Long Term Safety of Teriflunomide When Added to Interferon-Beta or Glatiramer Acetate in Patients With Multiple Sclerosis

Study Overview
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Brief Summary
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The primary objective was to evaluate the long-term safety and tolerability of teriflunomide when added to treatment with interferon-β [IFN-β] or glatiramer Acetate [GA] in patients with multiple sclerosis [MS] with relapses. Secondary objectives were to evaluate the long-term effect on relapse rate, disability progression and Magnetic Resonance Imaging [MRI] parameters. This study is the extension study of the PDY6045 (NCT00489489) and PDY6046 (NCT00475865) studies. Participants who successfully completed the initial study were offered to continue their treatment (same compound, same dose) for 24 additional weeks.

Detailed Description
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The duration of the extension study per participants was 40 weeks broken down as follows: 24-week double-blind treatment period, 16-week post-treatment elimination follow-up period.

Official Title
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Long-term Extension of the Multinational, Double-blind, Placebo Controlled Studies PDY6045 and PDY6046 to Document the Safety of Teriflunomide When Added to Treatment With Interferon-Beta or Glatiramer Acetate in Patients With Multiple Sclerosis With Relapses

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Drug: Teriflunomide
* Drug: Placebo (for teriflunomide)
* Drug: Interferon-β [IFN-β]
* Drug: Glatiramer Acetate [GA]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: PDY6045 or PDY6046 participant who: completed the week 24 visit of either study PDY6045 or PDY6046, was still meeting eligibility criteria for receiving treatment, had agreed to continue stable dose of Interferon-β [IFN-β] or Glatiramer Acetate [GA] and consented to continue on treatment. Exclusion Criteria: Any known condition or circumstance that would have prevented in the investigator's opinion, compliance or completion of the study The above information is not intended to contain all considerations relevant to 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 + IFN-β<br>Placebo (for teriflunomide) once daily concomitantly with interferon-β [IFN-β] for 24 additional weeks | Drug: Placebo (for teriflunomide)<br>* Film-coated tablet Oral administration<br>Drug: Interferon-β [IFN-β]<br>* Powder for reconstitution, of any licensed strength for either intramuscular or subcutaneous injection<br>* Other names: Betaseron®;|
| Experimental: Teriflunomide 7 mg + IFN-β<br>Teriflunomide 7 mg once daily concomitantly with interferon-β [IFN-β] for 24 additional weeks | Drug: Teriflunomide<br>* Film-coated tablet Oral administration<br>* Other names: HMR1726;Drug: Interferon-β [IFN-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 additional weeks | Drug: Teriflunomide<br>* Film-coated tablet Oral administration<br>* Other names: HMR1726;Drug: Interferon-β [IFN-β]<br>* Powder for reconstitution, of any licensed strength for either intramuscular or subcutaneous injection<br>* Other names: Betaseron®;|
| Placebo Comparator: Placebo + GA<br>Placebo (for teriflunomide) once daily concomitantly with glatiramer acetate [GA] for 24 additional 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 additional 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 additional 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 in PDY6045/PDY6046 study up to 112 days after last intake in initial study or in the extension study, whichever occured last (64 weeks max) | 
| Overview of AE With Potential Risk of Occurence | 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 in PDY6045/PDY6046 study up to 112 days after last intake in initial study or in the extension study, whichever occured last (64 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 in PDY6045/PDY6046 study up to 112 days after last intake in initial study or in the extension study, whichever occured last (64 weeks max) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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, two Poisson regression models with robust error variance were used (total number of confirmed relapses as response variable, log-transformed treatment duration as offset variable and: Model 1 (IFN-β groups): treatment group, region of enrollment and IFN-β dose level as covariates Model 2 (GA groups): treatment group and region of enrollment as covariates) | 48 weeks | 
| Overview of 12-week Sustained Disability Progression | 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. If no disability progression was observed on or before last EDSS evaluation before study drug discontinuation, then the participant was considered as free of disability progression. | 48 weeks | 
| Time to 12-week Sustained Disability Progression: Kaplan-Meier Estimates of the Rate of Disability Progression at Timepoints | Probability of disability progression at 24 and 48 weeks was estimated using Kaplan-Meier method on the time to disability progression defined as the time from randomization to first EDSS increase. Participants free of disability progression were censored at the date of the last on-treatment EDSS evaluation. 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. | 48 weeks | 
| 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 two Mixed-effect models with repeated measures [MMRM] on cubic root transformed volume data: Model 1 (IFN-β groups): 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; Model 2 (GA groups): 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 in PDY6045 or PDY6046) and 48 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, two Poisson regression models with robust error variance were used (total number of Gd-enhancing T1-lesions as response variable, log-transformed number of scans as offset variable and: Model 1 (IFN-β groups): Treatment group, region of enrollment, IFN-β dose level and baseline number of Gd-enhancing T1-lesions as covariates Model 2 (GA groups): Treatment group, region of enrollment and baseline number of Gd-enhancing T1-lesions as covariates) | 48 weeks | 
| Cerebral MRI Assessment: Total 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. | 48 weeks |