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Phase III Study With Teriflunomide Versus Placebo in Patients With First Clinical Symptom of Multiple Sclerosis (TOPIC)

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ClinicalTrials.gov Identifier: NCT00622700
Recruitment Status : Completed
First Posted : February 25, 2008
Results First Posted : December 19, 2014
Last Update Posted : March 13, 2017
Sponsor:
Information provided by (Responsible Party):
Sanofi

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Multiple Sclerosis
Interventions Drug: Teriflunomide
Drug: Placebo
Enrollment 618
Recruitment Details 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).
Pre-assignment Details Participants were randomized in 1:1:1 ratio to teriflunomide 7 mg,14 mg or placebo in core treatment period. Those completing core period, given opportunity to enter long-term extension period (participants originally given placebo re-randomized [1:1]to teriflunomide 7 mg/14 mg; those originally given 7 mg,14 mg continued with the same fixed dose).
Arm/Group Title 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
Hide Arm/Group Description Core treatment period: Placebo matched to teriflunomide tablet once daily orally. Core treatment period: Teriflunomide 7 mg tablet once daily orally. Core treatment period: Teriflunomide 14 mg tablet once daily orally.

Core treatment period: Placebo matched to teriflunomide tablet once daily orally.

Extension treatment period: Teriflunomide 7 mg tablet once daily orally.

Core treatment period: Teriflunomide 7 mg tablet once daily orally.

Extension treatment period: Teriflunomide 7 mg tablet once daily orally.

Core treatment period: Placebo matched to teriflunomide tablet once daily orally.

Extension treatment period: Teriflunomide 14 mg tablet once daily orally.

Core treatment period: Teriflunomide 14 mg tablet once daily orally.

Extension treatment period: Teriflunomide 14 mg tablet once daily orally.

Period Title: Core Treatment Period
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
Reason Not Completed
Randomized but Not Treated             0             2             2             0             0             0             0
Adverse Event             18             25             18             0             0             0             0
Lack of Efficacy             19             6             12             0             0             0             0
Lost to Follow-up             1             1             1             0             0             0             0
Death             1             0             0             0             0             0             0
Progressive Disease             3             1             0             0             0             0             0
Withdrawal by Subject             12             18             15             0             0             0             0
Other than specified above             2             2             5             0             0             0             0
Period Title: Extension Treatment Period
Started 0 [1] 0 0 64 [2] 142 [3] 67 [2] 150 [4]
Completed 0 0 0 43 103 50 120
Not Completed 0 0 0 21 39 17 30
Reason Not Completed
Adverse Event             0             0             0             5             9             6             8
Lack of Efficacy             0             0             0             2             8             1             9
Protocol Violation             0             0             0             0             0             2             0
Lost to Follow-up             0             0             0             0             1             0             0
Progressive Disease             0             0             0             1             2             0             2
Withdrawal by Subject             0             0             0             11             16             6             10
Missing             0             0             0             2             3             1             0
Other than specified above             0             0             0             0             0             1             1
[1]
Participants were re-randomized in a 1:1 ratio to either teriflunomide 7 mg or 14 mg treatment arm.
[2]
10 participants completed core treatment period but did not enter in extension treatment period.
[3]
8 participants completed core treatment period but did not enter in extension treatment period.
[4]
13 participants completed core treatment period but did not enter in extension treatment period.
Arm/Group Title Placebo Teriflunomide 7 mg Teriflunomide 14 mg Total
Hide Arm/Group Description Placebo matched to teriflunomide tablet once daily orally. Teriflunomide 7 mg tablet once daily orally. Teriflunomide 14 mg tablet once daily orally. Total of all reporting groups
Overall Number of Baseline Participants 197 205 216 618
Hide Baseline Analysis Population Description
Randomized population: all randomized participants according to the treatment group to which they were assigned in the core treatment period.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 197 participants 205 participants 216 participants 618 participants
32.0  (8.4) 31.6  (9.0) 32.8  (8.1) 32.7  (8.9)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 197 participants 205 participants 216 participants 618 participants
Female
135
  68.5%
130
  63.4%
154
  71.3%
419
  67.8%
Male
62
  31.5%
75
  36.6%
62
  28.7%
199
  32.2%
Region  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 197 participants 205 participants 216 participants 618 participants
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   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 197 participants 205 participants 216 participants 618 participants
1.71  (1.00) 1.50  (1.02) 1.80  (0.97) 1.67  (1.00)
[1]
Measure Description: 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).
1.Primary Outcome
Title Core Treatment Period: Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS)
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat (ITT) population included all randomized participants who had at least 1 day study medication exposure. Participants were analyzed in the treatment group to which they were randomized.
Arm/Group Title Placebo Teriflunomide 7 mg Teriflunomide 14 mg
Hide Arm/Group Description:
Placebo matched to teriflunomide tablet once daily orally.
Teriflunomide 7 mg tablet once daily orally.
Teriflunomide 14 mg tablet once daily orally.
Overall Number of Participants Analyzed 197 203 214
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percent probability
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)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Teriflunomide 14 mg
Comments A step-down hierarchical testing procedure, starting with the test of teriflunomide 14 mg versus placebo was used. Time to conversion to CDMS was analyzed using the Cox proportional hazard model with treatment, region, and baseline monofocal/multifocal status as covariates.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0087
Comments P value was derived using Wald chi-squared test in the Cox proportional hazard model.
Method Wald chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.574
Confidence Interval (2-Sided) 95%
0.379 to 0.869
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Teriflunomide 7 mg
Comments A step-down hierarchical testing procedure was used. The second step was the test of teriflunomide 7 mg versus placebo for time to conversion to CDMS. Time to conversion to CDMS was analyzed using the Cox proportional hazard model with treatment, region, and baseline monofocal/multifocal status as covariates.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0271
Comments P value was derived using Wald chi-squared test in the Cox proportional hazard model.
Method Wald chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.628
Confidence Interval (2-Sided) 95%
0.416 to 0.949
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Core Treatment Period: Time to Conversion to Definite Multiple Sclerosis (DMS)
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population.
Arm/Group Title Placebo Teriflunomide 7 mg Teriflunomide 14 mg
Hide Arm/Group Description:
Placebo matched to teriflunomide tablet once daily orally.
Teriflunomide 7 mg tablet once daily orally.
Teriflunomide 14 mg tablet once daily orally.
Overall Number of Participants Analyzed 197 203 214
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percent probability
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)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Teriflunomide 14 mg
Comments A step-down hierarchical testing procedure was used. The third step was the test of teriflunomide 14 mg versus placebo for time to conversion to DMS. This was analyzed using the Cox proportional hazard model with treatment, region, and baseline monofocal/multifocal status as covariates.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0003
Comments P value was derived using Wald chi-squared test in the Cox proportional hazard model.
Method Wald chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.651
Confidence Interval (2-Sided) 95%
0.515 to 0.822
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Teriflunomide 7 mg
Comments A step-down hierarchical testing procedure was used. The fourth step was the test of teriflunomide 7 mg versus placebo for time to conversion to DMS. This was analyzed using the Cox proportional hazard model with treatment, region, and baseline monofocal/multifocal status as covariates.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0020
Comments P value was derived using Wald chi-squared test in the Cox proportional hazard model.
Method Wald chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.686
Confidence Interval (2-Sided) 95%
0.540 to 0.871
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Core Treatment Period: Annualized Relapse Rate (ARR)
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population.
Arm/Group Title Placebo Teriflunomide 7 mg Teriflunomide 14 mg
Hide Arm/Group Description:
Placebo matched to teriflunomide tablet once daily orally.
Teriflunomide 7 mg tablet once daily orally.
Teriflunomide 14 mg tablet once daily orally.
Overall Number of Participants Analyzed 197 203 214
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: relapses per patient year
0.284
(0.214 to 0.378)
0.190
(0.139 to 0.260)
0.194
(0.143 to 0.263)
4.Secondary Outcome
Title Core Treatment Period: Brain Magnetic Resonance Imaging (MRI) Assessment: Change From Baseline in Total Lesion Volume at Week 108
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population, but including only participants who had post-baseline data.
Arm/Group Title Placebo Teriflunomide 7 mg Teriflunomide 14 mg
Hide Arm/Group Description:
Placebo matched to teriflunomide tablet once daily orally.
Teriflunomide 7 mg tablet once daily orally.
Teriflunomide 14 mg tablet once daily orally.
Overall Number of Participants Analyzed 68 75 99
Least Squares Mean (Standard Error)
Unit of Measure: milliliter
0.053  (0.033) 0.041  (0.032) -0.038  (0.029)
5.Secondary Outcome
Title Core Treatment Period: Brain MRI Assessment: Number of Gadolinium Enhancing (Gd-enhancing) T1-lesions Per MRI Scan (Poisson Regression Estimates)
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population, but including only participants who had post-baseline data.
Arm/Group Title Placebo Teriflunomide 7 mg Teriflunomide 14 mg
Hide Arm/Group Description:
Placebo matched to teriflunomide tablet once daily orally.
Teriflunomide 7 mg tablet once daily orally.
Teriflunomide 14 mg tablet once daily orally.
Overall Number of Participants Analyzed 109 84 74
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: lesions per scan
0.953
(0.708 to 1.284)
0.749
(0.433 to 1.294)
0.395
(0.262 to 0.598)
6.Secondary Outcome
Title Core Treatment Period: Brain MRI Assessment: Volume of Gadolinium Enhancing (Gd-enhancing) T1-lesions Per MRI Scan
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population, but including only participants who had post-baseline data.
Arm/Group Title Placebo Teriflunomide 7 mg Teriflunomide 14 mg
Hide Arm/Group Description:
Placebo matched to teriflunomide tablet once daily orally.
Teriflunomide 7 mg tablet once daily orally.
Teriflunomide 14 mg tablet once daily orally.
Overall Number of Participants Analyzed 109 84 74
Measure Type: Number
Unit of Measure: milliliters per scan
0.079 0.058 0.034
7.Secondary Outcome
Title Core Treatment Period: Brain MRI Assessment: Change From Baseline in Volume of Hypointense Post-Gadolinium T1 Lesion Component
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population, but including only participants who had post-baseline data.
Arm/Group Title Placebo Teriflunomide 7 mg Teriflunomide 14 mg
Hide Arm/Group Description:
Placebo matched to teriflunomide tablet once daily orally.
Teriflunomide 7 mg tablet once daily orally.
Teriflunomide 14 mg tablet once daily orally.
Overall Number of Participants Analyzed 68 75 99
Least Squares Mean (Standard Error)
Unit of Measure: milliliter
0.028  (0.018) 0.025  (0.018) -0.033  (0.016)
8.Secondary Outcome
Title Core Treatment Period: Brain MRI Assessment: Change From Baseline in Volume of T2 Lesion Component
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population, but including only participants who had post-baseline data.
Arm/Group Title Placebo Teriflunomide 7 mg Teriflunomide 14 mg
Hide Arm/Group Description:
Placebo matched to teriflunomide tablet once daily orally.
Teriflunomide 7 mg tablet once daily orally.
Teriflunomide 14 mg tablet once daily orally.
Overall Number of Participants Analyzed 68 75 99
Least Squares Mean (Standard Error)
Unit of Measure: milliliter
0.052  (0.033) 0.036  (0.032) -0.035  (0.029)
9.Secondary Outcome
Title Core Treatment Period: Brain MRI Assessment: Percent Change From Baseline in Atrophy
Hide Description Atrophy was measured by MRI scan.
Time Frame Baseline, Week 108
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population, but including only participants who had post-baseline data.
Arm/Group Title Placebo Teriflunomide 7 mg Teriflunomide 14 mg
Hide Arm/Group Description:
Placebo matched to teriflunomide tablet once daily orally.
Teriflunomide 7 mg tablet once daily orally.
Teriflunomide 14 mg tablet once daily orally.
Overall Number of Participants Analyzed 68 75 99
Mean (Standard Deviation)
Unit of Measure: percent change
-0.386  (1.326) -0.197  (1.218) -0.366  (1.151)
10.Secondary Outcome
Title Core Treatment Period: Time to 12-Week Sustained Disability Progression
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population.
Arm/Group Title Placebo Teriflunomide 7 mg Teriflunomide 14 mg
Hide Arm/Group Description:
Placebo matched to teriflunomide tablet once daily orally.
Teriflunomide 7 mg tablet once daily orally.
Teriflunomide 14 mg tablet once daily orally.
Overall Number of Participants Analyzed 197 203 214
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percent probability
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)
11.Secondary Outcome
Title Core Treatment Period: Change From Baseline in EDSS at Week 108
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population, but including only participants who had post-baseline data.
Arm/Group Title Placebo Teriflunomide 7 mg Teriflunomide 14 mg
Hide Arm/Group Description:
Placebo matched to teriflunomide tablet once daily orally.
Teriflunomide 7 mg tablet once daily orally.
Teriflunomide 14 mg tablet once daily orally.
Overall Number of Participants Analyzed 80 82 102
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
0.069  (0.087) -0.191  (0.086) -0.166  (0.080)
12.Secondary Outcome
Title Core Treatment Period: Change From Baseline in Fatigue Impact Scale (FIS) Total Score at Week 108
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population, but including only participants who had post-baseline data.
Arm/Group Title Placebo Teriflunomide 7 mg Teriflunomide 14 mg
Hide Arm/Group Description:
Placebo matched to teriflunomide tablet once daily orally.
Teriflunomide 7 mg tablet once daily orally.
Teriflunomide 14 mg tablet once daily orally.
Overall Number of Participants Analyzed 84 95 106
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-2.537  (2.794) -2.524  (2.710) -1.827  (2.551)
13.Secondary Outcome
Title Core Treatment Period: Overview of Adverse Events (AEs)
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population:all randomized participants exposed to study medication; analyzed according to drug actually received. In Placebo arm, 4 received teriflunomide 7mg & 2 received teriflunomide 14mg, hence they were included in respective teriflunomide arm. Participants who were randomized but not treated were excluded (2 in each teriflunomide arm).
Arm/Group Title Placebo Teriflunomide 7 mg Teriflunomide 14 mg
Hide Arm/Group Description:
Placebo matched to teriflunomide tablet once daily orally.
Teriflunomide 7 mg tablet once daily orally.
Teriflunomide 14 mg tablet once daily orally.
Overall Number of Participants Analyzed 191 207 216
Measure Type: Number
Unit of Measure: participants
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
14.Secondary Outcome
Title Extension Treatment Period: Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS)
Hide Description 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])
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population: all randomized participants in the extension who had at least 1 day IMP exposure. Participants were analyzed according to the treatment group allocated by the randomization in the core study followed by the re-randomized treatment group during the extension period.
Arm/Group Title Placebo/Teriflunomide 7 mg Teriflunomide 7 mg/ 7mg Placebo/ Teriflunomide 14 mg Teriflunomide 14 mg/14 mg
Hide Arm/Group Description:

Core treatment period: Placebo matched to teriflunomide tablet once daily orally.

Extension treatment period: Teriflunomide 7 mg tablet once daily orally.

Core treatment period: Placebo matched to teriflunomide tablet once daily orally.

Extension treatment period: Teriflunomide 7 mg tablet once daily orally.

Core treatment period: Placebo matched to teriflunomide tablet once daily orally.

Extension treatment period: Teriflunomide 14 mg tablet once daily orally.

Core treatment period: Teriflunomide 14 mg tablet once daily orally.

Extension treatment period: Teriflunomide 14 mg tablet once daily orally.

Overall Number of Participants Analyzed 64 142 67 150
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percent probability
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)
15.Secondary Outcome
Title Extension Treatment Period: Overview of Adverse Events (AEs)
Hide Description 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
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Hide Analysis Population Description
Analysis was performed on Safety population. In Placebo/teriflunomide 7mg arm, 2 received 7mg in the core period; In Placebo/teriflunomide 14mg, 1 received 7mg in the core period, hence, they were included in the 7mg/7mg arm in extension period as treatment received in the core period for consistency.
Arm/Group Title Placebo/Teriflunomide 7 mg Teriflunomide 7 mg/ 7mg Placebo/ Teriflunomide 14 mg Teriflunomide 14 mg/14 mg
Hide Arm/Group Description:

Core treatment period: Placebo matched to teriflunomide tablet once daily orally.

Extension treatment period: Teriflunomide 7 mg tablet once daily orally.

Core treatment period: Teriflunomide 7 mg tablet once daily orally.

Extension treatment period: Teriflunomide 7 mg tablet once daily orally.

Core treatment period: Placebo matched to teriflunomide tablet once daily orally.

Extension treatment period: Teriflunomide 14 mg tablet once daily orally.

Core treatment period: Teriflunomide 14 mg tablet once daily orally.

Extension treatment period: Teriflunomide 14 mg tablet once daily orally.

Overall Number of Participants Analyzed 62 145 66 150
Measure Type: Number
Unit of Measure: participants
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
16.Other Pre-specified Outcome
Title Core Treatment Period: Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA)
Hide Description

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
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Hide Analysis Population Description
Safety population as described in Outcome Measure 13. Here 'n' signifies the number of participants for the treatment group who had that parameter assessed at post-baseline.
Arm/Group Title Placebo Teriflunomide 7 mg Teriflunomide 14 mg
Hide Arm/Group Description:
Placebo matched to teriflunomide tablet once daily orally.
Teriflunomide 7 mg tablet once daily orally.
Teriflunomide 14 mg tablet once daily orally.
Overall Number of Participants Analyzed 191 207 216
Measure Type: Number
Unit of Measure: participants
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
Time Frame 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.
Adverse Event Reporting Description Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the ‘on treatment period’ (time from first dose of study drug up to 112 days after last intake in core treatment period [or up to 1st intake in extension period, whichever occurred first] or 28 days after last intake in extension treatment period). Analysis was performed on safety population as described in Outcome Measure 15.
 
Arm/Group Title 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
Hide Arm/Group Description Core treatment period: Placebo matched to teriflunomide tablet once daily orally. Core treatment period: Teriflunomide 7 mg tablet once daily orally. Core treatment period: Teriflunomide 14 mg tablet once daily orally.

Core treatment period: Placebo matched to teriflunomide tablet once daily orally.

Extension treatment period: Teriflunomide 7 mg tablet once daily orally.

Core treatment period: Teriflunomide 7 mg tablet once daily orally.

Extension treatment period: Teriflunomide 7 mg tablet once daily orally.

Core treatment period: Placebo matched to teriflunomide tablet once daily orally.

Extension treatment period: Teriflunomide 14 mg tablet once daily orally.

Core treatment period: Teriflunomide 14 mg tablet once daily orally.

Extension treatment period: Teriflunomide 14 mg tablet once daily orally.

All-Cause Mortality
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
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
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
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   18/191 (9.42%)   18/207 (8.70%)   24/216 (11.11%)   8/62 (12.90%)   17/145 (11.72%)   8/66 (12.12%)   24/150 (16.00%) 
Blood and lymphatic system disorders               
Iron deficiency anaemia  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  1/66 (1.52%)  0/150 (0.00%) 
Lymphadenitis  1  0/191 (0.00%)  1/207 (0.48%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Neutropenia  1  2/191 (1.05%)  0/207 (0.00%)  1/216 (0.46%)  0/62 (0.00%)  2/145 (1.38%)  1/66 (1.52%)  0/150 (0.00%) 
Cardiac disorders               
Supraventricular tachycardia  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  1/150 (0.67%) 
Tachycardia  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  1/150 (0.67%) 
Ear and labyrinth disorders               
Vertigo  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  1/150 (0.67%) 
Endocrine disorders               
Goitre  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  1/66 (1.52%)  0/150 (0.00%) 
Eye disorders               
Conjunctivitis allergic  1  0/191 (0.00%)  1/207 (0.48%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Gastrointestinal disorders               
Chronic gastritis  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  1/150 (0.67%) 
Duodenitis  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  1/150 (0.67%) 
Mallory-Weiss syndrome  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  1/150 (0.67%) 
Abdominal pain  1  1/191 (0.52%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Dental cyst  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  1/145 (0.69%)  0/66 (0.00%)  0/150 (0.00%) 
Gastroduodenal ulcer  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  1/66 (1.52%)  0/150 (0.00%) 
Inguinal hernia  1  1/191 (0.52%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  1/145 (0.69%)  0/66 (0.00%)  0/150 (0.00%) 
Pancreatitis  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  1/145 (0.69%)  0/66 (0.00%)  0/150 (0.00%) 
Pancreatitis acute  1  0/191 (0.00%)  1/207 (0.48%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Peptic ulcer  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  1/66 (1.52%)  0/150 (0.00%) 
Radicular cyst  1  0/191 (0.00%)  1/207 (0.48%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
General disorders               
Hernia  1  0/191 (0.00%)  0/207 (0.00%)  1/216 (0.46%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Hepatobiliary disorders               
Cholelithiasis  1  0/191 (0.00%)  1/207 (0.48%)  1/216 (0.46%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  1/150 (0.67%) 
Cholecystitis  1  1/191 (0.52%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Cholecystitis acute  1  1/191 (0.52%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Hepatocellular injury  1  0/191 (0.00%)  1/207 (0.48%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Infections and infestations               
Abdominal wall abscess  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  1/150 (0.67%) 
Acute sinusitis  1  0/191 (0.00%)  0/207 (0.00%)  1/216 (0.46%)  0/62 (0.00%)  1/145 (0.69%)  0/66 (0.00%)  1/150 (0.67%) 
Dengue fever  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  1/150 (0.67%) 
Gastroenteritis  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  1/150 (0.67%) 
Pneumonia  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  1/150 (0.67%) 
Abdominal abscess  1  1/191 (0.52%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Appendicitis  1  0/191 (0.00%)  0/207 (0.00%)  2/216 (0.93%)  1/62 (1.61%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Appendicitis perforated  1  0/191 (0.00%)  0/207 (0.00%)  1/216 (0.46%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Bronchitis  1  0/191 (0.00%)  1/207 (0.48%)  0/216 (0.00%)  0/62 (0.00%)  1/145 (0.69%)  0/66 (0.00%)  0/150 (0.00%) 
Clostridium difficile colitis  1  0/191 (0.00%)  1/207 (0.48%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Cystitis  1  0/191 (0.00%)  0/207 (0.00%)  1/216 (0.46%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Genital infection  1  0/191 (0.00%)  0/207 (0.00%)  1/216 (0.46%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Infectious mononucleosis  1  0/191 (0.00%)  1/207 (0.48%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Pharyngitis  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  1/62 (1.61%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Pilonidal cyst  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  1/145 (0.69%)  0/66 (0.00%)  0/150 (0.00%) 
Pulmonary tuberculosis  1  0/191 (0.00%)  1/207 (0.48%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Pyelonephritis acute  1  1/191 (0.52%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Rectal abscess  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  1/145 (0.69%)  0/66 (0.00%)  0/150 (0.00%) 
Sinusitis  1  0/191 (0.00%)  0/207 (0.00%)  1/216 (0.46%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Injury, poisoning and procedural complications               
Facial bones fracture  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  1/150 (0.67%) 
Upper limb fracture  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  1/150 (0.67%) 
Ankle fracture  1  0/191 (0.00%)  1/207 (0.48%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Craniocerebral injury  1  0/191 (0.00%)  1/207 (0.48%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Foot fracture  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  1/145 (0.69%)  0/66 (0.00%)  0/150 (0.00%) 
Intentional overdose  1  0/191 (0.00%)  0/207 (0.00%)  1/216 (0.46%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Ligament sprain  1  0/191 (0.00%)  0/207 (0.00%)  1/216 (0.46%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Overdose  1  1/191 (0.52%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Tibia fracture  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  2/145 (1.38%)  0/66 (0.00%)  0/150 (0.00%) 
Wound dehiscence  1  0/191 (0.00%)  0/207 (0.00%)  1/216 (0.46%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Investigations               
Amylase increased  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  2/150 (1.33%) 
Blood creatine phosphokinase increased  1  0/191 (0.00%)  1/207 (0.48%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  2/150 (1.33%) 
Aspartate aminotransferase increased  1  0/191 (0.00%)  1/207 (0.48%)  1/216 (0.46%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  1/150 (0.67%) 
Lipase increased  1  0/191 (0.00%)  1/207 (0.48%)  2/216 (0.93%)  0/62 (0.00%)  1/145 (0.69%)  0/66 (0.00%)  1/150 (0.67%) 
Transaminases increased  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  1/150 (0.67%) 
Alanine aminotransferase increased  1  3/191 (1.57%)  5/207 (2.42%)  4/216 (1.85%)  0/62 (0.00%)  1/145 (0.69%)  0/66 (0.00%)  0/150 (0.00%) 
Weight decreased  1  0/191 (0.00%)  1/207 (0.48%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Musculoskeletal and connective tissue disorders               
Intervertebral disc protrusion  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  1/62 (1.61%)  0/145 (0.00%)  0/66 (0.00%)  1/150 (0.67%) 
Synovial cyst  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  1/150 (0.67%) 
Intervertebral disc disorder  1  0/191 (0.00%)  1/207 (0.48%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Osteochondrosis  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  1/62 (1.61%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Rheumatoid arthritis  1  0/191 (0.00%)  1/207 (0.48%)  0/216 (0.00%)  0/62 (0.00%)  1/145 (0.69%)  0/66 (0.00%)  0/150 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)               
Cervix carcinoma  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  1/150 (0.67%) 
Uterine leiomyoma  1  2/191 (1.05%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  1/145 (0.69%)  0/66 (0.00%)  1/150 (0.67%) 
Breast cancer  1  1/191 (0.52%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Liposarcoma  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  1/62 (1.61%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Meningioma  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  1/145 (0.69%)  0/66 (0.00%)  0/150 (0.00%) 
Spinal meningioma benign  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  1/66 (1.52%)  0/150 (0.00%) 
Thyroid cancer  1  1/191 (0.52%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Nervous system disorders               
Carpal tunnel syndrome  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  1/150 (0.67%) 
Radicular syndrome  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  1/150 (0.67%) 
Axonal neuropathy  1  0/191 (0.00%)  0/207 (0.00%)  1/216 (0.46%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Loss of consciousness  1  1/191 (0.52%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Speech disorder  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  1/62 (1.61%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Pregnancy, puerperium and perinatal conditions               
Abortion spontaneous  1  0/191 (0.00%)  0/207 (0.00%)  1/216 (0.46%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  1/150 (0.67%) 
Abortion threatened  1  0/191 (0.00%)  1/207 (0.48%)  1/216 (0.46%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Pregnancy  1  0/191 (0.00%)  0/207 (0.00%)  2/216 (0.93%)  0/62 (0.00%)  1/145 (0.69%)  1/66 (1.52%)  0/150 (0.00%) 
Psychiatric disorders               
Adjustment disorder  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  1/150 (0.67%) 
Completed suicide  1  1/191 (0.52%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Depression  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  1/145 (0.69%)  0/66 (0.00%)  0/150 (0.00%) 
Psychiatric decompensation  1  1/191 (0.52%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Suicide attempt  1  0/191 (0.00%)  0/207 (0.00%)  1/216 (0.46%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Reproductive system and breast disorders               
Cervical cyst  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  1/62 (1.61%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Endometrial hyperplasia  1  0/191 (0.00%)  0/207 (0.00%)  1/216 (0.46%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Fallopian tube cyst  1  1/191 (0.52%)  0/207 (0.00%)  1/216 (0.46%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Menorrhagia  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  1/62 (1.61%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Ovarian cyst  1  0/191 (0.00%)  0/207 (0.00%)  1/216 (0.46%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Testicular torsion  1  0/191 (0.00%)  1/207 (0.48%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Uterine haemorrhage  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  1/145 (0.69%)  1/66 (1.52%)  0/150 (0.00%) 
Respiratory, thoracic and mediastinal disorders               
Nasal septum deviation  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  1/150 (0.67%) 
Dyspnoea  1  0/191 (0.00%)  0/207 (0.00%)  1/216 (0.46%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Skin and subcutaneous tissue disorders               
Diffuse alopecia  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  1/62 (1.61%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Erythema nodosum  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  1/145 (0.69%)  0/66 (0.00%)  0/150 (0.00%) 
Vascular disorders               
Circulatory collapse  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  1/150 (0.67%) 
Hypertension  1  0/191 (0.00%)  0/207 (0.00%)  1/216 (0.46%)  0/62 (0.00%)  0/145 (0.00%)  1/66 (1.52%)  1/150 (0.67%) 
Orthostatic hypotension  1  0/191 (0.00%)  0/207 (0.00%)  0/216 (0.00%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  1/150 (0.67%) 
Deep vein thrombosis  1  0/191 (0.00%)  0/207 (0.00%)  1/216 (0.46%)  0/62 (0.00%)  0/145 (0.00%)  0/66 (0.00%)  0/150 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA-18.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
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
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   117/191 (61.26%)   129/207 (62.32%)   135/216 (62.50%)   33/62 (53.23%)   66/145 (45.52%)   38/66 (57.58%)   70/150 (46.67%) 
Gastrointestinal disorders               
Diarrhoea  1  12/191 (6.28%)  22/207 (10.63%)  15/216 (6.94%)  4/62 (6.45%)  9/145 (6.21%)  4/66 (6.06%)  14/150 (9.33%) 
Nausea  1  9/191 (4.71%)  11/207 (5.31%)  9/216 (4.17%)  2/62 (3.23%)  7/145 (4.83%)  1/66 (1.52%)  9/150 (6.00%) 
General disorders               
Fatigue  1  14/191 (7.33%)  10/207 (4.83%)  9/216 (4.17%)  2/62 (3.23%)  3/145 (2.07%)  4/66 (6.06%)  3/150 (2.00%) 
Infections and infestations               
Nasopharyngitis  1  29/191 (15.18%)  24/207 (11.59%)  35/216 (16.20%)  9/62 (14.52%)  14/145 (9.66%)  9/66 (13.64%)  15/150 (10.00%) 
Bronchitis  1  5/191 (2.62%)  9/207 (4.35%)  8/216 (3.70%)  4/62 (6.45%)  7/145 (4.83%)  2/66 (3.03%)  8/150 (5.33%) 
Sinusitis  1  9/191 (4.71%)  7/207 (3.38%)  6/216 (2.78%)  6/62 (9.68%)  4/145 (2.76%)  4/66 (6.06%)  6/150 (4.00%) 
Influenza  1  9/191 (4.71%)  8/207 (3.86%)  16/216 (7.41%)  3/62 (4.84%)  5/145 (3.45%)  5/66 (7.58%)  4/150 (2.67%) 
Upper respiratory tract infection  1  14/191 (7.33%)  23/207 (11.11%)  20/216 (9.26%)  2/62 (3.23%)  5/145 (3.45%)  2/66 (3.03%)  4/150 (2.67%) 
Urinary tract infection  1  10/191 (5.24%)  10/207 (4.83%)  20/216 (9.26%)  3/62 (4.84%)  5/145 (3.45%)  5/66 (7.58%)  4/150 (2.67%) 
Investigations               
Alanine aminotransferase increased  1  28/191 (14.66%)  32/207 (15.46%)  35/216 (16.20%)  0/62 (0.00%)  5/145 (3.45%)  6/66 (9.09%)  3/150 (2.00%) 
Blood creatine phosphokinase increased  1  1/191 (0.52%)  9/207 (4.35%)  5/216 (2.31%)  4/62 (6.45%)  1/145 (0.69%)  1/66 (1.52%)  2/150 (1.33%) 
Musculoskeletal and connective tissue disorders               
Back pain  1  7/191 (3.66%)  14/207 (6.76%)  8/216 (3.70%)  4/62 (6.45%)  5/145 (3.45%)  4/66 (6.06%)  10/150 (6.67%) 
Arthralgia  1  6/191 (3.14%)  13/207 (6.28%)  7/216 (3.24%)  1/62 (1.61%)  4/145 (2.76%)  2/66 (3.03%)  4/150 (2.67%) 
Nervous system disorders               
Headache  1  25/191 (13.09%)  31/207 (14.98%)  30/216 (13.89%)  4/62 (6.45%)  8/145 (5.52%)  8/66 (12.12%)  6/150 (4.00%) 
Dizziness  1  7/191 (3.66%)  7/207 (3.38%)  11/216 (5.09%)  1/62 (1.61%)  4/145 (2.76%)  2/66 (3.03%)  4/150 (2.67%) 
Paraesthesia  1  9/191 (4.71%)  11/207 (5.31%)  22/216 (10.19%)  3/62 (4.84%)  1/145 (0.69%)  3/66 (4.55%)  4/150 (2.67%) 
Psychiatric disorders               
Depression  1  11/191 (5.76%)  8/207 (3.86%)  8/216 (3.70%)  2/62 (3.23%)  4/145 (2.76%)  3/66 (4.55%)  1/150 (0.67%) 
Respiratory, thoracic and mediastinal disorders               
Oropharyngeal pain  1  8/191 (4.19%)  11/207 (5.31%)  2/216 (0.93%)  0/62 (0.00%)  1/145 (0.69%)  2/66 (3.03%)  0/150 (0.00%) 
Skin and subcutaneous tissue disorders               
Alopecia  1  15/191 (7.85%)  12/207 (5.80%)  25/216 (11.57%)  2/62 (3.23%)  3/145 (2.07%)  7/66 (10.61%)  5/150 (3.33%) 
Vascular disorders               
Hypertension  1  2/191 (1.05%)  5/207 (2.42%)  12/216 (5.56%)  3/62 (4.84%)  4/145 (2.76%)  0/66 (0.00%)  5/150 (3.33%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA-18.1
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
If no publication has occurred within 12 months of the completion of the study, the Investigator shall have the right to publish/present independently the results of the study. The Investigator shall provide the Sponsor with a copy of any such presentation/publication for comment at least 30 days before any presentation/submission for publication. If requested by the Sponsor, any presentation/submission shall be delayed up to 90 days, to allow the Sponsor to preserve its proprietary rights.
Results Point of Contact
Name/Title: Trial Transparency Team
Organization: Sanofi
Responsible Party: Sanofi
ClinicalTrials.gov Identifier: NCT00622700     History of Changes
Other Study ID Numbers: EFC6260
HMR1726D-3005 ( Other Identifier: HMR )
2006-001152-12 ( EudraCT Number )
First Submitted: February 14, 2008
First Posted: February 25, 2008
Results First Submitted: November 7, 2014
Results First Posted: December 19, 2014
Last Update Posted: March 13, 2017