A Phase 3 interventional study of Teriflunomide and Placebo in Multiple Sclerosis, sponsored by Sanofi. Completed at 131 sites in 21 countries. Open to participants aged 18 Years to 55 Years. Per ClinicalTrials.gov, last updated 2017-03-13.
Sponsored by Sanofi · Phase 3, Interventional, and Treatment
The primary objective was to demonstrate the effect of teriflunomide (HMR1726) (14 milligram per day [mg/day] and 7 mg/day), in comparison to placebo, for reducing conversion of participants presenting with their first clinical episode consistent with multiple sclerosis (MS) to clinically definite multiple sclerosis (CDMS).
The secondary objectives were:
To demonstrate the effect of teriflunomide, in comparison to placebo, on:
The study consisted of 4 periods:
The maximal duration of the study period per participant was expected to be 116 weeks if he/she did not continue in the extension treatment period.
3,460 studies on the registry are indexed under Multiple Sclerosis; 661 are open to participants now.
This study's enrollment of 618 is above the median of 50 across 2,342 interventional studies indexed under Multiple Sclerosis.
Browse Multiple Sclerosis studies →Sanofi is the lead sponsor of 1,508 studies on the registry; 90 are open to participants now.
Of its 198 completed or terminated interventional studies of FDA-regulated products, 118 (60%) have results posted.
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Exclusion Criteria:
The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Core treatment period: Placebo matched to teriflunomide tablet once daily orally. Extension treatment period: Re-randomized in 1:1 ratio to either teriflunomide 7 mg or 14 mg once daily orally.
Drug: Teriflunomide · Drug: Placebo
Core treatment period: Teriflunomide 7 mg tablet once daily orally. Extension treatment period: Teriflunomide 7 mg tablet once daily orally.
Drug: Teriflunomide
Core treatment period: Teriflunomide 14 mg tablet once daily orally. Extension treatment period: Teriflunomide 14 mg tablet once daily orally.
Drug: Teriflunomide
Film-coated tablet Oral administration
Also known as: HMR1726, Aubagio
Film-coated tablet Oral administration
Core Treatment Period: Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS)
Conversion to CDMS was defined by the occurrence of a relapse, which was defined as a new neurological abnormality separated by at least 30 days from onset of a preceding clinical event, presented for at least 24 hours and occurred in the absence of fever or known infection. Percent probability of conversion at 24, 48, and 108 weeks was estimated using Kaplan-Meier method.
Time frame: Up to a maximum of 108 weeks depending on time of enrollment
Core Treatment Period: Time to Conversion to Definite Multiple Sclerosis (DMS)
Conversion to DMS was demonstrated by dissemination of MRI lesions in time (as per McDonald criteria) or a relapse, whichever occurs first. MRI Imaging criteria were detection of Gadolinium (Gd) enhancement at least 3 months after onset of initial clinical event, if not at site corresponding to initial event; detection of new T2 lesion if it appears at any time compared with reference scan (done at time of screening) done at least 30 days after onset of the initial clinical event. Occurrence of relapse was defined as new neurological abnormality separated by at least 30 days from onset of preceding clinical event, present for at least 24 hours and occurring in absence of fever or known infection. New clinical abnormality (neurological sign) that is consistent with participant's symptoms with increase in at least one Functional System (FS) or EDSS score compared to last EDSS assessment. Percent probability of conversion at 24, 48, and 108 weeks was estimated using Kaplan-Meier method.
Time frame: Up to a maximum of 108 weeks depending on time of enrollment
Core Treatment Period: Annualized Relapse Rate (ARR)
ARR is the total number of confirmed relapses that occurred during the treatment period divided by the total number of patient-years treated. Each episode of relapse (appearance, or worsening of a clinical symptom that was stable for at least 30 days, that persisted for a minimum of 24 hours in the absence of fever) was to be confirmed by an increase in EDSS score or Functional System scores. ARR was assessed using Poisson regression model with robust error variance. To account for the different treatment durations among participants, a Poisson regression model with robust error variance was used (total number of confirmed relapses onset between randomization date and last dose date as the response variable, treatment, region and baseline monofocal/multifocal status as covariates, and log-transformed treatment duration as an offset variable).
Time frame: Up to a maximum of 108 weeks depending on time of enrollment
Core Treatment Period: Brain Magnetic Resonance Imaging (MRI) Assessment: Change From Baseline in Total Lesion Volume at Week 108
The total lesion volume (burden of disease) is the total volumes of hyperintense on T2 plus hypointense on T1 as measured by MRI scan. Least-square means were estimated using a Mixed-effect model with repeated measures (MMRM) on cubic root transformed volume data with factors for treatment, baseline monofocal/multifocal status, region, visit, treatment-by-visit interaction, cubic root transformed baseline burden of disease, and baseline-by-visit interaction.
Time frame: Baseline, Week 108
Core Treatment Period: Brain MRI Assessment: Number of Gadolinium Enhancing (Gd-enhancing) T1-lesions Per MRI Scan (Poisson Regression Estimates)
Number of Gd-enhancing T1-lesions per scan is the total number of Gd-enhancing T1-lesions that occurred during the treatment period divided by the total number of scans performed during the treatment period. To account for the different numbers of scans performed among the participants, a Poisson regression model with robust error variance was used (total number of Gd-enhancing T1-lesions as response variable, treatment, baseline monofocal/multifocal status, region and baseline number of Gd-enhancing T1-lesions as covariates, and log-transformed number of scans as an offset variable).
Time frame: Up to a maximum of 108 weeks depending on time of enrollment
Core Treatment Period: Brain MRI Assessment: Volume of Gadolinium Enhancing (Gd-enhancing) T1-lesions Per MRI Scan
Total volume of Gd-enhancing T1-lesions per scan is the sum of the volumes of Gd-enhancing T1-lesions observed during the treatment period divided by the total number of scans performed during the treatment period. To account for the different numbers of scans performed among the participants, a Poisson regression model with robust error variance was used (total number of Gd-enhancing T1-lesions as response variable, treatment, baseline monofocal/multifocal status, region and baseline number of Gd-enhancing T1-lesions as covariates, and log-transformed number of scans as an offset variable).
Time frame: Up to a maximum of 108 weeks depending on time of enrollment
Core Treatment Period: Brain MRI Assessment: Change From Baseline in Volume of Hypointense Post-Gadolinium T1 Lesion Component
Volume of hypointense post-gadolinium T1 lesion component was measured by MRI scan. Least-square means were estimated using a Mixed-effect model with repeated measures (MMRM) on cubic root transformed volume data adjusted for baseline monofocal/multifocal status, region, visit, treatment-by-visit interaction, cubic root transformed baseline value, and baseline-by-visit interaction
Time frame: Baseline, Week 108
Core Treatment Period: Brain MRI Assessment: Change From Baseline in Volume of T2 Lesion Component
Volume of T2 lesion component was measured by MRI scan. Least-square means were estimated using a Mixed-effect model with repeated measures (MMRM) on cubic root transformed volume data adjusted for baseline monofocal/multifocal status, region, visit, treatment-by-visit interaction, cubic root transformed baseline value, and baseline-by-visit interaction.
Time frame: Baseline, Week 108
Core Treatment Period: Brain MRI Assessment: Percent Change From Baseline in Atrophy
Atrophy was measured by MRI scan.
Time frame: Baseline, Week 108
Core Treatment Period: Time to 12-Week Sustained Disability Progression
The 12-week sustained disability progression was defined as increase from baseline of at least 1-point in EDSS score (at least 0.5-point for participants with baseline EDSS score of greater than \[\>\] 5.5) that persisted for at least 12 weeks. Percent probability of participants free of 12-week sustained disability progression at 24, 48, and 108 weeks was estimated using Kaplan-Meier method.
Time frame: Up to a maximum of 108 weeks depending on time of enrollment
Core Treatment Period: Change From Baseline in EDSS at Week 108
EDSS is an ordinal scale in half-point increments that qualifies disability in participants with MS. It consists of 8 ordinal rating scales assessing seven functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder and cerebral) as well as ambulation. EDSS total score ranges from 0 (normal neurological examination) to 10 (death due to MS). Least-square means were estimated using a Mixed-effect model with repeated measures (MMRM) on cubic root transformed volume data adjusted for baseline monofocal/multifocal status, region, visit, treatment-by-visit interaction, baseline value and baseline-by-visit interaction
Time frame: Baseline, Week 108
Core Treatment Period: Change From Baseline in Fatigue Impact Scale (FIS) Total Score at Week 108
FIS is a participant-reported scale that qualifies the impact of fatigue on daily life in participants with MS. It consists of 40 statements that measure fatigue in three areas; physical, cognitive, and social. FIS total score ranges from 0 (no problem) to 160 (extreme problem). Least-square means were estimated using a Mixed-effect model with repeated measures \[MMRM\] on FIS total score data adjusted for or baseline monofocal/multifocal status, region, visit, treatment-by-visit interaction, baseline value and baseline-by-visit interaction.
Time frame: Baseline, Week 108
Core Treatment Period: Overview of Adverse Events (AEs)
AEs are any unfavorable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study.
Time frame: From first study drug intake up to 112 days after last intake in the placebo-controlled period or up to first intake in the extension treatment period, whichever occurred first
Extension Treatment Period: Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS)
Conversion to CDMS was defined by the occurrence of a relapse, which was defined as a new neurological abnormality separated by at least 30 days from onset of a preceding clinical event, presented for at least 24 hours and occurred in the absence of fever or known infection. Percent probability of conversion was estimated using Kaplan-Meier method.
Time frame: From randomization in the core period up to 390 Weeks (Extension treatment period [maximum exposure: 283 Weeks])
Extension Treatment Period: Overview of Adverse Events (AEs)
AEs are any unfavorable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study. Safety population included all randomized population who actually received at least 1 dose of the IMP in extension and analyzed according to the treatment actually received in core study followed by treatment actually received in the extension treatment period.
Time frame: From re-randomization up to 283 Weeks
Core Treatment Period: Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA)
PCSA values are abnormal values considered medically important by the Sponsor according to predefined criteria based on literature review. Hepatic parameters thresholds were defined as follows: * Alanine Aminotransferase (ALT) \>3, 5, 10 or 20 upper limit of normal(ULN); * Aspartate aminotransferase (AST) \>3, 5, 10 or 20 ULN; * Alkaline Phosphatase \>1.5 ULN; * Total Bilirubin (TB) \>1.5, 2, or 3 ULN; * ALT \>3 ULN and TB \>2 ULN.
Time frame: From first study drug intake up to 112 days after last intake in the placebo-controlled period or up to first intake in the extension treatment period, whichever occurred first
A total of 846 participants were screened, of which 618 randomized in core treatment period. Out of 618, 423 entered in extension treatment period. End date of core treatment period was 17 December 2012 (maximum treatment duration: 120 weeks). End date of extension treatment period was 05 February 2016 (maximum treatment duration: 283 weeks).
| Milestone | Placebo | Teriflunomide 7 mg | Teriflunomide 14 mg | Placebo/ Teriflunomide 7 mg | Teriflunomide 7 mg/7 mg | Placebo/Teriflunomide 14 mg | Teriflunomide 14 mg/14 mg |
|---|---|---|---|---|---|---|---|
| Started | 197 | 205 | 216 | 0 | 0 | 0 | 0 |
| Treated | 197 | 203 | 214 | 0 | 0 | 0 | 0 |
| Completed | 141 | 150 | 163 | 0 | 0 | 0 | 0 |
| Not completed | 56 | 55 | 53 | 0 | 0 | 0 | 0 |
| Withdrew: Randomized but not treated | 0 | 2 | 2 | 0 | 0 | 0 | 0 |
| Withdrew: Adverse event | 18 | 25 | 18 | 0 | 0 | 0 | 0 |
| Withdrew: Lack of efficacy | 19 | 6 | 12 | 0 | 0 | 0 | 0 |
| Withdrew: Lost to follow-up | 1 | 1 | 1 | 0 | 0 | 0 | 0 |
| Withdrew: Death | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Withdrew: Progressive disease | 3 | 1 | 0 | 0 | 0 | 0 | 0 |
| Withdrew: Withdrawal by subject | 12 | 18 | 15 | 0 | 0 | 0 | 0 |
| Withdrew: Other than specified above | 2 | 2 | 5 | 0 | 0 | 0 | 0 |
| Milestone | Placebo | Teriflunomide 7 mg | Teriflunomide 14 mg | Placebo/ Teriflunomide 7 mg | Teriflunomide 7 mg/7 mg | Placebo/Teriflunomide 14 mg | Teriflunomide 14 mg/14 mg |
|---|---|---|---|---|---|---|---|
| Started | 0 | 0 | 0 | 64 | 142 | 67 | 150 |
| Completed | 0 | 0 | 0 | 43 | 103 | 50 | 120 |
| Not completed | 0 | 0 | 0 | 21 | 39 | 17 | 30 |
| Withdrew: Adverse event | 0 | 0 | 0 | 5 | 9 | 6 | 8 |
| Withdrew: Lack of efficacy | 0 | 0 | 0 | 2 | 8 | 1 | 9 |
| Withdrew: Protocol violation | 0 | 0 | 0 | 0 | 0 | 2 | 0 |
| Withdrew: Lost to follow-up | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Withdrew: Progressive disease | 0 | 0 | 0 | 1 | 2 | 0 | 2 |
| Withdrew: Withdrawal by subject | 0 | 0 | 0 | 11 | 16 | 6 | 10 |
| Withdrew: Missing | 0 | 0 | 0 | 2 | 3 | 1 | 0 |
| Withdrew: Other than specified above | 0 | 0 | 0 | 0 | 0 | 1 | 1 |
Conversion to CDMS was defined by the occurrence of a relapse, which was defined as a new neurological abnormality separated by at least 30 days from onset of a preceding clinical event, presented for at least 24 hours and occurred in the absence of fever or known infection. Percent probability of conversion at 24, 48, and 108 weeks was estimated using Kaplan-Meier method.
| percent probability | Placebo | Teriflunomide 7 mg | Teriflunomide 14 mg |
|---|---|---|---|
| Percent Probability of Conversion at 24 weeks | 14.3 (9.2 to 19.4) | 8.7 (4.6 to 12.8) | 9.0 (5.0 to 13.0) |
| Percent Probability of Conversion at 48 weeks | 26.0 (19.2 to 32.8) | 14.2 (8.9 to 19.6) | 13.7 (8.6 to 18.7) |
| Percent Probability of Conversion at 108 weeks | 35.9 (27.8 to 43.9) | 27.6 (19.9 to 35.4) | 24.0 (17.0 to 31.0) |
Conversion to DMS was demonstrated by dissemination of MRI lesions in time (as per McDonald criteria) or a relapse, whichever occurs first. MRI Imaging criteria were detection of Gadolinium (Gd) enhancement at least 3 months after onset of initial clinical event, if not at site corresponding to initial event; detection of new T2 lesion if it appears at any time compared with reference scan (done at time of screening) done at least 30 days after onset of the initial clinical event. Occurrence of relapse was defined as new neurological abnormality separated by at least 30 days from onset of preceding clinical event, present for at least 24 hours and occurring in absence of fever or known infection. New clinical abnormality (neurological sign) that is consistent with participant's symptoms with increase in at least one Functional System (FS) or EDSS score compared to last EDSS assessment. Percent probability of conversion at 24, 48, and 108 weeks was estimated using Kaplan-Meier method.
| percent probability | Placebo | Teriflunomide 7 mg | Teriflunomide 14 mg |
|---|---|---|---|
| Percent Probability of Conversion at 24 weeks | 58.2 (51.0 to 65.4) | 45.7 (38.5 to 52.9) | 46.0 (39.0 to 53.0) |
| Percent Probability of Conversion at 48 weeks | 72.4 (65.7 to 79.1) | 57.3 (49.8 to 64.7) | 57.8 (50.6 to 64.9) |
| Percent Probability of Conversion at 108 weeks | 87.0 (81.2 to 92.7) | 73.3 (66.0 to 80.7) | 71.5 (64.5 to 78.4) |
ARR is the total number of confirmed relapses that occurred during the treatment period divided by the total number of patient-years treated. Each episode of relapse (appearance, or worsening of a clinical symptom that was stable for at least 30 days, that persisted for a minimum of 24 hours in the absence of fever) was to be confirmed by an increase in EDSS score or Functional System scores. ARR was assessed using Poisson regression model with robust error variance. To account for the different treatment durations among participants, a Poisson regression model with robust error variance was used (total number of confirmed relapses onset between randomization date and last dose date as the response variable, treatment, region and baseline monofocal/multifocal status as covariates, and log-transformed treatment duration as an offset variable).
| relapses per patient year | Placebo | Teriflunomide 7 mg | Teriflunomide 14 mg |
|---|---|---|---|
| Core Treatment Period: Annualized Relapse Rate (ARR) | 0.284 (0.214 to 0.378) | 0.190 (0.139 to 0.260) | 0.194 (0.143 to 0.263) |
The total lesion volume (burden of disease) is the total volumes of hyperintense on T2 plus hypointense on T1 as measured by MRI scan. Least-square means were estimated using a Mixed-effect model with repeated measures (MMRM) on cubic root transformed volume data with factors for treatment, baseline monofocal/multifocal status, region, visit, treatment-by-visit interaction, cubic root transformed baseline burden of disease, and baseline-by-visit interaction.
| milliliter | Placebo | Teriflunomide 7 mg | Teriflunomide 14 mg |
|---|---|---|---|
| Core Treatment Period: Brain Magnetic Resonance Imaging (MRI) Assessment: Change From Baseline in Total Lesion Volume at Week 108 | 0.053 ± 0.033 | 0.041 ± 0.032 | -0.038 ± 0.029 |
Number of Gd-enhancing T1-lesions per scan is the total number of Gd-enhancing T1-lesions that occurred during the treatment period divided by the total number of scans performed during the treatment period. To account for the different numbers of scans performed among the participants, a Poisson regression model with robust error variance was used (total number of Gd-enhancing T1-lesions as response variable, treatment, baseline monofocal/multifocal status, region and baseline number of Gd-enhancing T1-lesions as covariates, and log-transformed number of scans as an offset variable).
| lesions per scan | Placebo | Teriflunomide 7 mg | Teriflunomide 14 mg |
|---|---|---|---|
| Core Treatment Period: Brain MRI Assessment: Number of Gadolinium Enhancing (Gd-enhancing) T1-lesions Per MRI Scan (Poisson Regression Estimates) | 0.953 (0.708 to 1.284) | 0.749 (0.433 to 1.294) | 0.395 (0.262 to 0.598) |
Total volume of Gd-enhancing T1-lesions per scan is the sum of the volumes of Gd-enhancing T1-lesions observed during the treatment period divided by the total number of scans performed during the treatment period. To account for the different numbers of scans performed among the participants, a Poisson regression model with robust error variance was used (total number of Gd-enhancing T1-lesions as response variable, treatment, baseline monofocal/multifocal status, region and baseline number of Gd-enhancing T1-lesions as covariates, and log-transformed number of scans as an offset variable).
| milliliters per scan | Placebo | Teriflunomide 7 mg | Teriflunomide 14 mg |
|---|---|---|---|
| Core Treatment Period: Brain MRI Assessment: Volume of Gadolinium Enhancing (Gd-enhancing) T1-lesions Per MRI Scan | 0.079 | 0.058 | 0.034 |
Volume of hypointense post-gadolinium T1 lesion component was measured by MRI scan. Least-square means were estimated using a Mixed-effect model with repeated measures (MMRM) on cubic root transformed volume data adjusted for baseline monofocal/multifocal status, region, visit, treatment-by-visit interaction, cubic root transformed baseline value, and baseline-by-visit interaction
| milliliter | Placebo | Teriflunomide 7 mg | Teriflunomide 14 mg |
|---|---|---|---|
| Core Treatment Period: Brain MRI Assessment: Change From Baseline in Volume of Hypointense Post-Gadolinium T1 Lesion Component | 0.028 ± 0.018 | 0.025 ± 0.018 | -0.033 ± 0.016 |
Volume of T2 lesion component was measured by MRI scan. Least-square means were estimated using a Mixed-effect model with repeated measures (MMRM) on cubic root transformed volume data adjusted for baseline monofocal/multifocal status, region, visit, treatment-by-visit interaction, cubic root transformed baseline value, and baseline-by-visit interaction.
| milliliter | Placebo | Teriflunomide 7 mg | Teriflunomide 14 mg |
|---|---|---|---|
| Core Treatment Period: Brain MRI Assessment: Change From Baseline in Volume of T2 Lesion Component | 0.052 ± 0.033 | 0.036 ± 0.032 | -0.035 ± 0.029 |
Atrophy was measured by MRI scan.
| percent change | Placebo | Teriflunomide 7 mg | Teriflunomide 14 mg |
|---|---|---|---|
| Core Treatment Period: Brain MRI Assessment: Percent Change From Baseline in Atrophy | -0.386 ± 1.326 | -0.197 ± 1.218 | -0.366 ± 1.151 |
The 12-week sustained disability progression was defined as increase from baseline of at least 1-point in EDSS score (at least 0.5-point for participants with baseline EDSS score of greater than \[\>\] 5.5) that persisted for at least 12 weeks. Percent probability of participants free of 12-week sustained disability progression at 24, 48, and 108 weeks was estimated using Kaplan-Meier method.
| percent probability | Placebo | Teriflunomide 7 mg | Teriflunomide 14 mg |
|---|---|---|---|
| Percent Probability at 24 weeks | 96.0 (93.0 to 98.9) | 94.3 (90.9 to 97.8) | 97.9 (95.9 to 99.9) |
| Percent Probability at 48 weeks | 91.7 (87.3 to 96.1) | 90.1 (85.4 to 94.7) | 93.9 (90.2 to 97.6) |
| Percent Probability at 108 weeks | 85.5 (79.2 to 91.8) | 86.5 (80.8 to 92.1) | 89.2 (84.1 to 94.3) |
EDSS is an ordinal scale in half-point increments that qualifies disability in participants with MS. It consists of 8 ordinal rating scales assessing seven functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder and cerebral) as well as ambulation. EDSS total score ranges from 0 (normal neurological examination) to 10 (death due to MS). Least-square means were estimated using a Mixed-effect model with repeated measures (MMRM) on cubic root transformed volume data adjusted for baseline monofocal/multifocal status, region, visit, treatment-by-visit interaction, baseline value and baseline-by-visit interaction
| units on a scale | Placebo | Teriflunomide 7 mg | Teriflunomide 14 mg |
|---|---|---|---|
| Core Treatment Period: Change From Baseline in EDSS at Week 108 | 0.069 ± 0.087 | -0.191 ± 0.086 | -0.166 ± 0.080 |
FIS is a participant-reported scale that qualifies the impact of fatigue on daily life in participants with MS. It consists of 40 statements that measure fatigue in three areas; physical, cognitive, and social. FIS total score ranges from 0 (no problem) to 160 (extreme problem). Least-square means were estimated using a Mixed-effect model with repeated measures \[MMRM\] on FIS total score data adjusted for or baseline monofocal/multifocal status, region, visit, treatment-by-visit interaction, baseline value and baseline-by-visit interaction.
| units on a scale | Placebo | Teriflunomide 7 mg | Teriflunomide 14 mg |
|---|---|---|---|
| Core Treatment Period: Change From Baseline in Fatigue Impact Scale (FIS) Total Score at Week 108 | -2.537 ± 2.794 | -2.524 ± 2.710 | -1.827 ± 2.551 |
AEs are any unfavorable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study.
| participants | Placebo | Teriflunomide 7 mg | Teriflunomide 14 mg |
|---|---|---|---|
| Any AE | 155 | 161 | 183 |
| Any serious AE | 18 | 18 | 24 |
| Any AE leading to death | 1 | 0 | 0 |
| Any AE leading to treatment discontinuation | 19 | 25 | 18 |
Conversion to CDMS was defined by the occurrence of a relapse, which was defined as a new neurological abnormality separated by at least 30 days from onset of a preceding clinical event, presented for at least 24 hours and occurred in the absence of fever or known infection. Percent probability of conversion was estimated using Kaplan-Meier method.
| Percent probability | Placebo/Teriflunomide 7 mg | Teriflunomide 7 mg/ 7mg | Placebo/ Teriflunomide 14 mg | Teriflunomide 14 mg/14 mg |
|---|---|---|---|---|
| Percent Probability of Conversion at 24 Weeks | 4.7 (0.0 to 9.9) | 3.5 (0.5 to 6.6) | 13.5 (5.3 to 21.6) | 4.7 (1.3 to 8.0) |
| Percent Probability of Conversion at 48 Weeks | 12.5 (4.4 to 20.6) | 9.9 (5.0 to 14.8) | 21.2 (11.3 to 31.0) | 8.7 (4.2 to 13.3) |
| Percent Probability of Conversion at 72 Weeks | 15.7 (6.8 to 24.6) | 17.1 (10.9 to 23.4) | 24.3 (13.9 to 34.6) | 14.8 (9.1 to 20.6) |
| Percent Probability of Conversion at 96 Weeks | 18.9 (9.3 to 28.6) | 23.9 (16.7 to 31.0) | 27.4 (16.6 to 38.2) | 16.2 (10.3 to 22.1) |
| Percent Probability of Conversion at 120 Weeks | 22.3 (12.0 to 32.7) | 27.7 (20.2 to 35.2) | 32.2 (20.8 to 43.6) | 18.3 (12.1 to 24.6) |
| Percent Probability of Conversion at 144 Weeks | 22.3 (12.0 to 32.7) | 29.4 (21.7 to 37.1) | 33.9 (22.3 to 45.4) | 22.0 (15.3 to 28.8) |
| Percent Probability of Conversion at 168 Weeks | 22.3 (12.0 to 32.7) | 32.2 (24.2 to 40.3) | 33.9 (22.3 to 45.4) | 22.8 (16.0 to 29.7) |
| Percent Probability of Conversion at 192 Weeks | 22.3 (12.0 to 32.7) | 37.5 (28.6 to 46.4) | 35.9 (24.0 to 47.8) | 24.8 (17.6 to 32.0) |
| Percent Probability of Conversion at 216 Weeks | 25.6 (13.9 to 37.3) | 38.9 (29.8 to 48.1) | 39.3 (26.3 to 52.3) | 24.8 (17.6 to 32.0) |
| Percent Probability of Conversion at 240 Weeks | 29.5 (16.1 to 42.9) | 40.8 (31.3 to 50.4) | 39.3 (26.3 to 52.3) | 26.3 (18.7 to 34.0) |
| Percent Probability of Conversion at 264 Weeks | 29.5 (16.1 to 42.9) | 43.0 (32.9 to 53.2) | 39.3 (26.3 to 52.3) | 26.3 (18.7 to 34.0) |
| Percent Probability of Conversion at 288 Weeks | 29.5 (16.1 to 42.9) | 43.0 (32.9 to 53.2) | 39.3 (26.3 to 52.3) | 26.3 (18.7 to 34.0) |
| Percent Probability of Conversion at 312 Weeks | 29.5 (16.1 to 42.9) | 43.0 (32.9 to 53.2) | 49.4 (28.3 to 70.5) | 26.3 (18.7 to 34.0) |
| Percent Probability of Conversion at 336 Weeks | 29.5 (16.1 to 42.9) | 48.7 (34.7 to 62.7) | 49.4 (28.3 to 70.5) | 26.3 (18.7 to 34.0) |
AEs are any unfavorable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study. Safety population included all randomized population who actually received at least 1 dose of the IMP in extension and analyzed according to the treatment actually received in core study followed by treatment actually received in the extension treatment period.
| participants | Placebo/Teriflunomide 7 mg | Teriflunomide 7 mg/ 7mg | Placebo/ Teriflunomide 14 mg | Teriflunomide 14 mg/14 mg |
|---|---|---|---|---|
| Any AE | 47 | 110 | 57 | 120 |
| Any Serious AE | 8 | 17 | 8 | 24 |
| Any AE Leading to Death | 0 | 0 | 0 | 0 |
| Any AE leading to Permanent Discontinuation | 5 | 8 | 5 | 7 |
PCSA values are abnormal values considered medically important by the Sponsor according to predefined criteria based on literature review. Hepatic parameters thresholds were defined as follows: * Alanine Aminotransferase (ALT) \>3, 5, 10 or 20 upper limit of normal(ULN); * Aspartate aminotransferase (AST) \>3, 5, 10 or 20 ULN; * Alkaline Phosphatase \>1.5 ULN; * Total Bilirubin (TB) \>1.5, 2, or 3 ULN; * ALT \>3 ULN and TB \>2 ULN.
| participants | Placebo | Teriflunomide 7 mg | Teriflunomide 14 mg |
|---|---|---|---|
| ALT >3 ULN (n=190, 207, 216) | 18 | 25 | 26 |
| ALT >5 ULN (n=190, 207, 216) | 12 | 10 | 11 |
| ALT >10 ULN (n=190, 207, 216) | 5 | 1 | 3 |
| ALT >20 ULN (n=190, 207, 216) | 0 | 0 | 1 |
| AST >3 ULN (n=190, 207, 216) | 9 | 12 | 10 |
| AST >5 ULN (n=190, 207, 216) | 1 | 4 | 6 |
| AST >10 ULN (n=190, 207, 216) | 1 | 0 | 1 |
| AST >20 ULN (n=190, 207, 216) | 0 | 0 | 1 |
| Alkaline Phosphatase >1.5 ULN (n=190, 207, 216) | 0 | 0 | 1 |
| TB >1.5 ULN (n=190, 207, 216) | 14 | 9 | 8 |
| TB >2 ULN (n=190, 207, 216) | 8 | 0 | 3 |
| TB >3 ULN (n=190, 207, 216) | 0 | 0 | 1 |
| ALT >3 ULN and TB >2 ULN (n=190, 207, 216) | 2 | 0 | 2 |
Collected over All Adverse Events (AE) were collected from signature of the informed consent form up to the final visit (up to 390 weeks [maximum exposure in core treatment period: 120 weeks and maximum exposure in extension treatment period: 283 weeks]) regardless of seriousness or relationship to investigational product.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Placebo | — | 18/191 (9.4%) | 117/191 (61.3%) |
| Teriflunomide 7 mg | — | 18/207 (8.7%) | 129/207 (62.3%) |
| Teriflunomide 14 mg | — | 24/216 (11.1%) | 135/216 (62.5%) |
| Placebo/Teriflunomide 7 mg | — | 8/62 (12.9%) | 33/62 (53.2%) |
| Teriflunomide 7 mg/7 mg | — | 17/145 (11.7%) | 66/145 (45.5%) |
| Placebo/Teriflunomide 14 mg | — | 8/66 (12.1%) | 38/66 (57.6%) |
| Teriflunomide 14 mg/14 mg | — | 24/150 (16%) | 70/150 (46.7%) |
| Event | Placebo | Teriflunomide 7 mg | Teriflunomide 14 mg | Placebo/Teriflunomide 7 mg | Teriflunomide 7 mg/7 mg | Placebo/Teriflunomide 14 mg | Teriflunomide 14 mg/14 mg |
|---|---|---|---|---|---|---|---|
| Alanine aminotransferase increasedInvestigations | 3/191 | 5/207 | 4/216 | 0/62 | 1/145 | 0/66 | 0/150 |
| AppendicitisInfections and infestations | 0/191 | 0/207 | 2/216 | 1/62 | 0/145 | 0/66 | 0/150 |
| PharyngitisInfections and infestations | 0/191 | 0/207 | 0/216 | 1/62 | 0/145 | 0/66 | 0/150 |
| LiposarcomaNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 0/191 | 0/207 | 0/216 | 1/62 | 0/145 | 0/66 | 0/150 |
| Speech disorderNervous system disorders | 0/191 | 0/207 | 0/216 | 1/62 | 0/145 | 0/66 | 0/150 |
| Diffuse alopeciaSkin and subcutaneous tissue disorders | 0/191 | 0/207 | 0/216 | 1/62 | 0/145 | 0/66 | 0/150 |
| Intervertebral disc protrusionMusculoskeletal and connective tissue disorders | 0/191 | 0/207 | 0/216 | 1/62 | 0/145 | 0/66 | 1/150 |
| OsteochondrosisMusculoskeletal and connective tissue disorders | 0/191 | 0/207 | 0/216 | 1/62 | 0/145 | 0/66 | 0/150 |
| Cervical cystReproductive system and breast disorders | 0/191 | 0/207 | 0/216 | 1/62 | 0/145 | 0/66 | 0/150 |
| MenorrhagiaReproductive system and breast disorders | 0/191 | 0/207 | 0/216 | 1/62 | 0/145 | 0/66 | 0/150 |
| Event | Placebo | Teriflunomide 7 mg | Teriflunomide 14 mg | Placebo/Teriflunomide 7 mg | Teriflunomide 7 mg/7 mg | Placebo/Teriflunomide 14 mg | Teriflunomide 14 mg/14 mg |
|---|---|---|---|---|---|---|---|
| NasopharyngitisInfections and infestations | 29/191 | 24/207 | 35/216 | 9/62 | 14/145 | 9/66 | 15/150 |
| Alanine aminotransferase increasedInvestigations | 28/191 | 32/207 | 35/216 | 0/62 | 5/145 | 6/66 | 3/150 |
| HeadacheNervous system disorders | 25/191 | 31/207 | 30/216 | 4/62 | 8/145 | 8/66 | 6/150 |
| AlopeciaSkin and subcutaneous tissue disorders | 15/191 | 12/207 | 25/216 | 2/62 | 3/145 | 7/66 | 5/150 |
| Upper respiratory tract infectionInfections and infestations | 14/191 | 23/207 | 20/216 | 2/62 | 5/145 | 2/66 | 4/150 |
| DiarrhoeaGastrointestinal disorders | 12/191 | 22/207 | 15/216 | 4/62 | 9/145 | 4/66 | 14/150 |
| ParaesthesiaNervous system disorders | 9/191 | 11/207 | 22/216 | 3/62 | 1/145 | 3/66 | 4/150 |
| SinusitisInfections and infestations | 9/191 | 7/207 | 6/216 | 6/62 | 4/145 | 4/66 | 6/150 |
| Urinary tract infectionInfections and infestations | 10/191 | 10/207 | 20/216 | 3/62 | 5/145 | 5/66 | 4/150 |
| InfluenzaInfections and infestations | 9/191 | 8/207 | 16/216 | 3/62 | 5/145 | 5/66 | 4/150 |
Randomized population: all randomized participants according to the treatment group to which they were assigned in the core treatment period.
| Age, Continuous(years) | Placebo | Teriflunomide 7 mg | Teriflunomide 14 mg | Total |
|---|---|---|---|---|
| Mean | 32.0 ± 8.4 | 31.6 ± 9.0 | 32.8 ± 8.1 | 32.7 ± 8.9 |
| Sex: Female, Male(Participants) | Placebo | Teriflunomide 7 mg | Teriflunomide 14 mg | Total |
|---|---|---|---|---|
| Female | 135 | 130 | 154 | 419 |
| Male | 62 | 75 | 62 | 199 |
| Region(participants) | Placebo | Teriflunomide 7 mg | Teriflunomide 14 mg | Total |
|---|---|---|---|---|
| Eastern Europe | 94 | 96 | 101 | 291 |
| Western Europe | 76 | 74 | 74 | 224 |
| Americas and Australia | 27 | 35 | 41 | 103 |
| Expanded Disability Status Scale (EDSS) Score(units on a scale) | Placebo | Teriflunomide 7 mg | Teriflunomide 14 mg | Total |
|---|---|---|---|---|
| Mean | 1.71 ± 1.00 | 1.50 ± 1.02 | 1.80 ± 0.97 | 1.67 ± 1.00 |
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