Multiple Sclerosis
Conditions
Brief summary
Primary Objective: To assess the effect of teriflunomide in comparison to placebo on disease activity measured by time to first clinical relapse after randomization in children and adolescents 10 to 17 years of age with relapsing forms of multiple sclerosis (MS). Secondary Objective: * To assess the effect of teriflunomide in comparison to placebo on disease activity/progression measured by brain magnetic resonance imaging (MRI) and on cognitive function. * To evaluate the safety and tolerability of teriflunomide in comparison to placebo. * To evaluate the pharmacokinetics (PK) of teriflunomide.
Detailed description
The study duration included a screening period up to 4 weeks, a double-blind treatment period of up to 96 weeks, an open-label period which included the remainder of the initial 96 weeks, where applicable, and a 96-week extension, i.e., up to a maximum of 192 weeks after randomization. There was a follow-up period of 4 weeks for participants discontinuing treatment. Within the 96 weeks double-blind treatment period, the first 4 weeks were PK run-in phase in which PK samples (blood samples) were collected from participants and then 4 weeks of analysis (no samples drawn). The PK run-in phase (total 8 weeks) was intended to provide individual PK parameters to allow the dose adjustment to the 14 milligrams (mg) adult-equivalent dose for the rest of the study. Participants who experienced a relapse after the PK run-in phase (8 weeks) and confirmed by the Relapse Adjudication Panel and participants who fulfilled MRI criteria (high number of new lesions at weeks 36, 48 or 72 compared to previous images) had the option to continue in an open-label teriflunomide treatment arm up to 192 weeks from randomization. An optional additional extension period was available for young participants with teriflunomide until the participants are 18 years old and/or able to switch to commercial product, whichever comes first.
Interventions
DRUGTeriflunomide
Pharmaceutical form:film-coated tablet, Route of administration: oral
DRUGPlacebo
Pharmaceutical form:tablet, Route of administration: oral
Sponsors
Genzyme, a Sanofi Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
10 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* 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: * at least one relapse (or attack) in the 12 months preceding screening or, * at least two relapses (or attack) in the 24 months preceding screening. * Less than 18 years of age and greater than or equal to (\>=) 10 years of age at randomization. Specific for the Russian Federation from 18 December 2014 to 26 July 2016, less than or equal to 17 years of age and \>= 13 years of age at randomization. * Signed informed consent/assent obtained from participant and participant's legal representative (parents or guardians) according to local regulations.
Exclusion criteria
* Expanded disability status scale score greater than 5.5 at screening or randomization visits. * Relapse within 30 days prior to randomization. * Treated with: * glatiramer acetate, interferons, or dimethyl fumarate within 1 month prior to randomization. * fingolimod, or intravenous immunoglobulins within 3 months prior to randomization. * natalizumab, other immunosuppressant or immunomodulatory agents such as cyclophosphamide, azathioprine, cyclosporine, methotrexate, mycophenolate, within 6 months prior to randomization. * cladribine or mitoxantrone within 2 years prior to randomization. * Treated with alemtuzumab at any time. * History of human immunodeficiency virus infection. * Contraindication for MRI. * Pregnant or breast-feeding females or those who plan to become pregnant during the study. * Female participants of child-bearing potential not using highly effective contraceptive method (contraception in both female and male was required). The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Confirmed Clinical Relapse | Baseline up to Week 96 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Probability of Participants Who Were Clinical Relapse Free at Weeks 24, 48, 72, 96, 120, 144, 168 and 192 | 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. |
| Brain Magnetic Resonance Imaging (MRI) Assessment: Number of New or Enlarged T2 Lesions Per MRI Scan | Baseline up to Week 192 | 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. |
| Brain Magnetic Resonance Imaging Assessment: Number of T1 Gadolinium (Gd)-Enhancing T1 Lesions Per MRI Scan | Baseline up to Week 192 | 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. |
| Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T2 Lesions at Weeks 24, 36, 48, 72, 96, 144 and 192 | Baseline, DB period: Weeks 24, 36, 48, 72 and 96; OL period: Weeks 48, 96, 144 and 192 | Volume of T2 lesions was measured by MRI scan. |
| Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T1 Hypointense Lesions | Baseline, DB period: Weeks 24, 36, 48, 72 and 96; OL period: Weeks 48, 96, 144 and 192 | Volume of T1 hypointense lesions was measured by MRI scan. |
| Brain Magnetic Resonance Imaging Assessment: Number of New T1 Hypointense Lesions Per MRI Scan | Baseline up to Week 192 | The number of new T1 hypointense lesions were obtained from MRI scans. |
| Brain Magnetic Resonance Imaging Assessment: Percentage of Participants Free of New or Enlarged MRI T2-Lesions | Baseline, Weeks 24, 48, 72, 96, 144 and 192 | Percentage of participants who were free of new or enlarged T2 lesions at Weeks 24, 48, 72, 96, 144 and 192 were reported. |
| 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 | Baseline, DB period: Weeks 24, 48, 72 and 96; OL period: 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. |
| 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 | Baseline, DB period: Weeks 24, 48, 72 and 96; OL period: 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. |
| Cognitive Assessment: Change From Baseline in Brief Visuospatial Memory Test-Revised (BVMT-R) Scores at Weeks 96 and 192 | Baseline, 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. |
| Brain Magnetic Resonance Imaging Assessment: Percent Change From Baseline in Brain Volume at Weeks 24, 36, 48, 72, 96, 144 and 192 | Baseline, DB period: Weeks 24, 36, 48, 72 and 96; OL period: Weeks 48, 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. |
| Cognitive Assessment: Change From Baseline in Trail Making Test B (TMT-B) Test Scores (in Seconds) at Weeks 96 and 192 | Baseline, 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. |
| DB: Pharmacokinetics: Steady-state Trough Concentration (Ctrough) of Teriflunomide | Predose on Week 36 | 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. |
| Cognitive Assessment: Change From Baseline in Beery Visual-motor Integration (BVMI) Scores at Weeks 96 and 192 | Baseline, 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. |
| Cognitive Assessment: Change From Baseline in Wechsler Abbreviated Scale of Intelligence-II (WASI-II) Vocabulary Total Raw Scores at Weeks 96 and 192 | Baseline, 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. |
| Cognitive Assessment: Change From Baseline in Delis-Kaplan Executive Function System (D-KEFS) Letter Fluency Total Correct Raw Score at Weeks 96 and 192 | Baseline, 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. |
| Cognitive Assessment: Change From Baseline in Delis-Kaplan Executive Function System Category Fluency Total Correct Raw Score at Weeks 96 and 192 | Baseline, 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. |
| Cognitive Assessment - Selective Reminding Test (SRT): Change From Baseline in Total Number of Words on Delayed Recall at Weeks 96 and 192 | Baseline, 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. |
| OL: Time to First Confirmed Clinical Relapse | Baseline up to Week 192 | 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. |
| OL: Pharmacokinetics: Steady-state Trough Concentration (Ctrough) of Teriflunomide | Pre-dose at Week 36 | 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. |
| Cognitive Assessment: Change From Baseline in Trail Making Test- Part A (TMT-A) Test Scores (in Seconds) at Week 96 and 192 | Baseline, Weeks 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. |
Countries
Belgium, Bulgaria, Canada, China, Estonia, France, Greece, Israel, Lebanon, Lithuania, Morocco, Netherlands, North Macedonia, Portugal, Russia, Serbia, Spain, Tunisia, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Recruitment details
Study was conducted at 57 active centers in 21 countries. A total of 185 participants were screened between 16 July 2014 and 27 December 2017, of which 166 participants were enrolled and randomized. A total of 19 participants failed screening mainly due to meeting exclusion criteria.
Pre-assignment details
Participants were randomly assigned to receive either teriflunomide or placebo in a 2:1 ratio via Interactive Voice Response System. Randomization was stratified by the country and participant's pubertal status.
Participants by arm
| Arm | Count |
|---|---|
| Placebo/Teriflunomide 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. | 57 |
| Teriflunomide/Teriflunomide 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). | 109 |
| Total | 166 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Double-blind Period (up to Week 96) | Adverse Event | 0 | 6 | 0 |
| Double-blind Period (up to Week 96) | Lack of Efficacy | 2 | 1 | 0 |
| Double-blind Period (up to Week 96) | Withdrawal by Subject | 2 | 0 | 0 |
| Extension Period (Up to Week 492) | Adverse Event | 0 | 0 | 2 |
| Extension Period (Up to Week 492) | Poor compliance to protocol | 0 | 0 | 1 |
| Open Label Period (up to Week 192) | Adverse Event | 7 | 5 | 0 |
| Open Label Period (up to Week 192) | Lack of Efficacy | 10 | 14 | 0 |
| Open Label Period (up to Week 192) | Other reason | 4 | 7 | 0 |
| Open Label Period (up to Week 192) | Poor compliance to protocol | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Teriflunomide/Teriflunomide | Placebo/Teriflunomide | Total |
|---|---|---|---|
| Age, Continuous | 14.6 years STANDARD_DEVIATION 2 | 14.7 years STANDARD_DEVIATION 2.1 | 14.6 years STANDARD_DEVIATION 2 |
| Race/Ethnicity, Customized Race Asian/Oriental | 25 Participants | 12 Participants | 37 Participants |
| Race/Ethnicity, Customized Race Black | 4 Participants | 1 Participants | 5 Participants |
| Race/Ethnicity, Customized Race Caucasian/White | 75 Participants | 42 Participants | 117 Participants |
| Race/Ethnicity, Customized Race Other | 5 Participants | 2 Participants | 7 Participants |
| Sex: Female, Male Female | 72 Participants | 39 Participants | 111 Participants |
| Sex: Female, Male Male | 37 Participants | 18 Participants | 55 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 57 | 0 / 109 | 0 / 52 | 0 / 100 | 0 / 27 |
| other Total, other adverse events | 42 / 57 | 89 / 109 | 40 / 52 | 72 / 100 | 18 / 27 |
| serious Total, serious adverse events | 6 / 57 | 12 / 109 | 15 / 52 | 14 / 100 | 8 / 27 |
Outcome results
Primary
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
Population: Analysis was performed on Intent-to-treat (ITT) population, which consisted of all randomized participants analyzed according to the treatment allocated by randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Double-Blind Treatment Period: Placebo | Time to First Confirmed Clinical Relapse | 39.14 weeks |
| Double-Blind Treatment Period: Teriflunomide | Time to First Confirmed Clinical Relapse | 75.29 weeks |
p-value: 0.294995% CI: [0.388, 1.113]Stratified Log-Rank test
Secondary
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Double-Blind Treatment Period: Placebo | Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T1 Hypointense Lesions | DB Period: Week 36 | 0.8 milliliters | Standard Deviation 1.8 |
| Double-Blind Treatment Period: Placebo | Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T1 Hypointense Lesions | OL Period: Week 48 | 0.7 milliliters | Standard Deviation 1.9 |
| Double-Blind Treatment Period: Placebo | Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T1 Hypointense Lesions | DB Period: Week 72 | 0.1 milliliters | Standard Deviation 0.7 |
| Double-Blind Treatment Period: Placebo | Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T1 Hypointense Lesions | OL Period: Week 96 | 1.0 milliliters | Standard Deviation 2 |
| Double-Blind Treatment Period: Placebo | Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T1 Hypointense Lesions | DB Period: Week 48 | 0.2 milliliters | Standard Deviation 0.4 |
| Double-Blind Treatment Period: Placebo | Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T1 Hypointense Lesions | OL Period: Week 144 | 2.0 milliliters | Standard Deviation 3 |
| Double-Blind Treatment Period: Placebo | Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T1 Hypointense Lesions | DB Period: Week 96 | 0.1 milliliters | Standard Deviation 0.6 |
| Double-Blind Treatment Period: Placebo | Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T1 Hypointense Lesions | OL Period: Week 192 | 4.0 milliliters | Standard Deviation 5.8 |
| Double-Blind Treatment Period: Placebo | Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T1 Hypointense Lesions | DB Period: Week 24 | 0.3 milliliters | Standard Deviation 1.3 |
| Double-Blind Treatment Period: Teriflunomide | Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T1 Hypointense Lesions | OL Period: Week 192 | 2.5 milliliters | Standard Deviation 5.7 |
| Double-Blind Treatment Period: Teriflunomide | Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T1 Hypointense Lesions | DB Period: Week 24 | 0.0 milliliters | Standard Deviation 0.7 |
| Double-Blind Treatment Period: Teriflunomide | Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T1 Hypointense Lesions | DB Period: Week 36 | 0.2 milliliters | Standard Deviation 0.8 |
| Double-Blind Treatment Period: Teriflunomide | Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T1 Hypointense Lesions | DB Period: Week 48 | 0.4 milliliters | Standard Deviation 2.9 |
| Double-Blind Treatment Period: Teriflunomide | Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T1 Hypointense Lesions | DB Period: Week 72 | 0.1 milliliters | Standard Deviation 0.6 |
| Double-Blind Treatment Period: Teriflunomide | Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T1 Hypointense Lesions | DB Period: Week 96 | 0.1 milliliters | Standard Deviation 0.7 |
| Double-Blind Treatment Period: Teriflunomide | Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T1 Hypointense Lesions | OL Period: Week 48 | 0.5 milliliters | Standard Deviation 1.4 |
| Double-Blind Treatment Period: Teriflunomide | Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T1 Hypointense Lesions | OL Period: Week 96 | 0.6 milliliters | Standard Deviation 1.9 |
| Double-Blind Treatment Period: Teriflunomide | Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T1 Hypointense Lesions | OL Period: Week 144 | 1.9 milliliters | Standard Deviation 3.4 |
Secondary
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Double-Blind Treatment Period: Placebo | Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T2 Lesions at Weeks 24, 36, 48, 72, 96, 144 and 192 | DB Period: Week 36 | 4.6 milliliters | Standard Deviation 11.7 |
| Double-Blind Treatment Period: Placebo | Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T2 Lesions at Weeks 24, 36, 48, 72, 96, 144 and 192 | OL Period: Week 48 | 3.0 milliliters | Standard Deviation 9.7 |
| Double-Blind Treatment Period: Placebo | Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T2 Lesions at Weeks 24, 36, 48, 72, 96, 144 and 192 | DB Period: Week 72 | 1.2 milliliters | Standard Deviation 1.6 |
| Double-Blind Treatment Period: Placebo | Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T2 Lesions at Weeks 24, 36, 48, 72, 96, 144 and 192 | OL Period: Week 96 | 2.7 milliliters | Standard Deviation 8.1 |
| Double-Blind Treatment Period: Placebo | Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T2 Lesions at Weeks 24, 36, 48, 72, 96, 144 and 192 | DB Period: Week 48 | 0.5 milliliters | Standard Deviation 0.6 |
| Double-Blind Treatment Period: Placebo | Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T2 Lesions at Weeks 24, 36, 48, 72, 96, 144 and 192 | OL Period: Week 144 | 4.7 milliliters | Standard Deviation 10.7 |
| Double-Blind Treatment Period: Placebo | Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T2 Lesions at Weeks 24, 36, 48, 72, 96, 144 and 192 | DB Period: Week 96 | 0.9 milliliters | Standard Deviation 1.4 |
| Double-Blind Treatment Period: Placebo | Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T2 Lesions at Weeks 24, 36, 48, 72, 96, 144 and 192 | OL Period: Week 192 | 0.4 milliliters | Standard Deviation 9.4 |
| Double-Blind Treatment Period: Placebo | Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T2 Lesions at Weeks 24, 36, 48, 72, 96, 144 and 192 | DB Period: Week 24 | 3.0 milliliters | Standard Deviation 7 |
| Double-Blind Treatment Period: Teriflunomide | Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T2 Lesions at Weeks 24, 36, 48, 72, 96, 144 and 192 | OL Period: Week 192 | -3.6 milliliters | Standard Deviation 30.6 |
| Double-Blind Treatment Period: Teriflunomide | Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T2 Lesions at Weeks 24, 36, 48, 72, 96, 144 and 192 | DB Period: Week 24 | 0.5 milliliters | Standard Deviation 1.8 |
| Double-Blind Treatment Period: Teriflunomide | Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T2 Lesions at Weeks 24, 36, 48, 72, 96, 144 and 192 | DB Period: Week 36 | 4.4 milliliters | Standard Deviation 21.3 |
| Double-Blind Treatment Period: Teriflunomide | Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T2 Lesions at Weeks 24, 36, 48, 72, 96, 144 and 192 | DB Period: Week 48 | -0.2 milliliters | Standard Deviation 3.4 |
| Double-Blind Treatment Period: Teriflunomide | Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T2 Lesions at Weeks 24, 36, 48, 72, 96, 144 and 192 | DB Period: Week 72 | 0.1 milliliters | Standard Deviation 1.9 |
| Double-Blind Treatment Period: Teriflunomide | Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T2 Lesions at Weeks 24, 36, 48, 72, 96, 144 and 192 | DB Period: Week 96 | 0.2 milliliters | Standard Deviation 1.9 |
| Double-Blind Treatment Period: Teriflunomide | Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T2 Lesions at Weeks 24, 36, 48, 72, 96, 144 and 192 | OL Period: Week 48 | 0.6 milliliters | Standard Deviation 8.8 |
| Double-Blind Treatment Period: Teriflunomide | Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T2 Lesions at Weeks 24, 36, 48, 72, 96, 144 and 192 | OL Period: Week 96 | 1.9 milliliters | Standard Deviation 4 |
| Double-Blind Treatment Period: Teriflunomide | Brain Magnetic Resonance Imaging Assessment: Change From Baseline in Volume of T2 Lesions at Weeks 24, 36, 48, 72, 96, 144 and 192 | OL Period: Week 144 | 0.4 milliliters | Standard Deviation 17.1 |
Secondary
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
Population: Analysis was performed on efficacy population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Double-Blind Treatment Period: Placebo | Brain Magnetic Resonance Imaging Assessment: Number of New T1 Hypointense Lesions Per MRI Scan | 1561 lesions |
| Double-Blind Treatment Period: Teriflunomide | Brain Magnetic Resonance Imaging Assessment: Number of New T1 Hypointense Lesions Per MRI Scan | 1910 lesions |
95% CI: [0.296, 0.836]
Secondary
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
Population: Analysis was performed on efficacy population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Double-Blind Treatment Period: Placebo | Brain Magnetic Resonance Imaging Assessment: Number of T1 Gadolinium (Gd)-Enhancing T1 Lesions Per MRI Scan | 2.686 lesions per scan |
| Double-Blind Treatment Period: Teriflunomide | Brain Magnetic Resonance Imaging Assessment: Number of T1 Gadolinium (Gd)-Enhancing T1 Lesions Per MRI Scan | 1.532 lesions per scan |
95% CI: [0.331, 0.983]
Secondary
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
Population: Analysis was performed on efficacy population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Double-Blind Treatment Period: Placebo | Brain Magnetic Resonance Imaging Assessment: Percentage of Participants Free of New or Enlarged MRI T2-Lesions | Week 48 | 32.7 percentage of participants |
| Double-Blind Treatment Period: Placebo | Brain Magnetic Resonance Imaging Assessment: Percentage of Participants Free of New or Enlarged MRI T2-Lesions | Week 24 | 86.5 percentage of participants |
| Double-Blind Treatment Period: Placebo | Brain Magnetic Resonance Imaging Assessment: Percentage of Participants Free of New or Enlarged MRI T2-Lesions | Week 72 | 15.4 percentage of participants |
| Double-Blind Treatment Period: Placebo | Brain Magnetic Resonance Imaging Assessment: Percentage of Participants Free of New or Enlarged MRI T2-Lesions | Week 96 | 15.4 percentage of participants |
| Double-Blind Treatment Period: Placebo | Brain Magnetic Resonance Imaging Assessment: Percentage of Participants Free of New or Enlarged MRI T2-Lesions | Week 144 | 11.5 percentage of participants |
| Double-Blind Treatment Period: Placebo | Brain Magnetic Resonance Imaging Assessment: Percentage of Participants Free of New or Enlarged MRI T2-Lesions | Week 192 | 7.7 percentage of participants |
| Double-Blind Treatment Period: Teriflunomide | Brain Magnetic Resonance Imaging Assessment: Percentage of Participants Free of New or Enlarged MRI T2-Lesions | Week 144 | 14.0 percentage of participants |
| Double-Blind Treatment Period: Teriflunomide | Brain Magnetic Resonance Imaging Assessment: Percentage of Participants Free of New or Enlarged MRI T2-Lesions | Week 96 | 16.0 percentage of participants |
| Double-Blind Treatment Period: Teriflunomide | Brain Magnetic Resonance Imaging Assessment: Percentage of Participants Free of New or Enlarged MRI T2-Lesions | Week 24 | 86.0 percentage of participants |
| Double-Blind Treatment Period: Teriflunomide | Brain Magnetic Resonance Imaging Assessment: Percentage of Participants Free of New or Enlarged MRI T2-Lesions | Week 48 | 25.0 percentage of participants |
| Double-Blind Treatment Period: Teriflunomide | Brain Magnetic Resonance Imaging Assessment: Percentage of Participants Free of New or Enlarged MRI T2-Lesions | Week 192 | 9.0 percentage of participants |
| Double-Blind Treatment Period: Teriflunomide | Brain Magnetic Resonance Imaging Assessment: Percentage of Participants Free of New or Enlarged MRI T2-Lesions | Week 72 | 17.0 percentage of participants |
Secondary
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Double-Blind Treatment Period: Placebo | Brain Magnetic Resonance Imaging Assessment: Percent Change From Baseline in Brain Volume at Weeks 24, 36, 48, 72, 96, 144 and 192 | DB Period: Week 36 | -0.7 percent change | Standard Deviation 0.7 |
| Double-Blind Treatment Period: Placebo | Brain Magnetic Resonance Imaging Assessment: Percent Change From Baseline in Brain Volume at Weeks 24, 36, 48, 72, 96, 144 and 192 | OL Period: Week 48 | -1.4 percent change | Standard Deviation 1.6 |
| Double-Blind Treatment Period: Placebo | Brain Magnetic Resonance Imaging Assessment: Percent Change From Baseline in Brain Volume at Weeks 24, 36, 48, 72, 96, 144 and 192 | DB Period: Week 72 | -0.9 percent change | Standard Deviation 1.3 |
| Double-Blind Treatment Period: Placebo | Brain Magnetic Resonance Imaging Assessment: Percent Change From Baseline in Brain Volume at Weeks 24, 36, 48, 72, 96, 144 and 192 | OL Period: Week 96 | -1.8 percent change | Standard Deviation 1.9 |
| Double-Blind Treatment Period: Placebo | Brain Magnetic Resonance Imaging Assessment: Percent Change From Baseline in Brain Volume at Weeks 24, 36, 48, 72, 96, 144 and 192 | DB Period: Week 48 | -0.6 percent change | Standard Deviation 1.1 |
| Double-Blind Treatment Period: Placebo | Brain Magnetic Resonance Imaging Assessment: Percent Change From Baseline in Brain Volume at Weeks 24, 36, 48, 72, 96, 144 and 192 | OL Period: Week 144 | -3.1 percent change | Standard Deviation 2.8 |
| Double-Blind Treatment Period: Placebo | Brain Magnetic Resonance Imaging Assessment: Percent Change From Baseline in Brain Volume at Weeks 24, 36, 48, 72, 96, 144 and 192 | DB Period: Week 96 | -0.9 percent change | Standard Deviation 1.3 |
| Double-Blind Treatment Period: Placebo | Brain Magnetic Resonance Imaging Assessment: Percent Change From Baseline in Brain Volume at Weeks 24, 36, 48, 72, 96, 144 and 192 | OL Period: Week 192 | -2.2 percent change | Standard Deviation 1.2 |
| Double-Blind Treatment Period: Placebo | Brain Magnetic Resonance Imaging Assessment: Percent Change From Baseline in Brain Volume at Weeks 24, 36, 48, 72, 96, 144 and 192 | DB Period: Week 24 | -0.3 percent change | Standard Deviation 0.7 |
| Double-Blind Treatment Period: Teriflunomide | Brain Magnetic Resonance Imaging Assessment: Percent Change From Baseline in Brain Volume at Weeks 24, 36, 48, 72, 96, 144 and 192 | OL Period: Week 192 | -3.0 percent change | Standard Deviation 1.9 |
| Double-Blind Treatment Period: Teriflunomide | Brain Magnetic Resonance Imaging Assessment: Percent Change From Baseline in Brain Volume at Weeks 24, 36, 48, 72, 96, 144 and 192 | DB Period: Week 24 | -0.2 percent change | Standard Deviation 0.7 |
| Double-Blind Treatment Period: Teriflunomide | Brain Magnetic Resonance Imaging Assessment: Percent Change From Baseline in Brain Volume at Weeks 24, 36, 48, 72, 96, 144 and 192 | DB Period: Week 36 | -0.4 percent change | Standard Deviation 1 |
| Double-Blind Treatment Period: Teriflunomide | Brain Magnetic Resonance Imaging Assessment: Percent Change From Baseline in Brain Volume at Weeks 24, 36, 48, 72, 96, 144 and 192 | DB Period: Week 48 | -0.5 percent change | Standard Deviation 0.9 |
| Double-Blind Treatment Period: Teriflunomide | Brain Magnetic Resonance Imaging Assessment: Percent Change From Baseline in Brain Volume at Weeks 24, 36, 48, 72, 96, 144 and 192 | DB Period: Week 72 | -0.6 percent change | Standard Deviation 1.1 |
| Double-Blind Treatment Period: Teriflunomide | Brain Magnetic Resonance Imaging Assessment: Percent Change From Baseline in Brain Volume at Weeks 24, 36, 48, 72, 96, 144 and 192 | DB Period: Week 96 | -0.8 percent change | Standard Deviation 1.1 |
| Double-Blind Treatment Period: Teriflunomide | Brain Magnetic Resonance Imaging Assessment: Percent Change From Baseline in Brain Volume at Weeks 24, 36, 48, 72, 96, 144 and 192 | OL Period: Week 48 | -1.1 percent change | Standard Deviation 1.3 |
| Double-Blind Treatment Period: Teriflunomide | Brain Magnetic Resonance Imaging Assessment: Percent Change From Baseline in Brain Volume at Weeks 24, 36, 48, 72, 96, 144 and 192 | OL Period: Week 96 | -1.4 percent change | Standard Deviation 1.6 |
| Double-Blind Treatment Period: Teriflunomide | Brain Magnetic Resonance Imaging Assessment: Percent Change From Baseline in Brain Volume at Weeks 24, 36, 48, 72, 96, 144 and 192 | OL Period: Week 144 | -2.0 percent change | Standard Deviation 1.7 |
Secondary
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
Population: Analysis was performed on efficacy population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Double-Blind Treatment Period: Placebo | Brain Magnetic Resonance Imaging (MRI) Assessment: Number of New or Enlarged T2 Lesions Per MRI Scan | 11.087 lesions per scan |
| Double-Blind Treatment Period: Teriflunomide | Brain Magnetic Resonance Imaging (MRI) Assessment: Number of New or Enlarged T2 Lesions Per MRI Scan | 5.664 lesions per scan |
95% CI: [0.343, 0.762]
Secondary
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Double-Blind Treatment Period: Placebo | Cognitive Assessment: Change From Baseline in Beery Visual-motor Integration (BVMI) Scores at Weeks 96 and 192 | Baseline | 26.1 score on a scale | Standard Deviation 5.2 |
| Double-Blind Treatment Period: Placebo | Cognitive Assessment: Change From Baseline in Beery Visual-motor Integration (BVMI) Scores at Weeks 96 and 192 | Change at Week 96 | 0.6 score on a scale | Standard Deviation 2.4 |
| Double-Blind Treatment Period: Placebo | Cognitive Assessment: Change From Baseline in Beery Visual-motor Integration (BVMI) Scores at Weeks 96 and 192 | Change at Week 192 | 0.1 score on a scale | Standard Deviation 5.4 |
| Double-Blind Treatment Period: Teriflunomide | Cognitive Assessment: Change From Baseline in Beery Visual-motor Integration (BVMI) Scores at Weeks 96 and 192 | Baseline | 25.9 score on a scale | Standard Deviation 4 |
| Double-Blind Treatment Period: Teriflunomide | Cognitive Assessment: Change From Baseline in Beery Visual-motor Integration (BVMI) Scores at Weeks 96 and 192 | Change at Week 96 | -0.4 score on a scale | Standard Deviation 4.8 |
| Double-Blind Treatment Period: Teriflunomide | Cognitive Assessment: Change From Baseline in Beery Visual-motor Integration (BVMI) Scores at Weeks 96 and 192 | Change at Week 192 | 0.4 score on a scale | Standard Deviation 2.9 |
Secondary
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Double-Blind Treatment Period: Placebo | Cognitive Assessment: Change From Baseline in Brief Visuospatial Memory Test-Revised (BVMT-R) Scores at Weeks 96 and 192 | Baseline | 23.8 score on a scale | Standard Deviation 7.2 |
| Double-Blind Treatment Period: Placebo | Cognitive Assessment: Change From Baseline in Brief Visuospatial Memory Test-Revised (BVMT-R) Scores at Weeks 96 and 192 | Change at Week 96 | -0.8 score on a scale | Standard Deviation 9.3 |
| Double-Blind Treatment Period: Placebo | Cognitive Assessment: Change From Baseline in Brief Visuospatial Memory Test-Revised (BVMT-R) Scores at Weeks 96 and 192 | Change at Week 192 | 1.0 score on a scale | Standard Deviation 6.9 |
| Double-Blind Treatment Period: Teriflunomide | Cognitive Assessment: Change From Baseline in Brief Visuospatial Memory Test-Revised (BVMT-R) Scores at Weeks 96 and 192 | Baseline | 24.8 score on a scale | Standard Deviation 6.4 |
| Double-Blind Treatment Period: Teriflunomide | Cognitive Assessment: Change From Baseline in Brief Visuospatial Memory Test-Revised (BVMT-R) Scores at Weeks 96 and 192 | Change at Week 96 | 1.6 score on a scale | Standard Deviation 5.3 |
| Double-Blind Treatment Period: Teriflunomide | Cognitive Assessment: Change From Baseline in Brief Visuospatial Memory Test-Revised (BVMT-R) Scores at Weeks 96 and 192 | Change at Week 192 | 1.2 score on a scale | Standard Deviation 5.4 |
Secondary
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Double-Blind Treatment Period: Placebo | Cognitive Assessment: Change From Baseline in Delis-Kaplan Executive Function System Category Fluency Total Correct Raw Score at Weeks 96 and 192 | Baseline | 28.0 score on a scale | Standard Deviation 1.4 |
| Double-Blind Treatment Period: Placebo | Cognitive Assessment: Change From Baseline in Delis-Kaplan Executive Function System Category Fluency Total Correct Raw Score at Weeks 96 and 192 | Change at Week 96 | 6.0 score on a scale | — |
| Double-Blind Treatment Period: Placebo | Cognitive Assessment: Change From Baseline in Delis-Kaplan Executive Function System Category Fluency Total Correct Raw Score at Weeks 96 and 192 | Change at Week 192 | -2.0 score on a scale | — |
| Double-Blind Treatment Period: Teriflunomide | Cognitive Assessment: Change From Baseline in Delis-Kaplan Executive Function System Category Fluency Total Correct Raw Score at Weeks 96 and 192 | Baseline | 27.5 score on a scale | Standard Deviation 9.2 |
| Double-Blind Treatment Period: Teriflunomide | Cognitive Assessment: Change From Baseline in Delis-Kaplan Executive Function System Category Fluency Total Correct Raw Score at Weeks 96 and 192 | Change at Week 96 | 5.0 score on a scale | Standard Deviation 5.7 |
| Double-Blind Treatment Period: Teriflunomide | Cognitive Assessment: Change From Baseline in Delis-Kaplan Executive Function System Category Fluency Total Correct Raw Score at Weeks 96 and 192 | Change at Week 192 | -13.5 score on a scale | Standard Deviation 17.7 |
Secondary
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Double-Blind Treatment Period: Placebo | Cognitive Assessment: Change From Baseline in Delis-Kaplan Executive Function System (D-KEFS) Letter Fluency Total Correct Raw Score at Weeks 96 and 192 | Baseline | 32.5 score on a scale | Standard Deviation 3.5 |
| Double-Blind Treatment Period: Placebo | Cognitive Assessment: Change From Baseline in Delis-Kaplan Executive Function System (D-KEFS) Letter Fluency Total Correct Raw Score at Weeks 96 and 192 | Change at Week 96 | -3.0 score on a scale | — |
| Double-Blind Treatment Period: Placebo | Cognitive Assessment: Change From Baseline in Delis-Kaplan Executive Function System (D-KEFS) Letter Fluency Total Correct Raw Score at Weeks 96 and 192 | Change at Week 192 | 5.0 score on a scale | — |
| Double-Blind Treatment Period: Teriflunomide | Cognitive Assessment: Change From Baseline in Delis-Kaplan Executive Function System (D-KEFS) Letter Fluency Total Correct Raw Score at Weeks 96 and 192 | Baseline | 21.0 score on a scale | Standard Deviation 6 |
| Double-Blind Treatment Period: Teriflunomide | Cognitive Assessment: Change From Baseline in Delis-Kaplan Executive Function System (D-KEFS) Letter Fluency Total Correct Raw Score at Weeks 96 and 192 | Change at Week 96 | 4.0 score on a scale | Standard Deviation 9.9 |
| Double-Blind Treatment Period: Teriflunomide | Cognitive Assessment: Change From Baseline in Delis-Kaplan Executive Function System (D-KEFS) Letter Fluency Total Correct Raw Score at Weeks 96 and 192 | Change at Week 192 | -6.5 score on a scale | Standard Deviation 16.3 |
Secondary
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Double-Blind Treatment Period: Placebo | 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 | DB Period: Week 24 | 3.8 score on a scale | Standard Deviation 11.7 |
| Double-Blind Treatment Period: Placebo | 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 | DB Period: Week 48 | 6.3 score on a scale | Standard Deviation 13.8 |
| Double-Blind Treatment Period: Placebo | 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 | DB Period: Week 72 | 5.1 score on a scale | Standard Deviation 13.4 |
| Double-Blind Treatment Period: Placebo | 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 | DB Period: Week 96 | 7.1 score on a scale | Standard Deviation 11.2 |
| Double-Blind Treatment Period: Placebo | 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 | OL Period: Week 24 | 4.8 score on a scale | Standard Deviation 13.5 |
| Double-Blind Treatment Period: Placebo | 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 | OL Period: Week 48 | 5.5 score on a scale | Standard Deviation 12.8 |
| Double-Blind Treatment Period: Placebo | 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 | OL Period: Week 72 | 6.4 score on a scale | Standard Deviation 15.4 |
| Double-Blind Treatment Period: Placebo | 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 | OL Period: Week 96 | 6.3 score on a scale | Standard Deviation 16.6 |
| Double-Blind Treatment Period: Placebo | 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 | OL Period: Week 120 | 3.7 score on a scale | Standard Deviation 14.7 |
| Double-Blind Treatment Period: Placebo | 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 | OL Period: Week 144 | 4.8 score on a scale | Standard Deviation 15.1 |
| Double-Blind Treatment Period: Placebo | 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 | OL Period: Week 168 | 2.7 score on a scale | Standard Deviation 15.5 |
| Double-Blind Treatment Period: Placebo | 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 | OL Period: Week 192 | 12.0 score on a scale | — |
| Double-Blind Treatment Period: Teriflunomide | 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 | OL Period: Week 168 | -0.3 score on a scale | Standard Deviation 15.6 |
| Double-Blind Treatment Period: Teriflunomide | 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 | DB Period: Week 24 | 3.6 score on a scale | Standard Deviation 9 |
| Double-Blind Treatment Period: Teriflunomide | 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 | OL Period: Week 72 | 8.1 score on a scale | Standard Deviation 12.8 |
| Double-Blind Treatment Period: Teriflunomide | 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 | DB Period: Week 48 | 4.7 score on a scale | Standard Deviation 10.3 |
| Double-Blind Treatment Period: Teriflunomide | 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 | OL Period: Week 144 | 3.7 score on a scale | Standard Deviation 13.4 |
| Double-Blind Treatment Period: Teriflunomide | 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 | DB Period: Week 72 | 4.5 score on a scale | Standard Deviation 11.4 |
| Double-Blind Treatment Period: Teriflunomide | 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 | OL Period: Week 96 | 7.6 score on a scale | Standard Deviation 12.5 |
| Double-Blind Treatment Period: Teriflunomide | 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 | DB Period: Week 96 | 6.9 score on a scale | Standard Deviation 11.1 |
| Double-Blind Treatment Period: Teriflunomide | 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 | OL Period: Week 192 | -1.5 score on a scale | Standard Deviation 18.3 |
| Double-Blind Treatment Period: Teriflunomide | 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 | OL Period: Week 24 | 7.1 score on a scale | Standard Deviation 12.4 |
| Double-Blind Treatment Period: Teriflunomide | 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 | OL Period: Week 120 | 6.3 score on a scale | Standard Deviation 11.5 |
| Double-Blind Treatment Period: Teriflunomide | 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 | OL Period: Week 48 | 6.4 score on a scale | Standard Deviation 13 |
Secondary
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Double-Blind Treatment Period: Placebo | 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 | DB Period: Week 24 | 5.1 score on a scale | Standard Deviation 12 |
| Double-Blind Treatment Period: Placebo | 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 | DB Period: Week 48 | 7.3 score on a scale | Standard Deviation 14.1 |
| Double-Blind Treatment Period: Placebo | 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 | DB Period: Week 72 | 6.4 score on a scale | Standard Deviation 12.9 |
| Double-Blind Treatment Period: Placebo | 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 | DB Period: Week 96 | 8.8 score on a scale | Standard Deviation 10.7 |
| Double-Blind Treatment Period: Placebo | 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 | OL Period: Week 24 | 6.3 score on a scale | Standard Deviation 13.9 |
| Double-Blind Treatment Period: Placebo | 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 | OL Period: Week 48 | 6.7 score on a scale | Standard Deviation 13.3 |
| Double-Blind Treatment Period: Placebo | 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 | OL Period: Week 72 | 8.0 score on a scale | Standard Deviation 15.5 |
| Double-Blind Treatment Period: Placebo | 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 | OL Period: Week 96 | 7.6 score on a scale | Standard Deviation 16.7 |
| Double-Blind Treatment Period: Placebo | 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 | OL Period: Week 120 | 3.7 score on a scale | Standard Deviation 15.9 |
| Double-Blind Treatment Period: Placebo | 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 | OL Period: Week 144 | 6.6 score on a scale | Standard Deviation 14.4 |
| Double-Blind Treatment Period: Placebo | 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 | OL Period: Week 168 | 3.5 score on a scale | Standard Deviation 17.9 |
| Double-Blind Treatment Period: Placebo | 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 | OL Period: Week 192 | 12.0 score on a scale | — |
| Double-Blind Treatment Period: Teriflunomide | 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 | OL Period: Week 168 | 1.7 score on a scale | Standard Deviation 14 |
| Double-Blind Treatment Period: Teriflunomide | 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 | DB Period: Week 24 | 4.6 score on a scale | Standard Deviation 9.1 |
| Double-Blind Treatment Period: Teriflunomide | 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 | OL Period: Week 72 | 9.2 score on a scale | Standard Deviation 13 |
| Double-Blind Treatment Period: Teriflunomide | 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 | DB Period: Week 48 | 5.7 score on a scale | Standard Deviation 10.3 |
| Double-Blind Treatment Period: Teriflunomide | 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 | OL Period: Week 144 | 5.2 score on a scale | Standard Deviation 13 |
| Double-Blind Treatment Period: Teriflunomide | 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 | DB Period: Week 72 | 5.6 score on a scale | Standard Deviation 11.5 |
| Double-Blind Treatment Period: Teriflunomide | 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 | OL Period: Week 96 | 8.0 score on a scale | Standard Deviation 14.8 |
| Double-Blind Treatment Period: Teriflunomide | 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 | DB Period: Week 96 | 8.1 score on a scale | Standard Deviation 11.1 |
| Double-Blind Treatment Period: Teriflunomide | 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 | OL Period: Week 192 | -0.3 score on a scale | Standard Deviation 18.2 |
| Double-Blind Treatment Period: Teriflunomide | 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 | OL Period: Week 24 | 8.3 score on a scale | Standard Deviation 12.3 |
| Double-Blind Treatment Period: Teriflunomide | 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 | OL Period: Week 120 | 7.2 score on a scale | Standard Deviation 10.3 |
| Double-Blind Treatment Period: Teriflunomide | 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 | OL Period: Week 48 | 7.6 score on a scale | Standard Deviation 13 |
Secondary
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Double-Blind Treatment Period: Placebo | Cognitive Assessment: Change From Baseline in Trail Making Test B (TMT-B) Test Scores (in Seconds) at Weeks 96 and 192 | Baseline | 113.8 seconds | Standard Deviation 81.5 |
| Double-Blind Treatment Period: Placebo | Cognitive Assessment: Change From Baseline in Trail Making Test B (TMT-B) Test Scores (in Seconds) at Weeks 96 and 192 | Change at Week 96 | -19.8 seconds | Standard Deviation 33.7 |
| Double-Blind Treatment Period: Placebo | Cognitive Assessment: Change From Baseline in Trail Making Test B (TMT-B) Test Scores (in Seconds) at Weeks 96 and 192 | Change at Week 192 | -37.0 seconds | Standard Deviation 83.3 |
| Double-Blind Treatment Period: Teriflunomide | Cognitive Assessment: Change From Baseline in Trail Making Test B (TMT-B) Test Scores (in Seconds) at Weeks 96 and 192 | Baseline | 115.0 seconds | Standard Deviation 44.6 |
| Double-Blind Treatment Period: Teriflunomide | Cognitive Assessment: Change From Baseline in Trail Making Test B (TMT-B) Test Scores (in Seconds) at Weeks 96 and 192 | Change at Week 96 | -29.5 seconds | Standard Deviation 56.6 |
| Double-Blind Treatment Period: Teriflunomide | Cognitive Assessment: Change From Baseline in Trail Making Test B (TMT-B) Test Scores (in Seconds) at Weeks 96 and 192 | Change at Week 192 | -18.8 seconds | Standard Deviation 37.3 |
Secondary
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Double-Blind Treatment Period: Placebo | Cognitive Assessment: Change From Baseline in Trail Making Test- Part A (TMT-A) Test Scores (in Seconds) at Week 96 and 192 | Baseline | 43.4 seconds | Standard Deviation 24.2 |
| Double-Blind Treatment Period: Placebo | Cognitive Assessment: Change From Baseline in Trail Making Test- Part A (TMT-A) Test Scores (in Seconds) at Week 96 and 192 | Change at Week 96 | 8.4 seconds | Standard Deviation 9 |
| Double-Blind Treatment Period: Placebo | Cognitive Assessment: Change From Baseline in Trail Making Test- Part A (TMT-A) Test Scores (in Seconds) at Week 96 and 192 | Change at Week 192 | 6.3 seconds | Standard Deviation 20.7 |
| Double-Blind Treatment Period: Teriflunomide | Cognitive Assessment: Change From Baseline in Trail Making Test- Part A (TMT-A) Test Scores (in Seconds) at Week 96 and 192 | Baseline | 47.1 seconds | Standard Deviation 23.7 |
| Double-Blind Treatment Period: Teriflunomide | Cognitive Assessment: Change From Baseline in Trail Making Test- Part A (TMT-A) Test Scores (in Seconds) at Week 96 and 192 | Change at Week 96 | -3.1 seconds | Standard Deviation 19.5 |
| Double-Blind Treatment Period: Teriflunomide | Cognitive Assessment: Change From Baseline in Trail Making Test- Part A (TMT-A) Test Scores (in Seconds) at Week 96 and 192 | Change at Week 192 | -6.6 seconds | Standard Deviation 17.4 |
Secondary
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Double-Blind Treatment Period: Placebo | Cognitive Assessment: Change From Baseline in Wechsler Abbreviated Scale of Intelligence-II (WASI-II) Vocabulary Total Raw Scores at Weeks 96 and 192 | Baseline | 39.0 score on a scale | — |
| Double-Blind Treatment Period: Placebo | Cognitive Assessment: Change From Baseline in Wechsler Abbreviated Scale of Intelligence-II (WASI-II) Vocabulary Total Raw Scores at Weeks 96 and 192 | Change at Week 96 | 5.0 score on a scale | — |
| Double-Blind Treatment Period: Placebo | Cognitive Assessment: Change From Baseline in Wechsler Abbreviated Scale of Intelligence-II (WASI-II) Vocabulary Total Raw Scores at Weeks 96 and 192 | Change at Week 192 | 3.0 score on a scale | — |
| Double-Blind Treatment Period: Teriflunomide | Cognitive Assessment: Change From Baseline in Wechsler Abbreviated Scale of Intelligence-II (WASI-II) Vocabulary Total Raw Scores at Weeks 96 and 192 | Baseline | 34.3 score on a scale | Standard Deviation 7 |
| Double-Blind Treatment Period: Teriflunomide | Cognitive Assessment: Change From Baseline in Wechsler Abbreviated Scale of Intelligence-II (WASI-II) Vocabulary Total Raw Scores at Weeks 96 and 192 | Change at Week 96 | 4.0 score on a scale | — |
| Double-Blind Treatment Period: Teriflunomide | Cognitive Assessment: Change From Baseline in Wechsler Abbreviated Scale of Intelligence-II (WASI-II) Vocabulary Total Raw Scores at Weeks 96 and 192 | Change at Week 192 | 5.0 score on a scale | — |
Secondary
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Double-Blind Treatment Period: Placebo | Cognitive Assessment - Selective Reminding Test (SRT): Change From Baseline in Total Number of Words on Delayed Recall at Weeks 96 and 192 | Baseline | 3.5 score on a scale | Standard Deviation 4.9 |
| Double-Blind Treatment Period: Placebo | Cognitive Assessment - Selective Reminding Test (SRT): Change From Baseline in Total Number of Words on Delayed Recall at Weeks 96 and 192 | Change at Week 96 | 1.0 score on a scale | — |
| Double-Blind Treatment Period: Placebo | Cognitive Assessment - Selective Reminding Test (SRT): Change From Baseline in Total Number of Words on Delayed Recall at Weeks 96 and 192 | Change at Week 192 | 0.0 score on a scale | — |
| Double-Blind Treatment Period: Teriflunomide | Cognitive Assessment - Selective Reminding Test (SRT): Change From Baseline in Total Number of Words on Delayed Recall at Weeks 96 and 192 | Baseline | 10.0 score on a scale | Standard Deviation 1.4 |
| Double-Blind Treatment Period: Teriflunomide | Cognitive Assessment - Selective Reminding Test (SRT): Change From Baseline in Total Number of Words on Delayed Recall at Weeks 96 and 192 | Change at Week 96 | -0.5 score on a scale | Standard Deviation 2.1 |
| Double-Blind Treatment Period: Teriflunomide | Cognitive Assessment - Selective Reminding Test (SRT): Change From Baseline in Total Number of Words on Delayed Recall at Weeks 96 and 192 | Change at Week 192 | 0.0 score on a scale | — |
Secondary
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Double-Blind Treatment Period: Teriflunomide | DB: Pharmacokinetics: Steady-state Trough Concentration (Ctrough) of Teriflunomide | 53.1 micrograms per milliliter | Standard Deviation 25.3 |
| Teriflunomide 14 mg | DB: Pharmacokinetics: Steady-state Trough Concentration (Ctrough) of Teriflunomide | 67.8 micrograms per milliliter | Standard Deviation 41.7 |
Secondary
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Double-Blind Treatment Period: Teriflunomide | OL: Pharmacokinetics: Steady-state Trough Concentration (Ctrough) of Teriflunomide | 45.8 micrograms per milliliter | Standard Deviation 35.3 |
| Teriflunomide 14 mg | OL: Pharmacokinetics: Steady-state Trough Concentration (Ctrough) of Teriflunomide | 50.4 micrograms per milliliter | Standard Deviation 23.8 |
| Teriflunomide / Teriflunomide 7 mg | OL: Pharmacokinetics: Steady-state Trough Concentration (Ctrough) of Teriflunomide | 33.7 micrograms per milliliter | Standard Deviation 10.7 |
| Teriflunomide / Teriflunomide 14 mg | OL: Pharmacokinetics: Steady-state Trough Concentration (Ctrough) of Teriflunomide | 63.6 micrograms per milliliter | Standard Deviation 35.5 |
Secondary
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
Population: Analysis was performed on efficacy population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Double-Blind Treatment Period: Placebo | OL: Time to First Confirmed Clinical Relapse | 95.86 weeks |
| Double-Blind Treatment Period: Teriflunomide | OL: Time to First Confirmed Clinical Relapse | 96.00 weeks |
95% CI: [0.37, 1.296]
Secondary
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
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Double-Blind Treatment Period: Placebo | Probability of Participants Who Were Clinical Relapse Free at Weeks 24, 48, 72, 96, 120, 144, 168 and 192 | Week 24 | 0.750 probability of relapse free participants |
| Double-Blind Treatment Period: Placebo | Probability of Participants Who Were Clinical Relapse Free at Weeks 24, 48, 72, 96, 120, 144, 168 and 192 | Week 48 | 0.596 probability of relapse free participants |
| Double-Blind Treatment Period: Placebo | Probability of Participants Who Were Clinical Relapse Free at Weeks 24, 48, 72, 96, 120, 144, 168 and 192 | Week 72 | 0.519 probability of relapse free participants |
| Double-Blind Treatment Period: Placebo | Probability of Participants Who Were Clinical Relapse Free at Weeks 24, 48, 72, 96, 120, 144, 168 and 192 | Week 96 | 0.442 probability of relapse free participants |
| Double-Blind Treatment Period: Placebo | Probability of Participants Who Were Clinical Relapse Free at Weeks 24, 48, 72, 96, 120, 144, 168 and 192 | Week 120 | 0.404 probability of relapse free participants |
| Double-Blind Treatment Period: Placebo | Probability of Participants Who Were Clinical Relapse Free at Weeks 24, 48, 72, 96, 120, 144, 168 and 192 | Week 144 | 0.365 probability of relapse free participants |
| Double-Blind Treatment Period: Placebo | Probability of Participants Who Were Clinical Relapse Free at Weeks 24, 48, 72, 96, 120, 144, 168 and 192 | Week 168 | 0.365 probability of relapse free participants |
| Double-Blind Treatment Period: Placebo | Probability of Participants Who Were Clinical Relapse Free at Weeks 24, 48, 72, 96, 120, 144, 168 and 192 | Week 192 | 0.365 probability of relapse free participants |
| Double-Blind Treatment Period: Teriflunomide | Probability of Participants Who Were Clinical Relapse Free at Weeks 24, 48, 72, 96, 120, 144, 168 and 192 | Week 192 | 0.518 probability of relapse free participants |
| Double-Blind Treatment Period: Teriflunomide | Probability of Participants Who Were Clinical Relapse Free at Weeks 24, 48, 72, 96, 120, 144, 168 and 192 | Week 24 | 0.820 probability of relapse free participants |
| Double-Blind Treatment Period: Teriflunomide | Probability of Participants Who Were Clinical Relapse Free at Weeks 24, 48, 72, 96, 120, 144, 168 and 192 | Week 120 | 0.570 probability of relapse free participants |
| Double-Blind Treatment Period: Teriflunomide | Probability of Participants Who Were Clinical Relapse Free at Weeks 24, 48, 72, 96, 120, 144, 168 and 192 | Week 48 | 0.700 probability of relapse free participants |
| Double-Blind Treatment Period: Teriflunomide | Probability of Participants Who Were Clinical Relapse Free at Weeks 24, 48, 72, 96, 120, 144, 168 and 192 | Week 168 | 0.518 probability of relapse free participants |
| Double-Blind Treatment Period: Teriflunomide | Probability of Participants Who Were Clinical Relapse Free at Weeks 24, 48, 72, 96, 120, 144, 168 and 192 | Week 72 | 0.630 probability of relapse free participants |
| Double-Blind Treatment Period: Teriflunomide | Probability of Participants Who Were Clinical Relapse Free at Weeks 24, 48, 72, 96, 120, 144, 168 and 192 | Week 144 | 0.540 probability of relapse free participants |
| Double-Blind Treatment Period: Teriflunomide | Probability of Participants Who Were Clinical Relapse Free at Weeks 24, 48, 72, 96, 120, 144, 168 and 192 | Week 96 | 0.600 probability of relapse free participants |