Trial Outcomes & Findings for Phase II Study of Teriflunomide as Adjunctive Therapy to Glatiramer Acetate in Subjects With Multiple Sclerosis (NCT NCT00475865)

NCT ID: NCT00475865

Last Updated: 2012-11-06

Results Overview

AE are any unfavorable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 123 participants
• Primary outcome timeframe: from first study drug intake up to 112 days after last intake or up to the first intake in the extension study LTS6047, whichever occured first (40 weeks max)
• Results posted on: 2012-11-06

Participant Flow

The recruitment initiated in April 2007 was completed in December 2008. A total of 148 patients were screened at 24 sites in 6 countries.

Randomization was stratified by country. 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. 123 participants were randomized.

Participant milestones

Measure	Placebo + GA Placebo (for teriflunomide) once daily concomitantly with Glatiramer Acetate \[GA\] for 24 weeks	Teriflunomide 7 mg + GA Teriflunomide 7 mg once daily concomitantly with Glatiramer Acetate \[GA\] for 24 weeks	Teriflunomide 14 mg + GA Teriflunomide 14 mg once daily concomitantly with Glatiramer Acetate \[GA\] for 24 weeks
Overall Study STARTED	41	42	40
Overall Study Treated	41	42	40
Overall Study COMPLETED	39	37	34
Overall Study NOT COMPLETED	2	5	6

Reasons for withdrawal

Measure	Placebo + GA Placebo (for teriflunomide) once daily concomitantly with Glatiramer Acetate \[GA\] for 24 weeks	Teriflunomide 7 mg + GA Teriflunomide 7 mg once daily concomitantly with Glatiramer Acetate \[GA\] for 24 weeks	Teriflunomide 14 mg + GA Teriflunomide 14 mg once daily concomitantly with Glatiramer Acetate \[GA\] for 24 weeks
Overall Study Adverse Event	0	3	4
Overall Study Lack of Efficacy	1	0	0
Overall Study Progressive disease	0	1	2
Overall Study Participant did not wish to continue	1	0	0
Overall Study Other than above	0	1	0

Baseline Characteristics

Phase II Study of Teriflunomide as Adjunctive Therapy to Glatiramer Acetate in Subjects With Multiple Sclerosis

Baseline characteristics by cohort

Measure	Placebo + GA n=41 Participants Placebo (for Teriflunomide) once daily concomitantly with glatiramer acetate \[GA\] for 24 weeks	Teriflunomide 7 mg + GA n=42 Participants Teriflunomide 7 mg once daily concomitantly with glatiramer acetate \[GA\] for 24 weeks	Teriflunomide 14 mg + GA n=40 Participants Teriflunomide 14 mg once daily concomitantly with glatiramer acetate \[GA\] for 24 weeks	Total n=123 Participants Total of all reporting groups
Age Continuous	41.8 years STANDARD_DEVIATION 8.5 • n=5 Participants	42.1 years STANDARD_DEVIATION 7.8 • n=7 Participants	40.3 years STANDARD_DEVIATION 7.5 • n=5 Participants	41.4 years STANDARD_DEVIATION 7.9 • n=4 Participants
Sex: Female, Male Female	32 Participants n=5 Participants	33 Participants n=7 Participants	32 Participants n=5 Participants	97 Participants n=4 Participants
Sex: Female, Male Male	9 Participants n=5 Participants	9 Participants n=7 Participants	8 Participants n=5 Participants	26 Participants n=4 Participants
Region of Enrollment Europe	23 participants n=5 Participants	22 participants n=7 Participants	21 participants n=5 Participants	66 participants n=4 Participants
Region of Enrollment North America	18 participants n=5 Participants	20 participants n=7 Participants	19 participants n=5 Participants	57 participants n=4 Participants
Time since first diagnosis of Multiple Sclerosis [MS]	7.61 years STANDARD_DEVIATION 6.04 • n=5 Participants	8.82 years STANDARD_DEVIATION 5.85 • n=7 Participants	7.60 years STANDARD_DEVIATION 6.03 • n=5 Participants	8.02 years STANDARD_DEVIATION 5.95 • n=4 Participants
Number of MS relapses Within the past year	1 MS relapses n=5 Participants	1 MS relapses n=7 Participants	1 MS relapses n=5 Participants	1 MS relapses n=4 Participants
Number of MS relapses Within the past 2 years	1 MS relapses n=5 Participants	1 MS relapses n=7 Participants	1 MS relapses n=5 Participants	1 MS relapses n=4 Participants
Time since most recent MS relapse onset	24.90 months STANDARD_DEVIATION 34.84 • n=5 Participants	21.52 months STANDARD_DEVIATION 30.48 • n=7 Participants	23.88 months STANDARD_DEVIATION 31.53 • n=5 Participants	23.41 months STANDARD_DEVIATION 32.09 • n=4 Participants
MS subtype Relapsing Remitting	39 participants n=5 Participants	40 participants n=7 Participants	37 participants n=5 Participants	116 participants n=4 Participants
MS subtype Secondary Progressive	2 participants n=5 Participants	2 participants n=7 Participants	3 participants n=5 Participants	7 participants n=4 Participants
MS subtype Progressive Relapsing	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants	0 participants n=4 Participants
Baseline Expanded Disability Status Scale [EDSS] score	2.54 units on a scale STANDARD_DEVIATION 1.11 • n=5 Participants	2.43 units on a scale STANDARD_DEVIATION 1.23 • n=7 Participants	2.60 units on a scale STANDARD_DEVIATION 1.28 • n=5 Participants	2.52 units on a scale STANDARD_DEVIATION 1.20 • n=4 Participants

PRIMARY outcome

Timeframe: from first study drug intake up to 112 days after last intake or up to the first intake in the extension study LTS6047, whichever occured first (40 weeks max)

Population: All randomized and treated participants; Participants were included in the treatment group according to the drug actually received.

AE are any unfavorable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study.

Outcome measures

Measure	Placebo + GA n=41 Participants Placebo (for Teriflunomide) once daily concomitantly with glatiramer acetate \[GA\] for 24 weeks	Teriflunomide 7 mg + GA n=42 Participants Teriflunomide 7 mg once daily concomitantly with glatiramer acetate \[GA\] for 24 weeks	Teriflunomide 14 mg + GA n=40 Participants Teriflunomide 14 mg once daily concomitantly with glatiramer acetate \[GA\] for 24 weeks
Overview of Adverse Events (AE] Any AE	32 participants	35 participants	35 participants
Overview of Adverse Events (AE] - serious AE	3 participants	3 participants	1 participants
Overview of Adverse Events (AE] - AE leading to death	0 participants	0 participants	0 participants
Overview of Adverse Events (AE] - AE leading to study drug discontinuation	0 participants	3 participants	4 participants

PRIMARY outcome

Timeframe: from first study drug intake up to 112 days after last intake or up to the first intake in the extension study LTS6047, whichever occured first (40 weeks max)

Population: All randomized and treated participants; Participants were included in the treatment group according to the drug actually received.

AE with potential risk of occurrence were defined as follows:

• Hepatic disorders;
• Immune effects, mainly effects on bone marrow and infection;
• Pancreatic disorders;
• Malignancy;
• Skin disorders, mainly hair loss and hair thinning;
• Pulmonary disorders;
• Hypertension;
• Peripheral neuropathy;
• Psychiatric disorders;
• Hypersensitivity.

Outcome measures

Measure	Placebo + GA n=41 Participants Placebo (for Teriflunomide) once daily concomitantly with glatiramer acetate \[GA\] for 24 weeks	Teriflunomide 7 mg + GA n=42 Participants Teriflunomide 7 mg once daily concomitantly with glatiramer acetate \[GA\] for 24 weeks	Teriflunomide 14 mg + GA n=40 Participants Teriflunomide 14 mg once daily concomitantly with glatiramer acetate \[GA\] for 24 weeks
Overview of AE With Potential Risk of Occurrence Any AE with potential risk of occurence	24 participants	28 participants	28 participants
Overview of AE With Potential Risk of Occurrence - Hepatic disorder AE	4 participants	2 participants	5 participants
Overview of AE With Potential Risk of Occurrence - Pancreatic disorder AE	6 participants	5 participants	6 participants
Overview of AE With Potential Risk of Occurrence - Pulmonary disorder AE	0 participants	1 participants	0 participants
Overview of AE With Potential Risk of Occurrence - Immune effects related AE	18 participants	18 participants	15 participants
Overview of AE With Potential Risk of Occurrence - Hair loss / Hair thinning AE	1 participants	5 participants	7 participants
Overview of AE With Potential Risk of Occurrence - Hypertension-related AE	0 participants	1 participants	0 participants
Overview of AE With Potential Risk of Occurrence - Peripheral neuropathy AE	2 participants	1 participants	5 participants
Overview of AE With Potential Risk of Occurrence - Hypersensitivity AE	3 participants	3 participants	8 participants
Overview of AE With Potential Risk of Occurrence - Malignancy AE	0 participants	0 participants	0 participants
Overview of AE With Potential Risk of Occurrence - Psychiatric disorder AE	1 participants	3 participants	1 participants

PRIMARY outcome

Timeframe: from first study drug intake up to 112 days after last intake or up to the first intake in the extension study LTS6047, whichever occured first (40 weeks max)

Population: All randomized and treated participants; Participants were included in the treatment group according to the drug actually received.

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 Normal Limit [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.

Outcome measures

Measure	Placebo + GA n=41 Participants Placebo (for Teriflunomide) once daily concomitantly with glatiramer acetate \[GA\] for 24 weeks	Teriflunomide 7 mg + GA n=42 Participants Teriflunomide 7 mg once daily concomitantly with glatiramer acetate \[GA\] for 24 weeks	Teriflunomide 14 mg + GA n=40 Participants Teriflunomide 14 mg once daily concomitantly with glatiramer acetate \[GA\] for 24 weeks
Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) ALT >3 ULN	1 participants	0 participants	1 participants
Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) - ALT >5 ULN	1 participants	0 participants	1 participants
Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) - ALT >10 ULN	1 participants	0 participants	0 participants
Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) AST >3 ULN	1 participants	0 participants	0 participants
Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) - AST >5 ULN	1 participants	0 participants	0 participants
Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) Alkaline Phosphatase >1.5 ULN	0 participants	0 participants	0 participants
Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) TB >1.5 ULN	0 participants	0 participants	0 participants
Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) ALT >3 ULN and TB >2 ULN	0 participants	0 participants	0 participants

SECONDARY outcome

Timeframe: baseline (before randomization) and 24 weeks

Population: All randomized and treated participants; Participants were included in the treatment group according to the drug actually received.

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.

Least-square means were estimated using a Mixed-effect model with repeated measures [MMRM] on cubic root transformed volume data (treatment group, region of enrollment, visit, treatment-by-visit interaction, baseline value (cubic root transformed), and baseline-by-visit interaction as factors).

Outcome measures

Measure	Placebo + GA n=41 Participants Placebo (for Teriflunomide) once daily concomitantly with glatiramer acetate \[GA\] for 24 weeks	Teriflunomide 7 mg + GA n=42 Participants Teriflunomide 7 mg once daily concomitantly with glatiramer acetate \[GA\] for 24 weeks	Teriflunomide 14 mg + GA n=40 Participants Teriflunomide 14 mg once daily concomitantly with glatiramer acetate \[GA\] for 24 weeks
Cerebral Magnetic Resonance Imaging [MRI] Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease)	-0.006 mililiters (mL) Standard Error 0.036	-0.030 mililiters (mL) Standard Error 0.036	-0.036 mililiters (mL) Standard Error 0.037

SECONDARY outcome

Timeframe: 24 weeks

Population: All randomized and treated participants; Participants were included in the treatment group according to the drug actually received.

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 and baseline number of Gd-enhancing T1-lesions as covariates).

Outcome measures

Measure	Placebo + GA n=41 Participants Placebo (for Teriflunomide) once daily concomitantly with glatiramer acetate \[GA\] for 24 weeks	Teriflunomide 7 mg + GA n=42 Participants Teriflunomide 7 mg once daily concomitantly with glatiramer acetate \[GA\] for 24 weeks	Teriflunomide 14 mg + GA n=40 Participants Teriflunomide 14 mg once daily concomitantly with glatiramer acetate \[GA\] for 24 weeks
Cerebral MRI Assessment: Number of Gd-enhancing T1-lesions Per Scan (Poisson Regression Estimates)	0.367 lesions per scan Interval 0.183 to 0.736	0.109 lesions per scan Interval 0.054 to 0.22	0.171 lesions per scan Interval 0.093 to 0.313

SECONDARY outcome

Timeframe: 24 weeks

Population: All randomized and treated participants; Participants were included in the treatment group according to the drug actually received.

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.

Outcome measures

Measure	Placebo + GA n=41 Participants Placebo (for Teriflunomide) once daily concomitantly with glatiramer acetate \[GA\] for 24 weeks	Teriflunomide 7 mg + GA n=42 Participants Teriflunomide 7 mg once daily concomitantly with glatiramer acetate \[GA\] for 24 weeks	Teriflunomide 14 mg + GA n=40 Participants Teriflunomide 14 mg once daily concomitantly with glatiramer acetate \[GA\] for 24 weeks
Cerebral MRI Assessment: Volume of Gd-enhancing T1-lesions Per Scan	0.063 mililiters per scan	0.028 mililiters per scan	0.017 mililiters per scan

SECONDARY outcome

Timeframe: 24 weeks

Population: All randomized and treated participants; Participants were included in the treatment group according to the drug actually received.

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 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 and region of enrollment as covariates).

Outcome measures

Measure	Placebo + GA n=41 Participants Placebo (for Teriflunomide) once daily concomitantly with glatiramer acetate \[GA\] for 24 weeks	Teriflunomide 7 mg + GA n=42 Participants Teriflunomide 7 mg once daily concomitantly with glatiramer acetate \[GA\] for 24 weeks	Teriflunomide 14 mg + GA n=40 Participants Teriflunomide 14 mg once daily concomitantly with glatiramer acetate \[GA\] for 24 weeks
Annualized Relapse Rate [ARR]: Poisson Regression Estimates	0.475 relapses per year Interval 0.26 to 0.867	0.311 relapses per year Interval 0.151 to 0.642	0.647 relapses per year Interval 0.379 to 1.103

SECONDARY outcome

Timeframe: 24 weeks

Population: All randomized and treated participants who had at least one PK sample. Participants were included in the treatment group according to the drug actually received.

Plasma concentrations of teriflunomide were measured using validated liquid chromatography-tandem mass spectrometry methods.

Outcome measures

Measure	Placebo + GA n=37 Participants Placebo (for Teriflunomide) once daily concomitantly with glatiramer acetate \[GA\] for 24 weeks	Teriflunomide 7 mg + GA n=33 Participants Teriflunomide 7 mg once daily concomitantly with glatiramer acetate \[GA\] for 24 weeks	Teriflunomide 14 mg + GA Teriflunomide 14 mg once daily concomitantly with glatiramer acetate \[GA\] for 24 weeks
Pharmacokinetic [PK]: Teriflunomide Plasma Concentration	23.443 micrograms/mililiter (μg/mL) Standard Deviation 10.917	46.992 micrograms/mililiter (μg/mL) Standard Deviation 32.154	—

Adverse Events

Placebo + GA

Serious events: 3 serious events

Other events: 20 other events

Deaths: 0 deaths

Teriflunomide 7 mg + GA

Serious events: 3 serious events

Other events: 20 other events

Deaths: 0 deaths

Teriflunomide 14 mg + GA

Serious events: 1 serious events

Other events: 25 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo + GA n=41 participants at risk Placebo (for Teriflunomide) once daily concomitantly with glatiramer acetate \[GA\] for 24 weeks	Teriflunomide 7 mg + GA n=42 participants at risk Teriflunomide 7 mg once daily concomitantly with glatiramer acetate \[GA\] for 24 weeks	Teriflunomide 14 mg + GA n=40 participants at risk Teriflunomide 14 mg once daily concomitantly with glatiramer acetate \[GA\] for 24 weeks
Infections and infestations Abscess	2.4% 1/41 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	0.00% 0/42 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	0.00% 0/40 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)
Psychiatric disorders Suicidal ideation	0.00% 0/41 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	0.00% 0/42 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	2.5% 1/40 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)
Nervous system disorders Cerebral ischaemia	2.4% 1/41 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	0.00% 0/42 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	0.00% 0/40 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)
Nervous system disorders Epilepsy	0.00% 0/41 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	2.4% 1/42 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	0.00% 0/40 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)
Respiratory, thoracic and mediastinal disorders Interstitial lung disease	0.00% 0/41 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	2.4% 1/42 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	0.00% 0/40 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)
Investigations Alanine aminotransferase increased	0.00% 0/41 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	2.4% 1/42 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	0.00% 0/40 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)
Investigations Hepatic enzyme increased	2.4% 1/41 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	0.00% 0/42 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	0.00% 0/40 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)
Injury, poisoning and procedural complications Facial bones fracture	2.4% 1/41 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	0.00% 0/42 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	0.00% 0/40 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)

Other adverse events

Measure	Placebo + GA n=41 participants at risk Placebo (for Teriflunomide) once daily concomitantly with glatiramer acetate \[GA\] for 24 weeks	Teriflunomide 7 mg + GA n=42 participants at risk Teriflunomide 7 mg once daily concomitantly with glatiramer acetate \[GA\] for 24 weeks	Teriflunomide 14 mg + GA n=40 participants at risk Teriflunomide 14 mg once daily concomitantly with glatiramer acetate \[GA\] for 24 weeks
Infections and infestations Gastroenteritis	7.3% 3/41 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	0.00% 0/42 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	0.00% 0/40 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)
Infections and infestations Nasopharyngitis	7.3% 3/41 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	14.3% 6/42 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	10.0% 4/40 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)
Infections and infestations Upper respiratory tract infection	9.8% 4/41 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	2.4% 1/42 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	5.0% 2/40 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)
Infections and infestations Urinary tract infection	7.3% 3/41 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	9.5% 4/42 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	5.0% 2/40 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)
Nervous system disorders Dizziness	7.3% 3/41 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	2.4% 1/42 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	0.00% 0/40 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)
Nervous system disorders Headache	12.2% 5/41 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	14.3% 6/42 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	15.0% 6/40 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)
Nervous system disorders Paraesthesia	0.00% 0/41 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	0.00% 0/42 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	7.5% 3/40 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)
Gastrointestinal disorders Constipation	0.00% 0/41 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	0.00% 0/42 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	10.0% 4/40 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)
Gastrointestinal disorders Diarrhoea	0.00% 0/41 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	7.1% 3/42 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	20.0% 8/40 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)
Gastrointestinal disorders Nausea	4.9% 2/41 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	9.5% 4/42 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	7.5% 3/40 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)
Skin and subcutaneous tissue disorders Alopecia	2.4% 1/41 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	11.9% 5/42 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	17.5% 7/40 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)
Skin and subcutaneous tissue disorders Rash	0.00% 0/41 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	2.4% 1/42 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	12.5% 5/40 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)
General disorders Fatigue	14.6% 6/41 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	7.1% 3/42 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)	17.5% 7/40 • 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. 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 study drug intake or up to the first study drug intake in the extension study LTS6047, whichever occured first (40 weeks max)

Additional Information

Trial Transparency Team

sanofi-aventis

Email: Contact_US@sanofi.com

Results disclosure agreements

• Principal investigator is a sponsor employee 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.
• Publication restrictions are in place

Restriction type: OTHER