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

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ClinicalTrials.gov Identifier: NCT02201108
Recruitment Status : Active, not recruiting
First Posted : July 25, 2014
Results First Posted : November 30, 2020
Last Update Posted : July 15, 2022
Sponsor:
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
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 via Interactive Voice Response System. Randomization was stratified by the country and participant's pubertal status.
Arm/Group Title Placebo/Teriflunomide Teriflunomide/Teriflunomide
Hide Arm/Group Description Participants received Placebo matching to teriflunomide tablet orally once daily for 96 weeks in double blind (DB) treatment period. After completion of DB period, eligible participants entered in open label (OL) period and received 1 teriflunomide tablet, 3.5 milligrams (mg) (in case of body weight [BW] up to 40 kilograms [kg]) or 7 mg (BW greater than [>] 40 kg) for first 8 weeks. After 8 weeks if individual predicted PK parameter was less than or equal to (<=) 95th percentile of adult range after 7 mg once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW>40 kg) in the OL period for additional 96 weeks (i.e., up to Week 192). If individual predicted PK parameters >95th percentile of adult range then participant received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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 maximum concentration observed (Cmax) ranging from 8.03 to 49.10 micrograms per milliliter (mcg/mL) and area under the curve from time 0 hour to 24 hours (AUC0-24) ranging from 184 to 1160 micrograms*hour per milliliter (mcg*h/mL). 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 once daily for 8 weeks. After 8 weeks, based on individual 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 once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW >40 kg); or if individual predicted PK parameters >95th percentile of adult range then participants received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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. After completion of DB period, eligible participants entered in OL period and continued receiving teriflunomide at the same dose in the OL period for additional 96 weeks (i.e., up to Week 192).
Period Title: Double-blind Period (up to Week 96)
Started [1] 57 109
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.
Period Title: Open Label Period (up to Week 192)
Started [1] 52 100
Completed 31 73
Not Completed 21 27
Reason Not Completed
Lack of Efficacy             10             14
Poor compliance to protocol             0             1
Other reason             4             7
Adverse Event             7             5
[1]
Post completion of DB treatment period, only eligible participants entered OL treatment period.
Arm/Group Title Placebo/Teriflunomide Teriflunomide/Teriflunomide Total
Hide Arm/Group Description Participants received Placebo matching to teriflunomide tablet orally once daily for 96 weeks in DB treatment period. After completion of DB period, eligible participants entered in OL period and received 1 teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) for first 8 weeks. After 8 weeks if individual predicted PK parameter was <= 95th percentile of adult range after 7 mg once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW>40 kg) in the OL period for additional 96 weeks (i.e., up to Week 192). If individual predicted PK parameters >95th percentile of adult range then participant received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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. 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 once daily for 8 weeks. After 8 weeks, based on individual 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 once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW >40 kg); or if individual predicted PK parameters >95th percentile of adult range then participants received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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. After completion of DB period, eligible participants entered in OL period and continued receiving teriflunomide at the same dose in the OL period for additional 96 weeks (i.e., up to Week 192). Total of all reporting groups
Overall Number of Baseline Participants 57 109 166
Hide 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%
1.Primary Outcome
Title Time to First Confirmed Clinical Relapse
Hide 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
Hide Outcome Measure Data
Hide 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 Double-Blind Treatment Period: Placebo Double-Blind Treatment Period: Teriflunomide
Hide Arm/Group Description:
Participants received Placebo matching to teriflunomide tablet orally once daily for 96 weeks in DB period.
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 once daily for 8 weeks. After 8 weeks, based on individual 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 once daily: 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW >40 kg); or if individual predicted PK parameters >95th percentile of adult range then participants received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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 in DB period.
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)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment Period: Placebo, Double-Blind Treatment Period: 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 P-value 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, 96, 120, 144, 168 and 192
Hide Description Participant was considered free of clinical relapse if the participant had no confirmed clinical relapse before treatment discontinuation/completion in 192 weeks treatment period. Clinical relapses: 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: 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 & ambulation on scale of 0 to 12, where higher score in each scale indicated worsened neurological function. New/recurrent symptoms 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 were estimated by Kaplan-Meier method and reported.
Time Frame Weeks 24, 48, 72, 96, 120, 144, 168 and 192
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on efficacy population which included all participants enrolled and treated with at least 1 dose of teriflunomide in OL period analyzed according to the treatment group allocated by randomization in the DB period.
Arm/Group Title Placebo/Teriflunomide Teriflunomide/ Teriflunomide
Hide Arm/Group Description:
Participants received Placebo matching to teriflunomide tablet orally once daily for 96 weeks in DB treatment period. After completion of DB period, eligible participants entered in OL period and received 1 teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) for first 8 weeks. After 8 weeks if individual predicted PK parameter was <= 95th percentile of adult range after 7 mg once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW>40 kg) in the OL period for additional 96 weeks (i.e., up to Week 192). If individual predicted PK parameters >95th percentile of adult range then participant received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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.
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 once daily for 8 weeks. After 8 weeks, based on individual 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 once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW >40 kg); or if individual predicted PK parameters >95th percentile of adult range then participants received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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. After completion of DB period, eligible participants entered in OL period and continued receiving teriflunomide at the same dose in the OL period for additional 96 weeks (i.e., up to Week 192).
Overall Number of Participants Analyzed 52 100
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: probability of relapse free participants
Week 24
0.750
(0.609 to 0.846)
0.820
(0.730 to 0.883)
Week 48
0.596
(0.451 to 0.715)
0.700
(0.600 to 0.780)
Week 72
0.519
(0.377 to 0.644)
0.630
(0.528 to 0.716)
Week 96
0.442
(0.305 to 0.571)
0.600
(0.497 to 0.688)
Week 120
0.404
(0.271 to 0.533)
0.570
(0.467 to 0.660)
Week 144
0.365
(0.238 to 0.494)
0.540
(0.437 to 0.631)
Week 168
0.365
(0.238 to 0.494)
0.518
(0.416 to 0.611)
Week 192
0.365
(0.238 to 0.494)
0.518
(0.416 to 0.611)
3.Secondary Outcome
Title Brain Magnetic Resonance Imaging (MRI) Assessment: Number of New or Enlarged T2 Lesions Per MRI Scan
Hide 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 192 weeks treatment period divided by the total number of scans performed during 192 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 192
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on efficacy population.
Arm/Group Title Placebo/Teriflunomide Teriflunomide/ Teriflunomide
Hide Arm/Group Description:
Participants received Placebo matching to teriflunomide tablet orally once daily for 96 weeks in DB treatment period. After completion of DB period, eligible participants entered in OL period and received 1 teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) for first 8 weeks. After 8 weeks if individual predicted PK parameter was <= 95th percentile of adult range after 7 mg once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW>40 kg) in the OL period for additional 96 weeks (i.e., up to Week 192). If individual predicted PK parameters >95th percentile of adult range then participant received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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.
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 once daily for 8 weeks. After 8 weeks, based on individual 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 once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW >40 kg); or if individual predicted PK parameters >95th percentile of adult range then participants received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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. After completion of DB period, eligible participants entered in OL period and continued receiving teriflunomide at the same dose in the OL period for additional 96 weeks (i.e., up to Week 192).
Overall Number of Participants Analyzed 52 100
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: lesions per scan
11.087
(6.586 to 18.662)
5.664
(3.417 to 9.389)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo/Teriflunomide, Teriflunomide/ Teriflunomide
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Relative risk ratio
Estimated Value 0.511
Confidence Interval (2-Sided) 95%
0.343 to 0.762
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Brain Magnetic Resonance Imaging Assessment: Number of T1 Gadolinium (Gd)-Enhancing T1 Lesions Per MRI Scan
Hide Description The number of T1 Gd-Enhancing lesions per scan was defined as the total number of Gd-enhancing lesions that occurred during the 192 weeks treatment period divided by the total number of scans performed during 192 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 192
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on efficacy population.
Arm/Group Title Placebo/Teriflunomide Teriflunomide/ Teriflunomide
Hide Arm/Group Description:
Participants received Placebo matching to teriflunomide tablet orally once daily for 96 weeks in DB treatment period. After completion of DB period, eligible participants entered in OL period and received 1 teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) for first 8 weeks. After 8 weeks if individual predicted PK parameter was <= 95th percentile of adult range after 7 mg once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW>40 kg) in the OL period for additional 96 weeks (i.e., up to Week 192). If individual predicted PK parameters >95th percentile of adult range then participant received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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.
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 once daily for 8 weeks. After 8 weeks, based on individual 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 once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW >40 kg); or if individual predicted PK parameters >95th percentile of adult range then participants received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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. After completion of DB period, eligible participants entered in OL period and continued receiving teriflunomide at the same dose in the OL period for additional 96 weeks (i.e., up to Week 192).
Overall Number of Participants Analyzed 52 100
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: lesions per scan
2.686
(1.263 to 5.712)
1.532
(0.624 to 3.762)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo/Teriflunomide, Teriflunomide/ Teriflunomide
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Relative risk ratio
Estimated Value 0.57
Confidence Interval (2-Sided) 95%
0.331 to 0.983
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T2 Lesions at Weeks 24, 36, 48, 72, 96, 144 and 192
Hide Description Volume of T2 lesions was measured by MRI scan.
Time Frame Baseline, DB period: Weeks 24, 36, 48, 72 and 96; OL period: Weeks 48, 96, 144 and 192
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on efficacy population. Here, 'overall number of participants analyzed' = participants evaluable for this outcome measure and 'number analyzed' = participants with available data for each specified category.
Arm/Group Title Placebo/Teriflunomide Teriflunomide/ Teriflunomide
Hide Arm/Group Description:
Participants received Placebo matching to teriflunomide tablet orally once daily for 96 weeks in DB treatment period. After completion of DB period, eligible participants entered in OL period and received 1 teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) for first 8 weeks. After 8 weeks if individual predicted PK parameter was <= 95th percentile of adult range after 7 mg once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW>40 kg) in the OL period for additional 96 weeks (i.e., up to Week 192). If individual predicted PK parameters >95th percentile of adult range then participant received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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.
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 once daily for 8 weeks. After 8 weeks, based on individual 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 once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW >40 kg); or if individual predicted PK parameters >95th percentile of adult range then participants received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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. After completion of DB period, eligible participants entered in OL period and continued receiving teriflunomide at the same dose in the OL period for additional 96 weeks (i.e., up to Week 192).
Overall Number of Participants Analyzed 52 98
Mean (Standard Deviation)
Unit of Measure: milliliters
DB Period: Week 24 Number Analyzed 40 participants 88 participants
3.0  (7.0) 0.5  (1.8)
DB Period: Week 36 Number Analyzed 19 participants 39 participants
4.6  (11.7) 4.4  (21.3)
DB Period: Week 48 Number Analyzed 21 participants 68 participants
0.5  (0.6) -0.2  (3.4)
DB Period: Week 72 Number Analyzed 16 participants 59 participants
1.2  (1.6) 0.1  (1.9)
DB Period: Week 96 Number Analyzed 14 participants 51 participants
0.9  (1.4) 0.2  (1.9)
OL Period: Week 48 Number Analyzed 51 participants 88 participants
3.0  (9.7) 0.6  (8.8)
OL Period: Week 96 Number Analyzed 37 participants 74 participants
2.7  (8.1) 1.9  (4.0)
OL Period: Week 144 Number Analyzed 20 participants 23 participants
4.7  (10.7) 0.4  (17.1)
OL Period: Week 192 Number Analyzed 5 participants 8 participants
0.4  (9.4) -3.6  (30.6)
6.Secondary Outcome
Title Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T1 Hypointense Lesions
Hide Description Volume of T1 hypointense lesions was measured by MRI scan.
Time Frame Baseline, DB period: Weeks 24, 36, 48, 72 and 96; OL period: Weeks 48, 96, 144 and 192
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on efficacy population. Here, 'overall number of participants analyzed' = participants evaluable for this outcome measure and 'number analyzed' = participants with available data for each specified category.
Arm/Group Title Placebo/Teriflunomide Teriflunomide/ Teriflunomide
Hide Arm/Group Description:
Participants received Placebo matching to teriflunomide tablet orally once daily for 96 weeks in DB treatment period. After completion of DB period, eligible participants entered in OL period and received 1 teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) for first 8 weeks. After 8 weeks if individual predicted PK parameter was <= 95th percentile of adult range after 7 mg once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW>40 kg) in the OL period for additional 96 weeks (i.e., up to Week 192). If individual predicted PK parameters >95th percentile of adult range then participant received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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.
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 once daily for 8 weeks. After 8 weeks, based on individual 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 once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW >40 kg); or if individual predicted PK parameters >95th percentile of adult range then participants received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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. After completion of DB period, eligible participants entered in OL period and continued receiving teriflunomide at the same dose in the OL period for additional 96 weeks (i.e., up to Week 192).
Overall Number of Participants Analyzed 52 98
Mean (Standard Deviation)
Unit of Measure: milliliters
DB Period: Week 24 Number Analyzed 40 participants 88 participants
0.3  (1.3) 0.0  (0.7)
DB Period: Week 36 Number Analyzed 19 participants 39 participants
0.8  (1.8) 0.2  (0.8)
DB Period: Week 48 Number Analyzed 20 participants 68 participants
0.2  (0.4) 0.4  (2.9)
DB Period: Week 72 Number Analyzed 16 participants 58 participants
0.1  (0.7) 0.1  (0.6)
DB Period: Week 96 Number Analyzed 14 participants 50 participants
0.1  (0.6) 0.1  (0.7)
OL Period: Week 48 Number Analyzed 51 participants 86 participants
0.7  (1.9) 0.5  (1.4)
OL Period: Week 96 Number Analyzed 37 participants 73 participants
1.0  (2.0) 0.6  (1.9)
OL Period: Week 144 Number Analyzed 20 participants 22 participants
2.0  (3.0) 1.9  (3.4)
OL Period: Week 192 Number Analyzed 5 participants 8 participants
4.0  (5.8) 2.5  (5.7)
7.Secondary Outcome
Title Brain Magnetic Resonance Imaging Assessment: Number of New T1 Hypointense Lesions Per MRI Scan
Hide Description The number of new T1 hypointense lesions were obtained from MRI scans.
Time Frame Baseline up to Week 192
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on efficacy population.
Arm/Group Title Placebo/Teriflunomide Teriflunomide/ Teriflunomide
Hide Arm/Group Description:
Participants received Placebo matching to teriflunomide tablet orally once daily for 96 weeks in DB treatment period. After completion of DB period, eligible participants entered in OL period and received 1 teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) for first 8 weeks. After 8 weeks if individual predicted PK parameter was <= 95th percentile of adult range after 7 mg once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW>40 kg) in the OL period for additional 96 weeks (i.e., up to Week 192). If individual predicted PK parameters >95th percentile of adult range then participant received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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.
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 once daily for 8 weeks. After 8 weeks, based on individual 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 once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW >40 kg); or if individual predicted PK parameters >95th percentile of adult range then participants received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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. After completion of DB period, eligible participants entered in OL period and continued receiving teriflunomide at the same dose in the OL period for additional 96 weeks (i.e., up to Week 192).
Overall Number of Participants Analyzed 52 100
Measure Type: Number
Unit of Measure: lesions
1561 1910
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo/Teriflunomide, Teriflunomide/ Teriflunomide
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Relative risk ratio
Estimated Value 0.498
Confidence Interval (2-Sided) 95%
0.296 to 0.836
Estimation Comments [Not Specified]
8.Secondary Outcome
Title Brain Magnetic Resonance Imaging Assessment: Percentage of Participants Free of New or Enlarged MRI T2-Lesions
Hide Description Percentage of participants who were free of new or enlarged T2 lesions at Weeks 24, 48, 72, 96, 144 and 192 were reported.
Time Frame Baseline, Weeks 24, 48, 72, 96, 144 and 192
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on efficacy population.
Arm/Group Title Placebo/Teriflunomide Teriflunomide/ Teriflunomide
Hide Arm/Group Description:
Participants received Placebo matching to teriflunomide tablet orally once daily for 96 weeks in DB treatment period. After completion of DB period, eligible participants entered in OL period and received 1 teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) for first 8 weeks. After 8 weeks if individual predicted PK parameter was <= 95th percentile of adult range after 7 mg once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW>40 kg) in the OL period for additional 96 weeks (i.e., up to Week 192). If individual predicted PK parameters >95th percentile of adult range then participant received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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.
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 once daily for 8 weeks. After 8 weeks, based on individual 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 once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW >40 kg); or if individual predicted PK parameters >95th percentile of adult range then participants received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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. After completion of DB period, eligible participants entered in OL period and continued receiving teriflunomide at the same dose in the OL period for additional 96 weeks (i.e., up to Week 192).
Overall Number of Participants Analyzed 52 100
Measure Type: Number
Unit of Measure: percentage of participants
Week 24 86.5 86.0
Week 48 32.7 25.0
Week 72 15.4 17.0
Week 96 15.4 16.0
Week 144 11.5 14.0
Week 192 7.7 9.0
9.Secondary Outcome
Title Brain Magnetic Resonance Imaging Assessment: Percent Change From Baseline in Brain Volume at Weeks 24, 36, 48, 72, 96, 144 and 192
Hide Description Percent change from baseline in brain volume (assessed using MRI scans of the Brain) at Weeks 24, 36, 48,72, 96, 144 and 192 was reported.
Time Frame Baseline, DB period: Weeks 24, 36, 48, 72 and 96; OL period: Weeks 48, 96, 144 and 192
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on efficacy population. Here, 'overall number of participants analyzed' = participants evaluable for this outcome measure and 'number analyzed' = participants with available data for each specified category.
Arm/Group Title Placebo/Teriflunomide Teriflunomide/ Teriflunomide
Hide Arm/Group Description:
Participants received Placebo matching to teriflunomide tablet orally once daily for 96 weeks in DB treatment period. After completion of DB period, eligible participants entered in OL period and received 1 teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) for first 8 weeks. After 8 weeks if individual predicted PK parameter was <= 95th percentile of adult range after 7 mg once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW>40 kg) in the OL period for additional 96 weeks (i.e., up to Week 192). If individual predicted PK parameters >95th percentile of adult range then participant received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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.
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 once daily for 8 weeks. After 8 weeks, based on individual 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 once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW >40 kg); or if individual predicted PK parameters >95th percentile of adult range then participants received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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. After completion of DB period, eligible participants entered in OL period and continued receiving teriflunomide at the same dose in the OL period for additional 96 weeks (i.e., up to Week 192).
Overall Number of Participants Analyzed 52 97
Mean (Standard Deviation)
Unit of Measure: percent change
DB Period: Week 24 Number Analyzed 38 participants 83 participants
-0.3  (0.7) -0.2  (0.7)
DB Period: Week 36 Number Analyzed 17 participants 39 participants
-0.7  (0.7) -0.4  (1.0)
DB Period: Week 48 Number Analyzed 20 participants 64 participants
-0.6  (1.1) -0.5  (0.9)
DB Period: Week 72 Number Analyzed 16 participants 53 participants
-0.9  (1.3) -0.6  (1.1)
DB Period: Week 96 Number Analyzed 13 participants 47 participants
-0.9  (1.3) -0.8  (1.1)
OL Period: Week 48 Number Analyzed 43 participants 73 participants
-1.4  (1.6) -1.1  (1.3)
OL Period: Week 96 Number Analyzed 33 participants 60 participants
-1.8  (1.9) -1.4  (1.6)
OL Period: Week 144 Number Analyzed 16 participants 17 participants
-3.1  (2.8) -2.0  (1.7)
OL Period: Week 192 Number Analyzed 4 participants 6 participants
-2.2  (1.2) -3.0  (1.9)
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, 96, 120, 144, 168 and 192
Hide 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 SDMT 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, DB period: Weeks 24, 48, 72 and 96; OL period: Weeks 24, 48, 72, 96, 120, 144, 168 and 192
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on efficacy population. Here, 'overall number of participants analyzed' = participants evaluable for this outcome measure and 'number analyzed' = participants with available data for each specified category.
Arm/Group Title Placebo/Teriflunomide Teriflunomide/ Teriflunomide
Hide Arm/Group Description:
Participants received Placebo matching to teriflunomide tablet orally once daily for 96 weeks in DB treatment period. After completion of DB period, eligible participants entered in OL period and received 1 teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) for first 8 weeks. After 8 weeks if individual predicted PK parameter was <= 95th percentile of adult range after 7 mg once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW>40 kg) in the OL period for additional 96 weeks (i.e., up to Week 192). If individual predicted PK parameters >95th percentile of adult range then participant received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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.
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 once daily for 8 weeks. After 8 weeks, based on individual 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 once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW >40 kg); or if individual predicted PK parameters >95th percentile of adult range then participants received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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. After completion of DB period, eligible participants entered in OL period and continued receiving teriflunomide at the same dose in the OL period for additional 96 weeks (i.e., up to Week 192).
Overall Number of Participants Analyzed 51 96
Mean (Standard Deviation)
Unit of Measure: score on a scale
DB Period: Week 24 Number Analyzed 40 participants 85 participants
5.1  (12.0) 4.6  (9.1)
DB Period: Week 48 Number Analyzed 20 participants 64 participants
7.3  (14.1) 5.7  (10.3)
DB Period: Week 72 Number Analyzed 17 participants 58 participants
6.4  (12.9) 5.6  (11.5)
DB Period: Week 96 Number Analyzed 14 participants 52 participants
8.8  (10.7) 8.1  (11.1)
OL Period: Week 24 Number Analyzed 51 participants 91 participants
6.3  (13.9) 8.3  (12.3)
OL Period: Week 48 Number Analyzed 44 participants 88 participants
6.7  (13.3) 7.6  (13.0)
OL Period: Week 72 Number Analyzed 41 participants 76 participants
8.0  (15.5) 9.2  (13.0)
OL Period: Week 96 Number Analyzed 36 participants 73 participants
7.6  (16.7) 8.0  (14.8)
OL Period: Week 120 Number Analyzed 22 participants 28 participants
3.7  (15.9) 7.2  (10.3)
OL Period: Week 144 Number Analyzed 18 participants 19 participants
6.6  (14.4) 5.2  (13.0)
OL Period: Week 168 Number Analyzed 13 participants 15 participants
3.5  (17.9) 1.7  (14.0)
OL Period: Week 192 Number Analyzed 1 participants 4 participants
12.0 -0.3  (18.2)
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, 96, 120, 144, 168 and 192
Hide 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 SDMT 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, DB period: Weeks 24, 48, 72 and 96; OL period: Weeks 24, 48, 72, 96, 120, 144, 168 and 192
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on efficacy population. Here, 'overall number of participants analyzed' = participants evaluable for this outcome measure and 'number analyzed' = participants with available data for each specified category.
Arm/Group Title Placebo/Teriflunomide Teriflunomide/ Teriflunomide
Hide Arm/Group Description:
Participants received Placebo matching to teriflunomide tablet orally once daily for 96 weeks in DB treatment period. After completion of DB period, eligible participants entered in OL period and received 1 teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) for first 8 weeks. After 8 weeks if individual predicted PK parameter was <= 95th percentile of adult range after 7 mg once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW>40 kg) in the OL period for additional 96 weeks (i.e., up to Week 192). If individual predicted PK parameters >95th percentile of adult range then participant received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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.
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 once daily for 8 weeks. After 8 weeks, based on individual 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 once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW >40 kg); or if individual predicted PK parameters >95th percentile of adult range then participants received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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. After completion of DB period, eligible participants entered in OL period and continued receiving teriflunomide at the same dose in the OL period for additional 96 weeks (i.e., up to Week 192).
Overall Number of Participants Analyzed 51 96
Mean (Standard Deviation)
Unit of Measure: score on a scale
DB Period: Week 24 Number Analyzed 40 participants 85 participants
3.8  (11.7) 3.6  (9.0)
DB Period: Week 48 Number Analyzed 20 participants 64 participants
6.3  (13.8) 4.7  (10.3)
DB Period: Week 72 Number Analyzed 17 participants 58 participants
5.1  (13.4) 4.5  (11.4)
DB Period: Week 96 Number Analyzed 14 participants 52 participants
7.1  (11.2) 6.9  (11.1)
OL Period: Week 24 Number Analyzed 51 participants 91 participants
4.8  (13.5) 7.1  (12.4)
OL Period: Week 48 Number Analyzed 44 participants 88 participants
5.5  (12.8) 6.4  (13.0)
OL Period: Week 72 Number Analyzed 41 participants 76 participants
6.4  (15.4) 8.1  (12.8)
OL Period: Week 96 Number Analyzed 36 participants 73 participants
6.3  (16.6) 7.6  (12.5)
OL Period: Week 120 Number Analyzed 22 participants 28 participants
3.7  (14.7) 6.3  (11.5)
OL Period: Week 144 Number Analyzed 18 participants 19 participants
4.8  (15.1) 3.7  (13.4)
OL Period: Week 168 Number Analyzed 13 participants 15 participants
2.7  (15.5) -0.3  (15.6)
OL Period: Week 192 Number Analyzed 1 participants 4 participants
12.0 -1.5  (18.3)
12.Secondary Outcome
Title Cognitive Assessment: Change From Baseline in Brief Visuospatial Memory Test-Revised (BVMT-R) Scores at Weeks 96 and 192
Hide 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, Weeks 96 and 192
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on efficacy population. Here, 'overall number of participants analyzed' = participants evaluable for this outcome measure and 'number analyzed' = participants with available data for each specified category.
Arm/Group Title Placebo/Teriflunomide Teriflunomide/ Teriflunomide
Hide Arm/Group Description:
Participants received Placebo matching to teriflunomide tablet orally once daily for 96 weeks in DB treatment period. After completion of DB period, eligible participants entered in OL period and received 1 teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) for first 8 weeks. After 8 weeks if individual predicted PK parameter was <= 95th percentile of adult range after 7 mg once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW>40 kg) in the OL period for additional 96 weeks (i.e., up to Week 192). If individual predicted PK parameters >95th percentile of adult range then participant received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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.
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 once daily for 8 weeks. After 8 weeks, based on individual 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 once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW >40 kg); or if individual predicted PK parameters >95th percentile of adult range then participants received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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. After completion of DB period, eligible participants entered in OL period and continued receiving teriflunomide at the same dose in the OL period for additional 96 weeks (i.e., up to Week 192).
Overall Number of Participants Analyzed 31 69
Mean (Standard Deviation)
Unit of Measure: score on a scale
Baseline Number Analyzed 31 participants 69 participants
23.8  (7.2) 24.8  (6.4)
Change at Week 96 Number Analyzed 5 participants 35 participants
-0.8  (9.3) 1.6  (5.3)
Change at Week 192 Number Analyzed 16 participants 45 participants
1.0  (6.9) 1.2  (5.4)
13.Secondary Outcome
Title Cognitive Assessment: Change From Baseline in Trail Making Test- Part A (TMT-A) Test Scores (in Seconds) at Week 96 and 192
Hide 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 indicated better cognitive function.
Time Frame Baseline, Weeks 96 and 192
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on efficacy population. Here, 'overall number of participants analyzed' = participants evaluable for this outcome measure and 'number analyzed' = participants with available data for each specified category.
Arm/Group Title Placebo/Teriflunomide Teriflunomide/ Teriflunomide
Hide Arm/Group Description:
Participants received Placebo matching to teriflunomide tablet orally once daily for 96 weeks in DB treatment period. After completion of DB period, eligible participants entered in OL period and received 1 teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) for first 8 weeks. After 8 weeks if individual predicted PK parameter was <= 95th percentile of adult range after 7 mg once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW>40 kg) in the OL period for additional 96 weeks (i.e., up to Week 192). If individual predicted PK parameters >95th percentile of adult range then participant received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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.
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 once daily for 8 weeks. After 8 weeks, based on individual 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 once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW >40 kg); or if individual predicted PK parameters >95th percentile of adult range then participants received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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. After completion of DB period, eligible participants entered in OL period and continued receiving teriflunomide at the same dose in the OL period for additional 96 weeks (i.e., up to Week 192).
Overall Number of Participants Analyzed 14 29
Mean (Standard Deviation)
Unit of Measure: seconds
Baseline Number Analyzed 14 participants 29 participants
43.4  (24.2) 47.1  (23.7)
Change at Week 96 Number Analyzed 3 participants 13 participants
8.4  (9.0) -3.1  (19.5)
Change at Week 192 Number Analyzed 8 participants 21 participants
6.3  (20.7) -6.6  (17.4)
14.Secondary Outcome
Title Cognitive Assessment: Change From Baseline in Trail Making Test B (TMT-B) Test Scores (in Seconds) at Weeks 96 and 192
Hide 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 consisted of 25 circles containing 13 sequential numbers (1 to 13) and 12 sequential letters (A to 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 indicated better cognitive function/performance.
Time Frame Baseline, Weeks 96 and 192
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Hide Analysis Population Description
Analysis was performed on efficacy population. Here, 'overall number of participants analyzed' = participants evaluable for this outcome measure and 'number analyzed' = participants with available data for each specified category.
Arm/Group Title Placebo/Teriflunomide Teriflunomide/ Teriflunomide
Hide Arm/Group Description:
Participants received Placebo matching to teriflunomide tablet orally once daily for 96 weeks in DB treatment period. After completion of DB period, eligible participants entered in OL period and received 1 teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) for first 8 weeks. After 8 weeks if individual predicted PK parameter was <= 95th percentile of adult range after 7 mg once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW>40 kg) in the OL period for additional 96 weeks (i.e., up to Week 192). If individual predicted PK parameters >95th percentile of adult range then participant received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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.
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 once daily for 8 weeks. After 8 weeks, based on individual 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 once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW >40 kg); or if individual predicted PK parameters >95th percentile of adult range then participants received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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. After completion of DB period, eligible participants entered in OL period and continued receiving teriflunomide at the same dose in the OL period for additional 96 weeks (i.e., up to Week 192).
Overall Number of Participants Analyzed 14 28
Mean (Standard Deviation)
Unit of Measure: seconds
Baseline Number Analyzed 14 participants 28 participants
113.8  (81.5) 115.0  (44.6)
Change at Week 96 Number Analyzed 3 participants 13 participants
-19.8  (33.7) -29.5  (56.6)
Change at Week 192 Number Analyzed 8 participants 21 participants
-37.0  (83.3) -18.8  (37.3)
15.Secondary Outcome
Title Cognitive Assessment: Change From Baseline in Beery Visual-motor Integration (BVMI) Scores at Weeks 96 and 192
Hide 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, Weeks 96 and 192
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Hide Analysis Population Description
Analysis was performed on efficacy population. Here, 'overall number of participants analyzed' = participants evaluable for this outcome measure and 'number analyzed' = participants with available data for each specified category.
Arm/Group Title Placebo/Teriflunomide Teriflunomide/ Teriflunomide
Hide Arm/Group Description:
Participants received Placebo matching to teriflunomide tablet orally once daily for 96 weeks in DB treatment period. After completion of DB period, eligible participants entered in OL period and received 1 teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) for first 8 weeks. After 8 weeks if individual predicted PK parameter was <= 95th percentile of adult range after 7 mg once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW>40 kg) in the OL period for additional 96 weeks (i.e., up to Week 192). If individual predicted PK parameters >95th percentile of adult range then participant received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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.
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 once daily for 8 weeks. After 8 weeks, based on individual 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 once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW >40 kg); or if individual predicted PK parameters >95th percentile of adult range then participants received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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. After completion of DB period, eligible participants entered in OL period and continued receiving teriflunomide at the same dose in the OL period for additional 96 weeks (i.e., up to Week 192).
Overall Number of Participants Analyzed 39 82
Mean (Standard Deviation)
Unit of Measure: score on a scale
Baseline Number Analyzed 39 participants 82 participants
26.1  (5.2) 25.9  (4.0)
Change at Week 96 Number Analyzed 10 participants 47 participants
0.6  (2.4) -0.4  (4.8)
Change at Week 192 Number Analyzed 26 participants 58 participants
0.1  (5.4) 0.4  (2.9)
16.Secondary Outcome
Title Cognitive Assessment: Change From Baseline in Wechsler Abbreviated Scale of Intelligence-II (WASI-II) Vocabulary Total Raw Scores at Weeks 96 and 192
Hide 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 required 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 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, Weeks 96 and 192
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Hide Analysis Population Description
Analysis was performed on efficacy population. Here, "overall number of participants analyzed" = participants evaluable for this outcome measure and 'number analyzed' = participants with available data for each specified category.
Arm/Group Title Placebo/Teriflunomide Teriflunomide/ Teriflunomide
Hide Arm/Group Description:
Participants received Placebo matching to teriflunomide tablet orally once daily for 96 weeks in DB treatment period. After completion of DB period, eligible participants entered in OL period and received 1 teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) for first 8 weeks. After 8 weeks if individual predicted PK parameter was <= 95th percentile of adult range after 7 mg once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW>40 kg) in the OL period for additional 96 weeks (i.e., up to Week 192). If individual predicted PK parameters >95th percentile of adult range then participant received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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.
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 once daily for 8 weeks. After 8 weeks, based on individual 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 once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW >40 kg); or if individual predicted PK parameters >95th percentile of adult range then participants received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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. After completion of DB period, eligible participants entered in OL period and continued receiving teriflunomide at the same dose in the OL period for additional 96 weeks (i.e., up to Week 192).
Overall Number of Participants Analyzed 1 3
Mean (Standard Deviation)
Unit of Measure: score on a scale
Baseline Number Analyzed 1 participants 3 participants
39.0 34.3  (7.0)
Change at Week 96 Number Analyzed 1 participants 1 participants
5.0 4.0
Change at Week 192 Number Analyzed 1 participants 1 participants
3.0 5.0
17.Secondary Outcome
Title Cognitive Assessment: Change From Baseline in Delis-Kaplan Executive Function System (D-KEFS) Letter Fluency Total Correct Raw Score at Weeks 96 and 192
Hide Description Letter Fluency is a condition measured in the D-KEFS. Participants were 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 were not scored as a correct response. There were 3 trials, with 3 different letters. The total number of correct responses was totaled for all 3 trials and a letter fluency score was given. A higher score was considered better. There was no set range as the score depends on how many correct words the participant relays in the given time period.
Time Frame Baseline, Weeks 96 and 192
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Hide Analysis Population Description
Analysis was performed on efficacy population. Here, "overall number of participants analyzed" = participants evaluable for this outcome measure and 'number analyzed' = participants with available data for each specified category.
Arm/Group Title Placebo/Teriflunomide Teriflunomide/ Teriflunomide
Hide Arm/Group Description:
Participants received Placebo matching to teriflunomide tablet orally once daily for 96 weeks in DB treatment period. After completion of DB period, eligible participants entered in OL period and received 1 teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) for first 8 weeks. After 8 weeks if individual predicted PK parameter was <= 95th percentile of adult range after 7 mg once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW>40 kg) in the OL period for additional 96 weeks (i.e., up to Week 192). If individual predicted PK parameters >95th percentile of adult range then participant received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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.
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 once daily for 8 weeks. After 8 weeks, based on individual 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 once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW >40 kg); or if individual predicted PK parameters >95th percentile of adult range then participants received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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. After completion of DB period, eligible participants entered in OL period and continued receiving teriflunomide at the same dose in the OL period for additional 96 weeks (i.e., up to Week 192).
Overall Number of Participants Analyzed 2 6
Mean (Standard Deviation)
Unit of Measure: score on a scale
Baseline Number Analyzed 2 participants 6 participants
32.5  (3.5) 21.0  (6.0)
Change at Week 96 Number Analyzed 1 participants 2 participants
-3.0 4.0  (9.9)
Change at Week 192 Number Analyzed 1 participants 2 participants
5.0 -6.5  (16.3)
18.Secondary Outcome
Title Cognitive Assessment: Change From Baseline in Delis-Kaplan Executive Function System Category Fluency Total Correct Raw Score at Weeks 96 and 192
Hide Description Category Fluency is a condition measured in the D-KEFS. It measured participant's ability to generate words from three different categories (e.g., fruits, vegetables and animals), within a minute for each category. Total score was number of correct words for each category with no points for repetitions or non-words. Score ranged from 0 to unlimited, where 0 = low score, higher score indicated better performance.
Time Frame Baseline, Weeks 96 and 192
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Hide Analysis Population Description
Analysis was performed on efficacy population. Here, "overall number of participants analyzed" = participants evaluable for this outcome measure and 'number analyzed' = participants with available data for each specified category.
Arm/Group Title Placebo/Teriflunomide Teriflunomide/ Teriflunomide
Hide Arm/Group Description:
Participants received Placebo matching to teriflunomide tablet orally once daily for 96 weeks in DB treatment period. After completion of DB period, eligible participants entered in OL period and received 1 teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) for first 8 weeks. After 8 weeks if individual predicted PK parameter was <= 95th percentile of adult range after 7 mg once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW>40 kg) in the OL period for additional 96 weeks (i.e., up to Week 192). If individual predicted PK parameters >95th percentile of adult range then participant received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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.
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 once daily for 8 weeks. After 8 weeks, based on individual 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 once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW >40 kg); or if individual predicted PK parameters >95th percentile of adult range then participants received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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. After completion of DB period, eligible participants entered in OL period and continued receiving teriflunomide at the same dose in the OL period for additional 96 weeks (i.e., up to Week 192).
Overall Number of Participants Analyzed 2 6
Mean (Standard Deviation)
Unit of Measure: score on a scale
Baseline Number Analyzed 2 participants 6 participants
28.0  (1.4) 27.5  (9.2)
Change at Week 96 Number Analyzed 1 participants 2 participants
6.0 5.0  (5.7)
Change at Week 192 Number Analyzed 1 participants 2 participants
-2.0 -13.5  (17.7)
19.Secondary Outcome
Title Cognitive Assessment - Selective Reminding Test (SRT): Change From Baseline in Total Number of Words on Delayed Recall at Weeks 96 and 192
Hide 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 was 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 were missed on the preceding trial were given in the consecutive trial. The total score represented a sum score of total 6 trials, therefore the score range was from 0 to 72. The lower the score the worse the outcome, higher score indicated better recall.
Time Frame Baseline, Weeks 96 and 192
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Hide Analysis Population Description
Analysis was performed on efficacy population. Here, 'overall number of participants analyzed' = participants evaluable for this outcome measure and 'number analyzed' = participants with available data for each specified category.
Arm/Group Title Placebo/Teriflunomide Teriflunomide/ Teriflunomide
Hide Arm/Group Description:
Participants received Placebo matching to teriflunomide tablet orally once daily for 96 weeks in DB treatment period. After completion of DB period, eligible participants entered in OL period and received 1 teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) for first 8 weeks. After 8 weeks if individual predicted PK parameter was <= 95th percentile of adult range after 7 mg once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW>40 kg) in the OL period for additional 96 weeks (i.e., up to Week 192). If individual predicted PK parameters >95th percentile of adult range then participant received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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.
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 once daily for 8 weeks. After 8 weeks, based on individual 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 once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW >40 kg); or if individual predicted PK parameters >95th percentile of adult range then participants received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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. After completion of DB period, eligible participants entered in OL period and continued receiving teriflunomide at the same dose in the OL period for additional 96 weeks (i.e., up to Week 192).
Overall Number of Participants Analyzed 2 4
Mean (Standard Deviation)
Unit of Measure: score on a scale
Baseline Number Analyzed 2 participants 4 participants
3.5  (4.9) 10.0  (1.4)
Change at Week 96 Number Analyzed 1 participants 2 participants
1.0 -0.5  (2.1)
Change at Week 192 Number Analyzed 1 participants 1 participants
0.0 0.0
20.Secondary Outcome
Title DB: Pharmacokinetics: Steady-state Trough Concentration (Ctrough) of Teriflunomide
Hide Description Ctrough was defined as the concentration reached by the drug before the next dose administered. Data for this outcome measure was planned to be collected and analyzed separately for each dose of Teriflunomide. PK samples for teriflunomide 3.5 mg were collected during the first 8 weeks but all participants were switched to teriflunomide 7 mg after Week 8. Hence, plasma concentration of teriflunomide 7 mg and 14 mg were reported.
Time Frame Predose on Week 36
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Hide Analysis Population Description
Analysis was performed on PK population which included all randomized participants exposed to DB 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
Hide Arm/Group Description:
Participants with BW up to 40 kg received 1 teriflunomide tablet, 3.5 mg orally once daily for 8 weeks. After 8 weeks, based on individual predicted PK parameters, teriflunomide was administered in following manner up to 96 weeks: if predicted PK parameters <= 95th percentile of adult range then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW >40 kg); or if predicted PK parameters >95th percentile of adult range then participants received 1 tablet of 3.5 mg teriflunomide daily (for BW <= 40 kg) or 1 tablet of 7 mg teriflunomide daily (for BW >40 kg).
Participants with BW >40 kg received 1 teriflunomide tablet, 7 mg orally once daily for 8 weeks. After 8 weeks, based on individual 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 once daily then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW >40 kg); or if predicted PK parameters >95th percentile of adult range then participants received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide daily (for BW >40 kg).
After 8 weeks, based on individual 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 once daily then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW >40 kg); or if predicted PK parameters >95th percentile of adult range then participants received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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)
21.Secondary Outcome
Title OL: Time to First Confirmed Clinical Relapse
Hide Description Time to first clinical relapse was defined as duration (in weeks) after enrollment in OL period and first confirmed clinical relapse. Clinical relapses were defined as new or recurrent neurological symptoms not associated with fever or 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 and items were rated on different scales: brain stem, cerebellar & 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. Confirmed clinical relapse were reviewed and confirmed by independent RAP. Participant without confirmed clinical relapse, was considered as clinical relapse free until end of Week 192.
Time Frame Baseline up to Week 192
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Hide Analysis Population Description
Analysis was performed on efficacy population.
Arm/Group Title Placebo/Teriflunomide Teriflunomide/ Teriflunomide
Hide Arm/Group Description:
Participants received Placebo matching to teriflunomide tablet orally once daily for 96 weeks in DB treatment period. After completion of DB period, eligible participants entered in OL period and received 1 teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (in case of BW >40 kg) for first 8 weeks. After 8 weeks if individual predicted PK parameter was <= 95th percentile of adult range after 7 mg once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW>40 kg) in the OL period for additional 96 weeks (i.e., up to Week 192). If individual predicted PK parameters >95th percentile of adult range then participant received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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.
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 once daily for 8 weeks. After 8 weeks, based on individual 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 once daily, then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW >40 kg); or if individual predicted PK parameters >95th percentile of adult range then participants received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide 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. After completion of DB period, eligible participants entered in OL period and continued receiving teriflunomide at the same dose in the OL period for additional 96 weeks (i.e., up to Week 192).
Overall Number of Participants Analyzed 52 100
Median (Full Range)
Unit of Measure: weeks
95.86
(0.6 to 176.0)
96.00
(1.0 to 183.4)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo/Teriflunomide, Teriflunomide/ Teriflunomide
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.693
Confidence Interval (2-Sided) 95%
0.37 to 1.296
Estimation Comments Hazard ratio estimated using a Cox proportional-hazards model using treatment group, region, pubertal status, age, and number of relapses in the year prior to randomisation as covariates and with robust variance estimation.
22.Secondary Outcome
Title OL: Pharmacokinetics: Steady-state Trough Concentration (Ctrough) of Teriflunomide
Hide 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. PK samples for teriflunomide 3.5 mg were collected during the first 8 weeks but all participants were switched to teriflunomide 7 mg after Week 8. Hence, plasma concentration of teriflunomide 7 mg and 14 mg were reported.
Time Frame Pre-dose at Week 36
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on PK population which included all randomized participants exposed to study medication, regardless of the amount of treatment administered who had at least one PK sample taken in OL period. Here, 'overall number of participants analyzed' = participants evaluable for this outcome measure and "0'' signifies that none of the participant was evaluable for Placebo/Teriflunomide 3.5 mg and Teriflunomide/Teriflunomide 3.5 mg arms.
Arm/Group Title Placebo / Teriflunomide 3.5 mg Placebo / Teriflunomide 7 mg Placebo / Teriflunomide 14 mg Teriflunomide / Teriflunomide 3.5 mg Teriflunomide / Teriflunomide 7 mg Teriflunomide / Teriflunomide 14 mg
Hide Arm/Group Description:
Participants previously treated with placebo in DB period received 1 teriflunomide tablet 3.5 mg orally once daily for first 8 weeks of OL period. After 8 weeks, based on individual predicted PK parameters, teriflunomide was administered in following manner up to Week 192: if predicted PK parameters <= 95th percentile of adult range then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW >40 kg); or if predicted PK parameters >95th percentile of adult range then participants received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide daily (for BW >40 kg).
Participants previously treated with placebo during the DB period received teriflunomide 7 mg for 96 weeks in the OL period (i.e., up to Week 192).
Participants previously treated with placebo during the DB period received teriflunomide 14 mg for 96 weeks in OL period (i.e., up to Week 192).
Participants previously treated with teriflunomide during the DB period received 1 teriflunomide tablet 3.5 mg orally once daily for first 8 weeks of OL period. After 8 weeks, based on individual predicted PK parameters, teriflunomide was administered in following manner up to Week 192: if predicted PK parameters <= 95th percentile of adult range then participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW >40 kg); or if predicted PK parameters >95th percentile of adult range then participants received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 7 mg teriflunomide daily (for BW >40 kg).
Participants previously treated with teriflunomide 7 mg during DB period continued receiving teriflunomide 7mg in the OL period for additional 96 weeks (i.e., up to Week 192).
Participants previously treated with teriflunomide 14 mg during DB period continued receiving teriflunomide 14mg in the OL period for additional 96 weeks (i.e., up to Week 192).
Overall Number of Participants Analyzed 0 12 31 0 2 79
Mean (Standard Deviation)
Unit of Measure: micrograms per milliliter
45.8  (35.3) 50.4  (23.8) 33.7  (10.7) 63.6  (35.5)
Time Frame Adverse events (AEs) were collected from first dose of study drug up to 96 weeks (for DB period arms) and from first dose of study drug in OL period up to Week 192 (for OL period arms).
Adverse Event Reporting Description Reported AEs were treatment-emergent AEs (TEAEs), which developed/worsened during TEAE period (defined as time from first intake of investigational medicinal product [IMP] in DB period up to last intake of IMP in OL period). Safety population included all randomized participants exposed to study medication, regardless of the amount of treatment administered.
 
Arm/Group Title Double-Blind Treatment Period: Placebo Double-Blind Treatment Period: Teriflunomide Open-Label Treatment Period: Placebo/Teriflunomide Open-Label Treatment Period: Teriflunomide/ Teriflunomide
Hide Arm/Group Description Participants received placebo matching to teriflunomide tablet orally once daily 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 >40kg) orally once daily for 8 weeks. After 8 weeks, based on individual 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 once daily then, participants received 1 tablet of 7 mg teriflunomide daily (for BW up to 40 kg) or 1 tablet of 14 mg teriflunomide daily (for BW>40kg); or if individual predicted PK parameters >95th percentile of adult range then participants received 1 tablet of 3.5 mg teriflunomide daily (for BW up to 40kg) or 1 tablet of 7 mg teriflunomide 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. Participants received Placebo matching to teriflunomide tablet orally once daily for 96 weeks in DB treatment period. After completion of DB period, eligible participants entered in OL period and received 1 teriflunomide tablet, 3.5 mg (in case of BW up to 40 kg) or 7 mg (BW >40 kg) for first 8 weeks. After 8 weeks if individual predicted PK parameter was <= 95th percentile of adult range at 7 mg once daily, then participants received 7 mg teriflunomide (for BW up to 40 kg) or 14 mg teriflunomide (for BW>40 kg) in the OL period for additional 96 weeks (i.e., up to Week 192). If individual predicted PK parameters >95th percentile of adult range then participant received 3.5 mg teriflunomide daily (for BW up to 40 kg) or 7 mg teriflunomide 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. Participants previously treated with Teriflunomide during DB period continued receiving Teriflunomide at the same dose in the OL period for additional 96 weeks (i.e., up to Week 192).
All-Cause Mortality
Double-Blind Treatment Period: Placebo Double-Blind Treatment Period: Teriflunomide Open-Label Treatment Period: Placebo/Teriflunomide Open-Label Treatment Period: Teriflunomide/ Teriflunomide
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/57 (0.00%)      0/109 (0.00%)      0/52 (0.00%)      0/100 (0.00%)    
Hide Serious Adverse Events
Double-Blind Treatment Period: Placebo Double-Blind Treatment Period: Teriflunomide Open-Label Treatment Period: Placebo/Teriflunomide Open-Label Treatment Period: Teriflunomide/ Teriflunomide
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   6/57 (10.53%)      12/109 (11.01%)      15/52 (28.85%)      14/100 (14.00%)    
Blood and lymphatic system disorders         
Neutropenia † 1  0/57 (0.00%)  0 1/109 (0.92%)  1 0/52 (0.00%)  0 1/100 (1.00%)  1
Cardiac disorders         
Cardiomyopathy † 1  0/57 (0.00%)  0 1/109 (0.92%)  1 0/52 (0.00%)  0 0/100 (0.00%)  0
Congenital, familial and genetic disorders         
Familial Mediterranean Fever † 1  1/57 (1.75%)  1 0/109 (0.00%)  0 0/52 (0.00%)  0 0/100 (0.00%)  0
Eye disorders         
Diplopia † 1  0/57 (0.00%)  0 1/109 (0.92%)  1 0/52 (0.00%)  0 0/100 (0.00%)  0
Gastrointestinal disorders         
Anal Fissure † 1  1/57 (1.75%)  1 0/109 (0.00%)  0 0/52 (0.00%)  0 0/100 (0.00%)  0
Anal Fistula † 1  0/57 (0.00%)  0 1/109 (0.92%)  1 0/52 (0.00%)  0 0/100 (0.00%)  0
Constipation † 1  0/57 (0.00%)  0 0/109 (0.00%)  0 0/52 (0.00%)  0 1/100 (1.00%)  1
Food Poisoning † 1  0/57 (0.00%)  0 0/109 (0.00%)  0 1/52 (1.92%)  1 0/100 (0.00%)  0
Pancreatic Disorder † 1  0/57 (0.00%)  0 0/109 (0.00%)  0 0/52 (0.00%)  0 1/100 (1.00%)  1
Pancreatitis Acute † 1  0/57 (0.00%)  0 1/109 (0.92%)  1 0/52 (0.00%)  0 2/100 (2.00%)  2
General disorders         
Asthenia † 1  0/57 (0.00%)  0 0/109 (0.00%)  0 1/52 (1.92%)  1 0/100 (0.00%)  0
Gait Disturbance † 1  0/57 (0.00%)  0 0/109 (0.00%)  0 0/52 (0.00%)  0 1/100 (1.00%)  1
Pyrexia † 1  0/57 (0.00%)  0 0/109 (0.00%)  0 1/52 (1.92%)  1 0/100 (0.00%)  0
Hepatobiliary disorders         
Hepatic Function Abnormal † 1  0/57 (0.00%)  0 0/109 (0.00%)  0 1/52 (1.92%)  1 0/100 (0.00%)  0
Infections and infestations         
Acute Sinusitis † 1  0/57 (0.00%)  0 0/109 (0.00%)  0 1/52 (1.92%)  1 0/100 (0.00%)  0
Appendicitis † 1  1/57 (1.75%)  1 0/109 (0.00%)  0 0/52 (0.00%)  0 0/100 (0.00%)  0
Bronchitis † 1  0/57 (0.00%)  0 0/109 (0.00%)  0 1/52 (1.92%)  1 0/100 (0.00%)  0
Coronavirus Infection † 1  0/57 (0.00%)  0 0/109 (0.00%)  0 0/52 (0.00%)  0 1/100 (1.00%)  1
Encephalitis Viral † 1  0/57 (0.00%)  0 0/109 (0.00%)  0 0/52 (0.00%)  0 1/100 (1.00%)  1
Pneumonia † 1  0/57 (0.00%)  0 0/109 (0.00%)  0 0/52 (0.00%)  0 1/100 (1.00%)  1
Pulmonary Tuberculosis † 1  0/57 (0.00%)  0 1/109 (0.92%)  1 0/52 (0.00%)  0 0/100 (0.00%)  0
Tonsillitis † 1  0/57 (0.00%)  0 0/109 (0.00%)  0 1/52 (1.92%)  2 0/100 (0.00%)  0
Upper Respiratory Tract Infection † 1  0/57 (0.00%)  0 1/109 (0.92%)  1 0/52 (0.00%)  0 1/100 (1.00%)  1
Injury, poisoning and procedural complications         
Intentional Overdose † 1  0/57 (0.00%)  0 0/109 (0.00%)  0 0/52 (0.00%)  0 1/100 (1.00%)  1
Joint Dislocation † 1  1/57 (1.75%)  1 0/109 (0.00%)  0 0/52 (0.00%)  0 0/100 (0.00%)  0
Lumbar Vertebral Fracture † 1  0/57 (0.00%)  0 1/109 (0.92%)  1 0/52 (0.00%)  0 0/100 (0.00%)  0
Peripheral Nerve Injury † 1  0/57 (0.00%)  0 1/109 (0.92%)  1 0/52 (0.00%)  0 0/100 (0.00%)  0
Skin Laceration † 1  0/57 (0.00%)  0 0/109 (0.00%)  0 0/52 (0.00%)  0 1/100 (1.00%)  1
Investigations         
Alanine Aminotransferase Increased † 1  0/57 (0.00%)  0 1/109 (0.92%)  1 2/52 (3.85%)  2 0/100 (0.00%)  0
Blood Creatine Phosphokinase Increased † 1  0/57 (0.00%)  0 2/109 (1.83%)  2 1/52 (1.92%)  1 2/100 (2.00%)  2
Transaminases Increased † 1  0/57 (0.00%)  0 1/109 (0.92%)  1 0/52 (0.00%)  0 0/100 (0.00%)  0
Nervous system disorders         
Dizziness † 1  0/57 (0.00%)  0 0/109 (0.00%)  0 0/52 (0.00%)  0 1/100 (1.00%)  1
Epilepsy † 1  1/57 (1.75%)  1 1/109 (0.92%)  2 0/52 (0.00%)  0 1/100 (1.00%)  1
Headache † 1  0/57 (0.00%)  0 0/109 (0.00%)  0 1/52 (1.92%)  1 0/100 (0.00%)  0
Hypoaesthesia † 1  0/57 (0.00%)  0 0/109 (0.00%)  0 1/52 (1.92%)  1 1/100 (1.00%)  1
Multiple Sclerosis † 1  0/57 (0.00%)  0 0/109 (0.00%)  0 0/52 (0.00%)  0 1/100 (1.00%)  1
Syncope † 1  1/57 (1.75%)  1 2/109 (1.83%)  3 0/52 (0.00%)  0 1/100 (1.00%)  1
Uhthoff's Phenomenon † 1  0/57 (0.00%)  0 0/109 (0.00%)  0 0/52 (0.00%)  0 2/100 (2.00%)  2
Pregnancy, puerperium and perinatal conditions         
Pregnancy † 1  0/57 (0.00%)  0 0/109 (0.00%)  0 1/52 (1.92%)  1 0/100 (0.00%)  0
Psychiatric disorders         
Adjustment Disorder † 1  0/57 (0.00%)  0 0/109 (0.00%)  0 1/52 (1.92%)  1 0/100 (0.00%)  0
Depression Suicidal † 1  0/57 (0.00%)  0 0/109 (0.00%)  0 0/52 (0.00%)  0 1/100 (1.00%)  1
Emotional Disorder Of Childhood † 1  0/57 (0.00%)  0 0/109 (0.00%)  0 1/52 (1.92%)  1 0/100 (0.00%)  0
Suicide Attempt † 1  0/57 (0.00%)  0 0/109 (0.00%)  0 0/52 (0.00%)  0 2/100 (2.00%)  2
Respiratory, thoracic and mediastinal disorders         
Asthma † 1  1/57 (1.75%)  1 0/109 (0.00%)  0 2/52 (3.85%)  2 0/100 (0.00%)  0
Skin and subcutaneous tissue disorders         
Drug Eruption † 1  0/57 (0.00%)  0 0/109 (0.00%)  0 0/52 (0.00%)  0 1/100 (1.00%)  1
1
Term from vocabulary, MedDra 24.0
†
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 2%
Double-Blind Treatment Period: Placebo Double-Blind Treatment Period: Teriflunomide Open-Label Treatment Period: Placebo/Teriflunomide Open-Label Treatment Period: Teriflunomide/ Teriflunomide
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   41/57 (71.93%)      89/109 (81.65%)      40/52 (76.92%)      72/100 (72.00%)    
Blood and lymphatic system disorders         
Anaemia † 1  1/57 (1.75%)  1 3/109 (2.75%)  3 0/52 (0.00%)  0 6/100 (6.00%)  6
Neutropenia † 1  0/57 (0.00%)  0 3/109 (2.75%)  5 0/52 (0.00%)  0 1/100 (1.00%)  1
Cardiac disorders         
Palpitations † 1  0/57 (0.00%)  0 3/109 (2.75%)  3 0/52 (0.00%)  0 2/100 (2.00%)  2
Ear and labyrinth disorders         
Ear Pain † 1  2/57 (3.51%)  2 3/109 (2.75%)  3 1/52 (1.92%)  1 1/100 (1.00%)  1
Tinnitus † 1  1/57 (1.75%)  1 3/109 (2.75%)  3 1/52 (1.92%)  1 0/100 (0.00%)  0
Endocrine disorders         
Autoimmune Thyroiditis † 1  2/57 (3.51%)  2 1/109 (0.92%)  1 0/52 (0.00%)  0 0/100 (0.00%)  0
Eye disorders         
Eye Pain † 1  4/57 (7.02%)  8 4/109 (3.67%)  4 0/52 (0.00%)  0 3/100 (3.00%)  3
Vision Blurred † 1  2/57 (3.51%)  3 2/109 (1.83%)  3 0/52 (0.00%)  0 3/100 (3.00%)  3
Visual Impairment † 1  2/57 (3.51%)  3 0/109 (0.00%)  0 2/52 (3.85%)  2 1/100 (1.00%)  1
Gastrointestinal disorders         
Abdominal Pain † 1  1/57 (1.75%)  1 11/109 (10.09%)  13 2/52 (3.85%)  2 8/100 (8.00%)  11
Abdominal Pain Upper † 1  2/57 (3.51%)  2 6/109 (5.50%)  9 0/52 (0.00%)  0 3/100 (3.00%)  4
Aphthous Ulcer † 1  0/57 (0.00%)  0 2/109 (1.83%)  2 2/52 (3.85%)  2 1/100 (1.00%)  1
Constipation † 1  1/57 (1.75%)  1 1/109 (0.92%)  1 2/52 (3.85%)  2 3/100 (3.00%)  3
Diarrhoea † 1  4/57 (7.02%)  4 8/109 (7.34%)  9 6/52 (11.54%)  8 7/100 (7.00%)  9
Mouth Ulceration † 1  0/57 (0.00%)  0 2/109 (1.83%)  2 2/52 (3.85%)  4 2/100 (2.00%)  3
Nausea † 1  4/57 (7.02%)  5 10/109 (9.17%)  12 3/52 (5.77%)  3 4/100 (4.00%)  4
Vomiting † 1  5/57 (8.77%)  5 6/109 (5.50%)  7 2/52 (3.85%)  2 1/100 (1.00%)  1
General disorders         
Asthenia † 1  0/57 (0.00%)  0 2/109 (1.83%)  2 2/52 (3.85%)  4 1/100 (1.00%)  1
Fatigue † 1  3/57 (5.26%)  5 4/109 (3.67%)  6 4/52 (7.69%)  7 4/100 (4.00%)  4
Influenza Like Illness † 1  1/57 (1.75%)  1 3/109 (2.75%)  3 0/52 (0.00%)  0 2/100 (2.00%)  2
Non-Cardiac Chest Pain † 1  0/57 (0.00%)  0 4/109 (3.67%)  4 0/52 (0.00%)  0 2/100 (2.00%)  2
Pyrexia † 1  2/57 (3.51%)  2 5/109 (4.59%)  8 0/52 (0.00%)  0 3/100 (3.00%)  3
Infections and infestations         
Acute Sinusitis † 1  0/57 (0.00%)  0 0/109 (0.00%)  0 2/52 (3.85%)  2 0/100 (0.00%)  0
Bronchitis † 1  1/57 (1.75%)  1 5/109 (4.59%)  5 2/52 (3.85%)  2 0/100 (0.00%)  0
Cystitis † 1  0/57 (0.00%)  0 1/109 (0.92%)  2 2/52 (3.85%)  2 0/100 (0.00%)  0
Gastroenteritis † 1  3/57 (5.26%)  3 3/109 (2.75%)  3 2/52 (3.85%)  2 5/100 (5.00%)  6
Influenza † 1  4/57 (7.02%)  4 10/109 (9.17%)  16 5/52 (9.62%)  6 5/100 (5.00%)  6
Nasopharyngitis † 1  5/57 (8.77%)  6 28/109 (25.69%)  50 8/52 (15.38%)  13 20/100 (20.00%)  37
Pharyngitis † 1  1/57 (1.75%)  1 7/109 (6.42%)  8 1/52 (1.92%)  2 4/100 (4.00%)  8
Respiratory Tract Infection † 1  1/57 (1.75%)  1 1/109 (0.92%)  1 1/52 (1.92%)  1 5/100 (5.00%)  5
Respiratory Tract Infection Viral † 1  0/57 (0.00%)  0 4/109 (3.67%)  7 0/52 (0.00%)  0 1/100 (1.00%)  1
Rhinitis † 1  2/57 (3.51%)  3 4/109 (3.67%)  8 2/52 (3.85%)  4 6/100 (6.00%)  7
Sinusitis † 1  2/57 (3.51%)  2 4/109 (3.67%)  4 2/52 (3.85%)  3 2/100 (2.00%)  2
Tinea Versicolour † 1  2/57 (3.51%)  2 1/109 (0.92%)  1 0/52 (0.00%)  0 0/100 (0.00%)  0
Tonsillitis † 1  2/57 (3.51%)  2 4/109 (3.67%)  4 2/52 (3.85%)  4 4/100 (4.00%)  5
Tracheitis † 1  0/57 (0.00%)  0 0/109 (0.00%)  0 2/52 (3.85%)  2 0/100 (0.00%)  0
Tracheobronchitis † 1  1/57 (1.75%)  1 0/109 (0.00%)  0 2/52 (3.85%)  2 0/100 (0.00%)  0
Upper Respiratory Tract Infection † 1  6/57 (10.53%)  23 24/109 (22.02%)  66 7/52 (13.46%)  32 22/100 (22.00%)  59
Urinary Tract Infection † 1  1/57 (1.75%)  1 3/109 (2.75%)  3 2/52 (3.85%)  2 5/100 (5.00%)  5
Injury, poisoning and procedural complications         
Accidental Overdose † 1  4/57 (7.02%)  7 5/109 (4.59%)  5 2/52 (3.85%)  2 10/100 (10.00%)  12
Contusion † 1  0/57 (0.00%)  0 4/109 (3.67%)  4 1/52 (1.92%)  1 1/100 (1.00%)  1
Fall † 1  4/57 (7.02%)  5 6/109 (5.50%)  8 2/52 (3.85%)  3 1/100 (1.00%)  1
Ligament Sprain † 1  2/57 (3.51%)  2 1/109 (0.92%)  1 1/52 (1.92%)  3 2/100 (2.00%)  2
Thermal Burn † 1  0/57 (0.00%)  0 1/109 (0.92%)  1 2/52 (3.85%)  2 0/100 (0.00%)  0
Investigations         
Alanine Aminotransferase Increased † 1  1/57 (1.75%)  1 2/109 (1.83%)  3 6/52 (11.54%)  6 3/100 (3.00%)  3
Blood Creatine Phosphokinase Increased † 1  0/57 (0.00%)  0 4/109 (3.67%)  6 1/52 (1.92%)  1 0/100 (0.00%)  0
Neutrophil Count Decreased † 1  0/57 (0.00%)  0 3/109 (2.75%)  5 1/52 (1.92%)  4 2/100 (2.00%)  4
Protein Urine Present † 1  1/57 (1.75%)  1 4/109 (3.67%)  5 2/52 (3.85%)  2 1/100 (1.00%)  1
Weight Decreased † 1  3/57 (5.26%)  3 6/109 (5.50%)  7 2/52 (3.85%)  2 3/100 (3.00%)  5
Weight Increased † 1  0/57 (0.00%)  0 3/109 (2.75%)  4 0/52 (0.00%)  0 2/100 (2.00%)  3
White Blood Cell Count Decreased † 1  1/57 (1.75%)  1 5/109 (4.59%)  8 2/52 (3.85%)  5 5/100 (5.00%)  6
Metabolism and nutrition disorders         
Decreased Appetite † 1  0/57 (0.00%)  0 2/109 (1.83%)  3 0/52 (0.00%)  0 3/100 (3.00%)  3
Vitamin D Deficiency † 1  2/57 (3.51%)  2 3/109 (2.75%)  4 1/52 (1.92%)  1 4/100 (4.00%)  4
Musculoskeletal and connective tissue disorders         
Arthralgia † 1  3/57 (5.26%)  7 5/109 (4.59%)  5 2/52 (3.85%)  2 1/100 (1.00%)  1
Back Pain † 1  2/57 (3.51%)  3 5/109 (4.59%)  6 2/52 (3.85%)  3 3/100 (3.00%)  5
Muscle Spasms † 1  2/57 (3.51%)  2 2/109 (1.83%)  2 2/52 (3.85%)  2 0/100 (0.00%)  0
Muscular Weakness † 1  2/57 (3.51%)  2 1/109 (0.92%)  1 2/52 (3.85%)  2 0/100 (0.00%)  0
Pain In Extremity † 1  2/57 (3.51%)  2 3/109 (2.75%)  3 0/52 (0.00%)  0 3/100 (3.00%)  3
Nervous system disorders         
Disturbance In Attention † 1  2/57 (3.51%)  2 1/109 (0.92%)  1 0/52 (0.00%)  0 0/100 (0.00%)  0
Dizziness † 1  4/57 (7.02%)  5 9/109 (8.26%)  9 6/52 (11.54%)  12 2/100 (2.00%)  3
Headache † 1  13/57 (22.81%)  18 18/109 (16.51%)  30 7/52 (13.46%)  22 14/100 (14.00%)  28
Hypoaesthesia † 1  3/57 (5.26%)  5 6/109 (5.50%)  7 3/52 (5.77%)  4 3/100 (3.00%)  4
Paraesthesia † 1  1/57 (1.75%)  2 11/109 (10.09%)  19 1/52 (1.92%)  1 4/100 (4.00%)  7
Presyncope † 1  0/57 (0.00%)  0 3/109 (2.75%)  3 0/52 (0.00%)  0 1/100 (1.00%)  1
Syncope † 1  0/57 (0.00%)  0 1/109 (0.92%)  1 3/52 (5.77%)  3 0/100 (0.00%)  0
Tremor † 1  2/57 (3.51%)  3 1/109 (0.92%)  1 2/52 (3.85%)  2 1/100 (1.00%)  1
Psychiatric disorders         
Anxiety † 1  3/57 (5.26%)  3 4/109 (3.67%)  6 1/52 (1.92%)  1 2/100 (2.00%)  3
Depression † 1  2/57 (3.51%)  2 2/109 (1.83%)  2 4/52 (7.69%)  4 2/100 (2.00%)  2
Insomnia † 1  3/57 (5.26%)  3 1/109 (0.92%)  1 1/52 (1.92%)  3 1/100 (1.00%)  1
Renal and urinary disorders         
Micturition Urgency † 1  1/57 (1.75%)  1 2/109 (1.83%)  2 5/52 (9.62%)  6 0/100 (0.00%)  0
Pollakiuria † 1  0/57 (0.00%)  0 2/109 (1.83%)  2 2/52 (3.85%)  2 1/100 (1.00%)  1
Reproductive system and breast disorders         
Dysmenorrhoea † 1  3/57 (5.26%)  3 1/109 (0.92%)  1 1/52 (1.92%)  4 2/100 (2.00%)  5
Respiratory, thoracic and mediastinal disorders         
Cough † 1  3/57 (5.26%)  3 5/109 (4.59%)  6 2/52 (3.85%)  2 1/100 (1.00%)  1
Dyspnoea † 1  0/57 (0.00%)  0 3/109 (2.75%)  3 1/52 (1.92%)  1 0/100 (0.00%)  0
Nasal Congestion † 1  1/57 (1.75%)  1 3/109 (2.75%)  3 0/52 (0.00%)  0 1/100 (1.00%)  1
Oropharyngeal Pain † 1  2/57 (3.51%)  2 7/109 (6.42%)  8 2/52 (3.85%)  2 7/100 (7.00%)  9
Respiratory Disorder † 1  0/57 (0.00%)  0 0/109 (0.00%)  0 2/52 (3.85%)  3 0/100 (0.00%)  0
Rhinitis Allergic † 1  0/57 (0.00%)  0 3/109 (2.75%)  3 1/52 (1.92%)  1 0/100 (0.00%)  0
Skin and subcutaneous tissue disorders         
Acne † 1  4/57 (7.02%)  4 5/109 (4.59%)  5 0/52 (0.00%)  0 4/100 (4.00%)  5
Alopecia † 1  7/57 (12.28%)  7 24/109 (22.02%)  26 9/52 (17.31%)  10 10/100 (10.00%)  10
Dry Skin † 1  0/57 (0.00%)  0 0/109 (0.00%)  0 2/52 (3.85%)  2 0/100 (0.00%)  0
Eczema † 1  1/57 (1.75%)  1 1/109 (0.92%)  1 0/52 (0.00%)  0 3/100 (3.00%)  4
Rash † 1  2/57 (3.51%)  2 4/109 (3.67%)  4 2/52 (3.85%)  2 2/100 (2.00%)  2
Vascular disorders         
Orthostatic Hypotension † 1  2/57 (3.51%)  3 0/109 (0.00%)  0 0/52 (0.00%)  0 1/100 (1.00%)  1
1
Term from vocabulary, MedDra 24.0
†
Indicates events were collected by systematic assessment
[Not Specified]
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
Layout table for Results Point of Contact information
Name/Title: Trial Transparency Team
Organization: Genzyme, a Sanofi Company
Phone: 800-633-1610 ext 6#
EMail: Contact-US@sanofi.com
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
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: July 15, 2022