Phase II Study of Teriflunomide as Adjunctive Therapy to Glatiramer Acetate 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 to placebo, in patients with multiple sclerosis [MS] with relapses who were on a stable dose of Glatiramer Acetate [GA]. The secondary objectives were: to estimate the effect of the 2 doses of Teriflunomide, compared to placebo, in combination with a stable dose of GA 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 GA.

Detailed Description
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The duration of the study period for a 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 Glatiramer Acetate 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: Glatiramer Acetate (GA)


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 Glatiramer Acetate [GA] 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 |
| --- | --- |
| Placebo Comparator: Placebo + GA<br>Placebo (for teriflunomide) once daily concomitantly with glatiramer acetate (GA) for 24 weeks | Drug: Placebo (for teriflunomide)<br>* Film-coated tablet Oral administration<br>Drug: Glatiramer Acetate (GA)<br>* Solution in prefilled syringe for subcutaneous injection<br>* Other names: Copaxone®;|
| Experimental: Teriflunomide 7 mg + GA<br>Teriflunomide 7 mg once daily concomitantly with glatiramer acetate (GA) for 24 weeks | Drug: Teriflunomide<br>* Film-coated tablet Oral administration<br>* Other names: HMR1726;Drug: Glatiramer Acetate (GA)<br>* Solution in prefilled syringe for subcutaneous injection<br>* Other names: Copaxone®;|
| Experimental: Teriflunomide 14 mg + GA<br>Teriflunomide 14 mg once daily concomitantly with glatiramer acetate (GA) for 24 weeks | Drug: Teriflunomide<br>* Film-coated tablet Oral administration<br>* Other names: HMR1726;Drug: Glatiramer Acetate (GA)<br>* Solution in prefilled syringe for subcutaneous injection<br>* Other names: Copaxone®;|

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 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, 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 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 and region of enrollment 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, glatiramer acetate, adjunctive therapy, relapses