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Trial record 51 of 78 for:    sanofi-aventis and sweden

An Efficacy Study of Teriflunomide in Participants With Relapsing Multiple Sclerosis (TOWER)

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ClinicalTrials.gov Identifier: NCT00751881
Recruitment Status : Completed
First Posted : September 12, 2008
Results First Posted : June 26, 2013
Last Update Posted : July 7, 2016
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: Placebo
Drug: Teriflunomide
Enrollment 1169
Recruitment Details A total of 1493 participants were screened at 193 sites in 26 countries. The common end date for core treatment period was on 17 April 2012 (maximum treatment duration of 173 weeks). The extension study was completed on 18 June 2015 (maximum treatment duration was 174 weeks in addition to core treatment period).
Pre-assignment Details Randomization was stratified by investigational site and Expanded Disability Status Scale (EDSS) score ≤3.5 or >3.5). Assignment to groups was done using an Interactive Voice Response System(IVRS) in 1:1:1 ratio. 1169 participants were randomized at 190 sites. 780 participants completed core treatment period and 751 were treated in extension study.
Arm/Group Title Placebo / Teriflunomide 14 mg Teriflunomide 7 mg / 14 mg Teriflunomide 14 mg / 14 mg
Hide Arm/Group Description Core treatment period: Placebo (for teriflunomide) once daily. Extension treatment period: Teriflunomide 14 mg once daily. Core treatment period: Teriflunomide 7 mg once daily. Extension treatment period: Teriflunomide 14 mg once daily. Core treatment period: Teriflunomide 14 mg once daily. Extension treatment period: Teriflunomide 14 mg once daily.
Period Title: Core Treatment Period
Started 389 [1] 408 [1] 372 [1]
Treated 388 [2] 407 [3] 370 [4]
Completed 263 273 244
Not Completed 126 135 128
Reason Not Completed
Not treated             1             1             2
Adverse Event             26             54             58
Lack of Efficacy             37             30             20
Poor compliance to protocol             15             3             4
Lost to Follow-up             6             4             3
Other: protocol deviation             3             3             7
Other: wish to parent             5             7             4
Other: personal/family constraints             6             7             10
Other: MS treatment change             6             4             4
Other: tolerability complaints             2             0             0
Other:participant's decision/unspecified             19             22             16
[1]
Randomized
[2]
1 participant received teriflunomide 7 mg and 2 participants teriflunomide 14 mg (at least 1 dose)
[3]
1 participant received placebo (at least 1 dose)
[4]
1 participant received teriflunomide 7 mg and 1 participant placebo (at least 1 dose)
Period Title: Extension Study Period
Started 253 [1] 265 [2] 233 [3]
Completed 188 194 167
Not Completed 65 71 66
Reason Not Completed
Adverse Event             18             20             21
Lack of Efficacy             14             10             20
Lost to Follow-up             4             9             6
Poor Compliance to Protocol             3             2             1
Other than specified above             26             30             18
[1]
10 participants completed core treatment period but did not enter in extension treatment period.
[2]
8 participants completed core treatment period but did not enter in extension treatment period.
[3]
11 participants completed core treatment period but did not enter in extension treatment period.
Arm/Group Title Placebo / Teriflunomide 14 mg Teriflunomide 7 mg / 14 mg Teriflunomide 14 mg / 14 mg Total
Hide Arm/Group Description Core treatment period: Placebo once daily. Extension treatment period: Teriflunomide 14 mg once daily. Core treatment period: Teriflunomide 7 mg once daily. Extension treatment period: Teriflunomide 14 mg once daily. Core treatment period: Teriflunomide 14 mg once daily. Extension treatment period: Teriflunomide 14 mg once daily. Total of all reporting groups
Overall Number of Baseline Participants 389 408 372 1169
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 389 participants 408 participants 372 participants 1169 participants
38.1  (9.1) 37.4  (9.4) 38.2  (9.4) 37.9  (9.3)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 389 participants 408 participants 372 participants 1169 participants
Female
273
  70.2%
300
  73.5%
258
  69.4%
831
  71.1%
Male
116
  29.8%
108
  26.5%
114
  30.6%
338
  28.9%
Region of Enrollment   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 389 participants 408 participants 372 participants 1169 participants
Eastern Europe 117 124 116 357
Western Europe and Africa 121 127 120 368
Asia and Australia 67 65 55 187
America 84 92 81 257
[1]
Measure Description:

Due to the small sample size in some countries, the countries were pooled as follows:

  • Eastern Europe: Belarus, Czech Republic, Estonia, Greece, Poland, Romania, Slovakia and Ukraine
  • Western Europe and Africa: Austria, Belgium, France, Germany, Netherlands, Spain, Sweden and United Kingdom, Tunisia and Turkey
  • Asia and Australia: China, Philippines, Thailand and Australia
  • America: Canada, Chile, Mexico and the USA
Time since first diagnosis of Multiple Sclerosis (MS)   [1] 
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 389 participants 408 participants 372 participants 1169 participants
4.92  (5.66) 5.30  (5.45) 5.27  (5.90) 5.16  (5.66)
[1]
Measure Description: The information was not available for one participant in the teriflunomide 14 mg group
Number of MS relapses   [1] 
Median (Full Range)
Unit of measure:  Relapses
Number Analyzed 389 participants 408 participants 372 participants 1169 participants
Within the past year
1
(0 to 7)
1
(0 to 5)
1
(0 to 5)
1
(0 to 7)
Within the past 2 years
2
(1 to 8)
2
(1 to 8)
2
(1 to 9)
2
(1 to 9)
[1]
Measure Description:

The information was not available for:

  • 'Within the past year': 1 participant in the placebo group and 1 participant in the teriflunomide 14 mg group
  • 'Within the past 2 years': 2 participants in the teriflunomide 14 mg group
Time since most recent MS relapse onset   [1] 
Mean (Standard Deviation)
Unit of measure:  Months
Number Analyzed 389 participants 408 participants 372 participants 1169 participants
5.29  (3.41) 5.18  (3.41) 5.33  (3.32) 5.26  (3.38)
[1]
Measure Description: The information was not available for one participant in the teriflunomide 14 mg group.
MS subtype  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 389 participants 408 participants 372 participants 1169 participants
Relapsing Remitting 379 393 366 1138
Secondary Progressive 4 3 2 9
Progressive Relapsing 6 12 2 20
Information not available 0 0 2 2
Baseline EDSS score   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 389 participants 408 participants 372 participants 1169 participants
≤3.5 294 301 276 871
>3.5 95 107 96 298
[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 7 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: Annualized Relapse Rate (ARR): Poisson Regression Estimate
Hide Description

ARR is obtained from the total number of confirmed relapses that occurred during the treatment period divided by the sum of 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 Expanded Disability Status Scale (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 Core treatment period between 48 - 152 weeks depending on time of enrollment
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: all randomized and treated participants. Participants were considered in the treatment group to which they were randomized regardless of the drug they actually received.
Arm/Group Title Placebo Teriflunomide 7 mg Teriflunomide 14 mg
Hide Arm/Group Description:
Placebo once daily
Teriflunomide 7 mg once daily
Teriflunomide 14 mg once daily
Overall Number of Participants Analyzed 388 407 370
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: relapses per year
0.501
(0.432 to 0.581)
0.389
(0.332 to 0.457)
0.319
(0.267 to 0.381)
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 have 94% power to detect a 25% relative risk reduction in ARR with teriflunomide compared to placebo at a 2-sided 0.05 significance level.

Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0001
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 36.3
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 0.0183
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 22.3
Estimation Comments Relative risk reduction with teriflunomide 7 mg compared to placebo
2.Secondary Outcome
Title Core Treatment Period: Time to Disability Progression
Hide Description

Probability of disability progression at 24, 48, 108 and 132 weeks was estimated using Kaplan-Meier method on the time to disability progression defined as the time from randomization to first 12-week sustained disability progression [i.e. 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].

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 Core treatment period between 48 - 152 weeks depending on time of enrollment
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population
Arm/Group Title Placebo Teriflunomide 7 mg Teriflunomide 14 mg
Hide Arm/Group Description:
Placebo once daily
Teriflunomide 7 mg once daily
Teriflunomide 14 mg once daily
Overall Number of Participants Analyzed 388 407 370
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percent probability
Probability of disability progression at 24 weeks
8.0
(5.2 to 10.7)
5.3
(3.0 to 7.6)
2.7
(0.9 to 4.4)
Probability of disability progression at 48 weeks
14.2
(10.6 to 17.9)
12.1
(8.7 to 15.5)
7.8
(4.9 to 10.8)
Probability of disability progression at 108 weeks
19.7
(15.2 to 24.1)
21.1
(16.1 to 26.1)
15.8
(11.2 to 20.4)
Probability of disability progression at 132 weeks
21.0
(15.9 to 26.0)
22.2
(16.8 to 27.6)
15.8
(11.2 to 20.4)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Teriflunomide 14 mg
Comments

Null hypothesis:

  • S1: No difference between teriflunomide 14 mg and placebo
  • S2: No difference between teriflunomide 7 mg and placebo

The study was also sized to have 75% power to detect a 37% hazard ratio reduction in time to disability progression with teriflunomide compared to placebo.

Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0442
Comments

Step down approach:

  • S1 tested only if both comparisons on the primary outcome measure were statistically significant
  • S2 tested only if the comparison S1 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 31.5
Estimation Comments Relative reduction in the hazard rate 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 0.7620
Comments

Step down approach:

  • S1 tested only if both comparisons on the primary outcome measure were statistically significant
  • S2 tested only if the comparison S1 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 4.5
Estimation Comments Relative reduction in the hazard rate 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 Core Treatment Period: Time Without Relapse
Hide Description

Probability of no relapse at 24, 48, 108 and 132 weeks was estimated using Kaplan-Meier method on the time to relapse defined as the time from randomization to first EDSS confirmed relapse.

Participants free of confirmed relapse (no EDSS confirmed relapse observed on treatment) were censored at the date of the last study drug intake.

Time Frame Core treatment period between 48 - 152 weeks depending on time of enrollment
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population
Arm/Group Title Placebo Teriflunomide 7 mg Teriflunomide 14 mg
Hide Arm/Group Description:
Placebo once daily
Teriflunomide 7 mg once daily
Teriflunomide 14 mg once daily
Overall Number of Participants Analyzed 388 407 370
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percent probability
Probability of no relapse at 24 weeks
76.4
(72.1 to 80.7)
81.5
(77.6 to 85.4)
85.5
(81.8 to 89.2)
Probability of no relapse at 48 weeks
60.6
(55.5 to 65.6)
71.9
(67.3 to 76.5)
76.3
(71.7 to 81.0)
Probability of no relapse at 108 weeks
46.8
(41.0 to 52.6)
58.2
(52.6 to 63.8)
57.1
(50.5 to 63.7)
Probability of no relapse at 132 weeks
37.7
(30.2 to 45.2)
55.4
(48.8 to 62.0)
51.5
(43.6 to 59.5)
4.Secondary Outcome
Title Core Treatment Period: Change From Baseline to Week 48 in EDSS Total Score
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 7 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).

Baseline adjusted least-squares means at Week 48 were estimated using a Mixed-effect model with repeated measures (MMRM) on EDSS score data (treatment group, region of enrollment, baseline EDSS stratum, visit, treatment-by-visit interaction, baseline value, and baseline-by-visit interaction as factors). All the timepoints from randomization up to Week 48 were included in the model.

Time Frame Baseline (before randomization), Week 12, Week 24, Week 36 and Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population
Arm/Group Title Placebo Teriflunomide 7 mg Teriflunomide 14 mg
Hide Arm/Group Description:
Placebo once daily
Teriflunomide 7 mg once daily
Teriflunomide 14 mg once daily
Overall Number of Participants Analyzed 388 407 370
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
0.089  (0.050) 0.042  (0.049) -0.050  (0.052)
5.Secondary Outcome
Title Core Treatment Period: Change From Baseline to Week 48 in Fatigue Impact Scale (FIS) Total Score
Hide Description

FIS is a participants-reported scale that qualifies the impact of fatigue on daily life in participants with MS. It consists of 40 statements that measure fatigue in 3 areas; physical, cognitive, and social.

FIS total score ranges from 0 (no problem) to 160 (extreme problem).

Baseline adjusted least-squares means at week 48 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). All the timepoints from randomization up to Week 48 were included in the model.

Time Frame Baseline (before randomization), Week 12, Week 24 and Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population
Arm/Group Title Placebo Teriflunomide 7 mg Teriflunomide 14 mg
Hide Arm/Group Description:
Placebo once daily
Teriflunomide 7 mg once daily
Teriflunomide 14 mg once daily
Overall Number of Participants Analyzed 388 407 370
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
4.669  (1.576) 2.512  (1.533) 1.915  (1.628)
6.Secondary Outcome
Title Core Treatment Period: Change From Baseline to Last Visit in Fatigue Impact Scale (FIS) Total Score
Hide Description Baseline adjusted least-squares means at last visit were estimated using an analysis of covariance (ANCOVA) model on collected data for FIS total score (treatment group, region of enrollment, baseline EDSS stratum, visit number for the last visit and baseline value as factors).
Time Frame Baseline (before randomization) and up to Week 152
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population
Arm/Group Title Placebo Teriflunomide 7 mg Teriflunomide 14 mg
Hide Arm/Group Description:
Placebo once daily
Teriflunomide 7 mg once daily
Teriflunomide 14 mg once daily
Overall Number of Participants Analyzed 388 407 370
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
6.311  (1.671) 4.464  (1.657) 2.043  (1.682)
7.Secondary Outcome
Title Core Treatment Period: Change From Baseline to Week 48 in Short Form Generic Health Survey - 36 Items (SF-36) Summary Scores
Hide Description

SF-36 scale is a generic, self-administered, health-related quality-of-life (QOL) instrument. It is constructed such that the 36 questions represent 8 of the most important health concepts: physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health.

Two summary scores are obtained:

  • the physical health component summary score,
  • the mental health component summary score.

Both scores range from 0 to 100 and a high score indicates a more favorable health state.

Baseline adjusted least-squares means at week 48 were estimated using a Mixed-effect model with repeated measures [MMRM] on each summary score data (treatment group, region of enrollment, baseline EDSS stratum, visit, treatment-by-visit interaction, baseline value, and baseline-by-visit interaction as factors). All the timepoints from randomization up to Week 48 were included in the model.

Time Frame Baseline (before randomization), Week 12, Week 24 and Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population
Arm/Group Title Placebo Teriflunomide 7 mg Teriflunomide 14 mg
Hide Arm/Group Description:
Placebo once daily
Teriflunomide 7 mg once daily
Teriflunomide 14 mg once daily
Overall Number of Participants Analyzed 388 407 370
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
Physical health component -1.082  (0.405) -0.397  (0.396) -0.105  (0.418)
Mental health component -2.913  (0.586) -2.031  (0.571) -1.434  (0.606)
8.Secondary Outcome
Title Core Treatment Period: Change From Baseline to Last Visit in Short Form Generic Health Survey - 36 Items (SF-36) Summary Scores
Hide Description Baseline adjusted least-squares means at last visit were estimated using an analysis of covariance (ANCOVA) model on collected data for each summary score (treatment group, region of enrollment, baseline EDSS stratum, visit number for the last visit and baseline value as factors).
Time Frame Baseline (before randomization) and up to Week 152
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population
Arm/Group Title Placebo Teriflunomide 7 mg Teriflunomide 14 mg
Hide Arm/Group Description:
Placebo once daily
Teriflunomide 7 mg once daily
Teriflunomide 14 mg once daily
Overall Number of Participants Analyzed 388 407 370
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
Physical Health component -1.629  (0.435) -0.909  (0.441) -0.638  (0.436)
Mental Health component -2.792  (0.592) -1.704  (0.597) -1.087  (0.593)
9.Secondary Outcome
Title Core Treatment Period: Overview of Adverse Events
Hide Description Adverse Events (AE) 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 core treatment period or up to first intake in the extension treatment period, whichever occurred first
Hide Outcome Measure Data
Hide Analysis Population Description

All randomized and treated participants. Participants were considered according to the drug actually received.

The 3 participants in the placebo group who received teriflunomide were analyzed according to the teriflunomide dose.

The participant in the teriflunomide 14 mg group who received 7 mg was analyzed in the teriflunomide 7 mg group.

Arm/Group Title Placebo Teriflunomide 7 mg Teriflunomide 14 mg
Hide Arm/Group Description:
Placebo once daily
Teriflunomide 7 mg once daily
Teriflunomide 14 mg once daily
Overall Number of Participants Analyzed 385 409 371
Measure Type: Number
Unit of Measure: participants
Any AE 320 344 320
- Any serious AE 47 52 44
- Any AE leading to death 1 1 2
- Any AE leading to treatment discontinuation 24 53 58
10.Secondary Outcome
Title Extension Treatment Period: Overview of Treatment Emergent Adverse Events (TEAE)
Hide Description AEs were any unfavourable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study.
Time Frame From first intake of study drug in extension treatment period up to 28 days after the last intake in the extension treatment period
Hide Outcome Measure Data
Hide Analysis Population Description

Safety population: all randomized participants who received at least 1 dose of investigational product.

Two participants in placebo of core study received teriflunomide and were analyzed according to teriflunomide dose.

One participant in teriflunomide 14 mg in core study group who received 7 mg was analyzed in teriflunomide 7 mg group.

Arm/Group Title Placebo / Teriflunomide 14 mg Teriflunomide 7 mg / 14 mg Teriflunomide 14 mg / 14 mg
Hide Arm/Group Description:
Core treatment period: Placebo once daily. Extension treatment period: Teriflunomide 14 mg once daily.
Core treatment period: Teriflunomide 7 mg once daily. Extension treatment period: Teriflunomide 14 mg once daily.
Core treatment period: Teriflunomide 14 mg once daily. Extension treatment period: Teriflunomide 14 mg once daily.
Overall Number of Participants Analyzed 251 267 233
Measure Type: Number
Unit of Measure: participants
Any TEAE 203 200 188
Any serious TEAE 16 33 29
Any TEAE leading to death 1 3 1
Any TEAE leading to treatment discontinuation 17 17 20
11.Secondary Outcome
Title Extension Treatment Period: Time to Disability Progression
Hide Description

Probability of disability progression since the randomization of the core period was estimated using Kaplan-Meier method on the time to disability progression defined as the time from randomization to first 12 week sustained disability progression [i.e. 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].

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 was 1 minus the probability of being event-free for the amount of time t.

Time Frame Core treatment period (maximum: 173 weeks) and Extension treatment period (maximum: 174 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population for extension treatment period consists of all participants with a signed informed consent form for the extension and with a date of treatment allocated or recorded in the IVRS/IWRS database, regardless of whether the treatment was actually taken.
Arm/Group Title Placebo / Teriflunomide 14 mg Teriflunomide 7 mg / 14 mg Teriflunomide 14 mg / 14 mg
Hide Arm/Group Description:
Core treatment period: Placebo once daily. Extension treatment period: Teriflunomide 14 mg once daily.
Core treatment period: Teriflunomide 7 mg once daily. Extension treatment period: Teriflunomide 14 mg once daily.
Core treatment period: Teriflunomide 14 mg once daily. Extension treatment period: Teriflunomide 14 mg once daily.
Overall Number of Participants Analyzed 253 265 233
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percent probability
1 year
0.130
(0.089 to 0.172)
0.117
(0.078 to 0.156)
0.077
(0.043 to 0.112)
2 year
0.190
(0.142 to 0.238)
0.175
(0.129 to 0.221)
0.147
(0.101 to 0.192)
3 year
0.245
(0.191 to 0.299)
0.233
(0.181 to 0.285)
0.190
(0.139 to 0.241)
4 year
0.307
(0.246 to 0.368)
0.270
(0.214 to 0.326)
0.248
(0.189 to 0.307)
5 year
0.328
(0.262 to 0.395)
0.317
(0.250 to 0.384)
0.265
(0.203 to 0.327)
12.Secondary Outcome
Title Extension Treatment Period: ARR: Poisson Regression Estimate
Hide Description ARR was obtained from the total number of confirmed relapses that occurred during the treatment period divided by the sum of treatment durations. A relapse is defined as the appearance of a new clinical sign/symptom or clinical worsening of a previous sign/symptom (one that had been stable for at least 30 days) that persists for a minimum of 24 hours in the absence of fever. Relapse was 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 enrolment and baseline EDSS stratum as covariates).
Time Frame Extension treatment period (Maximum: 174 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population for extension treatment period consists of all participants with a signed informed consent form for the extension and with a date of treatment allocated or recorded in the IVRS/IWRS database, regardless of whether the treatment was actually taken.
Arm/Group Title Placebo / Teriflunomide 14 mg Teriflunomide 7 mg / 14 mg Teriflunomide 14 mg / 14 mg
Hide Arm/Group Description:
Core treatment period: Placebo once daily. Extension treatment period: Teriflunomide 14 mg once daily.
Core treatment period: Teriflunomide 7 mg once daily. Extension treatment period: Teriflunomide 14 mg once daily.
Core treatment period: Teriflunomide 14 mg once daily. Extension treatment period: Teriflunomide 14 mg once daily.
Overall Number of Participants Analyzed 253 265 233
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: relapses per year
0.199
(0.156 to 0.254)
0.200
(0.155 to 0.257)
0.179
(0.132 to 0.243)
13.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 or 2 ULN;
  • ALT >3 ULN and TB >2 ULN.
Time Frame From first study drug intake up to 112 days after last intake in the core treatment period or up to first intake in the extension treatment period, whichever occurred first
Hide Outcome Measure Data
Hide Analysis Population Description

All randomized and treated participants. Participants were considered according to the drug actually received.

The 3 participants in the placebo group who received teriflunomide were analyzed according to the teriflunomide dose.

The participant in the teriflunomide 14 mg group who received 7 mg was analyzed in the teriflunomide 7 mg group.

Arm/Group Title Placebo Teriflunomide 7 mg Teriflunomide 14 mg
Hide Arm/Group Description:
Placebo once daily
Teriflunomide 7 mg once daily
Teriflunomide 14 mg once daily
Overall Number of Participants Analyzed 385 409 371
Measure Type: Number
Unit of Measure: participants
ALT >3 ULN 22 31 29
- ALT >5 ULN 14 10 11
- ALT >10 ULN 5 2 3
AST >3 ULN 13 9 9
- AST >5 ULN 9 3 3
Alkaline Phosphatase >1.5 ULN 5 4 2
TB >1.5 ULN 9 6 8
ALT >3 ULN and TB >2 ULN 2 2 0
Time Frame AEs were collected from signature of the Informed Consent Form up to the last visit (174 weeks) in the study.
Adverse Event Reporting Description The analysis was performed on the safety population as previously defined and included all AE that developed or worsened and death that occurred during first intake of study drug in extension treatment period up to 28 days after the last intake in the extension study treatment period.
 
Arm/Group Title Placebo Teriflunomide 7 mg Teriflunomide 14 mg Placebo / 14 mg Teriflunomide 7 mg / 14 mg Teriflunomide 14 mg / 14 mg
Hide Arm/Group Description Placebo once daily Teriflunomide 7 mg once daily Teriflunomide 14 mg once daily Core treatment period: Placebo once daily. Extension treatment period: Teriflunomide 14 mg once daily Core treatment period: Teriflunomide 7 mg once daily. Extension treatment period: Teriflunomide 14 mg once daily. Core treatment period: Teriflunomide 14 mg once daily. Extension treatment period: Teriflunomide 14 mg once daily.
All-Cause Mortality
Placebo Teriflunomide 7 mg Teriflunomide 14 mg Placebo / 14 mg Teriflunomide 7 mg / 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 (%)
Total   --/--   --/--   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Placebo Teriflunomide 7 mg Teriflunomide 14 mg Placebo / 14 mg Teriflunomide 7 mg / 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 (%)
Total   47/385 (12.21%)   52/409 (12.71%)   44/371 (11.86%)   16/251 (6.37%)   33/267 (12.36%)   29/233 (12.45%) 
Blood and lymphatic system disorders             
Microcytic anaemia  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  1/233 (0.43%) 
Anaemia  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  1/267 (0.37%)  0/233 (0.00%) 
Autoimmune thrombocytopenia  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Disseminated intravascular coagulation  1  0/385 (0.00%)  0/409 (0.00%)  1/371 (0.27%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Lymphadenitis  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Neutropenia  1  0/385 (0.00%)  2/409 (0.49%)  3/371 (0.81%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Thrombocytopenia  1  0/385 (0.00%)  0/409 (0.00%)  1/371 (0.27%)  0/251 (0.00%)  1/267 (0.37%)  0/233 (0.00%) 
Cardiac disorders             
Atrioventricular block complete  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  1/233 (0.43%) 
Ventricular tachycardia  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  1/233 (0.43%) 
Atrial fibrillation  1  0/385 (0.00%)  0/409 (0.00%)  1/371 (0.27%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Coronary artery disease  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  1/251 (0.40%)  0/267 (0.00%)  0/233 (0.00%) 
Coronary artery occlusion  1  0/385 (0.00%)  0/409 (0.00%)  1/371 (0.27%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Myocardial infarction  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Pericardial effusion  1  1/385 (0.26%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Sinus bradycardia  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  1/251 (0.40%)  0/267 (0.00%)  0/233 (0.00%) 
Supraventricular tachycardia  1  0/385 (0.00%)  0/409 (0.00%)  1/371 (0.27%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Congenital, familial and genetic disorders             
Developmental hip dysplasia  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  1/233 (0.43%) 
Choledochal cyst  1  1/385 (0.26%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Congenital flat feet  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Ear and labyrinth disorders             
Tinnitus  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Vertigo  1  1/385 (0.26%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  1/267 (0.37%)  0/233 (0.00%) 
Endocrine disorders             
Adrenal insufficiency  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  1/267 (0.37%)  0/233 (0.00%) 
Goitre  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Gastrointestinal disorders             
Gastropleural fistula  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  1/233 (0.43%) 
Haemorrhoids  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  1/267 (0.37%)  1/233 (0.43%) 
Intestinal obstruction  1  1/385 (0.26%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  1/233 (0.43%) 
Abdominal distension  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  1/267 (0.37%)  0/233 (0.00%) 
Abdominal pain  1  0/385 (0.00%)  0/409 (0.00%)  1/371 (0.27%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Abdominal pain lower  1  1/385 (0.26%)  0/409 (0.00%)  0/371 (0.00%)  1/251 (0.40%)  0/267 (0.00%)  0/233 (0.00%) 
Abdominal pain upper  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  1/251 (0.40%)  0/267 (0.00%)  0/233 (0.00%) 
Colitis ulcerative  1  1/385 (0.26%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Diarrhoea  1  0/385 (0.00%)  0/409 (0.00%)  1/371 (0.27%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Dysphagia  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  1/267 (0.37%)  0/233 (0.00%) 
Enterocolitis  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Gastric ulcer  1  1/385 (0.26%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Gastric ulcer haemorrhage  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  1/267 (0.37%)  0/233 (0.00%) 
Gastritis  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Haematemesis  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  1/267 (0.37%)  0/233 (0.00%) 
Haematochezia  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Inguinal hernia  1  1/385 (0.26%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Pancreatitis  1  1/385 (0.26%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Pancreatitis acute  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  1/267 (0.37%)  0/233 (0.00%) 
Small intestinal obstruction  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Stress ulcer  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Vomiting  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  1/267 (0.37%)  0/233 (0.00%) 
General disorders             
Asthenia  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  1/267 (0.37%)  0/233 (0.00%) 
General physical health deterioration  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  1/267 (0.37%)  0/233 (0.00%) 
Pain  1  1/385 (0.26%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Pyrexia  1  1/385 (0.26%)  2/409 (0.49%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Hepatobiliary disorders             
Cholelithiasis  1  1/385 (0.26%)  0/409 (0.00%)  1/371 (0.27%)  0/251 (0.00%)  0/267 (0.00%)  1/233 (0.43%) 
Cholecystitis  1  3/385 (0.78%)  0/409 (0.00%)  1/371 (0.27%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Cholecystitis acute  1  0/385 (0.00%)  0/409 (0.00%)  1/371 (0.27%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Cholecystitis chronic  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  1/251 (0.40%)  0/267 (0.00%)  0/233 (0.00%) 
Gallbladder perforation  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Hepatic dysplasia  1  0/385 (0.00%)  0/409 (0.00%)  1/371 (0.27%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Hepatitis toxic  1  0/385 (0.00%)  0/409 (0.00%)  1/371 (0.27%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Jaundice cholestatic  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Liver injury  1  1/385 (0.26%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Non-alcoholic steatohepatitis  1  1/385 (0.26%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Immune system disorders             
Anaphylactic reaction  1  1/385 (0.26%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Infections and infestations             
Bronchitis  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  1/233 (0.43%) 
Dengue fever  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  1/233 (0.43%) 
Furuncle  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  1/233 (0.43%) 
Gastroenteritis  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  1/233 (0.43%) 
Abscess jaw  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  1/251 (0.40%)  0/267 (0.00%)  0/233 (0.00%) 
Abscess soft tissue  1  1/385 (0.26%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Appendiceal abscess  1  0/385 (0.00%)  0/409 (0.00%)  1/371 (0.27%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Appendicitis  1  0/385 (0.00%)  1/409 (0.24%)  1/371 (0.27%)  1/251 (0.40%)  0/267 (0.00%)  0/233 (0.00%) 
Bacterial sepsis  1  0/385 (0.00%)  0/409 (0.00%)  1/371 (0.27%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Cellulitis  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Cytomegalovirus infection  1  1/385 (0.26%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Diarrhoea infectious  1  0/385 (0.00%)  0/409 (0.00%)  1/371 (0.27%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Endocarditis enterococcal  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Escherichia bacteraemia  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Hepatitis C  1  1/385 (0.26%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Infected bites  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Influenza  1  1/385 (0.26%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Lower respiratory tract infection  1  1/385 (0.26%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Lung abscess  1  1/385 (0.26%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Neuroborreliosis  1  0/385 (0.00%)  0/409 (0.00%)  1/371 (0.27%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Osteomyelitis  1  0/385 (0.00%)  0/409 (0.00%)  1/371 (0.27%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Paronychia  1  1/385 (0.26%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Pelvic abscess  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Perichondritis  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  1/267 (0.37%)  0/233 (0.00%) 
Peritonitis  1  0/385 (0.00%)  0/409 (0.00%)  1/371 (0.27%)  0/251 (0.00%)  1/267 (0.37%)  0/233 (0.00%) 
Pilonidal cyst  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Pneumonia  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  2/267 (0.75%)  0/233 (0.00%) 
Pneumonia bacterial  1  0/385 (0.00%)  0/409 (0.00%)  1/371 (0.27%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Post procedural infection  1  1/385 (0.26%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Pulmonary tuberculosis  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  1/251 (0.40%)  0/267 (0.00%)  0/233 (0.00%) 
Pyelonephritis  1  1/385 (0.26%)  0/409 (0.00%)  1/371 (0.27%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Pyelonephritis acute  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Respiratory tract infection  1  1/385 (0.26%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Salpingo-oophoritis  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  1/267 (0.37%)  0/233 (0.00%) 
Sepsis  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  1/251 (0.40%)  1/267 (0.37%)  0/233 (0.00%) 
Septic shock  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  1/267 (0.37%)  0/233 (0.00%) 
Staphylococcal bacteraemia  1  1/385 (0.26%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Staphylococcal infection  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Tonsillitis  1  0/385 (0.00%)  0/409 (0.00%)  1/371 (0.27%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Tuberculosis gastrointestinal  1  0/385 (0.00%)  0/409 (0.00%)  1/371 (0.27%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Urinary tract infection  1  2/385 (0.52%)  2/409 (0.49%)  2/371 (0.54%)  0/251 (0.00%)  2/267 (0.75%)  0/233 (0.00%) 
Wound infection  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Injury, poisoning and procedural complications             
Intentional overdose  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  1/251 (0.40%)  0/267 (0.00%)  1/233 (0.43%) 
Abdominal injury  1  0/385 (0.00%)  0/409 (0.00%)  1/371 (0.27%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Ankle fracture  1  0/385 (0.00%)  0/409 (0.00%)  1/371 (0.27%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Carbon monoxide poisoning  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  1/251 (0.40%)  0/267 (0.00%)  0/233 (0.00%) 
Contusion  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Face injury  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  1/267 (0.37%)  0/233 (0.00%) 
Fall  1  2/385 (0.52%)  2/409 (0.49%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Femoral neck fracture  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Femur fracture  1  1/385 (0.26%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Foot fracture  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  1/251 (0.40%)  0/267 (0.00%)  0/233 (0.00%) 
Multiple fractures  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Post procedural bile leak  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Post procedural haemorrhage  1  1/385 (0.26%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Postoperative fever  1  1/385 (0.26%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Radius fracture  1  1/385 (0.26%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Road traffic accident  1  0/385 (0.00%)  2/409 (0.49%)  0/371 (0.00%)  0/251 (0.00%)  1/267 (0.37%)  0/233 (0.00%) 
Spinal compression fracture  1  1/385 (0.26%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Splenic rupture  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Traumatic lung injury  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Investigations             
Alanine aminotransferase increased  1  6/385 (1.56%)  6/409 (1.47%)  3/371 (0.81%)  2/251 (0.80%)  1/267 (0.37%)  1/233 (0.43%) 
Amylase increased  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  1/233 (0.43%) 
Blood creatine phosphokinase increased  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  3/267 (1.12%)  1/233 (0.43%) 
Activated partial thromboplastin time prolonged  1  1/385 (0.26%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Aspartate aminotransferase increased  1  0/385 (0.00%)  1/409 (0.24%)  1/371 (0.27%)  0/251 (0.00%)  1/267 (0.37%)  0/233 (0.00%) 
Gamma-glutamyltransferase increased  1  0/385 (0.00%)  0/409 (0.00%)  1/371 (0.27%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Hepatic enzyme increased  1  2/385 (0.52%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  1/267 (0.37%)  0/233 (0.00%) 
Liver function test abnormal  1  0/385 (0.00%)  1/409 (0.24%)  1/371 (0.27%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Neutrophil count decreased  1  1/385 (0.26%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Platelet count decreased  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  1/267 (0.37%)  0/233 (0.00%) 
Transaminases increased  1  1/385 (0.26%)  0/409 (0.00%)  1/371 (0.27%)  1/251 (0.40%)  0/267 (0.00%)  0/233 (0.00%) 
Weight decreased  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  1/251 (0.40%)  1/267 (0.37%)  0/233 (0.00%) 
Metabolism and nutrition disorders             
Dehydration  1  0/385 (0.00%)  0/409 (0.00%)  1/371 (0.27%)  0/251 (0.00%)  1/267 (0.37%)  1/233 (0.43%) 
Diabetes mellitus  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  1/267 (0.37%)  0/233 (0.00%) 
Hyperamylasaemia  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  2/267 (0.75%)  0/233 (0.00%) 
Hyperlipasaemia  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  1/267 (0.37%)  0/233 (0.00%) 
Obesity  1  0/385 (0.00%)  0/409 (0.00%)  1/371 (0.27%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Type 1 diabetes mellitus  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Musculoskeletal and connective tissue disorders             
Foot deformity  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  1/233 (0.43%) 
Fracture nonunion  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  1/233 (0.43%) 
Intervertebral disc protrusion  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  1/233 (0.43%) 
Knee deformity  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  1/233 (0.43%) 
Back pain  1  1/385 (0.26%)  0/409 (0.00%)  0/371 (0.00%)  1/251 (0.40%)  1/267 (0.37%)  0/233 (0.00%) 
Muscle spasms  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Osteoarthritis  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  1/267 (0.37%)  0/233 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)             
Breast cancer  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  1/233 (0.43%) 
Papillary thyroid cancer  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  1/267 (0.37%)  1/233 (0.43%) 
Acoustic neuroma  1  1/385 (0.26%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Invasive ductal breast carcinoma  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  1/267 (0.37%)  0/233 (0.00%) 
Invasive lobular breast carcinoma  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  1/251 (0.40%)  0/267 (0.00%)  0/233 (0.00%) 
Lipoma  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  1/267 (0.37%)  0/233 (0.00%) 
Uterine leiomyoma  1  0/385 (0.00%)  0/409 (0.00%)  2/371 (0.54%)  0/251 (0.00%)  1/267 (0.37%)  0/233 (0.00%) 
Nervous system disorders             
Cervicobrachial syndrome  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  1/233 (0.43%) 
Multiple sclerosis relapse  1  2/385 (0.52%)  1/409 (0.24%)  1/371 (0.27%)  1/251 (0.40%)  1/267 (0.37%)  1/233 (0.43%) 
Partial seizures  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  1/233 (0.43%) 
Sciatica  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  1/267 (0.37%)  1/233 (0.43%) 
Status epilepticus  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  1/233 (0.43%) 
Carpal tunnel syndrome  1  0/385 (0.00%)  1/409 (0.24%)  1/371 (0.27%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Coma  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  1/251 (0.40%)  0/267 (0.00%)  0/233 (0.00%) 
Headache  1  3/385 (0.78%)  0/409 (0.00%)  1/371 (0.27%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Hydrocephalus  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  1/251 (0.40%)  0/267 (0.00%)  0/233 (0.00%) 
Hypoaesthesia  1  0/385 (0.00%)  0/409 (0.00%)  1/371 (0.27%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Hypoglycaemic coma  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  1/267 (0.37%)  0/233 (0.00%) 
Intracranial aneurysm  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  1/267 (0.37%)  0/233 (0.00%) 
Intraventricular haemorrhage  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  1/251 (0.40%)  0/267 (0.00%)  0/233 (0.00%) 
Neuropathy peripheral  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Polyneuropathy  1  0/385 (0.00%)  0/409 (0.00%)  1/371 (0.27%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Seizure  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  1/267 (0.37%)  0/233 (0.00%) 
Somnolence  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  1/251 (0.40%)  0/267 (0.00%)  0/233 (0.00%) 
Subarachnoid haemorrhage  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  1/251 (0.40%)  0/267 (0.00%)  0/233 (0.00%) 
Syncope  1  1/385 (0.26%)  1/409 (0.24%)  1/371 (0.27%)  1/251 (0.40%)  1/267 (0.37%)  0/233 (0.00%) 
Vertebrobasilar insufficiency  1  1/385 (0.26%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Pregnancy, puerperium and perinatal conditions             
Ectopic pregnancy  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  1/233 (0.43%) 
Pregnancy  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Psychiatric disorders             
Completed suicide  1  0/385 (0.00%)  0/409 (0.00%)  1/371 (0.27%)  0/251 (0.00%)  1/267 (0.37%)  1/233 (0.43%) 
Suicide attempt  1  0/385 (0.00%)  1/409 (0.24%)  3/371 (0.81%)  1/251 (0.40%)  0/267 (0.00%)  1/233 (0.43%) 
Anxiety  1  1/385 (0.26%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Depression  1  1/385 (0.26%)  1/409 (0.24%)  1/371 (0.27%)  0/251 (0.00%)  1/267 (0.37%)  0/233 (0.00%) 
Major depression  1  0/385 (0.00%)  0/409 (0.00%)  1/371 (0.27%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Mental disorder  1  0/385 (0.00%)  0/409 (0.00%)  1/371 (0.27%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Schizophrenia  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Suicidal behaviour  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  1/251 (0.40%)  0/267 (0.00%)  0/233 (0.00%) 
Suicidal ideation  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  1/267 (0.37%)  0/233 (0.00%) 
Renal and urinary disorders             
Acute kidney injury  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  2/267 (0.75%)  0/233 (0.00%) 
Glomerulonephritis chronic  1  0/385 (0.00%)  0/409 (0.00%)  1/371 (0.27%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Renal artery stenosis  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Renal cyst  1  1/385 (0.26%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Reproductive system and breast disorders             
Menorrhagia  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  1/233 (0.43%) 
Benign prostatic hyperplasia  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Cervical dysplasia  1  1/385 (0.26%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Menopausal symptoms  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Ovarian cyst  1  1/385 (0.26%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Respiratory, thoracic and mediastinal disorders             
Lung disorder  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  1/233 (0.43%) 
Asthma  1  2/385 (0.52%)  1/409 (0.24%)  1/371 (0.27%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Atelectasis  1  1/385 (0.26%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Haemoptysis  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  1/267 (0.37%)  0/233 (0.00%) 
Lung consolidation  1  1/385 (0.26%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Pleural effusion  1  1/385 (0.26%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Pulmonary embolism  1  0/385 (0.00%)  0/409 (0.00%)  1/371 (0.27%)  0/251 (0.00%)  1/267 (0.37%)  0/233 (0.00%) 
Pulmonary hypertension  1  0/385 (0.00%)  0/409 (0.00%)  0/371 (0.00%)  0/251 (0.00%)  1/267 (0.37%)  0/233 (0.00%) 
Skin and subcutaneous tissue disorders             
Angioedema  1  0/385 (0.00%)  1/409 (0.24%)  0/371 (0.00%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Vascular disorders             
Blood pressure fluctuation  1  0/385 (0.00%)  0/409 (0.00%)  1/371 (0.27%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Hypertension  1  0/385 (0.00%)  0/409 (0.00%)  1/371 (0.27%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Shock haemorrhagic  1  0/385 (0.00%)  0/409 (0.00%)  1/371 (0.27%)  0/251 (0.00%)  0/267 (0.00%)  0/233 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, meddra-18.0
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 Placebo / 14 mg Teriflunomide 7 mg / 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 (%)
Total   247/385 (64.16%)   270/409 (66.01%)   254/371 (68.46%)   152/251 (60.56%)   153/267 (57.30%)   138/233 (59.23%) 
Blood and lymphatic system disorders             
Neutropenia  1  10/385 (2.60%)  19/409 (4.65%)  18/371 (4.85%)  2/251 (0.80%)  13/267 (4.87%)  20/233 (8.58%) 
Gastrointestinal disorders             
Diarrhoea  1  39/385 (10.13%)  45/409 (11.00%)  35/371 (9.43%)  14/251 (5.58%)  18/267 (6.74%)  20/233 (8.58%) 
Nausea  1  27/385 (7.01%)  38/409 (9.29%)  36/371 (9.70%)  14/251 (5.58%)  10/267 (3.75%)  8/233 (3.43%) 
General disorders             
Fatigue  1  40/385 (10.39%)  33/409 (8.07%)  37/371 (9.97%)  9/251 (3.59%)  12/267 (4.49%)  6/233 (2.58%) 
Infections and infestations             
Nasopharyngitis  1  65/385 (16.88%)  51/409 (12.47%)  44/371 (11.86%)  22/251 (8.76%)  21/267 (7.87%)  22/233 (9.44%) 
Influenza  1  19/385 (4.94%)  22/409 (5.38%)  22/371 (5.93%)  8/251 (3.19%)  14/267 (5.24%)  16/233 (6.87%) 
Urinary tract infection  1  36/385 (9.35%)  38/409 (9.29%)  26/371 (7.01%)  8/251 (3.19%)  12/267 (4.49%)  10/233 (4.29%) 
Sinusitis  1  16/385 (4.16%)  25/409 (6.11%)  24/371 (6.47%)  5/251 (1.99%)  10/267 (3.75%)  9/233 (3.86%) 
Upper respiratory tract infection  1  42/385 (10.91%)  35/409 (8.56%)  33/371 (8.89%)  11/251 (4.38%)  12/267 (4.49%)  7/233 (3.00%) 
Injury, poisoning and procedural complications             
Fall  1  14/385 (3.64%)  22/409 (5.38%)  23/371 (6.20%)  4/251 (1.59%)  7/267 (2.62%)  7/233 (3.00%) 
Investigations             
Alanine aminotransferase increased  1  27/385 (7.01%)  43/409 (10.51%)  48/371 (12.94%)  27/251 (10.76%)  8/267 (3.00%)  9/233 (3.86%) 
Musculoskeletal and connective tissue disorders             
Back pain  1  30/385 (7.79%)  28/409 (6.85%)  32/371 (8.63%)  12/251 (4.78%)  13/267 (4.87%)  13/233 (5.58%) 
Arthralgia  1  15/385 (3.90%)  30/409 (7.33%)  20/371 (5.39%)  7/251 (2.79%)  9/267 (3.37%)  9/233 (3.86%) 
Pain in extremity  1  21/385 (5.45%)  19/409 (4.65%)  25/371 (6.74%)  7/251 (2.79%)  9/267 (3.37%)  9/233 (3.86%) 
Nervous system disorders             
Headache  1  41/385 (10.65%)  61/409 (14.91%)  47/371 (12.67%)  10/251 (3.98%)  15/267 (5.62%)  17/233 (7.30%) 
Hypoaesthesia  1  16/385 (4.16%)  22/409 (5.38%)  23/371 (6.20%)  12/251 (4.78%)  6/267 (2.25%)  8/233 (3.43%) 
Dizziness  1  23/385 (5.97%)  17/409 (4.16%)  25/371 (6.74%)  3/251 (1.20%)  8/267 (3.00%)  4/233 (1.72%) 
Paraesthesia  1  23/385 (5.97%)  27/409 (6.60%)  22/371 (5.93%)  12/251 (4.78%)  5/267 (1.87%)  4/233 (1.72%) 
Psychiatric disorders             
Depression  1  25/385 (6.49%)  28/409 (6.85%)  18/371 (4.85%)  8/251 (3.19%)  15/267 (5.62%)  10/233 (4.29%) 
Respiratory, thoracic and mediastinal disorders             
Cough  1  12/385 (3.12%)  21/409 (5.13%)  12/371 (3.23%)  5/251 (1.99%)  6/267 (2.25%)  3/233 (1.29%) 
Skin and subcutaneous tissue disorders             
Alopecia  1  16/385 (4.16%)  42/409 (10.27%)  50/371 (13.48%)  36/251 (14.34%)  6/267 (2.25%)  5/233 (2.15%) 
Vascular disorders             
Hypertension  1  8/385 (2.08%)  17/409 (4.16%)  16/371 (4.31%)  10/251 (3.98%)  13/267 (4.87%)  12/233 (5.15%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, meddra-18.0
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.

If no publication has occurred within 12 months after trial completion, the Investigator can present or publish results. The investigator provides the sponsor with a copy of the presentation or publication for review and comment at least 30 days in advance of its submission.

The sponsor can delay the submission for a period not exceeding 90 days to allow for filing a patent application or 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
Responsible Party: Sanofi
ClinicalTrials.gov Identifier: NCT00751881     History of Changes
Other Study ID Numbers: EFC10531
2007-004452-36 ( EudraCT Number )
First Submitted: May 7, 2008
First Posted: September 12, 2008
Results First Submitted: April 16, 2013
Results First Posted: June 26, 2013
Last Update Posted: July 7, 2016