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

Multiple Sclerosis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00811395
• Other study ID #: LTS6047
• Secondary ID: HMR1726D/2005200
• Status: Completed
• Phase: Phase 2
• First received: December 18, 2008
• Last updated: December 18, 2012
• Start date: October 2007
• Est. completion date: April 2010

Study information

• Verified date: December 2012
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Health authority: Canada: Health CanadaUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 182
• Est. completion date: April 2010
• Est. primary completion date: April 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 55 Years

Eligibility

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-ß [IFN-ß] 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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Multiple Sclerosis
• Sclerosis

Intervention

Drug:
• Teriflunomide
Film-coated tablet Oral administration
• Placebo (for teriflunomide)
Film-coated tablet Oral administration
• Interferon-ß [IFN-ß]
Powder for reconstitution, of any licensed strength for either intramuscular or subcutaneous injection
• Glatiramer Acetate [GA]
Solution in prefilled syringe for subcutaneous injection

Locations

Country	Name	City	State
Austria	Sanofi-Aventis Administrative Office	Wien
Canada	Sanofi-Aventis Administrative Office	Laval
Germany	Sanofi-Aventis Administrative Office	Berlin
Italy	Sanofi-Aventis Administrative Office	Milano
Spain	Sanofi-Aventis Administrative Office	Barcelona
United Kingdom	Sanofi-Aventis Administrative Office	Guildford
United States	Sanofi-Aventis Administrative Office	Bridgewater	New Jersey

Sponsors (1)

Lead Sponsor	Collaborator
Sanofi

Countries where clinical trial is conducted

United States,  Austria,  Canada,  Germany,  Italy,  Spain,  United Kingdom, 

References & Publications (1)

Freedman MS, Wolinsky JS, Wamil B, Confavreux C, Comi G, Kappos L, Olsson TP, Miller A, Benzerdjeb H, Li H, Simonson C, O'Connor PW; Teriflunomide Multiple Sclerosis Trial Group and the MRI Analysis Center. Teriflunomide added to interferon-ß in relapsing — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)	Yes
Primary	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)	Yes
Primary	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)	Yes
Secondary	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-ß groups): treatment group, region of enrollment and IFN-ß dose level as covariates; Model 2 (GA groups): treatment group and region of enrollment as covariates)	48 weeks	No
Secondary	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	No
Secondary	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	No
Secondary	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-ß groups): treatment group, region of enrollment, IFN-ß 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	No
Secondary	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-ß groups): Treatment group, region of enrollment, IFN-ß 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	No
Secondary	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	No