A Study Comparing the Effectiveness and Safety of Teriflunomide and Interferon Beta-1a in Patients With Relapsing Multiple Sclerosis (TENERE)

• ClinicalTrials.gov Identifier: NCT00883337
• Recruitment Status: Completed
• First Posted: April 17, 2009
• Results First Posted: November 6, 2012
• Last Update Posted: June 13, 2016
• Sponsor: Sanofi
• Information provided by (Responsible Party): Sanofi

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Single (Outcomes Assessor); Primary Purpose: Treatment
• Condition: Multiple Sclerosis
• Interventions: Drug: Interferon β-1a; Drug: Teriflunomide
• Enrollment: 324

Participant Flow

Recruitment Details	The recruitment initiated in April 2009 was completed in July 2010. A total of 369 participants were screened at 54 sites in 13 countries. The common end date of core treatment period was 14 September 2011 (maximum treatment duration of 115 weeks). The end date of extension was 13 May 2015 (maximum treatment duration of 197 weeks)
Pre-assignment Details	Randomization was stratified by country and baseline disability (Expanded Disability Status Scale [EDSS] score ≤3.5 or >3.5). Assignment to groups was done centrally using an Interactive Voice Response System (IVRS] in a 1:1:1 ratio after confirmation of the selection criteria. 324 participants were randomized at 53 sites.

Arm/Group Title	Teriflunomide 7 mg/14 mg	Teriflunomide 14 mg/14 mg	IFN-β-1a / Teriflunomide 14 mg
Arm/Group Description	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.	Core treatment period: Interferon β-1a 3 times a week. Extension treatment period: Teriflunomide 14 mg once daily.
Period Title: Core Treatment Period
Started	109	111	104
Treated	109	111 [1]	101 [2]
Completed	89	89	71
Not Completed	20	22	33
Reason Not Completed
Adverse Event	9	12	22
Lack of Efficacy	7	4	2
Lost to Follow-up	1	1	0
Withdrawal by Subject	2	2	6
Wish to be pregnant	1	2	1
Poor compliance to protocol	0	0	1
Other than above	0	1	1
[1] One participant received teriflunomide 7 mg instead of teriflunomide 14 mg; [2] 3 participants refused treatment with Rebif®
Period Title: Extension Treatment Period
Started	89	89	59 [1]
Completed	61	66	40
Not Completed	28	23	19
Reason Not Completed
Adverse Event	8	5	5
Lack of Efficacy	8	8	8
Poor compliance to protocol	1	1	1
Lost to Follow-up	1	0	0
Other than above	10	9	5
[1] 12 participants completed the core period but didn't enter the extension period.

Baseline Characteristics

Arm/Group Title		Teriflunomide 7 mg / 14 mg	Teriflunomide 14 mg/14 mg	IFNβ1a / Teriflunomide 14 mg	Total
Arm/Group Description		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.	Core treatment period: Interferon β-1a 3 times a week. Extension treatment period: Teriflunomide 14 mg once daily.	Total of all reporting groups
Overall Number of Baseline Participants		109	111	104	324
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	109 participants	111 participants	104 participants	324 participants
		32.5 (9.2)	36.8 (10.3)	37.0 (10.6)	36.3 (10.0)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	109 participants	111 participants	104 participants	324 participants
	Female	70 64.2%	78 70.3%	71 68.3%	219 67.6%
	Male	39 35.8%	33 29.7%	33 31.7%	105 32.4%
Region of enrollment [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	109 participants	111 participants	104 participants	324 participants
North America		8	6	7	21
Eastern Europe		39	41	35	115
Western Europe*		62	64	62	188
		[1] Measure Description: Due the small sample size in some countries, the countries were pooled as follows: North America: Canada;; Eastern Europe: Czech Republic, Greece, Hungary and Poland;; Western Europe: Belgium, France, Germany, Italy, Spain, Switzerland and United Kingdon; '*' the only participant in Tunisia was included in the Western Europe group.
Time since first diagnosis of Multiple Sclerosis [MS]; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	109 participants	111 participants	104 participants	324 participants
		3.72 (5.19)	3.68 (6.24)	3.82 (5.69)	3.74 (5.71)
Number of MS relapses; Median (Full Range); Unit of measure: Relapses	Number Analyzed	109 participants	111 participants	104 participants	324 participants
Within the past year		1; (0 to 3)	1; (0 to 4)	1; (0 to 5)	1; (0 to 5)
Within the past 2 years		2; (0 to 4)	2; (0 to 4)	2; (0 to 6)	2; (0 to 6)
Time since most recent MS relapse onset [1]; Mean (Standard Deviation); Unit of measure: Months
	Number Analyzed	109 participants	111 participants	104 participants	324 participants
		9.00 (13.96)	7.90 (10.34)	9.79 (10.72)	8.88 (11.79)
		[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	109 participants	111 participants	104 participants	324 participants
Relapsing Remitting		109	108	104	321
Secondary Progressive		0	1	0	1
Progressive Relapsing		0	2	0	2
Baseline EDSS score [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	109 participants	111 participants	104 participants	324 participants
≤3.5		96	95	93	284
>3.5		13	16	11	40
		[1] Measure Description: EDSS is an ordinal scale in half-point increments that qualifies disability in patients with MS. It consists of 8 ordinal rating scales assessing seven functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder and cerebral) as well as ambulation. EDSS total score ranges from 0 (normal neurological examination) to 10 (death due to MS).

Outcome Measures

1. Primary Outcome

Title	Core Treatment Period: Overview of Failures
Description	Failure was defined as the first occurence of confirmed relapse or permanent treatment discontinuation (for any cause) which ever came first. If no events occurred, the participant was considered free of failure. 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.
Time Frame	Core treatment period between 48 and 118 weeks depending on when the participant was enrolled

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: all randomized participants. Participants were considered in the treatment group to which they were randomized regardless of the drug they actually received.

Arm/Group Title	Teriflunomide 7 mg	Teriflunomide 14 mg	IFN-β-1a
Arm/Group Description:	Teriflunomide 7 mg once daily	Teriflunomide 14 mg once daily	Interferon β-1a 3 times a week
Overall Number of Participants Analyzed	109	111	104
Measure Type: Number; Unit of Measure: participants
Failure	53	42	44
Free of failure	56	69	60

2. Primary Outcome

Title	Core Treatment Period: Time to Failure: Kaplan-Meier Estimates of the Rate of Failure at Timepoints
Description	Probability of disability progression at 24, 48 and 96 weeks was estimated using Kaplan-Meier method on the time to failure defined as the time from randomization to failure. Participants free of failure were censored at the date of last treatment. 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 and 118 weeks depending on when the participant was enrolled

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Teriflunomide 7 mg	Teriflunomide 14 mg	IFN-β-1a
Arm/Group Description:	Teriflunomide 7 mg once daily	Teriflunomide 14 mg once daily	Interferon β-1a 3 times a week
Overall Number of Participants Analyzed	109	111	104
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percent probability
Probability of failure at 24 weeks	25.7; (17.5 to 33.9)	24.3; (16.3 to 32.3)	29.8; (21.0 to 38.6)
Probability of failure at 48 weeks	35.8; (26.8 to 44.8)	33.3; (24.6 to 42.1)	36.5; (27.3 to 45.8)
Probability of failure at 96 weeks	58.8; (46.1 to 71.4)	41.1; (30.9 to 51.4)	44.4; (34.3 to 54.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Teriflunomide 14 mg, IFN-β-1a
	Comments	The study was sized to detect a difference between Teriflunomide and Rebif groups in the time to failure at a significance level of 0.025 with a power of 81%. Null hypothesis: H1: No difference between Teriflunomide 14 mg and Rebif; H2: No difference between Teriflunomide 7 mg and Rebif
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5953
	Comments	Hochberg testing procedure: a-priori threshold for statistical significance ≤0.05 for the largest p-value of the 2 pair-wise comparisons; a-priori threshold for statistical significance ≤0.025 for the other p-value if the largest p-value >0.05
	Method	Log Rank
	Comments	Two-sided Log Rank test with the region of enrollment and baseline EDSS stratum as stratification factors

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Teriflunomide 7 mg, IFN-β-1a
	Comments	Null hypothesis: H1: No difference between Teriflunomide 14 mg and Rebif; H2: No difference between Teriflunomide 7 mg and Rebif
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5190
	Comments	Hochberg testing procedure: a-priori threshold for statistical significance ≤0.05 for the largest p-value of the 2 pair-wise comparisons; a-priori threshold for statistical significance ≤0.025 for the other p-value if the largest p-value >0.05
	Method	Log Rank
	Comments	Two-sided Log Rank test with the region of enrollment and baseline EDSS stratum as stratification factors

3. Secondary Outcome

Title	Core Treatment Period: Annualized Relapse Rate [ARR] - Poisson Regression Estimates
Description	ARR is obtained from the total number of confirmed relapses that occured during the treatment period divided by the sum of the treatment durations. 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 and 118 weeks depending on when the participant was enrolled

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Teriflunomide 7 mg	Teriflunomide 14 mg	IFN-β-1a
Arm/Group Description:	Teriflunomide 7 mg once daily	Teriflunomide 14 mg once daily	Interferon β-1a 3 times a week
Overall Number of Participants Analyzed	109	111	104
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: relapses per year
	0.410; (0.265 to 0.636)	0.259; (0.153 to 0.438)	0.216; (0.113 to 0.415)

4. Secondary Outcome

Title	Core Treatment Period: Change From Baseline in Fatigue Impact Scale (FIS) Total Score
Description	FIS is a subject-reported scale that qualifies the impact of fatigue on daily life in patients with MS. It consists of 40 statements that measure fatigue in three areas; physical, cognitive, and social. FIS total score ranges from 0 (no problem) to 160 (extreme problem). Least-square means were estimated using a Mixed-effect model with repeated measures [MMRM] on FIS total score data (treatment group, region of enrollment, baseline EDSS stratum, visit, treatment-by-visit interaction, baseline value, and baseline-by-visit interaction as factors).
Time Frame	Baseline (before randomization) and 48 weeks

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Teriflunomide 7 mg	Teriflunomide 14 mg	IFN-β-1a
Arm/Group Description:	Teriflunomide 7 mg once daily	Teriflunomide 14 mg once daily	Interferon β-1a 3 times a week
Overall Number of Participants Analyzed	109	111	104
Least Squares Mean (Standard Error); Unit of Measure: units on a scale
	0.97 (2.96)	4.10 (3.03)	9.10 (3.21)

5. Secondary Outcome

Title	Core Treatment Period: Treatment Satisfaction Questionnaire for Medication [TSQM] Scores
Description	TSQM version 1.4 is an instrument to assess patients' satisfaction with medication. It consists of 13 questions that cover three dimensions (effectiveness, side effects and convenience) plus a global satisfaction question. Four scores ranging from 0 to 100 (extremely satisfied) are obtained. Least-square means were estimated using a Mixed-effect model with repeated measures [MMRM] on TSQM score data (treatment group, region of enrollment, baseline EDSS stratum, visit, treatment-by-visit interaction as factors).
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Teriflunomide 7 mg	Teriflunomide 14 mg	IFN-β-1a
Arm/Group Description:	Teriflunomide 7 mg once daily	Teriflunomide 14 mg once daily	Interferon β-1a 3 times a week
Overall Number of Participants Analyzed	109	111	104
Least Squares Mean (Standard Error); Unit of Measure: units on a scale
Effectivness score	67.25 (2.70)	63.13 (2.75)	59.30 (2.97)
Side effects score	95.29 (2.31)	93.15 (2.34)	71.38 (2.50)
Convenience score	88.30 (1.97)	89.85 (1.98)	61.90 (2.11)
Global satisfaction score	68.29 (2.77)	68.82 (2.78)	60.98 (2.94)

6. Secondary Outcome

Title	Core Treatment Period: Overview of Adverse Events [AE]
Description	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

Outcome Measure Data

Analysis Population Description

Safety population: all randomized and treated participants. Participants were considered according to the drug actually received.

The participant randomized to Teriflunomide 14 mg group who received Teriflunomide 7 mg was analyzed in the Teriflunomide 7 mg group.

Arm/Group Title	Teriflunomide 7 mg	Teriflunomide 14 mg	IFN-β-1a
Arm/Group Description:	Teriflunomide 7 mg once daily	Teriflunomide 14 mg once daily	Interferon β-1a 3 times a week
Overall Number of Participants Analyzed	110	110	101
Measure Type: Number; Unit of Measure: participants
Any AE	103	102	97
- Any serious AE	12	6	7
- Any AE leading to death	0	0	0
- Any AE leading to treatment discontinuation	9	12	22

7. Secondary Outcome

Title	Extension Treatment Period: Overview of AEs
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

Outcome Measure Data

Analysis Population Description

Safety population. Participants were considered in the treatment group to which they were randomized regardless of the drug they actually received.

Arm/Group Title	Teriflunomide 7 mg / 14 mg	Teriflunomide 14 mg / 14 mg	IFN-β-1a / 14 mg
Arm/Group Description:	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.	Core treatment period: Interferon β1a 3 times a week. Extension treatment period: Teriflunomide 14 mg once daily.
Overall Number of Participants Analyzed	90	88	59
Measure Type: Number; Unit of Measure: participants
Any AE	83	76	48
Any serious AE	9	13	12
Any AE leading to death	0	0	0
Any AE leading to treatment discontinuation	8	6	5

8. Secondary Outcome

Title	Extension Treatment Period: ARR Poisson Regression Estimates
Description	ARR was obtained from the total number of confirmed relapses that occurred during the treatment period divided by the sum of the standardized treatment durations.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: 197 weeks)

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Teriflunomide 7 mg / 14 mg	Teriflunomide 14 mg / 14 mg	IFN-β-1a / 14 mg
Arm/Group Description:	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.	Core treatment period: Interferon β1a 3 times a week. Extension treatment period: Teriflunomide 14 mg once daily.
Overall Number of Participants Analyzed	89	89	59
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: relapses per year
	0.236; (0.154 to 0.362)	0.193; (0.121 to 0.307)	0.252; (0.145 to 0.438)

Adverse Events

Time Frame	AEs were collected from signature of the Informed Consent Form up to the last visit (197 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 from 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	Core Treatment Period: Teriflunomide 7 mg	Core Treatment:Teriflunomide 14 mg	Core Treatment: IFN-β-1a	Extended Treatment: Teriflunomide 14 mg (After 7 mg)	Extended Treatment: Teriflunomide 14 mg (After 14 mg)	Extended Treatment: Teriflunomide 14 mg (After IFN-β-1a)
Arm/Group Description	Teriflunomide 7 mg once daily (mean exposure of 456.62 days).	Teriflunomide 14 mg once daily (mean exposure of 434.43 days).	Interferon β-1a 3 times a week (mean exposure of 405.18 days).	Teriflunomide 14 mg once daily in extended treatment period after 7 mg in the core treatment period (mean exposure of 996.76 days).	Teriflunomide 14 mg once daily in extended treatment period after 14 mg in core treatment period (mean exposure of 1015.32 days).	Teriflunomide 14 mg once daily in extended treatment period after Interferon β-1a 3 times a week in core treatment period (mean exposure of 1000.03 days).
All-Cause Mortality
	Core Treatment Period: Teriflunomide 7 mg	Core Treatment:Teriflunomide 14 mg	Core Treatment: IFN-β-1a	Extended Treatment: Teriflunomide 14 mg (After 7 mg)	Extended Treatment: Teriflunomide 14 mg (After 14 mg)	Extended Treatment: Teriflunomide 14 mg (After IFN-β-1a)
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--	--/--	--/--	--/--	--/--
Serious Adverse Events
	Core Treatment Period: Teriflunomide 7 mg	Core Treatment:Teriflunomide 14 mg	Core Treatment: IFN-β-1a	Extended Treatment: Teriflunomide 14 mg (After 7 mg)	Extended Treatment: Teriflunomide 14 mg (After 14 mg)	Extended Treatment: Teriflunomide 14 mg (After IFN-β-1a)
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	12/110 (10.91%)	6/110 (5.45%)	7/101 (6.93%)	9/90 (10.00%)	13/88 (14.77%)	12/59 (20.34%)
Blood and lymphatic system disorders
Thrombocytopenia † 1	0/110 (0.00%)	0/110 (0.00%)	0/101 (0.00%)	0/90 (0.00%)	1/88 (1.14%)	0/59 (0.00%)
Haemolysis † 1	1/110 (0.91%)	0/110 (0.00%)	0/101 (0.00%)	0/90 (0.00%)	0/88 (0.00%)	0/59 (0.00%)
Neutropenia † 1	0/110 (0.00%)	1/110 (0.91%)	0/101 (0.00%)	0/90 (0.00%)	0/88 (0.00%)	0/59 (0.00%)
Cardiac disorders
Coronary artery disease † 1	0/110 (0.00%)	0/110 (0.00%)	0/101 (0.00%)	0/90 (0.00%)	1/88 (1.14%)	0/59 (0.00%)
Pericarditis † 1	0/110 (0.00%)	0/110 (0.00%)	0/101 (0.00%)	0/90 (0.00%)	1/88 (1.14%)	0/59 (0.00%)
Sinus tachycardia † 1	0/110 (0.00%)	0/110 (0.00%)	0/101 (0.00%)	1/90 (1.11%)	0/88 (0.00%)	0/59 (0.00%)
Supraventricular tachycardia † 1	1/110 (0.91%)	0/110 (0.00%)	0/101 (0.00%)	0/90 (0.00%)	0/88 (0.00%)	0/59 (0.00%)
Ear and labyrinth disorders
Vertigo † 1	0/110 (0.00%)	1/110 (0.91%)	0/101 (0.00%)	0/90 (0.00%)	0/88 (0.00%)	0/59 (0.00%)
Eye disorders
Eye oedema † 1	1/110 (0.91%)	0/110 (0.00%)	0/101 (0.00%)	0/90 (0.00%)	0/88 (0.00%)	0/59 (0.00%)
Optic ischaemic neuropathy † 1	1/110 (0.91%)	0/110 (0.00%)	0/101 (0.00%)	0/90 (0.00%)	0/88 (0.00%)	0/59 (0.00%)
Gastrointestinal disorders
Duodenal perforation † 1	0/110 (0.00%)	0/110 (0.00%)	0/101 (0.00%)	0/90 (0.00%)	1/88 (1.14%)	0/59 (0.00%)
Crohn's disease † 1	0/110 (0.00%)	0/110 (0.00%)	0/101 (0.00%)	0/90 (0.00%)	0/88 (0.00%)	1/59 (1.69%)
Diarrhoea † 1	1/110 (0.91%)	0/110 (0.00%)	0/101 (0.00%)	0/90 (0.00%)	0/88 (0.00%)	0/59 (0.00%)
Intestinal obstruction † 1	0/110 (0.00%)	0/110 (0.00%)	0/101 (0.00%)	0/90 (0.00%)	0/88 (0.00%)	1/59 (1.69%)
General disorders
Gait disturbance † 1	0/110 (0.00%)	0/110 (0.00%)	0/101 (0.00%)	0/90 (0.00%)	0/88 (0.00%)	1/59 (1.69%)
Hepatobiliary disorders
Cholecystitis † 1	0/110 (0.00%)	0/110 (0.00%)	1/101 (0.99%)	0/90 (0.00%)	0/88 (0.00%)	1/59 (1.69%)
Immune system disorders
Drug hypersensitivity † 1	0/110 (0.00%)	0/110 (0.00%)	0/101 (0.00%)	1/90 (1.11%)	0/88 (0.00%)	0/59 (0.00%)
Infections and infestations
Appendicitis perforated † 1	0/110 (0.00%)	0/110 (0.00%)	0/101 (0.00%)	0/90 (0.00%)	1/88 (1.14%)	0/59 (0.00%)
Bacterial pyelonephritis † 1	0/110 (0.00%)	0/110 (0.00%)	0/101 (0.00%)	0/90 (0.00%)	1/88 (1.14%)	0/59 (0.00%)
Peritonitis † 1	0/110 (0.00%)	0/110 (0.00%)	0/101 (0.00%)	0/90 (0.00%)	1/88 (1.14%)	0/59 (0.00%)
Pneumonia † 1	0/110 (0.00%)	0/110 (0.00%)	0/101 (0.00%)	0/90 (0.00%)	1/88 (1.14%)	0/59 (0.00%)
Tuberculosis † 1	0/110 (0.00%)	1/110 (0.91%)	0/101 (0.00%)	1/90 (1.11%)	1/88 (1.14%)	0/59 (0.00%)
Anal abscess † 1	0/110 (0.00%)	0/110 (0.00%)	1/101 (0.99%)	0/90 (0.00%)	0/88 (0.00%)	0/59 (0.00%)
Appendicitis † 1	0/110 (0.00%)	0/110 (0.00%)	0/101 (0.00%)	0/90 (0.00%)	0/88 (0.00%)	1/59 (1.69%)
Bacterial infection † 1	0/110 (0.00%)	0/110 (0.00%)	0/101 (0.00%)	0/90 (0.00%)	0/88 (0.00%)	1/59 (1.69%)
Cellulitis † 1	1/110 (0.91%)	0/110 (0.00%)	0/101 (0.00%)	1/90 (1.11%)	0/88 (0.00%)	0/59 (0.00%)
Cervicitis † 1	1/110 (0.91%)	0/110 (0.00%)	0/101 (0.00%)	0/90 (0.00%)	0/88 (0.00%)	0/59 (0.00%)
Chronic sinusitis † 1	0/110 (0.00%)	1/110 (0.91%)	0/101 (0.00%)	0/90 (0.00%)	0/88 (0.00%)	0/59 (0.00%)
Meningitis bacterial † 1	0/110 (0.00%)	0/110 (0.00%)	0/101 (0.00%)	0/90 (0.00%)	0/88 (0.00%)	1/59 (1.69%)
Pyelonephritis acute † 1	0/110 (0.00%)	0/110 (0.00%)	0/101 (0.00%)	0/90 (0.00%)	0/88 (0.00%)	1/59 (1.69%)
Urinary tract infection † 1	0/110 (0.00%)	0/110 (0.00%)	0/101 (0.00%)	1/90 (1.11%)	0/88 (0.00%)	0/59 (0.00%)
Urosepsis † 1	0/110 (0.00%)	0/110 (0.00%)	0/101 (0.00%)	1/90 (1.11%)	0/88 (0.00%)	0/59 (0.00%)
Injury, poisoning and procedural complications
Contusion † 1	0/110 (0.00%)	0/110 (0.00%)	0/101 (0.00%)	0/90 (0.00%)	0/88 (0.00%)	1/59 (1.69%)
Forearm fracture † 1	0/110 (0.00%)	0/110 (0.00%)	1/101 (0.99%)	0/90 (0.00%)	0/88 (0.00%)	0/59 (0.00%)
Tibia fracture † 1	1/110 (0.91%)	0/110 (0.00%)	0/101 (0.00%)	0/90 (0.00%)	0/88 (0.00%)	0/59 (0.00%)
Investigations
Alanine aminotransferase increased † 1	3/110 (2.73%)	1/110 (0.91%)	1/101 (0.99%)	2/90 (2.22%)	0/88 (0.00%)	0/59 (0.00%)
Metabolism and nutrition disorders
Hyperkalaemia † 1	0/110 (0.00%)	0/110 (0.00%)	0/101 (0.00%)	0/90 (0.00%)	1/88 (1.14%)	0/59 (0.00%)
Musculoskeletal and connective tissue disorders
Foot deformity † 1	0/110 (0.00%)	0/110 (0.00%)	0/101 (0.00%)	0/90 (0.00%)	1/88 (1.14%)	0/59 (0.00%)
Intervertebral disc disorder † 1	0/110 (0.00%)	0/110 (0.00%)	1/101 (0.99%)	0/90 (0.00%)	0/88 (0.00%)	1/59 (1.69%)
Intervertebral disc protrusion † 1	0/110 (0.00%)	1/110 (0.91%)	0/101 (0.00%)	0/90 (0.00%)	0/88 (0.00%)	1/59 (1.69%)
Spinal osteoarthritis † 1	0/110 (0.00%)	0/110 (0.00%)	0/101 (0.00%)	0/90 (0.00%)	0/88 (0.00%)	1/59 (1.69%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Uterine leiomyoma † 1	0/110 (0.00%)	0/110 (0.00%)	0/101 (0.00%)	0/90 (0.00%)	1/88 (1.14%)	0/59 (0.00%)
Uterine leiomyosarcoma † 1	1/110 (0.91%)	0/110 (0.00%)	0/101 (0.00%)	0/90 (0.00%)	0/88 (0.00%)	0/59 (0.00%)
Nervous system disorders
Carpal tunnel syndrome † 1	0/110 (0.00%)	0/110 (0.00%)	0/101 (0.00%)	0/90 (0.00%)	1/88 (1.14%)	0/59 (0.00%)
Haemorrhagic stroke † 1	0/110 (0.00%)	0/110 (0.00%)	0/101 (0.00%)	0/90 (0.00%)	1/88 (1.14%)	0/59 (0.00%)
Optic neuritis † 1	1/110 (0.91%)	0/110 (0.00%)	0/101 (0.00%)	1/90 (1.11%)	0/88 (0.00%)	0/59 (0.00%)
Sciatica † 1	0/110 (0.00%)	0/110 (0.00%)	0/101 (0.00%)	0/90 (0.00%)	0/88 (0.00%)	1/59 (1.69%)
Syncope † 1	0/110 (0.00%)	0/110 (0.00%)	0/101 (0.00%)	1/90 (1.11%)	0/88 (0.00%)	0/59 (0.00%)
Trigeminal neuralgia † 1	0/110 (0.00%)	0/110 (0.00%)	0/101 (0.00%)	0/90 (0.00%)	0/88 (0.00%)	1/59 (1.69%)
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous † 1	0/110 (0.00%)	0/110 (0.00%)	0/101 (0.00%)	0/90 (0.00%)	1/88 (1.14%)	0/59 (0.00%)
Psychiatric disorders
Suicide attempt † 1	0/110 (0.00%)	0/110 (0.00%)	0/101 (0.00%)	0/90 (0.00%)	1/88 (1.14%)	1/59 (1.69%)
Hypomania † 1	0/110 (0.00%)	0/110 (0.00%)	0/101 (0.00%)	0/90 (0.00%)	0/88 (0.00%)	1/59 (1.69%)
Renal and urinary disorders
Acute kidney injury † 1	0/110 (0.00%)	0/110 (0.00%)	0/101 (0.00%)	0/90 (0.00%)	1/88 (1.14%)	0/59 (0.00%)
Nephrolithiasis † 1	0/110 (0.00%)	0/110 (0.00%)	0/101 (0.00%)	1/90 (1.11%)	0/88 (0.00%)	0/59 (0.00%)
Reproductive system and breast disorders
Uterine haemorrhage † 1	0/110 (0.00%)	0/110 (0.00%)	0/101 (0.00%)	0/90 (0.00%)	1/88 (1.14%)	0/59 (0.00%)
Cervical polyp † 1	0/110 (0.00%)	0/110 (0.00%)	1/101 (0.99%)	0/90 (0.00%)	0/88 (0.00%)	0/59 (0.00%)
Respiratory, thoracic and mediastinal disorders
Nasal septum deviation † 1	0/110 (0.00%)	0/110 (0.00%)	0/101 (0.00%)	0/90 (0.00%)	0/88 (0.00%)	1/59 (1.69%)
Skin and subcutaneous tissue disorders
Erythema nodosum † 1	0/110 (0.00%)	0/110 (0.00%)	0/101 (0.00%)	1/90 (1.11%)	0/88 (0.00%)	0/59 (0.00%)
Vascular disorders
Varicose vein † 1	0/110 (0.00%)	0/110 (0.00%)	0/101 (0.00%)	0/90 (0.00%)	1/88 (1.14%)	0/59 (0.00%)
Deep vein thrombosis † 1	0/110 (0.00%)	0/110 (0.00%)	0/101 (0.00%)	1/90 (1.11%)	0/88 (0.00%)	0/59 (0.00%)
Haematoma † 1	0/110 (0.00%)	0/110 (0.00%)	0/101 (0.00%)	0/90 (0.00%)	0/88 (0.00%)	1/59 (1.69%)
Venous stenosis † 1	0/110 (0.00%)	0/110 (0.00%)	1/101 (0.99%)	0/90 (0.00%)	0/88 (0.00%)	0/59 (0.00%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, meddra-18.0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Core Treatment Period: Teriflunomide 7 mg	Core Treatment:Teriflunomide 14 mg	Core Treatment: IFN-β-1a	Extended Treatment: Teriflunomide 14 mg (After 7 mg)	Extended Treatment: Teriflunomide 14 mg (After 14 mg)	Extended Treatment: Teriflunomide 14 mg (After IFN-β-1a)
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	85/110 (77.27%)	92/110 (83.64%)	92/101 (91.09%)	72/90 (80.00%)	65/88 (73.86%)	48/59 (81.36%)
Blood and lymphatic system disorders
Neutropenia † 1	1/110 (0.91%)	2/110 (1.82%)	4/101 (3.96%)	1/90 (1.11%)	2/88 (2.27%)	3/59 (5.08%)
Ear and labyrinth disorders
Vertigo † 1	1/110 (0.91%)	1/110 (0.91%)	2/101 (1.98%)	5/90 (5.56%)	6/88 (6.82%)	5/59 (8.47%)
Gastrointestinal disorders
Diarrhoea † 1	19/110 (17.27%)	17/110 (15.45%)	9/101 (8.91%)	10/90 (11.11%)	15/88 (17.05%)	8/59 (13.56%)
Abdominal pain † 1	5/110 (4.55%)	7/110 (6.36%)	2/101 (1.98%)	6/90 (6.67%)	3/88 (3.41%)	2/59 (3.39%)
Abdominal pain upper † 1	7/110 (6.36%)	7/110 (6.36%)	3/101 (2.97%)	3/90 (3.33%)	3/88 (3.41%)	4/59 (6.78%)
Nausea † 1	10/110 (9.09%)	10/110 (9.09%)	4/101 (3.96%)	0/90 (0.00%)	2/88 (2.27%)	1/59 (1.69%)
Dyspepsia † 1	4/110 (3.64%)	4/110 (3.64%)	0/101 (0.00%)	3/90 (3.33%)	1/88 (1.14%)	3/59 (5.08%)
Vomiting † 1	6/110 (5.45%)	9/110 (8.18%)	4/101 (3.96%)	2/90 (2.22%)	1/88 (1.14%)	1/59 (1.69%)
General disorders
Fatigue † 1	7/110 (6.36%)	6/110 (5.45%)	5/101 (4.95%)	4/90 (4.44%)	4/88 (4.55%)	2/59 (3.39%)
Asthenia † 1	3/110 (2.73%)	1/110 (0.91%)	9/101 (8.91%)	0/90 (0.00%)	2/88 (2.27%)	3/59 (5.08%)
Pyrexia † 1	10/110 (9.09%)	2/110 (1.82%)	3/101 (2.97%)	1/90 (1.11%)	1/88 (1.14%)	0/59 (0.00%)
Influenza like illness † 1	4/110 (3.64%)	4/110 (3.64%)	49/101 (48.51%)	2/90 (2.22%)	0/88 (0.00%)	6/59 (10.17%)
Injection site erythema † 1	0/110 (0.00%)	0/110 (0.00%)	10/101 (9.90%)	0/90 (0.00%)	0/88 (0.00%)	0/59 (0.00%)
Infections and infestations
Nasopharyngitis † 1	26/110 (23.64%)	24/110 (21.82%)	17/101 (16.83%)	11/90 (12.22%)	9/88 (10.23%)	3/59 (5.08%)
Urinary tract infection † 1	8/110 (7.27%)	3/110 (2.73%)	6/101 (5.94%)	8/90 (8.89%)	7/88 (7.95%)	3/59 (5.08%)
Bronchitis † 1	8/110 (7.27%)	4/110 (3.64%)	2/101 (1.98%)	4/90 (4.44%)	5/88 (5.68%)	4/59 (6.78%)
Upper respiratory tract infection † 1	8/110 (7.27%)	11/110 (10.00%)	9/101 (8.91%)	2/90 (2.22%)	5/88 (5.68%)	3/59 (5.08%)
Oral herpes † 1	9/110 (8.18%)	0/110 (0.00%)	2/101 (1.98%)	1/90 (1.11%)	4/88 (4.55%)	0/59 (0.00%)
Pharyngitis † 1	8/110 (7.27%)	1/110 (0.91%)	3/101 (2.97%)	4/90 (4.44%)	4/88 (4.55%)	5/59 (8.47%)
Influenza † 1	8/110 (7.27%)	9/110 (8.18%)	5/101 (4.95%)	3/90 (3.33%)	2/88 (2.27%)	2/59 (3.39%)
Ear infection † 1	3/110 (2.73%)	2/110 (1.82%)	2/101 (1.98%)	0/90 (0.00%)	1/88 (1.14%)	3/59 (5.08%)
Gastroenteritis † 1	5/110 (4.55%)	6/110 (5.45%)	3/101 (2.97%)	7/90 (7.78%)	1/88 (1.14%)	1/59 (1.69%)
Injury, poisoning and procedural complications
Fall † 1	6/110 (5.45%)	2/110 (1.82%)	2/101 (1.98%)	3/90 (3.33%)	0/88 (0.00%)	1/59 (1.69%)
Investigations
Alanine aminotransferase increased † 1	12/110 (10.91%)	9/110 (8.18%)	30/101 (29.70%)	5/90 (5.56%)	8/88 (9.09%)	2/59 (3.39%)
Musculoskeletal and connective tissue disorders
Back pain † 1	10/110 (9.09%)	11/110 (10.00%)	7/101 (6.93%)	5/90 (5.56%)	6/88 (6.82%)	5/59 (8.47%)
Pain in extremity † 1	11/110 (10.00%)	7/110 (6.36%)	4/101 (3.96%)	6/90 (6.67%)	4/88 (4.55%)	4/59 (6.78%)
Arthralgia † 1	6/110 (5.45%)	7/110 (6.36%)	4/101 (3.96%)	6/90 (6.67%)	3/88 (3.41%)	4/59 (6.78%)
Muscle spasms † 1	6/110 (5.45%)	5/110 (4.55%)	3/101 (2.97%)	1/90 (1.11%)	2/88 (2.27%)	2/59 (3.39%)
Myalgia † 1	2/110 (1.82%)	3/110 (2.73%)	7/101 (6.93%)	2/90 (2.22%)	1/88 (1.14%)	1/59 (1.69%)
Nervous system disorders
Hypoaesthesia † 1	6/110 (5.45%)	3/110 (2.73%)	2/101 (1.98%)	3/90 (3.33%)	4/88 (4.55%)	3/59 (5.08%)
Dizziness † 1	4/110 (3.64%)	1/110 (0.91%)	6/101 (5.94%)	3/90 (3.33%)	3/88 (3.41%)	0/59 (0.00%)
Headache † 1	23/110 (20.91%)	17/110 (15.45%)	26/101 (25.74%)	5/90 (5.56%)	3/88 (3.41%)	10/59 (16.95%)
Sciatica † 1	0/110 (0.00%)	0/110 (0.00%)	3/101 (2.97%)	1/90 (1.11%)	3/88 (3.41%)	3/59 (5.08%)
Paraesthesia † 1	14/110 (12.73%)	11/110 (10.00%)	8/101 (7.92%)	3/90 (3.33%)	2/88 (2.27%)	3/59 (5.08%)
Psychiatric disorders
Insomnia † 1	7/110 (6.36%)	1/110 (0.91%)	5/101 (4.95%)	2/90 (2.22%)	1/88 (1.14%)	2/59 (3.39%)
Renal and urinary disorders
Micturition urgency † 1	2/110 (1.82%)	3/110 (2.73%)	1/101 (0.99%)	2/90 (2.22%)	2/88 (2.27%)	3/59 (5.08%)
Reproductive system and breast disorders
Dysmenorrhoea † 1	3/110 (2.73%)	6/110 (5.45%)	1/101 (0.99%)	1/90 (1.11%)	2/88 (2.27%)	0/59 (0.00%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	7/110 (6.36%)	4/110 (3.64%)	1/101 (0.99%)	4/90 (4.44%)	2/88 (2.27%)	5/59 (8.47%)
Skin and subcutaneous tissue disorders
Alopecia † 1	6/110 (5.45%)	22/110 (20.00%)	1/101 (0.99%)	4/90 (4.44%)	1/88 (1.14%)	4/59 (6.78%)
Vascular disorders
Hypertension † 1	0/110 (0.00%)	5/110 (4.55%)	4/101 (3.96%)	7/90 (7.78%)	9/88 (10.23%)	7/59 (11.86%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, meddra-18.0

Limitations and Caveats

[Not Specified]

More Information

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
• EMail: Contact-US@sanofi.com

Publications of Results:

Vermersch P, Czlonkowska A, Grimaldi LM, Confavreux C, Comi G, Kappos L, Olsson TP, Benamor M, Bauer D, Truffinet P, Church M, Miller AE, Wolinsky JS, Freedman MS, O'Connor P; TENERE Trial Group. Teriflunomide versus subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis: a randomised, controlled phase 3 trial. Mult Scler. 2014 May;20(6):705-16. doi: 10.1177/1352458513507821. Epub 2013 Oct 14.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Comi G, Freedman MS, Meca-Lallana JE, Vermersch P, Kim BJ, Parajeles A, Edwards KR, Gold R, Korideck H, Chavin J, Poole EM, Coyle PK. Prior treatment status: impact on the efficacy and safety of teriflunomide in multiple sclerosis. BMC Neurol. 2020 Oct 6;20(1):364. doi: 10.1186/s12883-020-01937-4.

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT00883337
• Other Study ID Numbers: EFC10891; 2008-006226-34 ( EudraCT Number )
• First Submitted: April 16, 2009
• First Posted: April 17, 2009
• Results First Submitted: October 3, 2012
• Results First Posted: November 6, 2012
• Last Update Posted: June 13, 2016