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

Phase 3

Terminated

Conditions: Multiple Sclerosis Relapse

Interventions: Drug: Teriflunomide
Drug: Placebo (for teriflunomide)
Drug: Interferon-beta (IFN-beta)

Registration Number: NCT01252355

Lead Sponsor: Sanofi

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)

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 534

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Teriflunomide 7 mg + IFN-beta	Teriflunomide	Teriflunomide 7 milligram (mg) once a day concomitantly with IFN-beta therapy.
Teriflunomide 14 mg + IFN-beta	Teriflunomide	Teriflunomide 14 mg once a day concomitantly with IFN-beta therapy.
Placebo + IFN-beta	Placebo (for teriflunomide)	Placebo (for teriflunomide) once a day concomitantly with IFN-beta therapy.
Teriflunomide 7 mg + IFN-beta	Interferon-beta (IFN-beta)	Teriflunomide 7 milligram (mg) once a day concomitantly with IFN-beta therapy.
Placebo + IFN-beta	Interferon-beta (IFN-beta)	Placebo (for teriflunomide) once a day concomitantly with IFN-beta therapy.
Teriflunomide 14 mg + IFN-beta	Interferon-beta (IFN-beta)	Teriflunomide 14 mg once a day concomitantly with IFN-beta therapy.

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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).
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.
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.
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.
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.
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.
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.
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.
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.

Trial Locations

Locations (185): Investigational Site Number 840049
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Cullman, Alabama, United States
Investigational Site Number 840005
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Cordova, Alaska, United States
Investigational Site Number 840003
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Phoenix, Arizona, United States
Investigational Site Number 840011
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Oceanside, California, United States
Investigational Site Number 840036
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Fort Collins, Colorado, United States
Investigational Site Number 840012
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Maitland, Florida, United States
Investigational Site Number 840013
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Ormond Beach, Florida, United States
Investigational Site Number 840055
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Pompano Beach, Florida, United States
Investigational Site Number 840021
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St. Petersburg, Florida, United States
Investigational Site Number 840004
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Tampa, Florida, United States
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Investigational Site Number 840049
🇺🇸Cullman, Alabama, United States