51%)	2	1/109 (0.92%)	1
Eye disorders
Eye Pain † 1	4/57 (7.02%)	8	4/109 (3.67%)	4
Vision Blurred † 1	2/57 (3.51%)	3	2/109 (1.83%)	3
Visual Impairment † 1	2/57 (3.51%)	3	0/109 (0.00%)	0
Gastrointestinal disorders
Abdominal Pain † 1	1/57 (1.75%)	1	12/109 (11.01%)	15
Abdominal Pain Upper † 1	2/57 (3.51%)	2	6/109 (5.50%)	9
Diarrhoea † 1	4/57 (7.02%)	4	8/109 (7.34%)	9
Nausea † 1	4/57 (7.02%)	5	9/109 (8.26%)	11
Vomiting † 1	5/57 (8.77%)	5	5/109 (4.59%)	6
General disorders
Fatigue † 1	3/57 (5.26%)	5	4/109 (3.67%)	6
Influenza Like Illness † 1	1/57 (1.75%)	1	3/109 (2.75%)	3
Non-Cardiac Chest Pain † 1	0/57 (0.00%)	0	4/109 (3.67%)	4
Pyrexia † 1	2/57 (3.51%)	2	6/109 (5.50%)	9
Hepatobiliary disorders
Cholelithiasis † 1	2/57 (3.51%)	2	0/109 (0.00%)	0
Infections and infestations
Bronchitis † 1	1/57 (1.75%)	1	5/109 (4.59%)	5
Gastroenteritis † 1	3/57 (5.26%)	3	3/109 (2.75%)	3
Influenza † 1	4/57 (7.02%)	4	10/109 (9.17%)	16
Nasopharyngitis † 1	5/57 (8.77%)	6	28/109 (25.69%)	49
Pharyngitis † 1	1/57 (1.75%)	1	7/109 (6.42%)	8
Respiratory Tract Infection Viral † 1	0/57 (0.00%)	0	4/109 (3.67%)	7
Rhinitis † 1	2/57 (3.51%)	3	4/109 (3.67%)	8
Sinusitis † 1	2/57 (3.51%)	2	4/109 (3.67%)	4
Tinea Versicolour † 1	2/57 (3.51%)	2	1/109 (0.92%)	1
Tonsillitis † 1	2/57 (3.51%)	2	4/109 (3.67%)	4
Upper Respiratory Tract Infection † 1	6/57 (10.53%)	23	23/109 (21.10%)	64
Injury, poisoning and procedural complications
Accidental Overdose † 1	3/57 (5.26%)	6	4/109 (3.67%)	4
Contusion † 1	0/57 (0.00%)	0	4/109 (3.67%)	4
Fall † 1	4/57 (7.02%)	5	6/109 (5.50%)	8
Ligament Sprain † 1	2/57 (3.51%)	2	1/109 (0.92%)	1
Investigations
Blood Creatine Phosphokinase Increased † 1	0/57 (0.00%)	0	4/109 (3.67%)	6
Neutrophil Count Decreased † 1	0/57 (0.00%)	0	3/109 (2.75%)	5
Protein Urine Present † 1	1/57 (1.75%)	1	3/109 (2.75%)	4
Weight Decreased † 1	2/57 (3.51%)	2	6/109 (5.50%)	7
Weight Increased † 1	0/57 (0.00%)	0	3/109 (2.75%)	4
White Blood Cell Count Decreased † 1	1/57 (1.75%)	1	4/109 (3.67%)	7
Metabolism and nutrition disorders
Vitamin D Deficiency † 1	2/57 (3.51%)	2	2/109 (1.83%)	2
Musculoskeletal and connective tissue disorders
Arthralgia † 1	3/57 (5.26%)	7	2/109 (1.83%)	2
Back Pain † 1	2/57 (3.51%)	3	5/109 (4.59%)	6
Muscle Spasms † 1	2/57 (3.51%)	2	2/109 (1.83%)	2
Muscular Weakness † 1	2/57 (3.51%)	2	1/109 (0.92%)	1
Musculoskeletal Pain † 1	0/57 (0.00%)	0	3/109 (2.75%)	3
Pain In Extremity † 1	2/57 (3.51%)	2	4/109 (3.67%)	4
Nervous system disorders
Dizziness † 1	4/57 (7.02%)	5	9/109 (8.26%)	9
Headache † 1	13/57 (22.81%)	18	18/109 (16.51%)	30
Hypoaesthesia † 1	3/57 (5.26%)	5	6/109 (5.50%)	7
Paraesthesia † 1	1/57 (1.75%)	2	12/109 (11.01%)	20
Presyncope † 1	0/57 (0.00%)	0	3/109 (2.75%)	3
Tremor † 1	2/57 (3.51%)	3	1/109 (0.92%)	1
Psychiatric disorders
Anxiety † 1	3/57 (5.26%)	3	4/109 (3.67%)	6
Depression † 1	2/57 (3.51%)	2	2/109 (1.83%)	2
Insomnia † 1	3/57 (5.26%)	3	0/109 (0.00%)	0
Reproductive system and breast disorders
Dysmenorrhoea † 1	3/57 (5.26%)	3	1/109 (0.92%)	1
Respiratory, thoracic and mediastinal disorders
Cough † 1	3/57 (5.26%)	3	6/109 (5.50%)	7
Dyspnoea † 1	0/57 (0.00%)	0	3/109 (2.75%)	3
Nasal Congestion † 1	1/57 (1.75%)	1	3/109 (2.75%)	3
Oropharyngeal Pain † 1	2/57 (3.51%)	2	7/109 (6.42%)	8
Rhinitis Allergic † 1	0/57 (0.00%)	0	3/109 (2.75%)	3
Skin and subcutaneous tissue disorders
Acne † 1	4/57 (7.02%)	4	5/109 (4.59%)	5
Alopecia † 1	7/57 (12.28%)	7	23/109 (21.10%)	25
Rash † 1	2/57 (3.51%)	2	4/109 (3.67%)	4
Vascular disorders
Orthostatic Hypotension † 1	2/57 (3.51%)	3	0/109 (0.00%)	0
1 Term from vocabulary, MedDRA 22.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The Sponsor supports publication of clinical trial results but may request that investigators temporarily delay or alter publications in order to protect proprietary information. The Sponsor may also require that the results of multicenter studies be published only in their entirety and not as individual site data.

Results Point of Contact

• Name/Title: Trial Transparency Team
• Organization: Genzyme, a Sanofi Company
• Phone: 800-633-1610 ext 1#
• EMail: Contact-US@sanofi.com

• Responsible Party: Sanofi ( Genzyme, a Sanofi Company )
• ClinicalTrials.gov Identifier: NCT02201108
• Other Study ID Numbers: EFC11759; 2011-005249-12 ( EudraCT Number ); U1111-1124-0983 ( Other Identifier: WHO Universal Trial Reference Number (UTRN) )
• First Submitted: July 17, 2014
• First Posted: July 25, 2014
• Results First Submitted: October 20, 2020
• Results First Posted: November 30, 2020
• Last Update Posted: November 30, 2020