A Phase 3 interventional study of Teriflunomide and Placebo in Multiple Sclerosis, sponsored by Genzyme, a Sanofi Company. Completed at 57 sites in 22 countries. Open to participants aged 10 Years to 17 Years. Per ClinicalTrials.gov, last updated 2025-02-06.
Sponsored by Genzyme, a Sanofi Company · Phase 3, Interventional, and Treatment
Primary Objective:
To assess the effect of teriflunomide in comparison to placebo on disease activity measured by time to first clinical relapse after randomization in children and adolescents 10 to 17 years of age with relapsing forms of multiple sclerosis (MS).
Secondary Objective:
The study duration included a screening period up to 4 weeks, a double-blind treatment period of up to 96 weeks, an open-label period which included the remainder of the initial 96 weeks, where applicable, and a 96-week extension, i.e., up to a maximum of 192 weeks after randomization. There was a follow-up period of 4 weeks for participants discontinuing treatment.
Within the 96 weeks double-blind treatment period, the first 4 weeks were PK run-in phase in which PK samples (blood samples) were collected from participants and then 4 weeks of analysis (no samples drawn). The PK run-in phase (total 8 weeks) was intended to provide individual PK parameters to allow the dose adjustment to the 14 milligrams (mg) adult-equivalent dose for the rest of the study.
Participants who experienced a relapse after the PK run-in phase (8 weeks) and confirmed by the Relapse Adjudication Panel and participants who fulfilled MRI criteria (high number of new lesions at weeks 36, 48 or 72 compared to previous images) had the option to continue in an open-label teriflunomide treatment arm up to 192 weeks from randomization.
An optional additional extension period was available for young participants with teriflunomide until the participants are 18 years old and/or able to switch to commercial product, whichever comes first.
Participants with relapsing MS were eligible. Participants who met the criteria of MS based on McDonald criteria 2010 and International Pediatric Multiple Sclerosis Study Group (IPMSSG) criteria for pediatric MS, version of 2012 and had:
Exclusion criteria:
Treated with:
The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Matching placebo tablets
Drug: Placebo
Teriflunomide oral tablet, three dosages (3.5, 7 or 14 mg) to reach 14 mg adult equivalent
Drug: Teriflunomide
Pharmaceutical form:film-coated tablet, Route of administration: oral
Also known as: AUBAGIO, HMR1726
Pharmaceutical form:tablet, Route of administration: oral
Time to First Confirmed Clinical Relapse
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
Probability of Participants Who Were Clinical Relapse Free at Weeks 24, 48, 72, 96, 120, 144, 168 and 192
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
Brain Magnetic Resonance Imaging (MRI) Assessment: Number of New or Enlarged T2 Lesions Per MRI Scan
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
Brain Magnetic Resonance Imaging Assessment: Number of T1 Gadolinium (Gd)-Enhancing T1 Lesions Per MRI Scan
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
Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T2 Lesions at Weeks 24, 36, 48, 72, 96, 144 and 192
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
Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T1 Hypointense Lesions
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
Brain Magnetic Resonance Imaging Assessment: Number of New T1 Hypointense Lesions Per MRI Scan
The number of new T1 hypointense lesions were obtained from MRI scans.
Time frame: Baseline up to Week 192
Brain Magnetic Resonance Imaging Assessment: Percentage of Participants Free of New or Enlarged MRI T2-Lesions
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
Brain Magnetic Resonance Imaging Assessment: Percent Change From Baseline in Brain Volume at Weeks 24, 36, 48, 72, 96, 144 and 192
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
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
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
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
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
Cognitive Assessment: Change From Baseline in Brief Visuospatial Memory Test-Revised (BVMT-R) Scores at Weeks 96 and 192
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
Cognitive Assessment: Change From Baseline in Trail Making Test- Part A (TMT-A) Test Scores (in Seconds) at Week 96 and 192
'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
Cognitive Assessment: Change From Baseline in Trail Making Test B (TMT-B) Test Scores (in Seconds) at Weeks 96 and 192
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
Cognitive Assessment: Change From Baseline in Beery Visual-motor Integration (BVMI) Scores at Weeks 96 and 192
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
Cognitive Assessment: Change From Baseline in Wechsler Abbreviated Scale of Intelligence-II (WASI-II) Vocabulary Total Raw Scores at Weeks 96 and 192
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
Cognitive Assessment: Change From Baseline in Delis-Kaplan Executive Function System (D-KEFS) Letter Fluency Total Correct Raw Score at Weeks 96 and 192
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
Cognitive Assessment: Change From Baseline in Delis-Kaplan Executive Function System Category Fluency Total Correct Raw Score at Weeks 96 and 192
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
Cognitive Assessment - Selective Reminding Test (SRT): Change From Baseline in Total Number of Words on Delayed Recall at Weeks 96 and 192
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
DB: Pharmacokinetics: Steady-state Trough Concentration (Ctrough) of Teriflunomide
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
OL: Time to First Confirmed Clinical Relapse
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
OL: Pharmacokinetics: Steady-state Trough Concentration (Ctrough) of Teriflunomide
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
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.
| Milestone | Placebo/Teriflunomide | Teriflunomide/Teriflunomide | Teriflunomide |
|---|---|---|---|
| Started | 57 | 109 | 0 |
| Completed | 53 | 102 | 0 |
| Not completed | 4 | 7 | 0 |
| Withdrew: Adverse event | 0 | 6 | 0 |
| Withdrew: Lack of efficacy | 2 | 1 | 0 |
| Withdrew: Withdrawal by subject | 2 | 0 | 0 |
| Milestone | Placebo/Teriflunomide | Teriflunomide/Teriflunomide | Teriflunomide |
|---|---|---|---|
| Started | 52 | 100 | 0 |
| Completed | 31 | 73 | 0 |
| Not completed | 21 | 27 | 0 |
| Withdrew: Lack of efficacy | 10 | 14 | 0 |
| Withdrew: Poor compliance to protocol | 0 | 1 | 0 |
| Withdrew: Other reason | 4 | 7 | 0 |
| Withdrew: Adverse event | 7 | 5 | 0 |
| Milestone | Placebo/Teriflunomide | Teriflunomide/Teriflunomide | Teriflunomide |
|---|---|---|---|
| Started | 0 | 0 | 27 |
| Completed | 0 | 0 | 24 |
| Not completed | 0 | 0 | 3 |
| Withdrew: Adverse event | 0 | 0 | 2 |
| Withdrew: Poor compliance to protocol | 0 | 0 | 1 |
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.
| weeks | Double-Blind Treatment Period: Placebo | Double-Blind Treatment Period: Teriflunomide |
|---|---|---|
| Time to First Confirmed Clinical Relapse | 39.14 (0.1 to 98.0) | 75.29 (0.1 to 98.7) |
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.
| probability of relapse free participants | Placebo/Teriflunomide | Teriflunomide/ Teriflunomide |
|---|---|---|
| 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) |
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.
| lesions per scan | Placebo/Teriflunomide | Teriflunomide/ Teriflunomide |
|---|---|---|
| Brain Magnetic Resonance Imaging (MRI) Assessment: Number of New or Enlarged T2 Lesions Per MRI Scan | 11.087 (6.586 to 18.662) | 5.664 (3.417 to 9.389) |
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.
| lesions per scan | Placebo/Teriflunomide | Teriflunomide/ Teriflunomide |
|---|---|---|
| Brain Magnetic Resonance Imaging Assessment: Number of T1 Gadolinium (Gd)-Enhancing T1 Lesions Per MRI Scan | 2.686 (1.263 to 5.712) | 1.532 (0.624 to 3.762) |
Volume of T2 lesions was measured by MRI scan.
| milliliters | Placebo/Teriflunomide | Teriflunomide/ Teriflunomide |
|---|---|---|
| DB Period: Week 24 | 3.0 ± 7.0 | 0.5 ± 1.8 |
| DB Period: Week 36 | 4.6 ± 11.7 | 4.4 ± 21.3 |
| DB Period: Week 48 | 0.5 ± 0.6 | -0.2 ± 3.4 |
| DB Period: Week 72 | 1.2 ± 1.6 | 0.1 ± 1.9 |
| DB Period: Week 96 | 0.9 ± 1.4 | 0.2 ± 1.9 |
| OL Period: Week 48 | 3.0 ± 9.7 | 0.6 ± 8.8 |
| OL Period: Week 96 | 2.7 ± 8.1 | 1.9 ± 4.0 |
| OL Period: Week 144 | 4.7 ± 10.7 | 0.4 ± 17.1 |
| OL Period: Week 192 | 0.4 ± 9.4 | -3.6 ± 30.6 |
Volume of T1 hypointense lesions was measured by MRI scan.
| milliliters | Placebo/Teriflunomide | Teriflunomide/ Teriflunomide |
|---|---|---|
| DB Period: Week 24 | 0.3 ± 1.3 | 0.0 ± 0.7 |
| DB Period: Week 36 | 0.8 ± 1.8 | 0.2 ± 0.8 |
| DB Period: Week 48 | 0.2 ± 0.4 | 0.4 ± 2.9 |
| DB Period: Week 72 | 0.1 ± 0.7 | 0.1 ± 0.6 |
| DB Period: Week 96 | 0.1 ± 0.6 | 0.1 ± 0.7 |
| OL Period: Week 48 | 0.7 ± 1.9 | 0.5 ± 1.4 |
| OL Period: Week 96 | 1.0 ± 2.0 | 0.6 ± 1.9 |
| OL Period: Week 144 | 2.0 ± 3.0 | 1.9 ± 3.4 |
| OL Period: Week 192 | 4.0 ± 5.8 | 2.5 ± 5.7 |
The number of new T1 hypointense lesions were obtained from MRI scans.
| lesions | Placebo/Teriflunomide | Teriflunomide/ Teriflunomide |
|---|---|---|
| Brain Magnetic Resonance Imaging Assessment: Number of New T1 Hypointense Lesions Per MRI Scan | 1561 | 1910 |
Percentage of participants who were free of new or enlarged T2 lesions at Weeks 24, 48, 72, 96, 144 and 192 were reported.
| percentage of participants | Placebo/Teriflunomide | Teriflunomide/ Teriflunomide |
|---|---|---|
| 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 |
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.
| percent change | Placebo/Teriflunomide | Teriflunomide/ Teriflunomide |
|---|---|---|
| DB Period: Week 24 | -0.3 ± 0.7 | -0.2 ± 0.7 |
| DB Period: Week 36 | -0.7 ± 0.7 | -0.4 ± 1.0 |
| DB Period: Week 48 | -0.6 ± 1.1 | -0.5 ± 0.9 |
| DB Period: Week 72 | -0.9 ± 1.3 | -0.6 ± 1.1 |
| DB Period: Week 96 | -0.9 ± 1.3 | -0.8 ± 1.1 |
| OL Period: Week 48 | -1.4 ± 1.6 | -1.1 ± 1.3 |
| OL Period: Week 96 | -1.8 ± 1.9 | -1.4 ± 1.6 |
| OL Period: Week 144 | -3.1 ± 2.8 | -2.0 ± 1.7 |
| OL Period: Week 192 | -2.2 ± 1.2 | -3.0 ± 1.9 |
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.
| score on a scale | Placebo/Teriflunomide | Teriflunomide/ Teriflunomide |
|---|---|---|
| DB Period: Week 24 | 5.1 ± 12.0 | 4.6 ± 9.1 |
| DB Period: Week 48 | 7.3 ± 14.1 | 5.7 ± 10.3 |
| DB Period: Week 72 | 6.4 ± 12.9 | 5.6 ± 11.5 |
| DB Period: Week 96 | 8.8 ± 10.7 | 8.1 ± 11.1 |
| OL Period: Week 24 | 6.3 ± 13.9 | 8.3 ± 12.3 |
| OL Period: Week 48 | 6.7 ± 13.3 | 7.6 ± 13.0 |
| OL Period: Week 72 | 8.0 ± 15.5 | 9.2 ± 13.0 |
| OL Period: Week 96 | 7.6 ± 16.7 | 8.0 ± 14.8 |
| OL Period: Week 120 | 3.7 ± 15.9 | 7.2 ± 10.3 |
| OL Period: Week 144 | 6.6 ± 14.4 | 5.2 ± 13.0 |
| OL Period: Week 168 | 3.5 ± 17.9 | 1.7 ± 14.0 |
| OL Period: Week 192 | 12.0 | -0.3 ± 18.2 |
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.
| score on a scale | Placebo/Teriflunomide | Teriflunomide/ Teriflunomide |
|---|---|---|
| DB Period: Week 24 | 3.8 ± 11.7 | 3.6 ± 9.0 |
| DB Period: Week 48 | 6.3 ± 13.8 | 4.7 ± 10.3 |
| DB Period: Week 72 | 5.1 ± 13.4 | 4.5 ± 11.4 |
| DB Period: Week 96 | 7.1 ± 11.2 | 6.9 ± 11.1 |
| OL Period: Week 24 | 4.8 ± 13.5 | 7.1 ± 12.4 |
| OL Period: Week 48 | 5.5 ± 12.8 | 6.4 ± 13.0 |
| OL Period: Week 72 | 6.4 ± 15.4 | 8.1 ± 12.8 |
| OL Period: Week 96 | 6.3 ± 16.6 | 7.6 ± 12.5 |
| OL Period: Week 120 | 3.7 ± 14.7 | 6.3 ± 11.5 |
| OL Period: Week 144 | 4.8 ± 15.1 | 3.7 ± 13.4 |
| OL Period: Week 168 | 2.7 ± 15.5 | -0.3 ± 15.6 |
| OL Period: Week 192 | 12.0 | -1.5 ± 18.3 |
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.
| score on a scale | Placebo/Teriflunomide | Teriflunomide/ Teriflunomide |
|---|---|---|
| Baseline | 23.8 ± 7.2 | 24.8 ± 6.4 |
| Change at Week 96 | -0.8 ± 9.3 | 1.6 ± 5.3 |
| Change at Week 192 | 1.0 ± 6.9 | 1.2 ± 5.4 |
'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.
| seconds | Placebo/Teriflunomide | Teriflunomide/ Teriflunomide |
|---|---|---|
| Baseline | 43.4 ± 24.2 | 47.1 ± 23.7 |
| Change at Week 96 | 8.4 ± 9.0 | -3.1 ± 19.5 |
| Change at Week 192 | 6.3 ± 20.7 | -6.6 ± 17.4 |
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.
| seconds | Placebo/Teriflunomide | Teriflunomide/ Teriflunomide |
|---|---|---|
| Baseline | 113.8 ± 81.5 | 115.0 ± 44.6 |
| Change at Week 96 | -19.8 ± 33.7 | -29.5 ± 56.6 |
| Change at Week 192 | -37.0 ± 83.3 | -18.8 ± 37.3 |
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.
| score on a scale | Placebo/Teriflunomide | Teriflunomide/ Teriflunomide |
|---|---|---|
| Baseline | 26.1 ± 5.2 | 25.9 ± 4.0 |
| Change at Week 96 | 0.6 ± 2.4 | -0.4 ± 4.8 |
| Change at Week 192 | 0.1 ± 5.4 | 0.4 ± 2.9 |
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.
| score on a scale | Placebo/Teriflunomide | Teriflunomide/ Teriflunomide |
|---|---|---|
| Baseline | 39.0 | 34.3 ± 7.0 |
| Change at Week 96 | 5.0 | 4.0 |
| Change at Week 192 | 3.0 | 5.0 |
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.
| score on a scale | Placebo/Teriflunomide | Teriflunomide/ Teriflunomide |
|---|---|---|
| Baseline | 32.5 ± 3.5 | 21.0 ± 6.0 |
| Change at Week 96 | -3.0 | 4.0 ± 9.9 |
| Change at Week 192 | 5.0 | -6.5 ± 16.3 |
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.
| score on a scale | Placebo/Teriflunomide | Teriflunomide/ Teriflunomide |
|---|---|---|
| Baseline | 28.0 ± 1.4 | 27.5 ± 9.2 |
| Change at Week 96 | 6.0 | 5.0 ± 5.7 |
| Change at Week 192 | -2.0 | -13.5 ± 17.7 |
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.
| score on a scale | Placebo/Teriflunomide | Teriflunomide/ Teriflunomide |
|---|---|---|
| Baseline | 3.5 ± 4.9 | 10.0 ± 1.4 |
| Change at Week 96 | 1.0 | -0.5 ± 2.1 |
| Change at Week 192 | 0.0 | 0.0 |
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.
| micrograms per milliliter | Teriflunomide 3.5 mg | Teriflunomide 7 mg | Teriflunomide 14 mg |
|---|---|---|---|
| DB: Pharmacokinetics: Steady-state Trough Concentration (Ctrough) of Teriflunomide | — | 53.1 ± 25.3 | 67.8 ± 41.7 |
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.
| weeks | Placebo/Teriflunomide | Teriflunomide/ Teriflunomide |
|---|---|---|
| OL: Time to First Confirmed Clinical Relapse | 95.86 (0.6 to 176.0) | 96.00 (1.0 to 183.4) |
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.
| micrograms per milliliter | 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 |
|---|---|---|---|---|---|---|
| OL: Pharmacokinetics: Steady-state Trough Concentration (Ctrough) of Teriflunomide | — | 45.8 ± 35.3 | 50.4 ± 23.8 | — | 33.7 ± 10.7 | 63.6 ± 35.5 |
Collected over Treatment-emergent adverse events (TEAEs), treatment-emergent serious AEs and deaths were collected from first dose of study drug (Day 1) up to 96 weeks (for DB period arms), first dose of study drug in OL period (Week 97) up to Week 192 (for OL period arms) and first dose of study drug in extension period (Week 193) up to Week 492 (for extension period arm).. Non-serious events are listed at a 2% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Double-Blind Treatment Period: Placebo | 0/57 (0%) | 6/57 (10.5%) | 42/57 (73.7%) |
| Double-Blind Treatment Period: Teriflunomide | 0/109 (0%) | 12/109 (11%) | 89/109 (81.7%) |
| Open-Label Treatment Period: Placebo/Teriflunomide | 0/52 (0%) | 15/52 (28.8%) | 40/52 (76.9%) |
| Open-Label Treatment Period: Teriflunomide/Teriflunomide | 0/100 (0%) | 14/100 (14%) | 72/100 (72%) |
| Extension Period/Teriflunomide | 0/27 (0%) | 8/27 (29.6%) | 18/27 (66.7%) |
| Event | Double-Blind Treatment Period: Placebo | Double-Blind Treatment Period: Teriflunomide | Open-Label Treatment Period: Placebo/Teriflunomide | Open-Label Treatment Period: Teriflunomide/Teriflunomide | Extension Period/Teriflunomide |
|---|---|---|---|---|---|
| Alanine Aminotransferase IncreasedInvestigations | 0/57 | 1/109 | 2/52 | 0/100 | 0/27 |
| AsthmaRespiratory, thoracic and mediastinal disorders | 1/57 | 0/109 | 2/52 | 0/100 | 0/27 |
| BradycardiaCardiac disorders | 0/57 | 0/109 | 0/52 | 0/100 | 1/27 |
| Sudden Hearing LossEar and labyrinth disorders | 0/57 | 0/109 | 0/52 | 0/100 | 1/27 |
| Complicated AppendicitisInfections and infestations | 0/57 | 0/109 | 0/52 | 0/100 | 1/27 |
| Salpingo-OophoritisInfections and infestations | 0/57 | 0/109 | 0/52 | 0/100 | 1/27 |
| Multiple Sclerosis RelapseNervous system disorders | 0/57 | 0/109 | 0/52 | 0/100 | 1/27 |
| Partial SeizuresNervous system disorders | 0/57 | 0/109 | 0/52 | 0/100 | 1/27 |
| SyncopeNervous system disorders | 1/57 | 2/109 | 0/52 | 1/100 | 1/27 |
| Transient Ischaemic AttackNervous system disorders | 0/57 | 0/109 | 0/52 | 0/100 | 1/27 |
| Event | Double-Blind Treatment Period: Placebo | Double-Blind Treatment Period: Teriflunomide | Open-Label Treatment Period: Placebo/Teriflunomide | Open-Label Treatment Period: Teriflunomide/Teriflunomide | Extension Period/Teriflunomide |
|---|---|---|---|---|---|
| NasopharyngitisInfections and infestations | 5/57 | 28/109 | 8/52 | 20/100 | 4/27 |
| HeadacheNervous system disorders | 13/57 | 18/109 | 7/52 | 14/100 | 1/27 |
| Upper Respiratory Tract InfectionInfections and infestations | 6/57 | 24/109 | 7/52 | 22/100 | 6/27 |
| AlopeciaSkin and subcutaneous tissue disorders | 7/57 | 24/109 | 9/52 | 10/100 | 1/27 |
| DiarrhoeaGastrointestinal disorders | 4/57 | 8/109 | 6/52 | 7/100 | 1/27 |
| Alanine Aminotransferase IncreasedInvestigations | 1/57 | 2/109 | 6/52 | 3/100 | 2/27 |
| DizzinessNervous system disorders | 4/57 | 9/109 | 6/52 | 2/100 | 0/27 |
| Covid-19Infections and infestations | 0/57 | 0/109 | 0/52 | 0/100 | 3/27 |
| Accidental OverdoseInjury, poisoning and procedural complications | 4/57 | 5/109 | 2/52 | 10/100 | 3/27 |
| Neutrophil Count DecreasedInvestigations | 0/57 | 3/109 | 1/52 | 2/100 | 3/27 |
Analysis was performed on all randomized participants.
| Age, Continuous(years) | Placebo/Teriflunomide | Teriflunomide/Teriflunomide | Total |
|---|---|---|---|
| Mean | 14.7 ± 2.1 | 14.6 ± 2.0 | 14.6 ± 2.0 |
| Sex: Female, Male(Participants) | Placebo/Teriflunomide | Teriflunomide/Teriflunomide | Total |
|---|---|---|---|
| Female | 39 | 72 | 111 |
| Male | 18 | 37 | 55 |
| Race/Ethnicity, Customized(Participants) | Placebo/Teriflunomide | Teriflunomide/Teriflunomide | Total |
|---|---|---|---|
| Race — Caucasian/White | 42 | 75 | 117 |
| Race — Black | 1 | 4 | 5 |
| Race — Asian/Oriental | 12 | 25 | 37 |
| Race — Other | 2 | 5 | 7 |
Documents are hosted by the registry — open the source record to download them.
Plan to share: Yes — Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org
This study is completed, as verified in Jan 2025. You cannot join it, but the record below documents what was studied.
Get an email when the registry record changes — status, dates, results — or when someone posts here.
Sign in to followQuestions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.
Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.
Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.
Genzyme, a Sanofi Company