Phase II Study of Teriflunomide as Adjunctive Therapy to Interferon-beta in Subjects With Multiple Sclerosis

Study Overview
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Brief Summary
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The primary objective was to estimate the tolerability and safety of 2 doses of teriflunomide administered once daily for 24 weeks, compared with placebo, in patients with multiple sclerosis [MS] with relapses who were on a stable dose of interferon-β [IFN-β]. Secondary objectives were: to estimate the effects of the 2 doses of teriflunomide, compared to placebo, in combination with a stable dose of IFN-β on Magnetic Resonance Imaging [MRI] parameters, relapse rate and patient-reported fatigue; to perform pharmacokinetic analyses of the 2 doses of teriflunomide in combination with a stable dose of IFN-β.

Detailed Description
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The study period per participant was approximatively 44 weeks broken down as follows: Screening period up to 4 weeks, 24-week double-blind treatment period*, 16-week post-treatment elimination follow-up period. '*' participants successfully completing the week 24 visit were offered the opportunity to enter the optional long-term extension study LTS6047 - NCT00811395.

Official Title
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A Randomized, Multinational, Double-Blind, Placebo-Controlled, Parallel-Group Design Pilot Study to Estimate the Tolerability, Safety, Pharmacokinetics, and Pharmacodynamic Effects of Teriflunomide for 24 Weeks When Added to Treatment With Interferon-beta in Subjects With Multiple Sclerosis.

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Drug: Teriflunomide
* Drug: Placebo (for Teriflunomide)
* Drug: Interferon-β


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Definite MS diagnosis according to McDonald's criteria; Relapsing clinical course, with or without progression; Expanded Disability Status Scale [EDSS] less or equal to 5.5 (ambulatory); Stable dose of IFN-β for at least 26 weeks prior to the screening visit; No onset of MS relapse in the preceding 60 days prior to randomization; Clinically stable for 4 weeks prior to randomization. Exclusion Criteria: Other chronic disease of the immune system, liver function impairment or chronic pancreatic disease; Pregnant or nursing woman; Alcohol or drug abuse; Use of cladribine, mitoxantrone, or other immunosuppressant agents such as azathioprine, cyclophosphamide, cyclosporin, methotrexate or mycophenolate before enrollment; Human immunodeficiency virus [HIV] positive status; 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 patient's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Teriflunomide 7 mg + IFN-β<br>Teriflunomide 7 mg once daily concomitantly with Interferon-β (IFN-β) for 24 weeks | Drug: Teriflunomide<br>* Film-coated tablet Oral administration<br>* Other names: HMR1726;Drug: Interferon-β<br>* Powder for reconstitution, of any licensed strength for either intramuscular or subcutaneous injection<br>* Other names: Betaseron®;|
| Experimental: Teriflunomide 14 mg + IFN-β<br>Teriflunomide 14 mg once daily concomitantly with Interferon-β (IFN-β) for 24 weeks | Drug: Teriflunomide<br>* Film-coated tablet Oral administration<br>* Other names: HMR1726;Drug: Interferon-β<br>* Powder for reconstitution, of any licensed strength for either intramuscular or subcutaneous injection<br>* Other names: Betaseron®;|
| Placebo Comparator: Placebo + IFN-β<br>Placebo (for Teriflunomide) once daily concomitantly with Interferon-β (IFN-β) for 24 weeks | Drug: Placebo (for Teriflunomide)<br>* Film-coated tablet Oral administration<br>Drug: Interferon-β<br>* Powder for reconstitution, of any licensed strength for either intramuscular or subcutaneous injection<br>* Other names: Betaseron®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | from first study drug intake up to 112 days after last intake or up to the first intake in the extension study LTS6047, whichever occured first (40 weeks max) | 
| Overview of AE With Potential Risk of Occurrence | AE with potential risk of occurrence were defined as follows: Hepatic disorders; Immune effects, mainly effects on bone marrow and infection; Pancreatic disorders; Malignancy; Skin disorders, mainly Hair loss and Hair thinning; Pulmonary disorders; Hypertension; Peripheral neuropathy; Psychiatric disorders; Hypersensitivity. | from first study drug intake up to 112 days after last intake or up to the first intake in the extension study LTS6047, whichever occured first (40 weeks max) | 
| Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) | 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 Normal Limit [ULN]; Aspartate aminotransferase [AST] >3, 5, 10 or 20 ULN; Alkaline Phosphatase >1.5 ULN; Total Bilirubin [TB] >1.5 or 2 ULN; ALT >3 ULN and TB >2 ULN; | from first study drug intake up to 112 days after last intake or up to the first intake in the extension study LTS6047, whichever occured first (40 weeks max) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cerebral Magnetic Resonance Imaging [MRI] Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease) | Total lesion volume is the sum of the total volume of all T2-lesions and the total volume of all T1-hypointense post-gadolinium lesions measured through T2/proton density scan analysis and gadolinium-enhanced T1 scan analysis. Least-square means were estimated using a Mixed-effect model with repeated measures [MMRM] on cubic root transformed volume data (treatment group, region of enrollment, IFN-β dose level, visit, treatment-by-visit interaction, baseline value (cubic root transformed), and baseline-by-visit interaction as factors). | baseline (before randomization) and 24 weeks | 
| Cerebral MRI Assessment: Number of Gd-enhancing T1-lesions Per Scan (Poisson Regression Estimates) | Number of Gd-enhancing T1-lesions per scan is obtained from the total number of Gd-enhancing T1-lesions observed during the study divided by the total number of scans performed during the study. 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-β dose level and baseline number of Gd-enhancing T1-lesions as covariates). | 24 weeks | 
| Cerebral MRI Assessment: Volume of Gd-enhancing T1-lesions Per Scan | Total volume of Gd-enhancing T1-lesions per scan is obtained from the sum of the volumes of Gd-enhancing T1-lesions observed during the study divided by the total number of scans performed during the study. | 24 weeks | 
| 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. 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-β dose level as covariates). | 24 weeks | 
| Pharmacokinetic [PK]: Teriflunomide Plasma Concentration | Plasma concentrations of teriflunomide were measured using validated liquid chromatography-tandem mass spectrometry methods. | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MS, interferon-beta, adjunctive therapy, relapses