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

Primary Purpose

Multiple Sclerosis

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Interferon β-1a

Teriflunomide

About this trial

This is an interventional treatment trial for Multiple Sclerosis focused on measuring Relapsing-remitting multiple sclerosis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Relapsing form of MS meeting McDonald's criteria for MS diagnosis and Expanded Disability Status Scale [EDSS] score ≤5.5 at screening visit.

Exclusion Criteria:

Significantly impaired bone marrow function or, significant anemia, leukopenia or thrombocytopenia;
Persistent significant or severe infection.
Liver function impairment or known history of hepatitis.
Use of adrenocorticotrophic hormone [ACTH] or systemic corticosteroids for 2 weeks prior to randomization.
Human immunodeficiency virus [HIV] positive.
Prior use of Rebif®, or prior or concomitant use of other interferons in the 3 months prior to randomization.
Prior or concomitant use of cladribine, mitoxantrone, or other immunosuppressant agents such as azathioprine, cyclophosphamide, cyclosporin, methotrexate, mycophenolate, or natalizumab.
Pregnant or breast-feeding woman.

Extension criteria:

The participants who met all the following criteria at the end of the core study period were eligible for enrolment into the open-label extension phase:

Participants who had not discontinued treatment in the core period and who had a minimum treatment of 48 weeks and completed the EOT visit (Visit 18).
Participants who had not met criteria for treatment withdrawal.
An informed consent must be obtained in writing from the participant for this open-label extension phase prior to entering and prior to completion of any extension phase procedure.
Participants who demonstrated a willingness and ability to roll over to the extension phase with the opportunity to continue treatment on 14 mg/day of teriflunomide under open-label.

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

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Active Comparator

Arm Label

Teriflunomide 7 mg / 14 mg

Teriflunomide 14 mg / 14 mg

IFN-β-1a / 14 mg

Arm Description

Teriflunomide 7 mg once daily (core treatment period) and teriflunomide 14 mg once daily (extended treatment period).

Teriflunomide 14 mg once daily (core treatment period) and teriflunomide 14 mg once daily (extension treatment period).

Interferon β-1a 3 times a week (core treatment period) and teriflunomide 14 mg once daily (extended treatment period).

Outcomes

Primary Outcome Measures

Core Treatment Period: Overview of Failures

Failure was defined as the first occurence of confirmed relapse or permanent treatment discontinuation (for any cause) which ever came first. If no events occurred, the participant was considered free of failure. Each episode of relapse - appearance, or worsening of a clinical symptom that was stable for at least 30 days, that persisted for a minimum of 24 hours in the absence of fever - was to be confirmed by an increase in Expanded Disability Status Scale [EDSS] score or Functional System scores.

Core Treatment Period: Time to Failure: Kaplan-Meier Estimates of the Rate of Failure at Timepoints

Probability of disability progression at 24, 48 and 96 weeks was estimated using Kaplan-Meier method on the time to failure defined as the time from randomization to failure. Participants free of failure were censored at the date of last treatment. Kaplan-Meier method consists in computing probabilities of non occurrence of event at any observed time of event and multiplying successive probabilities for time ≤t by any earlier computed probabilities to estimate the probability of being event-free for the amount of time t. Probability of event at time t is 1 minus the probability of being event-free for the amount of time t.

Secondary Outcome Measures

Core Treatment Period: Annualized Relapse Rate [ARR] - Poisson Regression Estimates

ARR is obtained from the total number of confirmed relapses that occured during the treatment period divided by the sum of the treatment durations. To account for the different treatment durations among participants, a Poisson regression model with robust error variance was used (total number of confirmed relapses as response variable; log-transformed treatment duration as "offset" variable; treatment group, region of enrollment and baseline EDSS stratum as covariates).

Core Treatment Period: Change From Baseline in Fatigue Impact Scale (FIS) Total Score

FIS is a subject-reported scale that qualifies the impact of fatigue on daily life in patients with MS. It consists of 40 statements that measure fatigue in three areas; physical, cognitive, and social. FIS total score ranges from 0 (no problem) to 160 (extreme problem). Least-square means were estimated using a Mixed-effect model with repeated measures [MMRM] on FIS total score data (treatment group, region of enrollment, baseline EDSS stratum, visit, treatment-by-visit interaction, baseline value, and baseline-by-visit interaction as factors).

Core Treatment Period: Treatment Satisfaction Questionnaire for Medication [TSQM] Scores

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

Core Treatment Period: Overview of Adverse Events [AE]

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

Extension Treatment Period: Overview of AEs

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

Extension Treatment Period: ARR Poisson Regression Estimates

ARR was obtained from the total number of confirmed relapses that occurred during the treatment period divided by the sum of the standardized treatment durations.To account for the different treatment durations among participants, a Poisson Regression Model with robust error variance was used (total number of confirmed relapses as response variable; log-transformed treatment duration as "offset" variable; treatment group, region of enrolment and baseline EDSS stratum as covariates).

Full Information

NCT ID

NCT00883337

First Posted

April 16, 2009

Last Updated

May 4, 2016

Sponsor

Sanofi

1. Study Identification

Unique Protocol Identification Number

NCT00883337

Brief Title

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

Acronym

TENERE

Official Title

A Multi-center, Randomized, Parallel-group, Rater-blinded Study Comparing the Effectiveness and Safety of Teriflunomide and Interferon Beta-1a in Patients With Relapsing Multiple Sclerosis Plus a Long Term Extension Period

Study Type

Interventional

2. Study Status

Record Verification Date

May 2016

Overall Recruitment Status

Completed

Study Start Date

April 2009 (undefined)

Primary Completion Date

September 2011 (Actual)

Study Completion Date

May 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Sanofi

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Primary objective was to assess the effectiveness evaluated by the time to failure of two doses of teriflunomide in comparison to interferon beta-1a in participants with relapsing Multiple Sclerosis [MS]. Secondary objectives were: To assess the effect of the two doses in comparison to interferon beta-1a on: Frequency of relapses, Fatigue, Participant's satisfaction with treatment. To evaluate the safety and tolerability of the two doses in comparison to interferon beta-1a. The study consisted of a core treatment period with a common end date defined as 48 weeks after randomization of the last participant, followed by an optional long-term extension treatment period until teriflunomide is commercially available in accordance with local regulations.

Detailed Description

The core treatment period per participant was variable depending on the enrollment in the study (maximum of approximatively 118 weeks). The two doses of teriflunomide were administered in double-blind fashion, whereas interferon beta-1a (Rebif®) was open-label. The opportunity to continue with the highest dose of teriflunomide in open-label fashion was offered to the participants who successfully completed treatment in the core study. The overall treatment period was followed by a 4-week elimination follow-up period.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Multiple Sclerosis

Keywords

Relapsing-remitting multiple sclerosis

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

Outcomes Assessor

Allocation

Randomized

Enrollment

324 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Teriflunomide 7 mg / 14 mg

Arm Type

Experimental

Arm Description

Teriflunomide 7 mg once daily (core treatment period) and teriflunomide 14 mg once daily (extended treatment period).

Arm Title

Teriflunomide 14 mg / 14 mg

Arm Type

Experimental

Arm Description

Teriflunomide 14 mg once daily (core treatment period) and teriflunomide 14 mg once daily (extension treatment period).

Arm Title

IFN-β-1a / 14 mg

Arm Type

Active Comparator

Arm Description

Interferon β-1a 3 times a week (core treatment period) and teriflunomide 14 mg once daily (extended treatment period).

Intervention Type

Drug

Intervention Name(s)

Interferon β-1a

Other Intervention Name(s)

Rebif®

Intervention Description

Sterile preservative-free solution packaged in graduated pre-filled syringes Subcutaneous injection Ascending doses from 8.8 to 44 mcg according to local standard for Rebif®

Intervention Type

Drug

Intervention Name(s)

Teriflunomide

Other Intervention Name(s)

HMR1726

Intervention Description

Film-coated tablet Oral administration

Primary Outcome Measure Information:

Title

Core Treatment Period: Overview of Failures

Description

Time Frame

Core treatment period between 48 and 118 weeks depending on when the participant was enrolled

Title

Core Treatment Period: Time to Failure: Kaplan-Meier Estimates of the Rate of Failure at Timepoints

Description

Time Frame

Core treatment period between 48 and 118 weeks depending on when the participant was enrolled

Secondary Outcome Measure Information:

Title

Core Treatment Period: Annualized Relapse Rate [ARR] - Poisson Regression Estimates

Description

Time Frame

Core treatment period between 48 and 118 weeks depending on when the participant was enrolled

Title

Core Treatment Period: Change From Baseline in Fatigue Impact Scale (FIS) Total Score

Description

Time Frame

Baseline (before randomization) and 48 weeks

Title

Core Treatment Period: Treatment Satisfaction Questionnaire for Medication [TSQM] Scores

Description

Time Frame

48 weeks

Title

Core Treatment Period: Overview of Adverse Events [AE]

Description

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

Time Frame

from first study drug intake up to 112 days after last intake in the core treatment period or up to first intake in the extension treatment period, whichever occurred first

Title

Extension Treatment Period: Overview of AEs

Description

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

Time Frame

From first intake of study drug in extension treatment period up to 28 days after the last intake in the extension treatment period

Title

Extension Treatment Period: ARR Poisson Regression Estimates

Description

Time Frame

Extension treatment period (Maximum: 197 weeks)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Relapsing form of MS meeting McDonald's criteria for MS diagnosis and Expanded Disability Status Scale [EDSS] score ≤5.5 at screening visit. Exclusion Criteria: Significantly impaired bone marrow function or, significant anemia, leukopenia or thrombocytopenia; Persistent significant or severe infection. Liver function impairment or known history of hepatitis. Use of adrenocorticotrophic hormone [ACTH] or systemic corticosteroids for 2 weeks prior to randomization. Human immunodeficiency virus [HIV] positive. Prior use of Rebif®, or prior or concomitant use of other interferons in the 3 months prior to randomization. Prior or concomitant use of cladribine, mitoxantrone, or other immunosuppressant agents such as azathioprine, cyclophosphamide, cyclosporin, methotrexate, mycophenolate, or natalizumab. Pregnant or breast-feeding woman. Extension criteria: The participants who met all the following criteria at the end of the core study period were eligible for enrolment into the open-label extension phase: Participants who had not discontinued treatment in the core period and who had a minimum treatment of 48 weeks and completed the EOT visit (Visit 18). Participants who had not met criteria for treatment withdrawal. An informed consent must be obtained in writing from the participant for this open-label extension phase prior to entering and prior to completion of any extension phase procedure. Participants who demonstrated a willingness and ability to roll over to the extension phase with the opportunity to continue treatment on 14 mg/day of teriflunomide under open-label. The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Clinical Sciences & Operations

Organizational Affiliation

Sanofi

Official's Role

Study Director

Facility Information:

Facility Name

Investigational Site Number 056003

City

Bruxelles

ZIP/Postal Code

1070

Country

Belgium

Facility Name

Investigational Site Number 056001

City

Gent

ZIP/Postal Code

9000

Country

Belgium

Facility Name

Investigational Site Number 056002

City

Hasselt

ZIP/Postal Code

B-3590

Country

Belgium

Facility Name

Investigational Site Number 124002

City

London

ZIP/Postal Code

N6A 5A5

Country

Canada

Facility Name

Investigational Site Number 124003

City

Lévis

ZIP/Postal Code

G6V 3Z1

Country

Canada

Facility Name

Investigational Site Number 124004

City

St. John'S

ZIP/Postal Code

A1B 3V6

Country

Canada

Facility Name

Investigational Site Number 203004

City

Jihlava

ZIP/Postal Code

58633

Country

Czech Republic

Facility Name

Investigational Site Number 203003

City

Praha 10

ZIP/Postal Code

10034

Country

Czech Republic

Facility Name

Investigational Site Number 203002

City

Praha 2

ZIP/Postal Code

12808

Country

Czech Republic

Facility Name

Investigational Site Number 250003

City

Bordeaux Cedex

ZIP/Postal Code

33076

Country

France

Facility Name

Investigational Site Number 250005

City

Clermont Ferrand Cedex 1

ZIP/Postal Code

63003

Country

France

Facility Name

Investigational Site Number 250004

City

Lille Cedex

ZIP/Postal Code

59037

Country

France

Facility Name

Investigational Site Number 250001

City

Montpellier Cedex 5

ZIP/Postal Code

34000

Country

France

Facility Name

Investigational Site Number 250002

City

Strasbourg Cedex

ZIP/Postal Code

67091

Country

France

Facility Name

Investigational Site Number 276003

City

Bad Mergentheim

ZIP/Postal Code

97980

Country

Germany

Facility Name

Investigational Site Number 276011

City

Berlin

ZIP/Postal Code

10117

Country

Germany

Facility Name

Investigational Site Number 276012

City

Berlin

ZIP/Postal Code

12099

Country

Germany

Facility Name

Investigational Site Number 276001

City

Bochum

ZIP/Postal Code

44791

Country

Germany

Facility Name

Investigational Site Number 276005

City

Dresden

ZIP/Postal Code

01307

Country

Germany

Facility Name

Investigational Site Number 276007

City

Erbach

ZIP/Postal Code

64711

Country

Germany

Facility Name

Investigational Site Number 276006

City

Essen

ZIP/Postal Code

45138

Country

Germany

Facility Name

Investigational Site Number 276004

City

Halle/Saale

ZIP/Postal Code

06120

Country

Germany

Facility Name

Investigational Site Number 276010

City

Hannover

ZIP/Postal Code

30559

Country

Germany

Facility Name

Investigational Site Number 276009

City

Mainz

ZIP/Postal Code

55131

Country

Germany

Facility Name

Investigational Site Number 276002

City

Münster

ZIP/Postal Code

48149

Country

Germany

Facility Name

Investigational Site Number 300001

City

Athens

ZIP/Postal Code

11527

Country

Greece

Facility Name

Investigational Site Number 300002

City

Thessaloniki

Country

Greece

Facility Name

Investigational Site Number 348001

City

Budapest

ZIP/Postal Code

1083

Country

Hungary

Facility Name

Investigational Site Number 348005

City

Budapest

ZIP/Postal Code

1096

Country

Hungary

Facility Name

Investigational Site Number 348003

City

Budapest

ZIP/Postal Code

1106

Country

Hungary

Facility Name

Investigational Site Number 348002

City

Esztergom

ZIP/Postal Code

2500

Country

Hungary

Facility Name

Investigational Site Number 348007

City

Kecskemét

ZIP/Postal Code

6000

Country

Hungary

Facility Name

Investigational Site Number 348004

City

Veszprém

ZIP/Postal Code

8200

Country

Hungary

Facility Name

Investigational Site Number 380010

City

Ancona

ZIP/Postal Code

60020

Country

Italy

Facility Name

Investigational Site Number 380005

City

Bari

ZIP/Postal Code

70124

Country

Italy

Facility Name

Investigational Site Number 380008

City

Cagliari

ZIP/Postal Code

09126

Country

Italy

Facility Name

Investigational Site Number 380003

City

Cefalù

ZIP/Postal Code

90015

Country

Italy

Facility Name

Investigational Site Number 380007

City

Genova

ZIP/Postal Code

16132

Country

Italy

Facility Name

Investigational Site Number 380001

City

Milano

ZIP/Postal Code

20132

Country

Italy

Facility Name

Investigational Site Number 380004

City

Pavia

ZIP/Postal Code

27100

Country

Italy

Facility Name

Investigational Site Number 380002

City

Roma

ZIP/Postal Code

00185

Country

Italy

Facility Name

Investigational Site Number 380006

City

Torino

ZIP/Postal Code

10126

Country

Italy

Facility Name

Investigational Site Number 616002

City

Bialystok

ZIP/Postal Code

15-276

Country

Poland

Facility Name

Investigational Site Number 616004

City

Gdansk

ZIP/Postal Code

80-803

Country

Poland

Facility Name

Investigational Site Number 616003

City

Lublin

ZIP/Postal Code

20-718

Country

Poland

Facility Name

Investigational Site Number 616001

City

Warszawa

ZIP/Postal Code

02-957

Country

Poland

Facility Name

Investigational Site Number 724007

City

Barcelona

ZIP/Postal Code

08036

Country

Spain

Facility Name

Investigational Site Number 724001

City

Bilbao

ZIP/Postal Code

48013

Country

Spain

Facility Name

Investigational Site Number 724002

City

Majadahonda

ZIP/Postal Code

28222

Country

Spain

Facility Name

Investigational Site Number 724003

City

Murcia

ZIP/Postal Code

30120

Country

Spain

Facility Name

Investigational Site Number 756002

City

St. Gallen

ZIP/Postal Code

9007

Country

Switzerland

Facility Name

Investigational Site Number 788002

City

Monastir

ZIP/Postal Code

5000

Country

Tunisia

Facility Name

Investigational Site Number 826002

City

London

ZIP/Postal Code

SW17 0QT

Country

United Kingdom

Facility Name

Investigational Site Number 826003

City

Plymouth

ZIP/Postal Code

PL6 5BX

Country

United Kingdom

12. IPD Sharing Statement

Citations:

PubMed Identifier

24126064

Citation

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

Results Reference

result

PubMed Identifier

33023488

Citation

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

Results Reference

derived

Learn more about this trial

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

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

Multiple Sclerosis

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial