A Study Comparing the Effectiveness and Safety of Teriflunomide and Interferon Beta-1a in Patients With Relapsing Multiple Sclerosis (TENERE)
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| ClinicalTrials.gov Identifier: NCT00883337 |
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Recruitment Status :
Completed
First Posted : April 17, 2009
Results First Posted : November 6, 2012
Last Update Posted : June 13, 2016
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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:
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Multiple Sclerosis | Drug: Interferon β-1a Drug: Teriflunomide | Phase 3 |
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.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 324 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Single (Outcomes Assessor) |
| Primary Purpose: | Treatment |
| 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 Start Date : | April 2009 |
| Actual Primary Completion Date : | September 2011 |
| Actual Study Completion Date : | May 2015 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Teriflunomide 7 mg / 14 mg
Teriflunomide 7 mg once daily (core treatment period) and teriflunomide 14 mg once daily (extended treatment period).
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Drug: Teriflunomide
Film-coated tablet Oral administration Other Name: HMR1726 |
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Experimental: Teriflunomide 14 mg / 14 mg
Teriflunomide 14 mg once daily (core treatment period) and teriflunomide 14 mg once daily (extension treatment period).
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Drug: Teriflunomide
Film-coated tablet Oral administration Other Name: HMR1726 |
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Active Comparator: IFN-β-1a / 14 mg
Interferon β-1a 3 times a week (core treatment period) and teriflunomide 14 mg once daily (extended treatment period).
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Drug: Interferon β-1a
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® Other Name: Rebif® Drug: Teriflunomide Film-coated tablet Oral administration Other Name: HMR1726 |
- Core Treatment Period: Overview of Failures [ Time Frame: Core treatment period between 48 and 118 weeks depending on when the participant was enrolled ]
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 [ Time Frame: Core treatment period between 48 and 118 weeks depending on when the participant was enrolled ]
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.
- Core Treatment Period: Annualized Relapse Rate [ARR] - Poisson Regression Estimates [ Time Frame: Core treatment period between 48 and 118 weeks depending on when the participant was enrolled ]
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 [ Time Frame: Baseline (before randomization) and 48 weeks ]
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 [ Time Frame: 48 weeks ]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] [ 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 ]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 [ 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 ]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 [ Time Frame: Extension treatment period (Maximum: 197 weeks) ]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).
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00883337
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| Study Director: | Clinical Sciences & Operations | Sanofi |
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | Sanofi |
| ClinicalTrials.gov Identifier: | NCT00883337 |
| Other Study ID Numbers: |
EFC10891 2008-006226-34 ( EudraCT Number ) |
| First Posted: | April 17, 2009 Key Record Dates |
| Results First Posted: | November 6, 2012 |
| Last Update Posted: | June 13, 2016 |
| Last Verified: | May 2016 |
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Relapsing-remitting multiple sclerosis |
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Multiple Sclerosis Sclerosis Pathologic Processes Demyelinating Autoimmune Diseases, CNS Autoimmune Diseases of the Nervous System Nervous System Diseases Demyelinating Diseases Autoimmune Diseases Immune System Diseases Interferons Interferon-beta Interferon beta-1a Teriflunomide Antineoplastic Agents |
Antiviral Agents Anti-Infective Agents Anti-Inflammatory Agents, Non-Steroidal Analgesics, Non-Narcotic Analgesics Sensory System Agents Peripheral Nervous System Agents Physiological Effects of Drugs Anti-Inflammatory Agents Antirheumatic Agents Immunosuppressive Agents Immunologic Factors Adjuvants, Immunologic |