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

• Sponsor: Sanofi (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00622700
• Collaborator: (none)
• Enrollment: 618
• Locations: 131
• Arms: 3
• Duration (Months): 96
• Patients Per Site: 4.7
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The primary objective was to demonstrate the effect of teriflunomide (HMR1726) (14 milligram per day [mg/day] and 7 mg/day), in comparison to placebo, for reducing conversion of participants presenting with their first clinical episode consistent with multiple sclerosis (MS) to clinically definite multiple sclerosis (CDMS).

The secondary objectives were:

• To demonstrate the effect of teriflunomide, in comparison to placebo, on:

• Reducing conversion to definite multiple sclerosis (DMS)

• Reducing annualized relapse rate (ARR)

• Reducing disease activity/progression as measured by Magnetic Resonance Imaging (MRI)

• Reducing accumulation of disability for at least 12 weeks as measured by the Expanded Disability Status Scale (EDSS)

• Proportion of disability-free participants as assessed by the EDSS

• Reducing participant-reported fatigue

• To evaluate the safety and tolerability of teriflunomide

• To evaluate the pharmacokinetics (PK) of teriflunomide

• Optional pharmacogenomic testing aimed at assessing the association between the main enzyme systems of teriflunomide metabolism and hepatic safety, and other potential associations between gene variations and clinical outcomes

Condition or Disease	Intervention/Treatment	Phase
Multiple Sclerosis	Drug: Teriflunomide; Drug: Placebo	Phase 3

Detailed Description

The study consisted of 4 periods:

• Screening period: up to 4 weeks,

• Placebo-controlled treatment period: up to 108 weeks (at least 24 weeks for participants who experienced conversion to CDMS),

• Extension treatment period (without placebo-control): the extension period continued until teriflunomide was commercially available in participant's country of residence.

• Post-treatment washout period: 4 weeks after last treatment intake.

The maximal duration of the study period per participant was expected to be 116 weeks if he/she did not continue in the extension treatment period.

Study Design

• Study Type: Interventional
• Actual Enrollment: 618 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: An International, Multi-center, Randomized, Double-blind, Placebo-controlled, Parallel Group Study to Evaluate the Efficacy and Safety of Two Year Treatment With Teriflunomide 7 mg Once Daily and 14 mg Once Daily Versus Placebo in Patients With a First Clinical Episode Suggestive of Multiple Sclerosis Plus a Long Term Extension Period
• Study Start Date: Feb 1, 2008
• Actual Primary Completion Date: Dec 1, 2012
• Actual Study Completion Date: Feb 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo/Teriflunomide 7 mg or Teriflunomide 14 mg Core treatment period: Placebo matched to teriflunomide tablet once daily orally. Extension treatment period: Re-randomized in 1:1 ratio to either teriflunomide 7 mg or 14 mg once daily orally.	Drug: Teriflunomide; Film-coated tablet Oral administration; Other Names: HMR1726 Aubagio ; Drug: Placebo; Film-coated tablet Oral administration
Experimental: Teriflunomide 7 mg/7 mg Core treatment period: Teriflunomide 7 mg tablet once daily orally. Extension treatment period: Teriflunomide 7 mg tablet once daily orally.	Drug: Teriflunomide; Film-coated tablet Oral administration; Other Names: HMR1726 Aubagio
Experimental: Teriflunomide 14 mg/14 mg Core treatment period: Teriflunomide 14 mg tablet once daily orally. Extension treatment period: Teriflunomide 14 mg tablet once daily orally.	Drug: Teriflunomide; Film-coated tablet Oral administration; Other Names: HMR1726 Aubagio

Outcome Measures

Primary Outcome Measures

1. Core Treatment Period: Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS) [Up to a maximum of 108 weeks depending on time of enrollment]

   Conversion to CDMS was defined by the occurrence of a relapse, which was defined as a new neurological abnormality separated by at least 30 days from onset of a preceding clinical event, presented for at least 24 hours and occurred in the absence of fever or known infection. Percent probability of conversion at 24, 48, and 108 weeks was estimated using Kaplan-Meier method.

Secondary Outcome Measures

1. Core Treatment Period: Time to Conversion to Definite Multiple Sclerosis (DMS) [Up to a maximum of 108 weeks depending on time of enrollment]

   Conversion to DMS was demonstrated by dissemination of MRI lesions in time (as per McDonald criteria) or a relapse, whichever occurs first. MRI Imaging criteria were detection of Gadolinium (Gd) enhancement at least 3 months after onset of initial clinical event, if not at site corresponding to initial event; detection of new T2 lesion if it appears at any time compared with reference scan (done at time of screening) done at least 30 days after onset of the initial clinical event. Occurrence of relapse was defined as new neurological abnormality separated by at least 30 days from onset of preceding clinical event, present for at least 24 hours and occurring in absence of fever or known infection. New clinical abnormality (neurological sign) that is consistent with participant's symptoms with increase in at least one Functional System (FS) or EDSS score compared to last EDSS assessment. Percent probability of conversion at 24, 48, and 108 weeks was estimated using Kaplan-Meier method.

2. Core Treatment Period: Annualized Relapse Rate (ARR) [Up to a maximum of 108 weeks depending on time of enrollment]

   ARR is the total number of confirmed relapses that occurred during the treatment period divided by the total number of patient-years treated. Each episode of relapse (appearance, or worsening of a clinical symptom that was stable for at least 30 days, that persisted for a minimum of 24 hours in the absence of fever) was to be confirmed by an increase in EDSS score or Functional System scores. ARR was assessed using Poisson regression model with robust error variance. To account for the different treatment durations among participants, a Poisson regression model with robust error variance was used (total number of confirmed relapses onset between randomization date and last dose date as the response variable, treatment, region and baseline monofocal/multifocal status as covariates, and log-transformed treatment duration as an offset variable).

3. Core Treatment Period: Brain Magnetic Resonance Imaging (MRI) Assessment: Change From Baseline in Total Lesion Volume at Week 108 [Baseline, Week 108]

   The total lesion volume (burden of disease) is the total volumes of hyperintense on T2 plus hypointense on T1 as measured by MRI scan. Least-square means were estimated using a Mixed-effect model with repeated measures (MMRM) on cubic root transformed volume data with factors for treatment, baseline monofocal/multifocal status, region, visit, treatment-by-visit interaction, cubic root transformed baseline burden of disease, and baseline-by-visit interaction.

4. Core Treatment Period: Brain MRI Assessment: Number of Gadolinium Enhancing (Gd-enhancing) T1-lesions Per MRI Scan (Poisson Regression Estimates) [Up to a maximum of 108 weeks depending on time of enrollment]

   Number of Gd-enhancing T1-lesions per scan is the total number of Gd-enhancing T1-lesions that occurred during the treatment period divided by the total number of scans performed during the treatment period. To account for the different numbers of scans performed among the participants, a Poisson regression model with robust error variance was used (total number of Gd-enhancing T1-lesions as response variable, treatment, baseline monofocal/multifocal status, region and baseline number of Gd-enhancing T1-lesions as covariates, and log-transformed number of scans as an offset variable).

5. Core Treatment Period: Brain MRI Assessment: Volume of Gadolinium Enhancing (Gd-enhancing) T1-lesions Per MRI Scan [Up to a maximum of 108 weeks depending on time of enrollment]

   Total volume of Gd-enhancing T1-lesions per scan is the sum of the volumes of Gd-enhancing T1-lesions observed during the treatment period divided by the total number of scans performed during the treatment period. To account for the different numbers of scans performed among the participants, a Poisson regression model with robust error variance was used (total number of Gd-enhancing T1-lesions as response variable, treatment, baseline monofocal/multifocal status, region and baseline number of Gd-enhancing T1-lesions as covariates, and log-transformed number of scans as an offset variable).

6. Core Treatment Period: Brain MRI Assessment: Change From Baseline in Volume of Hypointense Post-Gadolinium T1 Lesion Component [Baseline, Week 108]

   Volume of hypointense post-gadolinium T1 lesion component was measured by MRI scan. Least-square means were estimated using a Mixed-effect model with repeated measures (MMRM) on cubic root transformed volume data adjusted for baseline monofocal/multifocal status, region, visit, treatment-by-visit interaction, cubic root transformed baseline value, and baseline-by-visit interaction

7. Core Treatment Period: Brain MRI Assessment: Change From Baseline in Volume of T2 Lesion Component [Baseline, Week 108]

   Volume of T2 lesion component was measured by MRI scan. Least-square means were estimated using a Mixed-effect model with repeated measures (MMRM) on cubic root transformed volume data adjusted for baseline monofocal/multifocal status, region, visit, treatment-by-visit interaction, cubic root transformed baseline value, and baseline-by-visit interaction.

8. Core Treatment Period: Brain MRI Assessment: Percent Change From Baseline in Atrophy [Baseline, Week 108]

   Atrophy was measured by MRI scan.

9. Core Treatment Period: Time to 12-Week Sustained Disability Progression [Up to a maximum of 108 weeks depending on time of enrollment]

   The 12-week sustained disability progression was defined as increase from baseline of at least 1-point in EDSS score (at least 0.5-point for participants with baseline EDSS score of greater than [>] 5.5) that persisted for at least 12 weeks. Percent probability of participants free of 12-week sustained disability progression at 24, 48, and 108 weeks was estimated using Kaplan-Meier method.

10. Core Treatment Period: Change From Baseline in EDSS at Week 108 [Baseline, Week 108]

    EDSS is an ordinal scale in half-point increments that qualifies disability in participants with MS. It consists of 8 ordinal rating scales assessing seven functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder and cerebral) as well as ambulation. EDSS total score ranges from 0 (normal neurological examination) to 10 (death due to MS). Least-square means were estimated using a Mixed-effect model with repeated measures (MMRM) on cubic root transformed volume data adjusted for baseline monofocal/multifocal status, region, visit, treatment-by-visit interaction, baseline value and baseline-by-visit interaction

11. Core Treatment Period: Change From Baseline in Fatigue Impact Scale (FIS) Total Score at Week 108 [Baseline, Week 108]

    FIS is a participant-reported scale that qualifies the impact of fatigue on daily life in participants with MS. It consists of 40 statements that measure fatigue in three areas; physical, cognitive, and social. FIS total score ranges from 0 (no problem) to 160 (extreme problem). Least-square means were estimated using a Mixed-effect model with repeated measures [MMRM] on FIS total score data adjusted for or baseline monofocal/multifocal status, region, visit, treatment-by-visit interaction, baseline value and baseline-by-visit interaction.

12. Core Treatment Period: Overview of Adverse Events (AEs) [From first study drug intake up to 112 days after last intake in the placebo-controlled period or up to first intake in the extension treatment period, whichever occurred first]

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

13. Extension Treatment Period: Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS) [From randomization in the core period up to 390 Weeks (Extension treatment period [maximum exposure: 283 Weeks])]

    Conversion to CDMS was defined by the occurrence of a relapse, which was defined as a new neurological abnormality separated by at least 30 days from onset of a preceding clinical event, presented for at least 24 hours and occurred in the absence of fever or known infection. Percent probability of conversion was estimated using Kaplan-Meier method.

14. Extension Treatment Period: Overview of Adverse Events (AEs) [From re-randomization up to 283 Weeks]

    AEs are any unfavorable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study. Safety population included all randomized population who actually received at least 1 dose of the IMP in extension and analyzed according to the treatment actually received in core study followed by treatment actually received in the extension treatment period.

Other Outcome Measures

1. Core Treatment Period: Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) [From first study drug intake up to 112 days after last intake in the placebo-controlled period or up to first intake in the extension treatment period, whichever occurred first]

   PCSA values are abnormal values considered medically important by the Sponsor according to predefined criteria based on literature review. Hepatic parameters thresholds were defined as follows: Alanine Aminotransferase (ALT) >3, 5, 10 or 20 upper limit of normal(ULN); Aspartate aminotransferase (AST) >3, 5, 10 or 20 ULN; Alkaline Phosphatase >1.5 ULN; Total Bilirubin (TB) >1.5, 2, or 3 ULN; ALT >3 ULN and TB >2 ULN.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• First acute or subacute, well-defined neurological event consistent with demyelination (that is, optic neuritis confirmed by an ophthalmologist, spinal cord syndrome, brainstem/cerebellar syndromes)

• Onset of MS symptoms occurring within 90 days of randomization

• A screening MRI scan with 2 or more T2 lesions at least 3 millimeter (mm) in diameter that are characteristic of MS

Exclusion Criteria:

• Clinically relevant cardiovascular, hepatic, neurological, endocrine or other major systemic disease

• Significantly impaired bone marrow function

• Pregnancy or nursing

• Alcohol or drug abuse

• Use of cladribine, mitoxantrone, or other immunosuppressant agents such as azathioprine, cyclophosphamide, cyclosporin, methotrexate or mycophenolate before enrollment

• Any known condition or circumstance that would prevent in the investigator's opinion compliance or completion of the study

The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Investigational Site Number 8965	Cullman	Alabama	United States	35058
2	Investigational Site Number 8954	Phoenix	Arizona	United States	85013-4496
3	Investigational Site Number 8946	Phoenix	Arizona	United States	85060
4	Investigational Site Number 8962	Fort Collins	Colorado	United States	80528
5	Investigational Site Number 8920	Maitland	Florida	United States	32761
6	Investigational Site Number 8953	St. Petersburg	Florida	United States	33701
7	Investigational Site Number 8914	Ft. Wayne	Indiana	United States	63104
8	Investigational Site Number 8940	Indianapolis	Indiana	United States	46256
9	Investigational Site Number 8922	Shreveport	Louisiana	United States	71103
10	Investigational Site Number 8955	Grand Rapids	Michigan	United States	49503
11	Investigational Site Number 8949	Traverse City	Michigan	United States	49684
12	Investigational Site Number 8937	St Louis	Missouri	United States	63104
13	Investigational Site Number 8951	Albuquerque	New Mexico	United States	87131
14	Investigational Site Number 8925	New York	New York	United States	10029-6574
15	Investigational Site Number 8941	Charlotte	North Carolina	United States	28204
16	Investigational Site Number 8924	Dayton	Ohio	United States	45409
17	Investigational Site Number 8905	Round Rock	Tennessee	United States	78681
18	Investigational Site Number 8930	Burlington	Vermont	United States	05401
19	Investigational Site Number 8963	Seattle	Washington	United States	98122
20	Investigational Site Number 1405	Geelong		Australia	3220
21	Investigational Site Number 1404	Heidelberg		Australia	3081
22	Investigational Site Number 1407	Hobart		Australia	7001
23	Investigational Site Number 1401	Parkville		Australia	3050
24	Investigational Site Number 4004	Innsbruck		Austria	6020
25	Investigational Site Number 4005	Linz		Austria	4020
26	Investigational Site Number 4001	Wien		Austria	1010
27	Investigational Site Number 5312	Pleven		Bulgaria	5800
28	Investigational Site Number 5307	Sofia		Bulgaria	1000
29	Investigational Site Number 5304	Sofia		Bulgaria	1407
30	Investigational Site Number 5309	Sofia		Bulgaria	1431
31	Investigational Site Number 5303	Sofia		Bulgaria	1527
32	Investigational Site Number 5306	Sofia		Bulgaria	1606
33	Investigational Site Number 5402	Greenfield Park		Canada	J4V 2J2
34	Investigational Site Number 5403	London		Canada	N6A 5A5
35	Investigational Site Number 5409	Montreal		Canada	H1T 2M4
36	Investigational Site Number 5401	Ottawa		Canada	K1H 8L6
37	Investigational Site Number 5406	Quebec		Canada	G1J 1Z4
38	Investigational Site Number 5408	Sherbrooke		Canada	J1H 5N4
39	Investigational Site Number 5410	Toronto		Canada	M4N 3M5
40	Investigational Site Number 5404	Toronto		Canada	M5B 1W8
41	Investigational Site Number 5602	Santiago		Chile	760-0746
42	Investigational Site Number 5601	Santiago		Chile
43	Investigational Site Number 5606	Santiago		Chile
44	Investigational Site Number 5605	Viña Del Mar		Chile	2520997
45	Investigational Site Number 5801	Brno		Czech Republic	65691
46	Investigational Site Number 5803	Hradec Kralove		Czech Republic	50005
47	Investigational Site Number 5804	Olomouc		Czech Republic	77520
48	Investigational Site Number 5805	Ostrava - Poruba		Czech Republic	70852
49	Investigational Site Number 6002	Aarhus C		Denmark	8000
50	Investigational Site Number 6004	Esbjerg		Denmark	6700
51	Investigational Site Number 6201	Tallinn		Estonia	10617
52	Investigational Site Number 6203	Tartu		Estonia	50406
53	Investigational Site Number 6405	Helsinki		Finland	00100
54	Investigational Site Number 6403	Kuopio		Finland	70210
55	Investigational Site Number 6401	Turku		Finland	20100
56	Investigational Site Number 6611	Besancon		France	25030
57	Investigational Site Number 6601	Clermont Ferrand Cedex 1		France	63003
58	Investigational Site Number 6609	Lille Cedex		France	59037
59	Investigational Site Number 6604	Montpellier Cedex 05		France	34295
60	Investigational Site Number 6612	Nancy Cedex		France	54036
61	Investigational Site Number 6605	Nantes Cedex 01		France	44093
62	Investigational Site Number 6602	Nice Cedex		France	06002
63	Investigational Site Number 6614	Nimes		France	30029
64	Investigational Site Number 6607	Strasbourg Cedex		France	67091
65	Investigational Site Number 6801	Bayreuth		Germany	95445
66	Investigational Site Number 6810	Berlin		Germany	10713
67	Investigational Site Number 6805	Berlin		Germany	10785
68	Investigational Site Number 6807	Erbach		Germany	64711
69	Investigational Site Number 6803	Essen		Germany	45122
70	Investigational Site Number 6809	Hannover		Germany	30625
71	Investigational Site Number 6804	Ludwigshafen		Germany	67063
72	Investigational Site Number 6815	Minden		Germany	32429
73	Investigational Site Number 6802	Münster		Germany	48149
74	Investigational Site Number 6806	Wiesbaden		Germany	65191
75	Investigational Site Number 7101	Budapest		Hungary	1076
76	Investigational Site Number 7103	Budapest		Hungary	1145
77	Investigational Site Number 7108	Esztergom		Hungary	2500
78	Investigational Site Number 7105	Veszprém		Hungary	8200
79	Investigational Site Number 7402	Klaipeda		Lithuania	LT-92288
80	Investigational Site Number 7403	Siauliai		Lithuania	LT-76231
81	Investigational Site Number 7401	Vilnius		Lithuania	LT-08661
82	Investigational Site Number 7501	Chihuahua		Mexico	31203
83	Investigational Site Number 7502	Guadalajara		Mexico	45110
84	Investigational Site Number 7709	Gdansk		Poland	80-803
85	Investigational Site Number 7710	Lodz		Poland	93-513
86	Investigational Site Number 7707	Warszawa 44		Poland	04-141
87	Investigational Site Number 7701	Warszawa		Poland	02-097
88	Investigational Site Number 7703	Warszawa		Poland	02-957
89	Investigational Site Number 7803	Bucuresti		Romania	020125
90	Investigational Site Number 7806	Bucuresti		Romania	050098
91	Investigational Site Number 7805	Cluj-Napoca		Romania	400012
92	Investigational Site Number 7807	Cluj-Napoca		Romania	400012
93	Investigational Site Number 7808	Timisoara		Romania	300736
94	Investigational Site Number 7907	Kazan		Russian Federation	420021
95	Investigational Site Number 7909	Nizhny Novgorod		Russian Federation	603000
96	Investigational Site Number 7906	Nizhny Novgorod		Russian Federation	603076
97	Investigational Site Number 7904	Nizhny Novgorod		Russian Federation	603126
98	Investigational Site Number 7912	Novosibirsk		Russian Federation	630007
99	Investigational Site Number 7910	Rostov-On-Don		Russian Federation	344085
100	Investigational Site Number 7905	Smolensk		Russian Federation	214019
101	Investigational Site Number 7911	St-Petersburg		Russian Federation	194044
102	Investigational Site Number 8304	Edirne		Turkey
103	Investigational Site Number 8309	Istanbul		Turkey	34390
104	Investigational Site Number 8315	Istanbul		Turkey	34400
105	Investigational Site Number 8308	Istanbul		Turkey
106	Investigational Site Number 8310	Istanbul		Turkey
107	Investigational Site Number 8312	Istanbul		Turkey
108	Investigational Site Number 8305	Izmir		Turkey	35100
109	Investigational Site Number 8301	Izmir		Turkey	35340
110	Investigational Site Number 8303	Izmir		Turkey	35380
111	Investigational Site Number 8302	Izmit		Turkey	41380
112	Investigational Site Number 8314	Trabzon		Turkey	61080
113	Investigational Site Number 8507	Chernihiv		Ukraine	14029
114	Investigational Site Number 8501	Dnipropetrovsk		Ukraine	49027
115	Investigational Site Number 8511	Donets'K		Ukraine	83099
116	Investigational Site Number 8506	Kharkiv		Ukraine	61018
117	Investigational Site Number 8504	Kharkiv		Ukraine	61178
118	Investigational Site Number 8508	Kiev		Ukraine	03110
119	Investigational Site Number 8512	Lutsk		Ukraine	43005
120	Investigational Site Number 8505	Lviv		Ukraine	79010
121	Investigational Site Number 8510	Poltava		Ukraine	36011
122	Investigational Site Number 8503	Vinnytsya		Ukraine	21005
123	Investigational Site Number 8502	Zaporizhzhya		Ukraine	69000
124	Investigational Site Number 8709	Liverpool		United Kingdom	L9 7LJ
125	Investigational Site Number 8701	London		United Kingdom	E1 1BB
126	Investigational Site Number 8704	London		United Kingdom	SW17 0QT
127	Investigational Site Number 8706	Newcastle Upon Tyne		United Kingdom	NE1 4LP
128	Investigational Site Number 8705	Nottingham		United Kingdom	NG7 2UH
129	Investigational Site Number 8708	Plymouth		United Kingdom	PL6 5BX
130	Investigational Site Number 8707	Salford		United Kingdom	M6 8HD
131	Investigational Site Number 8702	Sheffield		United Kingdom	S10 2JF

Sponsors and Collaborators

• Sanofi

Investigators

• Study Director: Clinical Sciences & Operations, Sanofi

Study Documents (Full-Text)

None provided.

More Information

Publications

• Miller AE, Wolinsky JS, Kappos L, Comi G, Freedman MS, Olsson TP, Bauer D, Benamor M, Truffinet P, O'Connor PW; TOPIC Study Group. Oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis (TOPIC): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2014 Oct;13(10):977-86. doi: 10.1016/S1474-4422(14)70191-7. Epub 2014 Sep 2.

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT00622700
• Other Study ID Numbers: EFC6260; HMR1726D-3005; 2006-001152-12
• First Posted: Feb 25, 2008
• Last Update Posted: Mar 13, 2017
• Last Verified: Jan 1, 2017

• Keywords provided by Sanofi: MS; Clinically Isolated Syndrome; CIS; CDMS; relapses
• Additional relevant MeSH terms: Multiple Sclerosis; Sclerosis; Teriflunomide

Study Results

Participant Flow

Recruitment Details	A total of 846 participants were screened, of which 618 randomized in core treatment period. Out of 618, 423 entered in extension treatment period. End date of core treatment period was 17 December 2012 (maximum treatment duration: 120 weeks). End date of extension treatment period was 05 February 2016 (maximum treatment duration: 283 weeks).
Pre-assignment Detail	Participants were randomized in 1:1:1 ratio to teriflunomide 7 mg,14 mg or placebo in core treatment period. Those completing core period, given opportunity to enter long-term extension period (participants originally given placebo re-randomized [1:1]to teriflunomide 7 mg/14 mg; those originally given 7 mg,14 mg continued with the same fixed dose).

Arm/Group Title	Placebo	Teriflunomide 7 mg	Teriflunomide 14 mg	Placebo/ Teriflunomide 7 mg	Teriflunomide 7 mg/7 mg	Placebo/Teriflunomide 14 mg	Teriflunomide 14 mg/14 mg
Arm/Group Description	Core treatment period: Placebo matched to teriflunomide tablet once daily orally.	Core treatment period: Teriflunomide 7 mg tablet once daily orally.	Core treatment period: Teriflunomide 14 mg tablet once daily orally.	Core treatment period: Placebo matched to teriflunomide tablet once daily orally. Extension treatment period: Teriflunomide 7 mg tablet once daily orally.	Core treatment period: Teriflunomide 7 mg tablet once daily orally. Extension treatment period: Teriflunomide 7 mg tablet once daily orally.	Core treatment period: Placebo matched to teriflunomide tablet once daily orally. Extension treatment period: Teriflunomide 14 mg tablet once daily orally.	Core treatment period: Teriflunomide 14 mg tablet once daily orally. Extension treatment period: Teriflunomide 14 mg tablet once daily orally.
Period Title: Core Treatment Period
STARTED	197	205	216	0	0	0	0
Treated	197	203	214	0	0	0	0
COMPLETED	141	150	163	0	0	0	0
NOT COMPLETED	56	55	53	0	0	0	0
Period Title: Core Treatment Period
STARTED	0	0	0	64	142	67	150
COMPLETED	0	0	0	43	103	50	120
NOT COMPLETED	0	0	0	21	39	17	30

Baseline Characteristics

Arm/Group Title	Placebo	Teriflunomide 7 mg	Teriflunomide 14 mg	Total
Arm/Group Description	Placebo matched to teriflunomide tablet once daily orally.	Teriflunomide 7 mg tablet once daily orally.	Teriflunomide 14 mg tablet once daily orally.	Total of all reporting groups
Overall Participants	197	205	216	618
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	32.0 (8.4)	31.6 (9.0)	32.8 (8.1)	32.7 (8.9)
Sex: Female, Male (Count of Participants)
Female	135 68.5%	130 63.4%	154 71.3%	419 67.8%
Male	62 31.5%	75 36.6%	62 28.7%	199 32.2%
Region (participants) [Number]
Eastern Europe	94 47.7%	96 46.8%	101 46.8%	291 47.1%
Western Europe	76 38.6%	74 36.1%	74 34.3%	224 36.2%
Americas and Australia	27 13.7%	35 17.1%	41 19%	103 16.7%
Expanded Disability Status Scale (EDSS) Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	1.71 (1.00)	1.50 (1.02)	1.80 (0.97)	1.67 (1.00)

Outcome Measures

1. Primary Outcome

Title	Core Treatment Period: Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS)
Description	Conversion to CDMS was defined by the occurrence of a relapse, which was defined as a new neurological abnormality separated by at least 30 days from onset of a preceding clinical event, presented for at least 24 hours and occurred in the absence of fever or known infection. Percent probability of conversion at 24, 48, and 108 weeks was estimated using Kaplan-Meier method.
Time Frame	Up to a maximum of 108 weeks depending on time of enrollment

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population included all randomized participants who had at least 1 day study medication exposure. Participants were analyzed in the treatment group to which they were randomized.

Arm/Group Title	Placebo	Teriflunomide 7 mg	Teriflunomide 14 mg
Arm/Group Description	Placebo matched to teriflunomide tablet once daily orally.	Teriflunomide 7 mg tablet once daily orally.	Teriflunomide 14 mg tablet once daily orally.
Measure Participants	197	203	214
Percent Probability of Conversion at 24 weeks	14.3	8.7	9.0
Percent Probability of Conversion at 48 weeks	26.0	14.2	13.7
Percent Probability of Conversion at 108 weeks	35.9	27.6	24.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Teriflunomide 14 mg
	Comments	A step-down hierarchical testing procedure, starting with the test of teriflunomide 14 mg versus placebo was used. Time to conversion to CDMS was analyzed using the Cox proportional hazard model with treatment, region, and baseline monofocal/multifocal status as covariates.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0087
	Comments	P value was derived using Wald chi-squared test in the Cox proportional hazard model.
	Method	Wald chi-squared
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.574
	Confidence Interval	(2-Sided) 95%; 0.379 to 0.869
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Teriflunomide 7 mg
	Comments	A step-down hierarchical testing procedure was used. The second step was the test of teriflunomide 7 mg versus placebo for time to conversion to CDMS. Time to conversion to CDMS was analyzed using the Cox proportional hazard model with treatment, region, and baseline monofocal/multifocal status as covariates.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0271
	Comments	P value was derived using Wald chi-squared test in the Cox proportional hazard model.
	Method	Wald chi-squared
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.628
	Confidence Interval	(2-Sided) 95%; 0.416 to 0.949
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Core Treatment Period: Time to Conversion to Definite Multiple Sclerosis (DMS)
Description	Conversion to DMS was demonstrated by dissemination of MRI lesions in time (as per McDonald criteria) or a relapse, whichever occurs first. MRI Imaging criteria were detection of Gadolinium (Gd) enhancement at least 3 months after onset of initial clinical event, if not at site corresponding to initial event; detection of new T2 lesion if it appears at any time compared with reference scan (done at time of screening) done at least 30 days after onset of the initial clinical event. Occurrence of relapse was defined as new neurological abnormality separated by at least 30 days from onset of preceding clinical event, present for at least 24 hours and occurring in absence of fever or known infection. New clinical abnormality (neurological sign) that is consistent with participant's symptoms with increase in at least one Functional System (FS) or EDSS score compared to last EDSS assessment. Percent probability of conversion at 24, 48, and 108 weeks was estimated using Kaplan-Meier method.
Time Frame	Up to a maximum of 108 weeks depending on time of enrollment

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Placebo	Teriflunomide 7 mg	Teriflunomide 14 mg
Arm/Group Description	Placebo matched to teriflunomide tablet once daily orally.	Teriflunomide 7 mg tablet once daily orally.	Teriflunomide 14 mg tablet once daily orally.
Measure Participants	197	203	214
Percent Probability of Conversion at 24 weeks	58.2	45.7	46.0
Percent Probability of Conversion at 48 weeks	72.4	57.3	57.8
Percent Probability of Conversion at 108 weeks	87.0	73.3	71.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Teriflunomide 14 mg
	Comments	A step-down hierarchical testing procedure was used. The third step was the test of teriflunomide 14 mg versus placebo for time to conversion to DMS. This was analyzed using the Cox proportional hazard model with treatment, region, and baseline monofocal/multifocal status as covariates.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments	P value was derived using Wald chi-squared test in the Cox proportional hazard model.
	Method	Wald chi-squared
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.651
	Confidence Interval	(2-Sided) 95%; 0.515 to 0.822
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Teriflunomide 7 mg
	Comments	A step-down hierarchical testing procedure was used. The fourth step was the test of teriflunomide 7 mg versus placebo for time to conversion to DMS. This was analyzed using the Cox proportional hazard model with treatment, region, and baseline monofocal/multifocal status as covariates.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0020
	Comments	P value was derived using Wald chi-squared test in the Cox proportional hazard model.
	Method	Wald chi-squared
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.686
	Confidence Interval	(2-Sided) 95%; 0.540 to 0.871
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Core Treatment Period: Annualized Relapse Rate (ARR)
Description	ARR is the total number of confirmed relapses that occurred during the treatment period divided by the total number of patient-years treated. Each episode of relapse (appearance, or worsening of a clinical symptom that was stable for at least 30 days, that persisted for a minimum of 24 hours in the absence of fever) was to be confirmed by an increase in EDSS score or Functional System scores. ARR was assessed using Poisson regression model with robust error variance. To account for the different treatment durations among participants, a Poisson regression model with robust error variance was used (total number of confirmed relapses onset between randomization date and last dose date as the response variable, treatment, region and baseline monofocal/multifocal status as covariates, and log-transformed treatment duration as an offset variable).
Time Frame	Up to a maximum of 108 weeks depending on time of enrollment

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Placebo	Teriflunomide 7 mg	Teriflunomide 14 mg
Arm/Group Description	Placebo matched to teriflunomide tablet once daily orally.	Teriflunomide 7 mg tablet once daily orally.	Teriflunomide 14 mg tablet once daily orally.
Measure Participants	197	203	214
Number (95% Confidence Interval) [relapses per patient year]	0.284	0.190	0.194

4. Secondary Outcome

Title	Core Treatment Period: Brain Magnetic Resonance Imaging (MRI) Assessment: Change From Baseline in Total Lesion Volume at Week 108
Description	The total lesion volume (burden of disease) is the total volumes of hyperintense on T2 plus hypointense on T1 as measured by MRI scan. Least-square means were estimated using a Mixed-effect model with repeated measures (MMRM) on cubic root transformed volume data with factors for treatment, baseline monofocal/multifocal status, region, visit, treatment-by-visit interaction, cubic root transformed baseline burden of disease, and baseline-by-visit interaction.
Time Frame	Baseline, Week 108

Outcome Measure Data

Analysis Population Description

ITT population, but including only participants who had post-baseline data.

Arm/Group Title	Placebo	Teriflunomide 7 mg	Teriflunomide 14 mg
Arm/Group Description	Placebo matched to teriflunomide tablet once daily orally.	Teriflunomide 7 mg tablet once daily orally.	Teriflunomide 14 mg tablet once daily orally.
Measure Participants	68	75	99
Least Squares Mean (Standard Error) [milliliter]	0.053 (0.033)	0.041 (0.032)	-0.038 (0.029)

5. Secondary Outcome

Title	Core Treatment Period: Brain MRI Assessment: Number of Gadolinium Enhancing (Gd-enhancing) T1-lesions Per MRI Scan (Poisson Regression Estimates)
Description	Number of Gd-enhancing T1-lesions per scan is the total number of Gd-enhancing T1-lesions that occurred during the treatment period divided by the total number of scans performed during the treatment period. To account for the different numbers of scans performed among the participants, a Poisson regression model with robust error variance was used (total number of Gd-enhancing T1-lesions as response variable, treatment, baseline monofocal/multifocal status, region and baseline number of Gd-enhancing T1-lesions as covariates, and log-transformed number of scans as an offset variable).
Time Frame	Up to a maximum of 108 weeks depending on time of enrollment

Outcome Measure Data

Analysis Population Description

ITT population, but including only participants who had post-baseline data.

Arm/Group Title	Placebo	Teriflunomide 7 mg	Teriflunomide 14 mg
Arm/Group Description	Placebo matched to teriflunomide tablet once daily orally.	Teriflunomide 7 mg tablet once daily orally.	Teriflunomide 14 mg tablet once daily orally.
Measure Participants	109	84	74
Number (95% Confidence Interval) [lesions per scan]	0.953	0.749	0.395

6. Secondary Outcome

Title	Core Treatment Period: Brain MRI Assessment: Volume of Gadolinium Enhancing (Gd-enhancing) T1-lesions Per MRI Scan
Description	Total volume of Gd-enhancing T1-lesions per scan is the sum of the volumes of Gd-enhancing T1-lesions observed during the treatment period divided by the total number of scans performed during the treatment period. To account for the different numbers of scans performed among the participants, a Poisson regression model with robust error variance was used (total number of Gd-enhancing T1-lesions as response variable, treatment, baseline monofocal/multifocal status, region and baseline number of Gd-enhancing T1-lesions as covariates, and log-transformed number of scans as an offset variable).
Time Frame	Up to a maximum of 108 weeks depending on time of enrollment

Outcome Measure Data

Analysis Population Description

ITT population, but including only participants who had post-baseline data.

Arm/Group Title	Placebo	Teriflunomide 7 mg	Teriflunomide 14 mg
Arm/Group Description	Placebo matched to teriflunomide tablet once daily orally.	Teriflunomide 7 mg tablet once daily orally.	Teriflunomide 14 mg tablet once daily orally.
Measure Participants	109	84	74
Number [milliliters per scan]	0.079	0.058	0.034

7. Secondary Outcome

Title	Core Treatment Period: Brain MRI Assessment: Change From Baseline in Volume of Hypointense Post-Gadolinium T1 Lesion Component
Description	Volume of hypointense post-gadolinium T1 lesion component was measured by MRI scan. Least-square means were estimated using a Mixed-effect model with repeated measures (MMRM) on cubic root transformed volume data adjusted for baseline monofocal/multifocal status, region, visit, treatment-by-visit interaction, cubic root transformed baseline value, and baseline-by-visit interaction
Time Frame	Baseline, Week 108

Outcome Measure Data

Analysis Population Description

ITT population, but including only participants who had post-baseline data.

Arm/Group Title	Placebo	Teriflunomide 7 mg	Teriflunomide 14 mg
Arm/Group Description	Placebo matched to teriflunomide tablet once daily orally.	Teriflunomide 7 mg tablet once daily orally.	Teriflunomide 14 mg tablet once daily orally.
Measure Participants	68	75	99
Least Squares Mean (Standard Error) [milliliter]	0.028 (0.018)	0.025 (0.018)	-0.033 (0.016)

8. Secondary Outcome

Title	Core Treatment Period: Brain MRI Assessment: Change From Baseline in Volume of T2 Lesion Component
Description	Volume of T2 lesion component was measured by MRI scan. Least-square means were estimated using a Mixed-effect model with repeated measures (MMRM) on cubic root transformed volume data adjusted for baseline monofocal/multifocal status, region, visit, treatment-by-visit interaction, cubic root transformed baseline value, and baseline-by-visit interaction.
Time Frame	Baseline, Week 108

Outcome Measure Data

Analysis Population Description

ITT population, but including only participants who had post-baseline data.

Arm/Group Title	Placebo	Teriflunomide 7 mg	Teriflunomide 14 mg
Arm/Group Description	Placebo matched to teriflunomide tablet once daily orally.	Teriflunomide 7 mg tablet once daily orally.	Teriflunomide 14 mg tablet once daily orally.
Measure Participants	68	75	99
Least Squares Mean (Standard Error) [milliliter]	0.052 (0.033)	0.036 (0.032)	-0.035 (0.029)

9. Secondary Outcome

Title	Core Treatment Period: Brain MRI Assessment: Percent Change From Baseline in Atrophy
Description	Atrophy was measured by MRI scan.
Time Frame	Baseline, Week 108

Outcome Measure Data

Analysis Population Description

ITT population, but including only participants who had post-baseline data.

Arm/Group Title	Placebo	Teriflunomide 7 mg	Teriflunomide 14 mg
Arm/Group Description	Placebo matched to teriflunomide tablet once daily orally.	Teriflunomide 7 mg tablet once daily orally.	Teriflunomide 14 mg tablet once daily orally.
Measure Participants	68	75	99
Mean (Standard Deviation) [percent change]	-0.386 (1.326)	-0.197 (1.218)	-0.366 (1.151)

10. Secondary Outcome

Title	Core Treatment Period: Time to 12-Week Sustained Disability Progression
Description	The 12-week sustained disability progression was defined as increase from baseline of at least 1-point in EDSS score (at least 0.5-point for participants with baseline EDSS score of greater than [>] 5.5) that persisted for at least 12 weeks. Percent probability of participants free of 12-week sustained disability progression at 24, 48, and 108 weeks was estimated using Kaplan-Meier method.
Time Frame	Up to a maximum of 108 weeks depending on time of enrollment

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Placebo	Teriflunomide 7 mg	Teriflunomide 14 mg
Arm/Group Description	Placebo matched to teriflunomide tablet once daily orally.	Teriflunomide 7 mg tablet once daily orally.	Teriflunomide 14 mg tablet once daily orally.
Measure Participants	197	203	214
Percent Probability at 24 weeks	96.0	94.3	97.9
Percent Probability at 48 weeks	91.7	90.1	93.9
Percent Probability at 108 weeks	85.5	86.5	89.2

11. Secondary Outcome

Title	Core Treatment Period: Change From Baseline in EDSS at Week 108
Description	EDSS is an ordinal scale in half-point increments that qualifies disability in participants with MS. It consists of 8 ordinal rating scales assessing seven functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder and cerebral) as well as ambulation. EDSS total score ranges from 0 (normal neurological examination) to 10 (death due to MS). Least-square means were estimated using a Mixed-effect model with repeated measures (MMRM) on cubic root transformed volume data adjusted for baseline monofocal/multifocal status, region, visit, treatment-by-visit interaction, baseline value and baseline-by-visit interaction
Time Frame	Baseline, Week 108

Outcome Measure Data

Analysis Population Description

ITT population, but including only participants who had post-baseline data.

Arm/Group Title	Placebo	Teriflunomide 7 mg	Teriflunomide 14 mg
Arm/Group Description	Placebo matched to teriflunomide tablet once daily orally.	Teriflunomide 7 mg tablet once daily orally.	Teriflunomide 14 mg tablet once daily orally.
Measure Participants	80	82	102
Least Squares Mean (Standard Error) [units on a scale]	0.069 (0.087)	-0.191 (0.086)	-0.166 (0.080)

12. Secondary Outcome

Title	Core Treatment Period: Change From Baseline in Fatigue Impact Scale (FIS) Total Score at Week 108
Description	FIS is a participant-reported scale that qualifies the impact of fatigue on daily life in participants with MS. It consists of 40 statements that measure fatigue in three areas; physical, cognitive, and social. FIS total score ranges from 0 (no problem) to 160 (extreme problem). Least-square means were estimated using a Mixed-effect model with repeated measures [MMRM] on FIS total score data adjusted for or baseline monofocal/multifocal status, region, visit, treatment-by-visit interaction, baseline value and baseline-by-visit interaction.
Time Frame	Baseline, Week 108

Outcome Measure Data

Analysis Population Description

ITT population, but including only participants who had post-baseline data.

Arm/Group Title	Placebo	Teriflunomide 7 mg	Teriflunomide 14 mg
Arm/Group Description	Placebo matched to teriflunomide tablet once daily orally.	Teriflunomide 7 mg tablet once daily orally.	Teriflunomide 14 mg tablet once daily orally.
Measure Participants	84	95	106
Least Squares Mean (Standard Error) [units on a scale]	-2.537 (2.794)	-2.524 (2.710)	-1.827 (2.551)

13. Secondary Outcome

Title	Core Treatment Period: Overview of Adverse Events (AEs)
Description	AEs are any unfavorable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study.
Time Frame	From first study drug intake up to 112 days after last intake in the placebo-controlled period or up to first intake in the extension treatment period, whichever occurred first

Outcome Measure Data

Analysis Population Description

Safety population:all randomized participants exposed to study medication; analyzed according to drug actually received. In Placebo arm, 4 received teriflunomide 7mg & 2 received teriflunomide 14mg, hence they were included in respective teriflunomide arm. Participants who were randomized but not treated were excluded (2 in each teriflunomide arm).

Arm/Group Title	Placebo	Teriflunomide 7 mg	Teriflunomide 14 mg
Arm/Group Description	Placebo matched to teriflunomide tablet once daily orally.	Teriflunomide 7 mg tablet once daily orally.	Teriflunomide 14 mg tablet once daily orally.
Measure Participants	191	207	216
Any AE	155 78.7%	161 78.5%	183 84.7%
Any serious AE	18 9.1%	18 8.8%	24 11.1%
Any AE leading to death	1 0.5%	0 0%	0 0%
Any AE leading to treatment discontinuation	19 9.6%	25 12.2%	18 8.3%

14. Secondary Outcome

Title	Extension Treatment Period: Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS)
Description	Conversion to CDMS was defined by the occurrence of a relapse, which was defined as a new neurological abnormality separated by at least 30 days from onset of a preceding clinical event, presented for at least 24 hours and occurred in the absence of fever or known infection. Percent probability of conversion was estimated using Kaplan-Meier method.
Time Frame	From randomization in the core period up to 390 Weeks (Extension treatment period [maximum exposure: 283 Weeks])

Outcome Measure Data

Analysis Population Description

ITT Population: all randomized participants in the extension who had at least 1 day IMP exposure. Participants were analyzed according to the treatment group allocated by the randomization in the core study followed by the re-randomized treatment group during the extension period.

Arm/Group Title	Placebo/Teriflunomide 7 mg	Teriflunomide 7 mg/ 7mg	Placebo/ Teriflunomide 14 mg	Teriflunomide 14 mg/14 mg
Arm/Group Description	Core treatment period: Placebo matched to teriflunomide tablet once daily orally. Extension treatment period: Teriflunomide 7 mg tablet once daily orally.	Core treatment period: Placebo matched to teriflunomide tablet once daily orally. Extension treatment period: Teriflunomide 7 mg tablet once daily orally.	Core treatment period: Placebo matched to teriflunomide tablet once daily orally. Extension treatment period: Teriflunomide 14 mg tablet once daily orally.	Core treatment period: Teriflunomide 14 mg tablet once daily orally. Extension treatment period: Teriflunomide 14 mg tablet once daily orally.
Measure Participants	64	142	67	150
Percent Probability of Conversion at 24 Weeks	4.7	3.5	13.5	4.7
Percent Probability of Conversion at 48 Weeks	12.5	9.9	21.2	8.7
Percent Probability of Conversion at 72 Weeks	15.7	17.1	24.3	14.8
Percent Probability of Conversion at 96 Weeks	18.9	23.9	27.4	16.2
Percent Probability of Conversion at 120 Weeks	22.3	27.7	32.2	18.3
Percent Probability of Conversion at 144 Weeks	22.3	29.4	33.9	22.0
Percent Probability of Conversion at 168 Weeks	22.3	32.2	33.9	22.8
Percent Probability of Conversion at 192 Weeks	22.3	37.5	35.9	24.8
Percent Probability of Conversion at 216 Weeks	25.6	38.9	39.3	24.8
Percent Probability of Conversion at 240 Weeks	29.5	40.8	39.3	26.3
Percent Probability of Conversion at 264 Weeks	29.5	43.0	39.3	26.3
Percent Probability of Conversion at 288 Weeks	29.5	43.0	39.3	26.3
Percent Probability of Conversion at 312 Weeks	29.5	43.0	49.4	26.3
Percent Probability of Conversion at 336 Weeks	29.5	48.7	49.4	26.3

15. Secondary Outcome

Title	Extension Treatment Period: Overview of Adverse Events (AEs)
Description	AEs are any unfavorable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study. Safety population included all randomized population who actually received at least 1 dose of the IMP in extension and analyzed according to the treatment actually received in core study followed by treatment actually received in the extension treatment period.
Time Frame	From re-randomization up to 283 Weeks

Outcome Measure Data

Analysis Population Description

Analysis was performed on Safety population. In Placebo/teriflunomide 7mg arm, 2 received 7mg in the core period; In Placebo/teriflunomide 14mg, 1 received 7mg in the core period, hence, they were included in the 7mg/7mg arm in extension period as treatment received in the core period for consistency.

Arm/Group Title	Placebo/Teriflunomide 7 mg	Teriflunomide 7 mg/ 7mg	Placebo/ Teriflunomide 14 mg	Teriflunomide 14 mg/14 mg
Arm/Group Description	Core treatment period: Placebo matched to teriflunomide tablet once daily orally. Extension treatment period: Teriflunomide 7 mg tablet once daily orally.	Core treatment period: Teriflunomide 7 mg tablet once daily orally. Extension treatment period: Teriflunomide 7 mg tablet once daily orally.	Core treatment period: Placebo matched to teriflunomide tablet once daily orally. Extension treatment period: Teriflunomide 14 mg tablet once daily orally.	Core treatment period: Teriflunomide 14 mg tablet once daily orally. Extension treatment period: Teriflunomide 14 mg tablet once daily orally.
Measure Participants	62	145	66	150
Any AE	47 23.9%	110 53.7%	57 26.4%	120 19.4%
Any Serious AE	8 4.1%	17 8.3%	8 3.7%	24 3.9%
Any AE Leading to Death	0 0%	0 0%	0 0%	0 0%
Any AE leading to Permanent Discontinuation	5 2.5%	8 3.9%	5 2.3%	7 1.1%

16. Other Pre-specified Outcome

Title	Core Treatment Period: Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA)
Description	PCSA values are abnormal values considered medically important by the Sponsor according to predefined criteria based on literature review. Hepatic parameters thresholds were defined as follows: Alanine Aminotransferase (ALT) >3, 5, 10 or 20 upper limit of normal(ULN); Aspartate aminotransferase (AST) >3, 5, 10 or 20 ULN; Alkaline Phosphatase >1.5 ULN; Total Bilirubin (TB) >1.5, 2, or 3 ULN; ALT >3 ULN and TB >2 ULN.
Time Frame	From first study drug intake up to 112 days after last intake in the placebo-controlled period or up to first intake in the extension treatment period, whichever occurred first

Outcome Measure Data

Analysis Population Description

Safety population as described in Outcome Measure 13. Here 'n' signifies the number of participants for the treatment group who had that parameter assessed at post-baseline.

Arm/Group Title	Placebo	Teriflunomide 7 mg	Teriflunomide 14 mg
Arm/Group Description	Placebo matched to teriflunomide tablet once daily orally.	Teriflunomide 7 mg tablet once daily orally.	Teriflunomide 14 mg tablet once daily orally.
Measure Participants	191	207	216
ALT >3 ULN (n=190, 207, 216)	18 9.1%	25 12.2%	26 12%
ALT >5 ULN (n=190, 207, 216)	12 6.1%	10 4.9%	11 5.1%
ALT >10 ULN (n=190, 207, 216)	5 2.5%	1 0.5%	3 1.4%
ALT >20 ULN (n=190, 207, 216)	0 0%	0 0%	1 0.5%
AST >3 ULN (n=190, 207, 216)	9 4.6%	12 5.9%	10 4.6%
AST >5 ULN (n=190, 207, 216)	1 0.5%	4 2%	6 2.8%
AST >10 ULN (n=190, 207, 216)	1 0.5%	0 0%	1 0.5%
AST >20 ULN (n=190, 207, 216)	0 0%	0 0%	1 0.5%
Alkaline Phosphatase >1.5 ULN (n=190, 207, 216)	0 0%	0 0%	1 0.5%
TB >1.5 ULN (n=190, 207, 216)	14 7.1%	9 4.4%	8 3.7%
TB >2 ULN (n=190, 207, 216)	8 4.1%	0 0%	3 1.4%
TB >3 ULN (n=190, 207, 216)	0 0%	0 0%	1 0.5%
ALT >3 ULN and TB >2 ULN (n=190, 207, 216)	2 1%	0 0%	2 0.9%

Adverse Events

Time Frame	All Adverse Events (AE) were collected from signature of the informed consent form up to the final visit (up to 390 weeks [maximum exposure in core treatment period: 120 weeks and maximum exposure in extension treatment period: 283 weeks]) regardless of seriousness or relationship to investigational product.
Adverse Event Reporting Description	Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from first dose of study drug up to 112 days after last intake in core treatment period [or up to 1st intake in extension period, whichever occurred first] or 28 days after last intake in extension treatment period). Analysis was performed on safety population as described in Outcome Measure 15.
Arm/Group Title	Placebo		Teriflunomide 7 mg		Teriflunomide 14 mg		Placebo/Teriflunomide 7 mg		Teriflunomide 7 mg/7 mg		Placebo/Teriflunomide 14 mg		Teriflunomide 14 mg/14 mg
Arm/Group Description	Core treatment period: Placebo matched to teriflunomide tablet once daily orally.		Core treatment period: Teriflunomide 7 mg tablet once daily orally.		Core treatment period: Teriflunomide 14 mg tablet once daily orally.		Core treatment period: Placebo matched to teriflunomide tablet once daily orally. Extension treatment period: Teriflunomide 7 mg tablet once daily orally.		Core treatment period: Teriflunomide 7 mg tablet once daily orally. Extension treatment period: Teriflunomide 7 mg tablet once daily orally.		Core treatment period: Placebo matched to teriflunomide tablet once daily orally. Extension treatment period: Teriflunomide 14 mg tablet once daily orally.		Core treatment period: Teriflunomide 14 mg tablet once daily orally. Extension treatment period: Teriflunomide 14 mg tablet once daily orally.
All Cause Mortality
	Placebo		Teriflunomide 7 mg		Teriflunomide 14 mg		Placebo/Teriflunomide 7 mg		Teriflunomide 7 mg/7 mg		Placebo/Teriflunomide 14 mg		Teriflunomide 14 mg/14 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Teriflunomide 7 mg		Teriflunomide 14 mg		Placebo/Teriflunomide 7 mg		Teriflunomide 7 mg/7 mg		Placebo/Teriflunomide 14 mg		Teriflunomide 14 mg/14 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/191 (9.4%)		18/207 (8.7%)		24/216 (11.1%)		8/62 (12.9%)		17/145 (11.7%)		8/66 (12.1%)		24/150 (16%)
Blood and lymphatic system disorders
Iron deficiency anaemia	0/191 (0%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		1/66 (1.5%)		0/150 (0%)
Lymphadenitis	0/191 (0%)		1/207 (0.5%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Neutropenia	2/191 (1%)		0/207 (0%)		1/216 (0.5%)		0/62 (0%)		2/145 (1.4%)		1/66 (1.5%)		0/150 (0%)
Cardiac disorders
Supraventricular tachycardia	0/191 (0%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		1/150 (0.7%)
Tachycardia	0/191 (0%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		1/150 (0.7%)
Ear and labyrinth disorders
Vertigo	0/191 (0%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		1/150 (0.7%)
Endocrine disorders
Goitre	0/191 (0%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		1/66 (1.5%)		0/150 (0%)
Eye disorders
Conjunctivitis allergic	0/191 (0%)		1/207 (0.5%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Gastrointestinal disorders
Chronic gastritis	0/191 (0%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		1/150 (0.7%)
Duodenitis	0/191 (0%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		1/150 (0.7%)
Mallory-Weiss syndrome	0/191 (0%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		1/150 (0.7%)
Abdominal pain	1/191 (0.5%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Dental cyst	0/191 (0%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		1/145 (0.7%)		0/66 (0%)		0/150 (0%)
Gastroduodenal ulcer	0/191 (0%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		1/66 (1.5%)		0/150 (0%)
Inguinal hernia	1/191 (0.5%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		1/145 (0.7%)		0/66 (0%)		0/150 (0%)
Pancreatitis	0/191 (0%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		1/145 (0.7%)		0/66 (0%)		0/150 (0%)
Pancreatitis acute	0/191 (0%)		1/207 (0.5%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Peptic ulcer	0/191 (0%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		1/66 (1.5%)		0/150 (0%)
Radicular cyst	0/191 (0%)		1/207 (0.5%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
General disorders
Hernia	0/191 (0%)		0/207 (0%)		1/216 (0.5%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Hepatobiliary disorders
Cholelithiasis	0/191 (0%)		1/207 (0.5%)		1/216 (0.5%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		1/150 (0.7%)
Cholecystitis	1/191 (0.5%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Cholecystitis acute	1/191 (0.5%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Hepatocellular injury	0/191 (0%)		1/207 (0.5%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Infections and infestations
Abdominal wall abscess	0/191 (0%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		1/150 (0.7%)
Acute sinusitis	0/191 (0%)		0/207 (0%)		1/216 (0.5%)		0/62 (0%)		1/145 (0.7%)		0/66 (0%)		1/150 (0.7%)
Dengue fever	0/191 (0%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		1/150 (0.7%)
Gastroenteritis	0/191 (0%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		1/150 (0.7%)
Pneumonia	0/191 (0%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		1/150 (0.7%)
Abdominal abscess	1/191 (0.5%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Appendicitis	0/191 (0%)		0/207 (0%)		2/216 (0.9%)		1/62 (1.6%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Appendicitis perforated	0/191 (0%)		0/207 (0%)		1/216 (0.5%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Bronchitis	0/191 (0%)		1/207 (0.5%)		0/216 (0%)		0/62 (0%)		1/145 (0.7%)		0/66 (0%)		0/150 (0%)
Clostridium difficile colitis	0/191 (0%)		1/207 (0.5%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Cystitis	0/191 (0%)		0/207 (0%)		1/216 (0.5%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Genital infection	0/191 (0%)		0/207 (0%)		1/216 (0.5%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Infectious mononucleosis	0/191 (0%)		1/207 (0.5%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Pharyngitis	0/191 (0%)		0/207 (0%)		0/216 (0%)		1/62 (1.6%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Pilonidal cyst	0/191 (0%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		1/145 (0.7%)		0/66 (0%)		0/150 (0%)
Pulmonary tuberculosis	0/191 (0%)		1/207 (0.5%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Pyelonephritis acute	1/191 (0.5%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Rectal abscess	0/191 (0%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		1/145 (0.7%)		0/66 (0%)		0/150 (0%)
Sinusitis	0/191 (0%)		0/207 (0%)		1/216 (0.5%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Injury, poisoning and procedural complications
Facial bones fracture	0/191 (0%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		1/150 (0.7%)
Upper limb fracture	0/191 (0%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		1/150 (0.7%)
Ankle fracture	0/191 (0%)		1/207 (0.5%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Craniocerebral injury	0/191 (0%)		1/207 (0.5%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Foot fracture	0/191 (0%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		1/145 (0.7%)		0/66 (0%)		0/150 (0%)
Intentional overdose	0/191 (0%)		0/207 (0%)		1/216 (0.5%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Ligament sprain	0/191 (0%)		0/207 (0%)		1/216 (0.5%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Overdose	1/191 (0.5%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Tibia fracture	0/191 (0%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		2/145 (1.4%)		0/66 (0%)		0/150 (0%)
Wound dehiscence	0/191 (0%)		0/207 (0%)		1/216 (0.5%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Investigations
Amylase increased	0/191 (0%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		2/150 (1.3%)
Blood creatine phosphokinase increased	0/191 (0%)		1/207 (0.5%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		2/150 (1.3%)
Aspartate aminotransferase increased	0/191 (0%)		1/207 (0.5%)		1/216 (0.5%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		1/150 (0.7%)
Lipase increased	0/191 (0%)		1/207 (0.5%)		2/216 (0.9%)		0/62 (0%)		1/145 (0.7%)		0/66 (0%)		1/150 (0.7%)
Transaminases increased	0/191 (0%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		1/150 (0.7%)
Alanine aminotransferase increased	3/191 (1.6%)		5/207 (2.4%)		4/216 (1.9%)		0/62 (0%)		1/145 (0.7%)		0/66 (0%)		0/150 (0%)
Weight decreased	0/191 (0%)		1/207 (0.5%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion	0/191 (0%)		0/207 (0%)		0/216 (0%)		1/62 (1.6%)		0/145 (0%)		0/66 (0%)		1/150 (0.7%)
Synovial cyst	0/191 (0%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		1/150 (0.7%)
Intervertebral disc disorder	0/191 (0%)		1/207 (0.5%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Osteochondrosis	0/191 (0%)		0/207 (0%)		0/216 (0%)		1/62 (1.6%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Rheumatoid arthritis	0/191 (0%)		1/207 (0.5%)		0/216 (0%)		0/62 (0%)		1/145 (0.7%)		0/66 (0%)		0/150 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cervix carcinoma	0/191 (0%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		1/150 (0.7%)
Uterine leiomyoma	2/191 (1%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		1/145 (0.7%)		0/66 (0%)		1/150 (0.7%)
Breast cancer	1/191 (0.5%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Liposarcoma	0/191 (0%)		0/207 (0%)		0/216 (0%)		1/62 (1.6%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Meningioma	0/191 (0%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		1/145 (0.7%)		0/66 (0%)		0/150 (0%)
Spinal meningioma benign	0/191 (0%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		1/66 (1.5%)		0/150 (0%)
Thyroid cancer	1/191 (0.5%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Nervous system disorders
Carpal tunnel syndrome	0/191 (0%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		1/150 (0.7%)
Radicular syndrome	0/191 (0%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		1/150 (0.7%)
Axonal neuropathy	0/191 (0%)		0/207 (0%)		1/216 (0.5%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Loss of consciousness	1/191 (0.5%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Speech disorder	0/191 (0%)		0/207 (0%)		0/216 (0%)		1/62 (1.6%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	0/191 (0%)		0/207 (0%)		1/216 (0.5%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		1/150 (0.7%)
Abortion threatened	0/191 (0%)		1/207 (0.5%)		1/216 (0.5%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Pregnancy	0/191 (0%)		0/207 (0%)		2/216 (0.9%)		0/62 (0%)		1/145 (0.7%)		1/66 (1.5%)		0/150 (0%)
Psychiatric disorders
Adjustment disorder	0/191 (0%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		1/150 (0.7%)
Completed suicide	1/191 (0.5%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Depression	0/191 (0%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		1/145 (0.7%)		0/66 (0%)		0/150 (0%)
Psychiatric decompensation	1/191 (0.5%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Suicide attempt	0/191 (0%)		0/207 (0%)		1/216 (0.5%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Reproductive system and breast disorders
Cervical cyst	0/191 (0%)		0/207 (0%)		0/216 (0%)		1/62 (1.6%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Endometrial hyperplasia	0/191 (0%)		0/207 (0%)		1/216 (0.5%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Fallopian tube cyst	1/191 (0.5%)		0/207 (0%)		1/216 (0.5%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Menorrhagia	0/191 (0%)		0/207 (0%)		0/216 (0%)		1/62 (1.6%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Ovarian cyst	0/191 (0%)		0/207 (0%)		1/216 (0.5%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Testicular torsion	0/191 (0%)		1/207 (0.5%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Uterine haemorrhage	0/191 (0%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		1/145 (0.7%)		1/66 (1.5%)		0/150 (0%)
Respiratory, thoracic and mediastinal disorders
Nasal septum deviation	0/191 (0%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		1/150 (0.7%)
Dyspnoea	0/191 (0%)		0/207 (0%)		1/216 (0.5%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Skin and subcutaneous tissue disorders
Diffuse alopecia	0/191 (0%)		0/207 (0%)		0/216 (0%)		1/62 (1.6%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Erythema nodosum	0/191 (0%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		1/145 (0.7%)		0/66 (0%)		0/150 (0%)
Vascular disorders
Circulatory collapse	0/191 (0%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		1/150 (0.7%)
Hypertension	0/191 (0%)		0/207 (0%)		1/216 (0.5%)		0/62 (0%)		0/145 (0%)		1/66 (1.5%)		1/150 (0.7%)
Orthostatic hypotension	0/191 (0%)		0/207 (0%)		0/216 (0%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		1/150 (0.7%)
Deep vein thrombosis	0/191 (0%)		0/207 (0%)		1/216 (0.5%)		0/62 (0%)		0/145 (0%)		0/66 (0%)		0/150 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Teriflunomide 7 mg		Teriflunomide 14 mg		Placebo/Teriflunomide 7 mg		Teriflunomide 7 mg/7 mg		Placebo/Teriflunomide 14 mg		Teriflunomide 14 mg/14 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	117/191 (61.3%)		129/207 (62.3%)		135/216 (62.5%)		33/62 (53.2%)		66/145 (45.5%)		38/66 (57.6%)		70/150 (46.7%)
Gastrointestinal disorders
Diarrhoea	12/191 (6.3%)		22/207 (10.6%)		15/216 (6.9%)		4/62 (6.5%)		9/145 (6.2%)		4/66 (6.1%)		14/150 (9.3%)
Nausea	9/191 (4.7%)		11/207 (5.3%)		9/216 (4.2%)		2/62 (3.2%)		7/145 (4.8%)		1/66 (1.5%)		9/150 (6%)
General disorders
Fatigue	14/191 (7.3%)		10/207 (4.8%)		9/216 (4.2%)		2/62 (3.2%)		3/145 (2.1%)		4/66 (6.1%)		3/150 (2%)
Infections and infestations
Nasopharyngitis	29/191 (15.2%)		24/207 (11.6%)		35/216 (16.2%)		9/62 (14.5%)		14/145 (9.7%)		9/66 (13.6%)		15/150 (10%)
Bronchitis	5/191 (2.6%)		9/207 (4.3%)		8/216 (3.7%)		4/62 (6.5%)		7/145 (4.8%)		2/66 (3%)		8/150 (5.3%)
Sinusitis	9/191 (4.7%)		7/207 (3.4%)		6/216 (2.8%)		6/62 (9.7%)		4/145 (2.8%)		4/66 (6.1%)		6/150 (4%)
Influenza	9/191 (4.7%)		8/207 (3.9%)		16/216 (7.4%)		3/62 (4.8%)		5/145 (3.4%)		5/66 (7.6%)		4/150 (2.7%)
Upper respiratory tract infection	14/191 (7.3%)		23/207 (11.1%)		20/216 (9.3%)		2/62 (3.2%)		5/145 (3.4%)		2/66 (3%)		4/150 (2.7%)
Urinary tract infection	10/191 (5.2%)		10/207 (4.8%)		20/216 (9.3%)		3/62 (4.8%)		5/145 (3.4%)		5/66 (7.6%)		4/150 (2.7%)
Investigations
Alanine aminotransferase increased	28/191 (14.7%)		32/207 (15.5%)		35/216 (16.2%)		0/62 (0%)		5/145 (3.4%)		6/66 (9.1%)		3/150 (2%)
Blood creatine phosphokinase increased	1/191 (0.5%)		9/207 (4.3%)		5/216 (2.3%)		4/62 (6.5%)		1/145 (0.7%)		1/66 (1.5%)		2/150 (1.3%)
Musculoskeletal and connective tissue disorders
Back pain	7/191 (3.7%)		14/207 (6.8%)		8/216 (3.7%)		4/62 (6.5%)		5/145 (3.4%)		4/66 (6.1%)		10/150 (6.7%)
Arthralgia	6/191 (3.1%)		13/207 (6.3%)		7/216 (3.2%)		1/62 (1.6%)		4/145 (2.8%)		2/66 (3%)		4/150 (2.7%)
Nervous system disorders
Headache	25/191 (13.1%)		31/207 (15%)		30/216 (13.9%)		4/62 (6.5%)		8/145 (5.5%)		8/66 (12.1%)		6/150 (4%)
Dizziness	7/191 (3.7%)		7/207 (3.4%)		11/216 (5.1%)		1/62 (1.6%)		4/145 (2.8%)		2/66 (3%)		4/150 (2.7%)
Paraesthesia	9/191 (4.7%)		11/207 (5.3%)		22/216 (10.2%)		3/62 (4.8%)		1/145 (0.7%)		3/66 (4.5%)		4/150 (2.7%)
Psychiatric disorders
Depression	11/191 (5.8%)		8/207 (3.9%)		8/216 (3.7%)		2/62 (3.2%)		4/145 (2.8%)		3/66 (4.5%)		1/150 (0.7%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	8/191 (4.2%)		11/207 (5.3%)		2/216 (0.9%)		0/62 (0%)		1/145 (0.7%)		2/66 (3%)		0/150 (0%)
Skin and subcutaneous tissue disorders
Alopecia	15/191 (7.9%)		12/207 (5.8%)		25/216 (11.6%)		2/62 (3.2%)		3/145 (2.1%)		7/66 (10.6%)		5/150 (3.3%)
Vascular disorders
Hypertension	2/191 (1%)		5/207 (2.4%)		12/216 (5.6%)		3/62 (4.8%)		4/145 (2.8%)		0/66 (0%)		5/150 (3.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

If no publication has occurred within 12 months of the completion of the study, the Investigator shall have the right to publish/present independently the results of the study. The Investigator shall provide the Sponsor with a copy of any such presentation/publication for comment at least 30 days before any presentation/submission for publication. If requested by the Sponsor, any presentation/submission shall be delayed up to 90 days, to allow the Sponsor to preserve its proprietary rights.