TERACLES: Efficacy and Safety of Teriflunomide in Patients With Relapsing Multiple Sclerosis and Treated With Interferon-beta

• Sponsor: Sanofi (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01252355
• Collaborator: (none)
• Enrollment: 534
• Locations: 185
• Arms: 3
• Duration (Months): 27
• Patients Per Site: 2.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The primary objective was to demonstrate the effect of teriflunomide, in comparison to placebo, on frequency of Multiple Sclerosis (MS) relapses in patients with relapsing forms of MS who are treated with Interferon-beta (IFN-beta).

The secondary objectives were:

• Assess the effect of teriflunomide, in comparison to placebo, when added to IFN-beta on:

• Disease activity as measured by brain Magnetic Resonance Imaging (MRI)

• Disability progression

• Burden of disease and disease progression as measured by brain MRI

• Evaluate the safety and tolerability of teriflunomide when added to IFN-beta therapy

• Assess the pharmacokinetics of teriflunomide in use in addition to baseline IFN-beta therapy

• Assess associations between variations in genes and clinical outcomes (safety and efficacy)

• Assess other measures of efficacy of teriflunomide such as fatigue and health-related quality of life

• Assess measures of health economics (hospitalization due to relapse, including the length of stay and any admission to intensive care unit)

Condition or Disease	Intervention/Treatment	Phase
Multiple Sclerosis Relapse	Drug: Teriflunomide; Drug: Placebo (for teriflunomide); Drug: Interferon-beta (IFN-beta)	Phase 3

Detailed Description

The study period per patient was expected to be between 56 and 160 weeks depending on when the patient was randomized and this included the following:

• a screening period up to 4 weeks,

• a treatment period expected to be between 48 and 152 weeks,

• 4-week post rapid elimination follow-up period.

Patients were to continue on treatment until a fixed common end date which was approximately 48 weeks after randomization of the last patient.

For those patients who completed the treatment period, a long term extension study of approximately 1 year (including teriflunomide alone) was initially planned to be proposed.

Study Design

• Study Type: Interventional
• Actual Enrollment: 534 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multi-center Double-blind Parallel-group Placebo-controlled Study of the Efficacy and Safety of Teriflunomide in Patients With Relapsing Multiple Sclerosis Who Are Treated With Interferon-beta
• Study Start Date: Jan 1, 2011
• Actual Primary Completion Date: Apr 1, 2013
• Actual Study Completion Date: Apr 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Teriflunomide 7 mg + IFN-beta Teriflunomide 7 milligram (mg) once a day concomitantly with IFN-beta therapy.	Drug: Teriflunomide; Film-coated tablet Oral administration; Other Names: HMR1726 ; Drug: Interferon-beta (IFN-beta); Any of the IFN-beta which are approved for marketed use in the country where the patient is enrolled. Administration according to the package insert.
Experimental: Teriflunomide 14 mg + IFN-beta Teriflunomide 14 mg once a day concomitantly with IFN-beta therapy.	Drug: Teriflunomide; Film-coated tablet Oral administration; Other Names: HMR1726 ; Drug: Interferon-beta (IFN-beta); Any of the IFN-beta which are approved for marketed use in the country where the patient is enrolled. Administration according to the package insert.
Placebo Comparator: Placebo + IFN-beta Placebo (for teriflunomide) once a day concomitantly with IFN-beta therapy.	Drug: Placebo (for teriflunomide); Film-coated tablet Oral administration; Drug: Interferon-beta (IFN-beta); Any of the IFN-beta which are approved for marketed use in the country where the patient is enrolled. Administration according to the package insert.

Outcome Measures

Primary Outcome Measures

1. Annualized Relapse Rate (ARR) (Poisson Regression Estimates) [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 Expanded Disability Status Scale (EDSS) score or Functional System scores. To account for the different treatment durations among participants, a Poisson regression model with robust error variance was used (total number of confirmed relapses as response variable; log-transformed treatment duration as "offset" variable; treatment group, region of enrollment and IFN-beta dose stratum, and number of relapses in the year prior to randomization as covariates).

Secondary Outcome Measures

1. Brain Magnetic Resonance Imaging (MRI) Assessment: Number of Gadolinium Enhancing (Gd-enhancing) T1-lesions Per 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 number of scans among participants, a Poisson regression model with robust error variance was used (total number of Gd-enhancing T1-lesions as response variable; log-transformed number of scans as offset variable; treatment group, region of enrollment, IFN-beta dose stratum and baseline number of Gd-enhancing T1-lesions as covariates).

2. 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 an increase from baseline of at least 1-point in EDSS score (at least 0.5-point for participants with baseline EDSS score >5.5) that persisted for at least 12 weeks. Probability of disability progression was to be estimated using Kaplan-Meier method.

3. Brain MRI Assessment: Volume of 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.

4. Brain MRI Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease) at Week 24 [Baseline, Week 24]

   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, region, IFN-beta dose stratum, visit, treatment-by-visit interaction, cubic root transformed baseline burden of disease, and baseline-by-visit interaction.

5. Time to Relapse: Kaplan-Meier Estimates of the Probability of no Relapse at Week 24, 48, and 72 [Up to a maximum of 108 weeks depending on time of enrollment]

   Probability of no relapse at 24, 48 and 72 weeks was estimated using Kaplan-Meier method on the time to relapse defined as the time from randomization to first EDSS confirmed relapse. Participants free of confirmed relapse (no EDSS confirmed relapse observed on treatment) were censored at the date of the last study drug intake. 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.

6. Change From Baseline in Fatigue Impact Scale (FIS) Total Score at Week 24 [Baseline, Week 24]

   FIS is a participant-reported scale that qualifies the impact of fatigue on daily life in participants with MS.

7. Change From Baseline in Short Form Generic Health Survey - 36 Items, Version 2 (SF-36v2) Summary Scores at Week 24 [Baseline, Week 24]

   SF-36 scale is a generic, self-administered, health-related quality-of-life (QOL) instrument.

8. Resource Utilization When Relapse [Up to a maximum of 108 weeks depending on time of enrollment]

   Resource utilization each time a participant experiences an MS relapse, specifically the number of hospitalizations, the number of over night spent in the hospital and number of intensive care admissions if hospitalized were to be reported.

9. Overview of Adverse Events (AEs) [First study drug intake up to 28 days after last study drug intake, for up to 112 weeks]

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

Other Outcome Measures

1. Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) [First study drug intake up to 28 days after last study drug intake, for up to 112 weeks]

   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 or 10 Upper Limit of Normal (ULN); Aspartate Aminotransferase (AST) >3, 5 or 10 ULN; Alkaline Phosphatase >1.5 ULN; Total Bilirubin (TB) >1.5 ULN; and 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 :

• Patient with relapsing forms of MS treated with IFN-beta

• Stable dose of IFN-beta (approved brand) for at least 6 months prior to randomization

• Disease activity in the 12 months prior to randomization and after first 3 months of IFN-beta treatment (defined by at least 1 relapse supported by EDSS or equivalent neurological examination, or, at least 1 brain or spinal cord MRI with at least one T1 gadolinium enhancing lesion)

Exclusion criteria:

• McDonald criteria for MS diagnosis not met at time of screening visit

• EDSS score greater than (>) 5.5 at randomization visit

• A relapse within 30 days prior randomization

• Persistent significant or severe infection

• Patients must not have used adrenocorticotrophic hormone or systemic corticosteroids for 2 weeks prior to randomization

• Prior or concomitant use of cytokine therapy (except baseline interferons), glatiramer acetate or intravenous immunoglobulins in the 3 months preceding randomization

• Liver function impairment or persisting elevations (confirmed by retest) of alanine aminotransferase (ALT), aspartate aminotransferase (AST), or direct bilirubin greater than 2 times the upper limit of normal range (ULN)

• Active hepatitis or hepatobiliary disease or known history of severe hepatitis

• Pregnant or breast-feeding women or those who were planning to become pregnant during the study

• Significantly impaired bone marrow function or significant anemia, leukopenia, or thrombocytopenia

• Human Immunodeficiency Virus (HIV) positive

• Known history of active tuberculosis not adequately treated

• Prior use within 2 years preceding randomization or concomitant use of cladribine and mitoxantrone

• Prior use within 6 months preceding randomization or concomitant use of natalizumab, or any other immunosuppressive agents such as azathioprine, cyclophosphamide, cyclosporine, methotrexate, mycophenolate, or fingolimod

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Investigational Site Number 840049	Cullman	Alabama	United States	35058
2	Investigational Site Number 840005	Cordova	Alaska	United States	38018
3	Investigational Site Number 840003	Phoenix	Arizona	United States	85060
4	Investigational Site Number 840011	Oceanside	California	United States	92056
5	Investigational Site Number 840036	Fort Collins	Colorado	United States	80528
6	Investigational Site Number 840012	Maitland	Florida	United States	32761
7	Investigational Site Number 840013	Ormond Beach	Florida	United States	32174
8	Investigational Site Number 840055	Pompano Beach	Florida	United States	33060
9	Investigational Site Number 840021	St. Petersburg	Florida	United States	33713
10	Investigational Site Number 840004	Tampa	Florida	United States	33609-4052
11	Investigational Site Number 840047	Tampa	Florida	United States	33612
12	Investigational Site Number 840034	Chicago	Illinois	United States	60637
13	Investigational Site Number 840037	Elk Grove Village	Illinois	United States	60007
14	Investigational Site Number 840033	Louisville	Kentucky	United States	40217
15	Investigational Site Number 840041	Baltimore	Maryland	United States	21201
16	Investigational Site Number 840028	Baltimore	Maryland	United States	21287
17	Investigational Site Number 840016	Clinton Township	Michigan	United States	48035
18	Investigational Site Number 840031	St Louis	Missouri	United States	63104
19	Investigational Site Number 840030	St Louis	Missouri	United States	63110
20	Investigational Site Number 840009	Missoula	Montana	United States	59802
21	Investigational Site Number 840023	Albuquerque	New Mexico	United States	87131
22	Investigational Site Number 840015	New York	New York	United States	10029
23	Investigational Site Number 840027	Charlotte	North Carolina	United States	28204
24	Investigational Site Number 840006	Bismark	North Dakota	United States	58501
25	Investigational Site Number 840007	Fargo	North Dakota	United States	58103
26	Investigational Site Number 840046	Dayton	Ohio	United States	45409
27	Investigational Site Number 840017	Toledo	Ohio	United States	43699
28	Investigational Site Number 840043	Tulsa	Oklahoma	United States	74137
29	Investigational Site Number 840002	Nashville	Tennessee	United States	37232
30	Investigational Site Number 840040	Round Rock	Texas	United States	78681
31	Investigational Site Number 840020	San Antonio	Texas	United States	78231
32	Investigational Site Number 840032	Vienna	Virginia	United States	22182
33	Investigational Site Number 032002	Argentina		Argentina	1426
34	Investigational Site Number 032003	Buenos Aires		Argentina
35	Investigational Site Number 032004	Caba		Argentina
36	Investigational Site Number 036008	Bedford Park		Australia	5042
37	Investigational Site Number 036005	Chatswood		Australia	2067
38	Investigational Site Number 036001	Heidelberg West		Australia	3081
39	Investigational Site Number 036004	Kogarah		Australia	2217
40	Investigational Site Number 036010	New Lambton		Australia	2305
41	Investigational Site Number 040001	Graz		Austria	8036
42	Investigational Site Number 040004	Linz		Austria	4020
43	Investigational Site Number 056005	Charleroi		Belgium	6000
44	Investigational Site Number 056004	Gent		Belgium	9000
45	Investigational Site Number 056003	Hasselt		Belgium	B-3590
46	Investigational Site Number 056006	La Louvière		Belgium	7100
47	Investigational Site Number 056002	Leuven		Belgium	3000
48	Investigational Site Number 056001	Sijsele-Damme		Belgium	8340
49	Investigational Site Number 056007	Wilrijk		Belgium	2610
50	Investigational Site Number 076009	Joinville		Brazil	89202-165
51	Investigational Site Number 076012	Passo Fundo		Brazil	99010-180
52	Investigational Site Number 076003	Porto Alegre		Brazil	90020-090
53	Investigational Site Number 076007	Sao Paulo		Brazil	04024-002
54	Investigational Site Number 076013	Sao Paulo		Brazil	08270-070
55	Investigational Site Number 124005	Calgary		Canada	T2N 2T9
56	Investigational Site Number 124004	Edmonton		Canada	T6G 2G3
57	Investigational Site Number 124003	Gatineau		Canada	J9J 0A5
58	Investigational Site Number 124006	Kingston		Canada	K7L 2V7
59	Investigational Site Number 124007	Montreal		Canada	H3A 2B4
60	Investigational Site Number 124008	Ottawa		Canada	K1H 8L6
61	Investigational Site Number 124002	Regina		Canada	S4T 1A5
62	Investigational Site Number 124001	Sherbrooke		Canada	J1H 5N4
63	Investigational Site Number 124009	Winnipeg		Canada	R3A 1R9
64	Investigational Site Number 152003	Santiago		Chile	7500710
65	Investigational Site Number 152004	Santiago		Chile	838-0456
66	Investigational Site Number 152005	Viña Del Mar		Chile	2570017
67	Investigational Site Number 170001	Barranquilla		Colombia
68	Investigational Site Number 170005	Bogota		Colombia
69	Investigational Site Number 170007	Bogota		Colombia
70	Investigational Site Number 170009	Medellin		Colombia
71	Investigational Site Number 208002	Aarhus C		Denmark	8000
72	Investigational Site Number 233002	Tallinn		Estonia	10617
73	Investigational Site Number 233001	Tartu		Estonia	50406
74	Investigational Site Number 246003	Helsinki		Finland	00100
75	Investigational Site Number 246006	Hyvinkää		Finland	05800
76	Investigational Site Number 246004	Oulu		Finland	90220
77	Investigational Site Number 246002	Pori		Finland	28100
78	Investigational Site Number 246001	Turku		Finland	20100
79	Investigational Site Number 250003	Besancon		France	25030
80	Investigational Site Number 250010	Clermont Ferrand Cedex 1		France	63003
81	Investigational Site Number 250002	Lyon Cedex 03		France	69394
82	Investigational Site Number 250004	Montpellier Cedex 5		France	34000
83	Investigational Site Number 250001	Nancy Cedex		France	54036
84	Investigational Site Number 250006	Nantes Cedex 01		France	44093
85	Investigational Site Number 276009	Bad Mergentheim		Germany	97980
86	Investigational Site Number 276020	Bamberg		Germany	96047
87	Investigational Site Number 276003	Bayreuth		Germany	95445
88	Investigational Site Number 276015	Berlin		Germany	10117
89	Investigational Site Number 276016	Berlin		Germany	10713
90	Investigational Site Number 276021	Berlin		Germany	12099
91	Investigational Site Number 276012	Bonn		Germany	53105
92	Investigational Site Number 276005	Dresden		Germany	01307
93	Investigational Site Number 276032	Düsseldorf		Germany	40211
94	Investigational Site Number 276018	Erbach		Germany	64711
95	Investigational Site Number 276004	Erlangen		Germany	91054
96	Investigational Site Number 276028	Freiburg		Germany	79098
97	Investigational Site Number 276006	Gießen		Germany	35385
98	Investigational Site Number 276010	Hamburg		Germany	20249
99	Investigational Site Number 276022	Hennigsdorf		Germany	16761
100	Investigational Site Number 276024	Kassel		Germany	34121
101	Investigational Site Number 276001	Leipzig		Germany	04103
102	Investigational Site Number 276013	Mainz		Germany	55131
103	Investigational Site Number 276023	Minden		Germany	32429
104	Investigational Site Number 276002	Münster		Germany	48149
105	Investigational Site Number 276031	Rostock		Germany	18055
106	Investigational Site Number 276008	Wiesbaden		Germany	65191
107	Investigational Site Number 276026	Wuppertal		Germany	42283
108	Investigational Site Number 300002	Athens		Greece	11527
109	Investigational Site Number 300001	Athens		Greece	11535
110	Investigational Site Number 300003	Heraklion		Greece	71110
111	Investigational Site Number 300006	Thessaloniki		Greece	57010
112	Investigational Site Number 348002	Budapest		Hungary	1106
113	Investigational Site Number 348006	Budapest		Hungary	1145
114	Investigational Site Number 348010	Budapest		Hungary	1204
115	Investigational Site Number 348009	Eger		Hungary	3300
116	Investigational Site Number 348003	Esztergom		Hungary	2500
117	Investigational Site Number 348001	Szeged		Hungary	6720
118	Investigational Site Number 348005	Szekesfehervar		Hungary	8000
119	Investigational Site Number 348007	Zalaegerszeg		Hungary	8900
120	Investigational Site Number 380009	Catania		Italy	95123
121	Investigational Site Number 380002	Cefalù		Italy	90015
122	Investigational Site Number 380003	Fidenza		Italy	43036
123	Investigational Site Number 380004	Gallarate		Italy	21013
124	Investigational Site Number 380012	Montichiari		Italy	25012
125	Investigational Site Number 380010	Napoli		Italy	80131
126	Investigational Site Number 380011	Napoli		Italy	80131
127	Investigational Site Number 380006	Padova		Italy	35128
128	Investigational Site Number 380005	Roma		Italy	00133
129	Investigational Site Number 380008	Roma		Italy	00161
130	Investigational Site Number 380014	Verona		Italy	37134
131	Investigational Site Number 410002	Goyang-Si		Korea, Republic of	410-760
132	Investigational Site Number 410004	Seoul		Korea, Republic of	110-744
133	Investigational Site Number 410001	Seoul		Korea, Republic of	136-705
134	Investigational Site Number 440002	Kaunas		Lithuania	LT-50009
135	Investigational Site Number 440004	Klaipeda		Lithuania	LT-92288
136	Investigational Site Number 440003	Siauliai		Lithuania	LT-76231
137	Investigational Site Number 528001	Breda		Netherlands	4818 CK
138	Investigational Site Number 528005	Nieuwegein		Netherlands	3435 CM
139	Investigational Site Number 528002	Sittard-Geleen		Netherlands	6162 BG
140	Investigational Site Number 528006	Venray		Netherlands	5801 CE
141	Investigational Site Number 578002	Tønsberg		Norway	3116
142	Investigational Site Number 620001	Amadora		Portugal	2720-276
143	Investigational Site Number 620002	Coimbra		Portugal	3000-075
144	Investigational Site Number 620004	Coimbra		Portugal	3041-801
145	Investigational Site Number 620003	Setubal		Portugal	2910-446
146	Investigational Site Number 643012	Kaluga		Russian Federation	248007
147	Investigational Site Number 643007	Kazan		Russian Federation	420021
148	Investigational Site Number 643001	Kemerovo		Russian Federation	650066
149	Investigational Site Number 643013	Moscow		Russian Federation	129110
150	Investigational Site Number 643006	Nizhny Novgorod		Russian Federation	603076
151	Investigational Site Number 643004	Nizhny Novgorod		Russian Federation	603126
152	Investigational Site Number 643015	Novosibirsk		Russian Federation	630007
153	Investigational Site Number 643010	Rostov-On-Don		Russian Federation	344015
154	Investigational Site Number 643009	Rostov-On-Don		Russian Federation	344022
155	Investigational Site Number 643016	Samara		Russian Federation	443095
156	Investigational Site Number 643005	Smolensk		Russian Federation	214019
157	Investigational Site Number 643011	St-Petersburg		Russian Federation	194044
158	Investigational Site Number 643018	St-Petersburg		Russian Federation	194291
159	Investigational Site Number 643003	St-Petersburg		Russian Federation	194354
160	Investigational Site Number 643017	St-Petersburg		Russian Federation	197089
161	Investigational Site Number 643002	St-Petersburg		Russian Federation	197376
162	Investigational Site Number 643014	Yaroslavl		Russian Federation	150030
163	Investigational Site Number 703002	Martin		Slovakia	03659
164	Investigational Site Number 703001	Trnava		Slovakia	91775
165	Investigational Site Number 724001	Barcelona		Spain	08035
166	Investigational Site Number 724002	Barcelona		Spain	08036
167	Investigational Site Number 724009	Córdoba		Spain	14004
168	Investigational Site Number 724003	Girona		Spain	17007
169	Investigational Site Number 724004	Madrid		Spain	28005
170	Investigational Site Number 724005	Madrid		Spain	28040
171	Investigational Site Number 724007	Murcia		Spain	30120
172	Investigational Site Number 724008	Sevilla		Spain	41008
173	Investigational Site Number 752004	Göteborg		Sweden	413 45
174	Investigational Site Number 752003	Stockholm		Sweden	14186
175	Investigational Site Number 752001	Stockholm		Sweden	171 76
176	Investigational Site Number 788002	Manouba		Tunisia	2010
177	Investigational Site Number 788005	Monastir		Tunisia	5000
178	Investigational Site Number 788004	Sfax		Tunisia	3029
179	Investigational Site Number 788006	Tunis		Tunisia	1008
180	Investigational Site Number 826008	Birmingham		United Kingdom	B15 2TH
181	Investigational Site Number 826005	Leeds		United Kingdom	LS1 3EX
182	Investigational Site Number 826006	Liverpool		United Kingdom	L9 7LJ
183	Investigational Site Number 826003	London		United Kingdom	SW17 0QT
184	Investigational Site Number 826004	Plymouth		United Kingdom	PL6 8BX
185	Investigational Site Number 826001	Salford		United Kingdom	M6 8HD

Sponsors and Collaborators

• Sanofi

Investigators

• Study Director: Clinical Sciences & Operations, Sanofi

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT01252355
• Other Study ID Numbers: EFC6058; 2010-023172-12; U1111-1115-2414
• First Posted: Dec 3, 2010
• Last Update Posted: Jun 9, 2014
• Last Verified: May 1, 2014

• Additional relevant MeSH terms: Multiple Sclerosis; Sclerosis; Interferons; Interferon-beta; Teriflunomide

Study Results

Participant Flow

Recruitment Details	The recruitment initiated in January 2011, was discontinued in December 2012 following the decision of the Sponsor to discontinue the study, the common treatment end date was defined as February 28th, 2013 (treatment duration between 24 and 108 weeks). A total of 846 participants were screened at 185 sites in 28 countries.
Pre-assignment Detail	Randomization was stratified by investigational site and Interferon-beta (IFN-beta) dose level (high/low). Assignment to groups was done centrally using an Interactive Voice Response System (IVRS) in a 1:1:1 ratio after confirmation of selection criteria. A total of 534 participants were randomized.

Arm/Group Title	Placebo + IFN-beta	Teriflunomide 7 mg + IFN-beta	Teriflunomide 14 mg + IFN-beta
Arm/Group Description	Placebo (for teriflunomide) once daily concomitantly with IFN-beta.	Teriflunomide 7 mg once daily concomitantly with IFN-beta.	Teriflunomide 14 mg once daily concomitantly with IFN-beta.
Period Title: Overall Study
STARTED	177	178	179
Treated	175	178	179
COMPLETED	0	0	0
NOT COMPLETED	177	178	179

Baseline Characteristics

Arm/Group Title	Placebo + IFN-beta	Teriflunomide 7 mg + IFN-beta	Teriflunomide 14 mg + IFN-beta	Total
Arm/Group Description	Placebo (for teriflunomide) once daily concomitantly with IFN-beta.	Teriflunomide 7 mg once daily concomitantly with IFN-beta.	Teriflunomide 14 mg once daily concomitantly with IFN-beta.	Total of all reporting groups
Overall Participants	177	178	179	534
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	38.3 (8.9)	38.7 (9.5)	37.7 (9.2)	38.2 (9.2)
Sex: Female, Male (Count of Participants)
Female	113 63.8%	125 70.2%	114 63.7%	352 65.9%
Male	64 36.2%	53 29.8%	65 36.3%	182 34.1%
Region of Enrollment (participants) [Number]
America	33 18.6%	30 16.9%	37 20.7%	100 18.7%
Western Europe	86 48.6%	86 48.3%	79 44.1%	251 47%
Eastern Europe	51 28.8%	51 28.7%	56 31.3%	158 29.6%
Asia, Africa and Australia	7 4%	11 6.2%	7 3.9%	25 4.7%
Time Since First Diagnosis of Multiple Sclerosis (MS) (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	7.0 (5.6)	6.6 (5.6)	6.8 (5.9)	6.8 (5.7)
Number of MS Relapses (MS relapses) [Median (Full Range) ]
Within the past year	1	1	1	1
Within the past 2 years	2	2	2	2
Time Since Most Recent MS Relapse Onset (months) [Median (Full Range) ]
Median (Full Range) [months]	5.0 (8.29)	5.0 (4.83)	4.0 (15.36)	5.0 (10.47)
MS Subtype (participants) [Number]
Relapsing Remitting	174 98.3%	173 97.2%	175 97.8%	522 97.8%
Secondary Progressive	2 1.1%	3 1.7%	4 2.2%	9 1.7%
Progressive Relapsing	1 0.6%	2 1.1%	0 0%	3 0.6%
Baseline Expanded Disability Status Scale (EDSS) Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	2.67 (1.25)	2.63 (1.37)	2.64 (1.18)	2.65 (1.26)
Dose Level of Interferon-beta (IFN-beta) Based on IVRS (participants) [Number]
High dose	120 67.8%	128 71.9%	120 67%	368 68.9%
Low dose	57 32.2%	50 28.1%	59 33%	166 31.1%

Outcome Measures

1. Primary Outcome

Title	Annualized Relapse Rate (ARR) (Poisson Regression Estimates)
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 Expanded Disability Status Scale (EDSS) score or Functional System scores. To account for the different treatment durations among participants, a Poisson regression model with robust error variance was used (total number of confirmed relapses as response variable; log-transformed treatment duration as "offset" variable; treatment group, region of enrollment and IFN-beta dose stratum, and number of relapses in the year prior to randomization as covariates).
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: all randomized and treated participants. Participants were considered in the treatment group to which they were randomized regardless of the drug they actually received.

Arm/Group Title	Placebo + IFN-beta	Teriflunomide 7 mg + IFN-beta	Teriflunomide 14 mg + IFN-beta
Arm/Group Description	Placebo (for teriflunomide) once daily concomitantly with IFN-beta.	Teriflunomide 7 mg once daily concomitantly with IFN-beta.	Teriflunomide 14 mg once daily concomitantly with IFN-beta.
Measure Participants	175	178	179
Number (95% Confidence Interval) [relapses per patient-year]	0.298	0.242	0.238

2. Secondary Outcome

Title	Brain Magnetic Resonance Imaging (MRI) Assessment: Number of Gadolinium Enhancing (Gd-enhancing) T1-lesions Per 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 number of scans among participants, a Poisson regression model with robust error variance was used (total number of Gd-enhancing T1-lesions as response variable; log-transformed number of scans as offset variable; treatment group, region of enrollment, IFN-beta dose stratum and baseline number of Gd-enhancing T1-lesions as covariates).
Time Frame	Up to a maximum of 108 weeks depending on time of enrollment

Outcome Measure Data

Analysis Population Description

ITT population as previously defined but including only participants who had post-baseline data.

Arm/Group Title	Placebo + IFN-beta	Teriflunomide 7 mg + IFN-beta	Teriflunomide 14 mg + IFN-beta
Arm/Group Description	Placebo (for teriflunomide) once daily concomitantly with IFN-beta.	Teriflunomide 7 mg once daily concomitantly with IFN-beta.	Teriflunomide 14 mg once daily concomitantly with IFN-beta.
Measure Participants	151	142	151
Number (95% Confidence Interval) [lesions per scan]	0.542	0.257	0.158

3. Secondary Outcome

Title	Time to 12-Week Sustained Disability Progression
Description	The 12-week sustained disability progression was defined as an increase from baseline of at least 1-point in EDSS score (at least 0.5-point for participants with baseline EDSS score >5.5) that persisted for at least 12 weeks. Probability of disability progression was to be 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

Data for this outcome was not analyzed because of insufficient data after early study termination.

Arm/Group Title	Placebo + IFN-beta	Teriflunomide 7 mg + IFN-beta	Teriflunomide 14 mg + IFN-beta
Arm/Group Description	Placebo (for teriflunomide) once daily concomitantly with IFN-beta.	Teriflunomide 7 mg once daily concomitantly with IFN-beta.	Teriflunomide 14 mg once daily concomitantly with IFN-beta.
Measure Participants	0	0	0

4. Secondary Outcome

Title	Brain MRI Assessment: Volume of 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.
Time Frame	Up to a maximum of 108 weeks depending on time of enrollment

Outcome Measure Data

Analysis Population Description

ITT population as previously defined but including only participants who had post-baseline data.

Arm/Group Title	Placebo + IFN-beta	Teriflunomide 7 mg + IFN-beta	Teriflunomide 14 mg + IFN-beta
Arm/Group Description	Placebo (for teriflunomide) once daily concomitantly with IFN-beta.	Teriflunomide 7 mg once daily concomitantly with IFN-beta.	Teriflunomide 14 mg once daily concomitantly with IFN-beta.
Measure Participants	151	142	151
Number [milliliters per scan]	0.045	0.009	0.01

5. Secondary Outcome

Title	Brain MRI Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease) at Week 24
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, region, IFN-beta dose stratum, visit, treatment-by-visit interaction, cubic root transformed baseline burden of disease, and baseline-by-visit interaction.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

ITT population as previously defined but including only participants who had post-baseline data.

Arm/Group Title	Placebo + IFN-beta	Teriflunomide 7 mg + IFN-beta	Teriflunomide 14 mg + IFN-beta
Arm/Group Description	Placebo (for teriflunomide) once daily concomitantly with IFN-beta.	Teriflunomide 7 mg once daily concomitantly with IFN-beta.	Teriflunomide 14 mg once daily concomitantly with IFN-beta.
Measure Participants	142	132	141
Least Squares Mean (Standard Error) [milliliter]	-0.008 (0.021)	-0.011 (0.021)	-0.044 (0.020)

6. Secondary Outcome

Title	Time to Relapse: Kaplan-Meier Estimates of the Probability of no Relapse at Week 24, 48, and 72
Description	Probability of no relapse at 24, 48 and 72 weeks was estimated using Kaplan-Meier method on the time to relapse defined as the time from randomization to first EDSS confirmed relapse. Participants free of confirmed relapse (no EDSS confirmed relapse observed on treatment) were censored at the date of the last study drug intake. 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.
Time Frame	Up to a maximum of 108 weeks depending on time of enrollment

Outcome Measure Data

Analysis Population Description

ITT population as previously defined.

Arm/Group Title	Placebo + IFN-beta	Teriflunomide 7 mg + IFN-beta	Teriflunomide 14 mg + IFN-beta
Arm/Group Description	Placebo (for teriflunomide) once daily concomitantly with IFN-beta.	Teriflunomide 7 mg once daily concomitantly with IFN-beta.	Teriflunomide 14 mg once daily concomitantly with IFN-beta.
Measure Participants	175	178	179
Percent probability of no relapse at Week 24	81.9	86.8	87.1
Percent probability of no relapse at Week 48	67.3	80.6	80.8
Percent probability of no relapse at Week 72	58.3	78.2	73.1

7. Secondary Outcome

Title	Change From Baseline in Fatigue Impact Scale (FIS) Total Score at Week 24
Description	FIS is a participant-reported scale that qualifies the impact of fatigue on daily life in participants with MS.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

Data for this outcome was not analyzed because of insufficient data after early study termination.

Arm/Group Title	Placebo + IFN-beta	Teriflunomide 7 mg + IFN-beta	Teriflunomide 14 mg + IFN-beta
Arm/Group Description	Placebo (for teriflunomide) once daily concomitantly with IFN-beta.	Teriflunomide 7 mg once daily concomitantly with IFN-beta.	Teriflunomide 14 mg once daily concomitantly with IFN-beta.
Measure Participants	0	0	0

8. Secondary Outcome

Title	Change From Baseline in Short Form Generic Health Survey - 36 Items, Version 2 (SF-36v2) Summary Scores at Week 24
Description	SF-36 scale is a generic, self-administered, health-related quality-of-life (QOL) instrument.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

Data for this outcome was not analyzed because of insufficient data after early study termination.

Arm/Group Title	Placebo + IFN-beta	Teriflunomide 7 mg + IFN-beta	Teriflunomide 14 mg + IFN-beta
Arm/Group Description	Placebo (for teriflunomide) once daily concomitantly with IFN-beta.	Teriflunomide 7 mg once daily concomitantly with IFN-beta.	Teriflunomide 14 mg once daily concomitantly with IFN-beta.
Measure Participants	0	0	0

9. Secondary Outcome

Title	Resource Utilization When Relapse
Description	Resource utilization each time a participant experiences an MS relapse, specifically the number of hospitalizations, the number of over night spent in the hospital and number of intensive care admissions if hospitalized were to be reported.
Time Frame	Up to a maximum of 108 weeks depending on time of enrollment

Outcome Measure Data

Analysis Population Description

Data for this outcome was not analyzed because of insufficient data after early study termination.

Arm/Group Title	Placebo + IFN-beta	Teriflunomide 7 mg + IFN-beta	Teriflunomide 14 mg + IFN-beta
Arm/Group Description	Placebo (for teriflunomide) once daily concomitantly with IFN-beta.	Teriflunomide 7 mg once daily concomitantly with IFN-beta.	Teriflunomide 14 mg once daily concomitantly with IFN-beta.
Measure Participants	0	0	0

10. Secondary Outcome

Title	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	First study drug intake up to 28 days after last study drug intake, for up to 112 weeks

Outcome Measure Data

Analysis Population Description

Safety population: all randomized and treated participants. Participants were included in the treatment group 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	Placebo + IFN-beta	Teriflunomide 7 mg + IFN-beta	Teriflunomide 14 mg + IFN-beta
Arm/Group Description	Placebo (for teriflunomide) once daily concomitantly with IFN-beta.	Teriflunomide 7 mg once daily concomitantly with IFN-beta.	Teriflunomide 14 mg once daily concomitantly with IFN-beta.
Measure Participants	175	179	178
Any AE	119 67.2%	140 78.7%	140 78.2%
Any Serious AE	8 4.5%	13 7.3%	14 7.8%
Any AE Leading to Death	0 0%	0 0%	0 0%
Any AE Leading to Study Drug Discontinuation	9 5.1%	16 9%	22 12.3%

11. Other Pre-specified Outcome

Title	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 or 10 Upper Limit of Normal (ULN); Aspartate Aminotransferase (AST) >3, 5 or 10 ULN; Alkaline Phosphatase >1.5 ULN; Total Bilirubin (TB) >1.5 ULN; and ALT >3 ULN and TB >2 ULN.
Time Frame	First study drug intake up to 28 days after last study drug intake, for up to 112 weeks

Outcome Measure Data

Analysis Population Description

Safety population as previously defined but including only participants who had post-baseline values.

Arm/Group Title	Placebo + IFN-beta	Teriflunomide 7 mg + IFN-beta	Teriflunomide 14 mg + IFN-beta
Arm/Group Description	Placebo (for teriflunomide) once daily concomitantly with IFN-beta.	Teriflunomide 7 mg once daily concomitantly with IFN-beta.	Teriflunomide 14 mg once daily concomitantly with IFN-beta.
Measure Participants	174	179	178
ALT >3 ULN	6 3.4%	9 5.1%	9 5%
ALT >5 ULN	1 0.6%	6 3.4%	5 2.8%
ALT >10 ULN	1 0.6%	3 1.7%	2 1.1%
AST >3 ULN	3 1.7%	4 2.2%	4 2.2%
AST >5 ULN	2 1.1%	3 1.7%	3 1.7%
AST >10 ULN	1 0.6%	2 1.1%	0 0%
Alkaline Phosphatase >1.5 ULN	0 0%	2 1.1%	0 0%
TB >1.5 ULN	2 1.1%	0 0%	2 1.1%
ALT >3 ULN and TB >2 ULN	0 0%	0 0%	0 0%

Adverse Events

Time Frame	All AEs were collected regardless of seriousness or relationship to the drug, spanning from signature of the Informed Consent up to the last visit.
Adverse Event Reporting Description	The analysis was performed on the safety population and included all AEs that developed or worsened from first study drug intake up to 28 days after last study drug intake, for up to 112 weeks. Participants were included in the treatment group according to the drug actually received.
Arm/Group Title	Placebo + IFN-beta		Teriflunomide 7 mg + IFN-beta		Teriflunomide 14 mg + IFN-beta
Arm/Group Description	Placebo (for teriflunomide) once daily concomitantly with IFN-beta.		Teriflunomide 7 mg once daily concomitantly with IFN-beta.		Teriflunomide 14 mg once daily concomitantly with IFN-beta.
All Cause Mortality
	Placebo + IFN-beta		Teriflunomide 7 mg + IFN-beta		Teriflunomide 14 mg + IFN-beta
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo + IFN-beta		Teriflunomide 7 mg + IFN-beta		Teriflunomide 14 mg + IFN-beta
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/175 (4.6%)		13/179 (7.3%)		14/178 (7.9%)
Blood and lymphatic system disorders
Neutropenia	2/175 (1.1%)		0/179 (0%)		1/178 (0.6%)
Thrombocytopenia	1/175 (0.6%)		0/179 (0%)		0/178 (0%)
Cardiac disorders
Myocardial infarction	0/175 (0%)		0/179 (0%)		1/178 (0.6%)
Supraventricular tachycardia	0/175 (0%)		1/179 (0.6%)		0/178 (0%)
Gastrointestinal disorders
Diarrhoea	0/175 (0%)		1/179 (0.6%)		0/178 (0%)
Umbilical hernia	0/175 (0%)		1/179 (0.6%)		0/178 (0%)
General disorders
Chest pain	0/175 (0%)		0/179 (0%)		1/178 (0.6%)
Hepatobiliary disorders
Cholelithiasis	0/175 (0%)		1/179 (0.6%)		0/178 (0%)
Drug-induced liver injury	0/175 (0%)		1/179 (0.6%)		0/178 (0%)
Hepatotoxicity	1/175 (0.6%)		0/179 (0%)		0/178 (0%)
Infections and infestations
Cystitis	0/175 (0%)		0/179 (0%)		1/178 (0.6%)
Injury, poisoning and procedural complications
Facial bones fracture	1/175 (0.6%)		0/179 (0%)		0/178 (0%)
Humerus fracture	1/175 (0.6%)		0/179 (0%)		0/178 (0%)
Overdose	1/175 (0.6%)		0/179 (0%)		0/178 (0%)
Thermal burn	0/175 (0%)		1/179 (0.6%)		0/178 (0%)
Investigations
Alanine aminotransferase increased	0/175 (0%)		2/179 (1.1%)		2/178 (1.1%)
Aspartate aminotransferase increased	0/175 (0%)		1/179 (0.6%)		0/178 (0%)
Musculoskeletal and connective tissue disorders
Intervertebral disc disorder	0/175 (0%)		0/179 (0%)		1/178 (0.6%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Testicular seminoma (pure)	0/175 (0%)		0/179 (0%)		1/178 (0.6%)
Nervous system disorders
Convulsion	0/175 (0%)		1/179 (0.6%)		0/178 (0%)
Loss of consciousness	1/175 (0.6%)		0/179 (0%)		0/178 (0%)
Multiple sclerosis	0/175 (0%)		0/179 (0%)		1/178 (0.6%)
Multiple sclerosis relapse	1/175 (0.6%)		2/179 (1.1%)		1/178 (0.6%)
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	0/175 (0%)		0/179 (0%)		1/178 (0.6%)
Pregnancy	0/175 (0%)		0/179 (0%)		1/178 (0.6%)
Psychiatric disorders
Anxiety	1/175 (0.6%)		0/179 (0%)		0/178 (0%)
Depression	1/175 (0.6%)		0/179 (0%)		0/178 (0%)
Major depression	0/175 (0%)		1/179 (0.6%)		0/178 (0%)
Reproductive system and breast disorders
Menorrhagia	0/175 (0%)		0/179 (0%)		1/178 (0.6%)
Ovarian cyst	0/175 (0%)		0/179 (0%)		1/178 (0.6%)
Vascular disorders
Hypertension	0/175 (0%)		1/179 (0.6%)		0/178 (0%)
Other (Not Including Serious) Adverse Events
	Placebo + IFN-beta		Teriflunomide 7 mg + IFN-beta		Teriflunomide 14 mg + IFN-beta
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	85/175 (48.6%)		94/179 (52.5%)		104/178 (58.4%)
Blood and lymphatic system disorders
Neutropenia	4/175 (2.3%)		8/179 (4.5%)		10/178 (5.6%)
Gastrointestinal disorders
Diarrhoea	6/175 (3.4%)		16/179 (8.9%)		20/178 (11.2%)
Nausea	9/175 (5.1%)		18/179 (10.1%)		12/178 (6.7%)
General disorders
Influenza like illness	8/175 (4.6%)		9/179 (5%)		4/178 (2.2%)
Infections and infestations
Gastroenteritis	0/175 (0%)		1/179 (0.6%)		9/178 (5.1%)
Nasopharyngitis	20/175 (11.4%)		21/179 (11.7%)		20/178 (11.2%)
Upper respiratory tract infection	12/175 (6.9%)		9/179 (5%)		9/178 (5.1%)
Urinary tract infection	5/175 (2.9%)		10/179 (5.6%)		4/178 (2.2%)
Investigations
Alanine aminotransferase increased	15/175 (8.6%)		16/179 (8.9%)		26/178 (14.6%)
Musculoskeletal and connective tissue disorders
Back pain	9/175 (5.1%)		8/179 (4.5%)		7/178 (3.9%)
Nervous system disorders
Dizziness	5/175 (2.9%)		8/179 (4.5%)		9/178 (5.1%)
Headache	14/175 (8%)		19/179 (10.6%)		22/178 (12.4%)
Skin and subcutaneous tissue disorders
Alopecia	9/175 (5.1%)		11/179 (6.1%)		18/178 (10.1%)
Vascular disorders
Hypertension	8/175 (4.6%)		7/179 (3.9%)		15/178 (8.4%)

Limitations/Caveats

The early termination of study with reduced sample size and participant follow-up impacts the power and interpretability, and limits the ability to assess the overall benefit/risk of adjunctive therapy. Termination was not due to any safety concerns.

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.