Long Term Safety of Teriflunomide When Added to Interferon-Beta or Glatiramer Acetate in Patients With Multiple Sclerosis
- Conditions
- Multiple Sclerosis
- Interventions
- Drug: Placebo (for teriflunomide)Drug: Interferon-β [IFN-β]
- Registration Number
- NCT00811395
- Lead Sponsor
- Sanofi
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 182
-
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.
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo + IFN-β Placebo (for teriflunomide) Placebo (for teriflunomide) once daily concomitantly with interferon-β \[IFN-β\] for 24 additional weeks Placebo + IFN-β Interferon-β [IFN-β] Placebo (for teriflunomide) once daily concomitantly with interferon-β \[IFN-β\] for 24 additional weeks Teriflunomide 7 mg + IFN-β Teriflunomide Teriflunomide 7 mg once daily concomitantly with interferon-β \[IFN-β\] for 24 additional weeks Teriflunomide 7 mg + IFN-β Interferon-β [IFN-β] Teriflunomide 7 mg once daily concomitantly with interferon-β \[IFN-β\] for 24 additional weeks Teriflunomide 14 mg + IFN-β Interferon-β [IFN-β] Teriflunomide 14 mg once daily concomitantly with interferon-β \[IFN-β\] for 24 additional weeks Placebo + GA Placebo (for teriflunomide) Placebo (for teriflunomide) once daily concomitantly with glatiramer acetate \[GA\] for 24 additional weeks Placebo + GA Glatiramer Acetate [GA] Placebo (for teriflunomide) once daily concomitantly with glatiramer acetate \[GA\] for 24 additional weeks Teriflunomide 7 mg + GA Teriflunomide Teriflunomide 7 mg once daily concomitantly with glatiramer acetate \[GA\] for 24 additional weeks Teriflunomide 7 mg + GA Glatiramer Acetate [GA] Teriflunomide 7 mg once daily concomitantly with glatiramer acetate \[GA\] for 24 additional weeks Teriflunomide 14 mg + GA Teriflunomide Teriflunomide 14 mg once daily concomitantly with glatiramer acetate \[GA\] for 24 additional weeks Teriflunomide 14 mg + GA Glatiramer Acetate [GA] Teriflunomide 14 mg once daily concomitantly with glatiramer acetate \[GA\] for 24 additional weeks Teriflunomide 14 mg + IFN-β Teriflunomide Teriflunomide 14 mg once daily concomitantly with interferon-β \[IFN-β\] for 24 additional weeks
- Primary Outcome Measures
Name Time Method Overview of Adverse Events [AE] 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) AE are any unfavorable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study.
Overview of AE With Potential Risk of Occurence 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) 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.Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities [PCSA] 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) 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;
- Secondary Outcome Measures
Name Time Method Annualized Relapse Rate [ARR]: Poisson Regression Estimates 48 weeks 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)Overview of 12-week Sustained Disability Progression 48 weeks 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.Time to 12-week Sustained Disability Progression: Kaplan-Meier Estimates of the Rate of Disability Progression at Timepoints 48 weeks 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.Cerebral Magnetic Resonance Imaging [MRI] Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease) baseline (before randomization in PDY6045 or PDY6046) and 48 weeks 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.Cerebral MRI Assessment: Number of Gd-enhancing T1-lesions Per Scan (Poisson Regression Estimates) 48 weeks 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)Cerebral MRI Assessment: Total Volume of Gd-enhancing T1-lesions Per Scan 48 weeks 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.
Trial Locations
- Locations (1)
Sanofi-Aventis Administrative Office
🇬🇧Guildford, United Kingdom