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Trial record 58 of 78 for:    sanofi-aventis and sweden

Study of Teriflunomide in Reducing the Frequency of Relapses and Accumulation of Disability in Patients With Multiple Sclerosis (TEMSO)

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ClinicalTrials.gov Identifier: NCT00134563
Recruitment Status : Completed
First Posted : August 25, 2005
Results First Posted : November 6, 2012
Last Update Posted : January 4, 2013
Sponsor:
Information provided by (Responsible Party):
Sanofi

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Multiple Sclerosis
Interventions Drug: Teriflunomide
Drug: Placebo (for teriflunomide)
Enrollment 1088
Recruitment Details

The recruitment initiated in September 2004 was completed in February 2008.

A total of 1338 patients were screened at 127 sites in 21 countries.

Pre-assignment Details

Randomization was stratified by country and baseline disability (Expanded Disability Status Scale [EDSS] score ≤3.5 or >3.5).

Assignment to groups was done centrally using an Interactive Voice Response System (IVRS] in a 1:1:1 ratio after confirmation of the selection criteria.

1088 participants were randomized.

Arm/Group Title Placebo Teriflunomide 7 mg Teriflunomide 14 mg
Hide Arm/Group Description Placebo (for teriflunomide) once daily for 108 weeks Teriflunomide 7 mg once daily for 108 weeks Teriflunomide 14 mg once daily for 108 weeks
Period Title: Overall Study
Started 363 [1] 366 [1] 359 [1]
Treated 363 [2] 365 358 [3]
Completed 259 [4] 274 [4] 263 [4]
Not Completed 104 92 96
Reason Not Completed
Not treated due to protocol violation             0             1             1
Adverse Event             29             37             38
Lack of Efficacy             24             14             17
Protocol Violation             3             2             5
Lost to Follow-up             4             0             2
progressive disease             11             4             2
did not wish to continue             33             32             26
Reason other than above             0             2             5
[1]
Randomized
[2]
Two participants received doses of Teriflunomide 7 mg, one participant doses of Teriflunomide 14 mg
[3]
one participant received doses of Teriflunomide 7 mg
[4]
completed treatment period
Arm/Group Title Placebo Teriflunomide 7 mg Teriflunomide 14 mg Total
Hide Arm/Group Description Placebo (for teriflunomide) once daily for 108 weeks Teriflunomide 7 mg once daily for 108 weeks Teriflunomide 14 mg once daily for 108 weeks Total of all reporting groups
Overall Number of Baseline Participants 363 365 358 1086
Hide Baseline Analysis Population Description
[Not Specified]
Age Continuous   [1] 
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 363 participants 365 participants 358 participants 1086 participants
38.4  (9.0) 37.5  (9.0) 37.8  (8.2) 37.9  (8.8)
[1]
Measure Description: Baseline characteristics of the population included in analyses
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 363 participants 365 participants 358 participants 1086 participants
Female
275
  75.8%
254
  69.6%
254
  70.9%
783
  72.1%
Male
88
  24.2%
111
  30.4%
104
  29.1%
303
  27.9%
Region of enrollment   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 363 participants 365 participants 358 participants 1086 participants
America 82 83 80 245
Eastern Europe 114 116 108 338
Western Europe 167 166 170 503
[1]
Measure Description:

America: Canada, Chile, and United States;

Eastern Europe: Czech Republic, Estonia, Poland, Russia and Ukraine;

Western Europe: Austria, Denmark, Finland, France, Germany, Italy, Netherlands, Norway, Portugal, Sweden, Switzerland, Turkey, and United Kingdom;

Time since first diagnosis of multiple sclerosis (MS)   [1] 
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 363 participants 365 participants 358 participants 1086 participants
5.13  (5.59) 5.29  (5.36) 5.59  (5.44) 5.33  (5.48)
[1]
Measure Description: The information was missing for one participant in the Teriflunomide 7 mg group.
Number of MS relapses  
Median (Full Range)
Unit of measure:  MS relapses
Number Analyzed 363 participants 365 participants 358 participants 1086 participants
Within the past year
1
(0 to 6)
1
(0 to 6)
1
(0 to 4)
1
(0 to 6)
Within the past 2 years
2
(1 to 7)
2
(1 to 12)
2
(1 to 9)
2
(1 to 12)
Time since most recent MS relapse onset  
Mean (Standard Deviation)
Unit of measure:  Months
Number Analyzed 363 participants 365 participants 358 participants 1086 participants
6.28  (3.62) 6.29  (3.29) 6.50  (3.71) 6.35  (3.54)
MS subtype  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 363 participants 365 participants 358 participants 1086 participants
Relapsing Remitting 329 332 332 993
Secondary Progressive 22 17 12 51
Progressive Relapsing 12 16 14 42
MS medication in the past 2 years  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 363 participants 365 participants 358 participants 1086 participants
Yes 90 102 102 294
No 273 263 256 792
Baseline EDSS total score   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 363 participants 365 participants 358 participants 1086 participants
≤ 3.5 281 280 276 837
> 3.5 82 85 82 249
[1]
Measure Description:

EDSS is an ordinal scale in half-point increments that qualifies disability in patients 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 Annualized Relapse Rate [ARR]: Poisson Regression Estimates
Hide Description

ARR is obtained from the total number of confirmed relapses that occured during the treatment period divided by the sum of the treatment durations.

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.

To account for the different treatment durations among participants, a Poisson regression model with robust error variance was used (total number of confirmed relapses as response variable; log-transformed treatment duration as "offset" variable; treatment group, region of enrollment and baseline EDSS stratum as covariates).

Time Frame 108 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized and treated participants; Participants were included in the treatment group to which they were originally assigned (intent-to-treat analysis).
Arm/Group Title Placebo Teriflunomide 7 mg Teriflunomide 14 mg
Hide Arm/Group Description:
Placebo (for teriflunomide) once daily for 108 weeks
Teriflunomide 7 mg once daily for 108 weeks
Teriflunomide 14 mg once daily for 108 weeks
Overall Number of Participants Analyzed 363 365 358
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: relapses per year
0.539
(0.466 to 0.623)
0.370
(0.318 to 0.432)
0.369
(0.308 to 0.441)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Teriflunomide 14 mg
Comments

Null hypothesis:

  • H1: No difference between Teriflunomide 14 mg and placebo
  • H2: No difference between Teriflunomide 7 mg and placebo

The study was sized to detect a 25% relative risk reduction with teriflunomide in the 2-year relapse rate at a significance level of 0.050 with a power ≥95% anticipating a potential 20% 2-year dropout rate.

Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0005
Comments

Step down approach used to adjust for multiplicity:

  • H1 tested first
  • H2 tested only if the comparison H1 was statistically significant

A priori threshold for statistical significance for both comparisons ≤0.05

Method Regression, Poisson
Comments [Not Specified]
Method of Estimation Estimation Parameter Relative risk reduction (%)
Estimated Value 31.5
Estimation Comments Relative risk reduction with Teriflunomide 14 mg compared to placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Teriflunomide 7 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0002
Comments

Step down approach used to adjust for multiplicity:

  • H1 tested first
  • H2 tested only if the comparison H1 was statistically significant

A priori threshold for statistical significance for both comparisons ≤0.05

Method Regression, Poisson
Comments [Not Specified]
Method of Estimation Estimation Parameter Relative Risk Reduction (%)
Estimated Value 31.2
Estimation Comments Relative risk reduction with Teriflunomide 7 mg compared to placebo
2.Secondary Outcome
Title Time to 12-week Sustained Disability Progression: Kaplan-Meier Estimates of the Rate of Disability Progression at Timepoints
Hide Description

12-week sustained disability progression was defined as an increase from baseline of at least 1-point in EDSS score (at least 0.5-point for participants with baseline EDSS score >5.5) that persisted for at least 12 weeks.

Probability of disability progression at 24, 48 and 108 weeks was estimated using Kaplan-Meier method on the time to disability progression defined as the time from randomization to first EDSS increase. Participants free of disability progression (no disability progression observed on treatment) were censored at the date of the last on-treatment EDSS evaluation.

Kaplan-Meier method consists in computing probabilities of non occurrence of event at any observed time of event and multiplying successive probabilities for time ≤t by any earlier computed probabilities to estimate the probability of being event-free for the amount of time t. Probability of event at time t is 1 minus the probability of being event-free for the amount of time t.

Time Frame 108 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized and treated participants; Participants were included in the treatment group to which they were originally assigned (intent-to-treat analysis).
Arm/Group Title Placebo Teriflunomide 7 mg Teriflunomide 14 mg
Hide Arm/Group Description:
Placebo (for teriflunomide) once daily for 108 weeks
Teriflunomide 7 mg once daily for 108 weeks
Teriflunomide 14 mg once daily for 108 weeks
Overall Number of Participants Analyzed 363 365 358
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percent probability
Probability of disability progression at 24 weeks
8.6
(5.7 to 11.6)
5.8
(3.3 to 8.3)
6.2
(3.6 to 8.8)
Probability of disability progression at 48 weeks
16.0
(12.1 to 20.0)
13.1
(9.4 to 16.7)
11.3
(7.9 to 14.8)
Probability of disability progression at 108 weeks
27.3
(22.3 to 32.3)
21.7
(17.1 to 26.3)
20.2
(15.6 to 24.7)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Teriflunomide 14 mg
Comments

Null hypothesis:

  • H1: No difference between Teriflunomide 14 mg and placebo
  • H2: No difference between Teriflunomide 7 mg and placebo

The study was also sized to detect a 37% hazard rate reduction of an assumed disability progression hazard rate of 0.1783 in the placebo group and 0.1116 in the teriflunomide group by the end of 2 years with a power of 80% anticipating a potential 20% 2-year dropout rate.

Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0279
Comments

Step down approach:

  • H1 tested only if both comparisons on the primary outcome measure were statistically significant
  • H2 tested only if the comparison H1 was statistically significant

A priori threshold for statistical significance ≤0.05

Method Log Rank
Comments Two-sided Log-rank test stratified by region of enrollment and baseline EDSS stratum
Method of Estimation Estimation Parameter Hazard ratio reduction (%)
Estimated Value 29.8
Estimation Comments Relative risk reduction with Teriflunomide 14 mg compared to placebo (estimated from a Cox proportional hazard model with treatment arm, region of enrollment and baseline EDSS stratum as covariates)
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Teriflunomide 7 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0835
Comments

Step down approach:

  • H1 tested only if both comparisons on the primary outcome measure were statistically significant
  • H2 tested only if the comparison H1 was statistically significant

A priori threshold for statistical significance ≤0.05

Method Log Rank
Comments Two-sided Log-rank test stratified by region of enrollment and baseline EDSS stratum
Method of Estimation Estimation Parameter Hazard ratio reduction (%)
Estimated Value 23.7
Estimation Comments Relative risk reduction with Teriflunomide 7 mg compared to placebo (estimated from a Cox proportional hazard model with treatment arm, region of enrollment and baseline EDSS stratum as covariates)
3.Secondary Outcome
Title Cerebral Magnetic Resonance Imaging [MRI] Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease)
Hide Description Total lesion volume is the sum of the total volume of all T2-lesions and the total volume all T1-hypointense post-gadolinium lesions measured through T2/proton density scan analysis and gadolinium-enhanced T1 scan analysis.
Time Frame baseline (before randomization) and 108 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized and treated participants; Participants were included in the treatment group to which they were originally assigned (intent-to-treat analysis).
Arm/Group Title Placebo Teriflunomide 7 mg Teriflunomide 14 mg
Hide Arm/Group Description:
Placebo (for teriflunomide) once daily for 108 weeks
Teriflunomide 7 mg once daily for 108 weeks
Teriflunomide 14 mg once daily for 108 weeks
Overall Number of Participants Analyzed 363 365 358
Mean (Standard Deviation)
Unit of Measure: mililiters (mL)
Change in total lesion volume 2.208  (7.002) 1.308  (6.799) 0.723  (7.591)
- Change in T1-hypointense lesion component 0.533  (1.063) 0.499  (1.154) 0.331  (1.012)
- Change in T2-lesion component 1.674  (6.473) 0.810  (6.181) 0.392  (6.901)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Teriflunomide 14 mg
Comments Mixed-effect model with repeated measures [MMRM] on cubic root transformed total lesion volume data (treatment group, region of enrollment, baseline EDSS stratum, visit, treatment-by-visit interaction, baseline value (cubic root transformed) and baseline-by-visit interaction).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0003
Comments

A priori threshold for statistical significance ≤0.05

No adjustment for multiple comparisons

Method t-test, 2 sided
Comments 2-sided t-test on baseline adjusted least-square means
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Teriflunomide 7 mg
Comments Mixed-effect model with repeated measures [MMRM] on cubic root transformed total lesion volume data (treatment group, region of enrollment, baseline EDSS stratum, visit, treatment-by-visit interaction, baseline value (cubic root transformed) and baseline-by-visit interaction).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0317
Comments

A priori threshold for statistical significance ≤0.05

No adjustment for multiple comparisons

Method t-test, 2 sided
Comments 2-sided t-test on baseline adjusted least-square means
4.Secondary Outcome
Title Changes From Baseline in Fatigue Impact Scale [FIS] Total Score
Hide Description

FIS is a subject-reported scale that qualifies the impact of fatigue on daily life in patients 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 (treatment group, region of enrollment, baseline EDSS stratum, visit, treatment-by-visit interaction, baseline value, and baseline-by-visit interaction as factors).

Time Frame baseline (before randomization) and 108 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized and treated participants; Participants were included in the treatment group to which they were originally assigned (intent-to-treat analysis).
Arm/Group Title Placebo Teriflunomide 7 mg Teriflunomide 14 mg
Hide Arm/Group Description:
Placebo (for teriflunomide) once daily for 108 weeks
Teriflunomide 7 mg once daily for 108 weeks
Teriflunomide 14 mg once daily for 108 weeks
Overall Number of Participants Analyzed 363 365 358
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
4.300  (1.670) 2.343  (1.641) 3.804  (1.670)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Teriflunomide 14 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8271
Comments

A priori threshold for statistical significance ≤0.05

No adjustment for multiple comparisons

Method t-test, 2 sided
Comments 2-sided t-test on baseline adjusted least-square means
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Teriflunomide 7 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3861
Comments

A priori threshold for statistical significance ≤0.05

No adjustment for multiple comparisons

Method t-test, 2 sided
Comments 2-sided t-test on baseline adjusted least-square means
5.Other Pre-specified Outcome
Title Cerebral MRI Assessment: Number of Gd-enhancing T1-lesions Per Scan (Poisson Regression Estimates)
Hide Description

Number of Gd-enhancing T1-lesions per scan is obtained from the total number of Gd-enhancing T1-lesions observed during the study divided by the total number of scans performed during the study.

To account for the different number of scans among participants, a Poisson regression model with robust error variance was used (total number of Gd-enhancing T1-lesions as response variable; log-transformed number of scans as "offset" variable; treatment group, region of enrollment, baseline EDSS stratum and baseline number of Gd-enhancing T1-lesions as covariates).

Time Frame 108 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized and treated participants; Participants were included in the treatment group to which they were originally assigned (intent-to-treat analysis).
Arm/Group Title Placebo Teriflunomide 7 mg Teriflunomide 14 mg
Hide Arm/Group Description:
Placebo (for teriflunomide) once daily for 108 weeks
Teriflunomide 7 mg once daily for 108 weeks
Teriflunomide 14 mg once daily for 108 weeks
Overall Number of Participants Analyzed 346 350 340
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: lesions per scan
1.331
(1.059 to 1.673)
0.570
(0.434 to 0.748)
0.261
(0.167 to 0.407)
6.Other Pre-specified Outcome
Title Cerebral MRI Assessment: Volume of Gd-enhancing T1-lesions Per Scan
Hide Description Total volume of Gd-enhancing T1-lesions per scan is obtained from the sum of the volumes of Gd-enhancing T1-lesions observed during the study divided by the total number of scans performed during the study.
Time Frame 108 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized and treated participants; Participants were included in the treatment group to which they were originally assigned (intent-to-treat analysis).
Arm/Group Title Placebo Teriflunomide 7 mg Teriflunomide 14 mg
Hide Arm/Group Description:
Placebo (for teriflunomide) once daily for 108 weeks
Teriflunomide 7 mg once daily for 108 weeks
Teriflunomide 14 mg once daily for 108 weeks
Overall Number of Participants Analyzed 346 350 340
Mean (Standard Deviation)
Unit of Measure: mililiters (mL)
0.102  (0.329) 0.059  (0.247) 0.025  (0.079)
Time Frame All Adverse Events (AE) were collected regardless of seriousness or relationship to the drug, spanning from signature of the Informed Consent Form up to the last visit.
Adverse Event Reporting Description

The analysis was performed on the exposed population and included all AE that developed or worsened from first study drug intake up to 112 days after last intake or up to first intake in the extension study, whichever came first (124 weeks max).

Participants who received incorrect treatment were included considering the incorrect treatment.

 
Arm/Group Title Placebo Teriflunomide 7 mg Teriflunomide 14 mg
Hide Arm/Group Description Placebo (for teriflunomide) once daily for 108 weeks Teriflunomide 7 mg once daily for 108 weeks Teriflunomide 14 mg once daily for 108 weeks
All-Cause Mortality
Placebo Teriflunomide 7 mg Teriflunomide 14 mg
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
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   46/360 (12.78%)   52/368 (14.13%)   57/358 (15.92%) 
Blood and lymphatic system disorders       
Anaemia * 1  0/360 (0.00%)  1/368 (0.27%)  0/358 (0.00%) 
Lymphadenitis * 1  0/360 (0.00%)  1/368 (0.27%)  0/358 (0.00%) 
Neutropenia * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Cardiac disorders       
Angina pectoris * 1  1/360 (0.28%)  0/368 (0.00%)  0/358 (0.00%) 
Myocardial infarction * 1  1/360 (0.28%)  0/368 (0.00%)  0/358 (0.00%) 
Ear and labyrinth disorders       
Hypoacusis * 1  1/360 (0.28%)  0/368 (0.00%)  0/358 (0.00%) 
Gastrointestinal disorders       
Abdominal pain lower * 1  0/360 (0.00%)  1/368 (0.27%)  0/358 (0.00%) 
Abdominal wall haematoma * 1  0/360 (0.00%)  1/368 (0.27%)  0/358 (0.00%) 
Anal fissure * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Aphthous stomatitis * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Colitis * 1  0/360 (0.00%)  1/368 (0.27%)  0/358 (0.00%) 
Colitis ulcerative * 1  0/360 (0.00%)  1/368 (0.27%)  0/358 (0.00%) 
Crohn's disease * 1  0/360 (0.00%)  1/368 (0.27%)  0/358 (0.00%) 
Diarrhoea * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Duodenal ulcer * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Inguinal hernia * 1  0/360 (0.00%)  0/368 (0.00%)  4/358 (1.12%) 
Intestinal functional disorder * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Nausea * 1  0/360 (0.00%)  1/368 (0.27%)  0/358 (0.00%) 
Pancreatitis * 1  1/360 (0.28%)  0/368 (0.00%)  0/358 (0.00%) 
Peritonitis * 1  0/360 (0.00%)  1/368 (0.27%)  0/358 (0.00%) 
Toothache * 1  0/360 (0.00%)  1/368 (0.27%)  0/358 (0.00%) 
General disorders       
Asthenia * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Hepatobiliary disorders       
Cholecystitis * 1  0/360 (0.00%)  1/368 (0.27%)  0/358 (0.00%) 
Cholecystitis acute * 1  0/360 (0.00%)  1/368 (0.27%)  0/358 (0.00%) 
Cholecystitis chronic * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Cholelithiasis * 1  1/360 (0.28%)  6/368 (1.63%)  0/358 (0.00%) 
Hepatitis toxic * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Liver injury * 1  1/360 (0.28%)  1/368 (0.27%)  0/358 (0.00%) 
Infections and infestations       
Appendicitis * 1  0/360 (0.00%)  2/368 (0.54%)  0/358 (0.00%) 
Bacteraemia * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Cellulitis * 1  1/360 (0.28%)  0/368 (0.00%)  0/358 (0.00%) 
Cytomegalovirus hepatitis * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Erysipelas * 1  0/360 (0.00%)  1/368 (0.27%)  0/358 (0.00%) 
Gastroenteritis * 1  2/360 (0.56%)  0/368 (0.00%)  1/358 (0.28%) 
Hepatitis C * 1  1/360 (0.28%)  0/368 (0.00%)  0/358 (0.00%) 
Herpes zoster * 1  1/360 (0.28%)  0/368 (0.00%)  0/358 (0.00%) 
Infected cyst * 1  0/360 (0.00%)  1/368 (0.27%)  0/358 (0.00%) 
Influenza * 1  1/360 (0.28%)  0/368 (0.00%)  0/358 (0.00%) 
Lung infection * 1  1/360 (0.28%)  0/368 (0.00%)  0/358 (0.00%) 
Pneumonia * 1  0/360 (0.00%)  2/368 (0.54%)  0/358 (0.00%) 
Pyelonephritis * 1  0/360 (0.00%)  0/368 (0.00%)  3/358 (0.84%) 
Renal abscess * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Urinary tract infection * 1  1/360 (0.28%)  0/368 (0.00%)  1/358 (0.28%) 
Urinary tract infection enterococcal * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Injury, poisoning and procedural complications       
Ankle fracture * 1  0/360 (0.00%)  0/368 (0.00%)  2/358 (0.56%) 
Burns third degree * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Concussion * 1  0/360 (0.00%)  1/368 (0.27%)  0/358 (0.00%) 
Contrast media reaction * 1  0/360 (0.00%)  1/368 (0.27%)  0/358 (0.00%) 
Facial bones fracture * 1  1/360 (0.28%)  0/368 (0.00%)  1/358 (0.28%) 
Fall * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Femoral neck fracture * 1  0/360 (0.00%)  1/368 (0.27%)  0/358 (0.00%) 
Foot fracture * 1  1/360 (0.28%)  1/368 (0.27%)  1/358 (0.28%) 
Hand fracture * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Ligament injury * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Lower limb fracture * 1  1/360 (0.28%)  0/368 (0.00%)  0/358 (0.00%) 
Multiple drug overdose * 1  0/360 (0.00%)  1/368 (0.27%)  0/358 (0.00%) 
Muscle strain * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Post-traumatic pain * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Spinal compression fracture * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Tibia fracture * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Traumatic brain injury * 1  1/360 (0.28%)  0/368 (0.00%)  0/358 (0.00%) 
Investigations       
Alanine aminotransferase increased * 1  5/360 (1.39%)  5/368 (1.36%)  5/358 (1.40%) 
Hepatic enzyme increased * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Lipase increased * 1  0/360 (0.00%)  2/368 (0.54%)  0/358 (0.00%) 
Neutrophil count decreased * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Nuclear magnetic resonance imaging abdominal abnormal * 1  1/360 (0.28%)  0/368 (0.00%)  0/358 (0.00%) 
Transaminases increased * 1  2/360 (0.56%)  1/368 (0.27%)  1/358 (0.28%) 
Metabolism and nutrition disorders       
Dehydration * 1  1/360 (0.28%)  0/368 (0.00%)  0/358 (0.00%) 
Musculoskeletal and connective tissue disorders       
Arthralgia * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Back pain * 1  1/360 (0.28%)  0/368 (0.00%)  1/358 (0.28%) 
Costochondritis * 1  0/360 (0.00%)  1/368 (0.27%)  0/358 (0.00%) 
Intervertebral disc protrusion * 1  3/360 (0.83%)  2/368 (0.54%)  1/358 (0.28%) 
Osteochondrosis * 1  0/360 (0.00%)  1/368 (0.27%)  0/358 (0.00%) 
Tendonitis * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Adrenal adenoma * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Breast cancer * 1  1/360 (0.28%)  0/368 (0.00%)  0/358 (0.00%) 
Cervix carcinoma stage 0 * 1  1/360 (0.28%)  0/368 (0.00%)  1/358 (0.28%) 
Meningioma * 1  1/360 (0.28%)  0/368 (0.00%)  0/358 (0.00%) 
Ovarian germ cell teratoma benign * 1  0/360 (0.00%)  1/368 (0.27%)  0/358 (0.00%) 
Thyroid adenoma * 1  1/360 (0.28%)  0/368 (0.00%)  0/358 (0.00%) 
Thyroid cancer * 1  1/360 (0.28%)  0/368 (0.00%)  0/358 (0.00%) 
Uterine leiomyoma * 1  0/360 (0.00%)  1/368 (0.27%)  1/358 (0.28%) 
Nervous system disorders       
Cervical myelopathy * 1  0/360 (0.00%)  1/368 (0.27%)  0/358 (0.00%) 
Convulsion * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Facial nerve disorder * 1  0/360 (0.00%)  1/368 (0.27%)  0/358 (0.00%) 
Glossopharyngeal neuralgia * 1  1/360 (0.28%)  0/368 (0.00%)  0/358 (0.00%) 
Hypertonia * 1  1/360 (0.28%)  0/368 (0.00%)  0/358 (0.00%) 
Monoparesis * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Multiple sclerosis * 1  3/360 (0.83%)  0/368 (0.00%)  3/358 (0.84%) 
Muscle spasticity * 1  1/360 (0.28%)  0/368 (0.00%)  0/358 (0.00%) 
Parkinsonism * 1  0/360 (0.00%)  1/368 (0.27%)  0/358 (0.00%) 
Status epilepticus * 1  0/360 (0.00%)  1/368 (0.27%)  0/358 (0.00%) 
Syncope * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Pregnancy, puerperium and perinatal conditions       
Abortion missed * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Abortion spontaneous * 1  1/360 (0.28%)  0/368 (0.00%)  2/358 (0.56%) 
Post abortion haemorrhage * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Psychiatric disorders       
Abnormal behaviour * 1  1/360 (0.28%)  0/368 (0.00%)  0/358 (0.00%) 
Conversion disorder * 1  1/360 (0.28%)  0/368 (0.00%)  0/358 (0.00%) 
Depression * 1  1/360 (0.28%)  0/368 (0.00%)  0/358 (0.00%) 
Major depression * 1  0/360 (0.00%)  2/368 (0.54%)  0/358 (0.00%) 
Mood altered * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Panic attack * 1  1/360 (0.28%)  0/368 (0.00%)  0/358 (0.00%) 
Psychosomatic disease * 1  0/360 (0.00%)  1/368 (0.27%)  0/358 (0.00%) 
Somatoform disorder * 1  0/360 (0.00%)  1/368 (0.27%)  0/358 (0.00%) 
Suicide attempt * 1  1/360 (0.28%)  0/368 (0.00%)  0/358 (0.00%) 
Renal and urinary disorders       
Renal colic * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Urethral stenosis * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Reproductive system and breast disorders       
Benign prostatic hyperplasia * 1  0/360 (0.00%)  1/368 (0.27%)  0/358 (0.00%) 
Endometriosis * 1  0/360 (0.00%)  2/368 (0.54%)  0/358 (0.00%) 
Fallopian tube cyst * 1  0/360 (0.00%)  1/368 (0.27%)  0/358 (0.00%) 
Menorrhagia * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Metrorrhagia * 1  0/360 (0.00%)  1/368 (0.27%)  0/358 (0.00%) 
Ovarian cyst * 1  1/360 (0.28%)  0/368 (0.00%)  0/358 (0.00%) 
Uterine haemorrhage * 1  0/360 (0.00%)  1/368 (0.27%)  1/358 (0.28%) 
Uterine polyp * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Respiratory, thoracic and mediastinal disorders       
Haemothorax * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Pulmonary embolism * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Skin and subcutaneous tissue disorders       
Decubitus ulcer * 1  1/360 (0.28%)  0/368 (0.00%)  0/358 (0.00%) 
Eczema * 1  0/360 (0.00%)  1/368 (0.27%)  0/358 (0.00%) 
Skin necrosis * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Surgical and medical procedures       
Meniscus operation * 1  0/360 (0.00%)  1/368 (0.27%)  0/358 (0.00%) 
Vascular disorders       
Circulatory collapse * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Orthostatic hypotension * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Thrombophlebitis * 1  0/360 (0.00%)  0/368 (0.00%)  1/358 (0.28%) 
Varicose vein * 1  0/360 (0.00%)  1/368 (0.27%)  0/358 (0.00%) 
Venous thrombosis * 1  0/360 (0.00%)  1/368 (0.27%)  0/358 (0.00%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA 13.0
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
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   259/360 (71.94%)   271/368 (73.64%)   265/358 (74.02%) 
Gastrointestinal disorders       
Abdominal pain * 1  24/360 (6.67%)  17/368 (4.62%)  21/358 (5.87%) 
Abdominal pain upper * 1  15/360 (4.17%)  19/368 (5.16%)  20/358 (5.59%) 
Diarrhoea * 1  32/360 (8.89%)  54/368 (14.67%)  64/358 (17.88%) 
Nausea * 1  26/360 (7.22%)  32/368 (8.70%)  49/358 (13.69%) 
Vomiting * 1  14/360 (3.89%)  15/368 (4.08%)  18/358 (5.03%) 
General disorders       
Fatigue * 1  51/360 (14.17%)  47/368 (12.77%)  52/358 (14.53%) 
Infections and infestations       
Bronchitis * 1  22/360 (6.11%)  18/368 (4.89%)  29/358 (8.10%) 
Gastroenteritis * 1  15/360 (4.17%)  22/368 (5.98%)  20/358 (5.59%) 
Influenza * 1  35/360 (9.72%)  34/368 (9.24%)  43/358 (12.01%) 
Nasopharyngitis * 1  98/360 (27.22%)  94/368 (25.54%)  93/358 (25.98%) 
Sinusitis * 1  16/360 (4.44%)  15/368 (4.08%)  23/358 (6.42%) 
Upper respiratory tract infection * 1  25/360 (6.94%)  34/368 (9.24%)  32/358 (8.94%) 
Urinary tract infection * 1  35/360 (9.72%)  27/368 (7.34%)  36/358 (10.06%) 
Investigations       
Alanine aminotransferase increased * 1  21/360 (5.83%)  41/368 (11.14%)  47/358 (13.13%) 
Musculoskeletal and connective tissue disorders       
Arthralgia * 1  30/360 (8.33%)  30/368 (8.15%)  28/358 (7.82%) 
Back pain * 1  46/360 (12.78%)  39/368 (10.60%)  40/358 (11.17%) 
Muscle spasms * 1  22/360 (6.11%)  16/368 (4.35%)  13/358 (3.63%) 
Muscular weakness * 1  23/360 (6.39%)  15/368 (4.08%)  14/358 (3.91%) 
Pain in extremity * 1  47/360 (13.06%)  26/368 (7.07%)  33/358 (9.22%) 
Nervous system disorders       
Dizziness * 1  16/360 (4.44%)  22/368 (5.98%)  17/358 (4.75%) 
Headache * 1  64/360 (17.78%)  81/368 (22.01%)  67/358 (18.72%) 
Hypoaesthesia * 1  30/360 (8.33%)  18/368 (4.89%)  20/358 (5.59%) 
Paraesthesia * 1  30/360 (8.33%)  34/368 (9.24%)  35/358 (9.78%) 
Psychiatric disorders       
Depression * 1  27/360 (7.50%)  26/368 (7.07%)  33/358 (9.22%) 
Insomnia * 1  23/360 (6.39%)  20/368 (5.43%)  15/358 (4.19%) 
Respiratory, thoracic and mediastinal disorders       
Cough * 1  16/360 (4.44%)  15/368 (4.08%)  19/358 (5.31%) 
Skin and subcutaneous tissue disorders       
Alopecia * 1  12/360 (3.33%)  38/368 (10.33%)  47/358 (13.13%) 
Rash * 1  15/360 (4.17%)  14/368 (3.80%)  19/358 (5.31%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA 13.0
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The investigator can publish only the results of the work performed pursuant to this protocol. Prior to publication, the investigator provides the sponsor with the manuscript for review and comment at least 45 days in advance of its submission for publication.

The sponsor can require the investigator to withhold publication an additional 90 days to allow for filing a patent application or taking such other measures as sponsor deems appropriate to establish and preserve its proprietary rights.

Results Point of Contact
Name/Title: Trial Transparency Team
Organization: sanofi-aventis
Responsible Party: Sanofi
ClinicalTrials.gov Identifier: NCT00134563     History of Changes
Other Study ID Numbers: EFC6049
2004-000555-42 ( EudraCT Number )
HMR1726D/3001 ( Other Identifier: HMR )
First Submitted: August 23, 2005
First Posted: August 25, 2005
Results First Submitted: October 3, 2012
Results First Posted: November 6, 2012
Last Update Posted: January 4, 2013