Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials
Trial record 8 of 20 for:    teriflunomide

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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Sanofi
ClinicalTrials.gov Identifier:
NCT00811395
First received: December 18, 2008
Last updated: December 18, 2012
Last verified: December 2012
  Purpose

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.


Condition Intervention Phase
Multiple Sclerosis
Drug: Teriflunomide
Drug: Placebo (for teriflunomide)
Drug: Interferon-β [IFN-β]
Drug: Glatiramer Acetate [GA]
Phase 2

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

Resource links provided by NLM:


Further study details as provided by Sanofi:

Primary Outcome Measures:
  • Overview of Adverse Events [AE] [ Time Frame: 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) ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: 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) ] [ Designated as safety issue: Yes ]

    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] [ Time Frame: 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) ] [ Designated as safety issue: Yes ]

    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:
  • Annualized Relapse Rate [ARR]: Poisson Regression Estimates [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]

    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 [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]

    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 [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]

    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) [ Time Frame: baseline (before randomization in PDY6045 or PDY6046) and 48 weeks ] [ Designated as safety issue: No ]

    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) [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]

    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 [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
    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.


Enrollment: 182
Study Start Date: October 2007
Study Completion Date: April 2010
Primary Completion Date: April 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Placebo + IFN-β
Placebo (for teriflunomide) once daily concomitantly with interferon-β [IFN-β] for 24 additional weeks
Drug: Placebo (for teriflunomide)

Film-coated tablet

Oral administration

Drug: Interferon-β [IFN-β]
Powder for reconstitution, of any licensed strength for either intramuscular or subcutaneous injection
Other Names:
  • Avonex®
  • Rebif®
  • Betaseron®
Experimental: Teriflunomide 7 mg + IFN-β
Teriflunomide 7 mg once daily concomitantly with interferon-β [IFN-β] for 24 additional weeks
Drug: Teriflunomide

Film-coated tablet

Oral administration

Other Name: HMR1726
Drug: Interferon-β [IFN-β]
Powder for reconstitution, of any licensed strength for either intramuscular or subcutaneous injection
Other Names:
  • Avonex®
  • Rebif®
  • Betaseron®
Experimental: Teriflunomide 14 mg + IFN-β
Teriflunomide 14 mg once daily concomitantly with interferon-β [IFN-β] for 24 additional weeks
Drug: Teriflunomide

Film-coated tablet

Oral administration

Other Name: HMR1726
Drug: Interferon-β [IFN-β]
Powder for reconstitution, of any licensed strength for either intramuscular or subcutaneous injection
Other Names:
  • Avonex®
  • Rebif®
  • Betaseron®
Placebo Comparator: Placebo + GA
Placebo (for teriflunomide) once daily concomitantly with glatiramer acetate [GA] for 24 additional weeks
Drug: Placebo (for teriflunomide)

Film-coated tablet

Oral administration

Drug: Glatiramer Acetate [GA]
Solution in prefilled syringe for subcutaneous injection
Other Name: Copaxone®
Experimental: Teriflunomide 7 mg + GA
Teriflunomide 7 mg once daily concomitantly with glatiramer acetate [GA] for 24 additional weeks
Drug: Teriflunomide

Film-coated tablet

Oral administration

Other Name: HMR1726
Drug: Glatiramer Acetate [GA]
Solution in prefilled syringe for subcutaneous injection
Other Name: Copaxone®
Experimental: Teriflunomide 14 mg + GA
Teriflunomide 14 mg once daily concomitantly with glatiramer acetate [GA] for 24 additional weeks
Drug: Teriflunomide

Film-coated tablet

Oral administration

Other Name: HMR1726
Drug: Glatiramer Acetate [GA]
Solution in prefilled syringe for subcutaneous injection
Other Name: Copaxone®

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.
  Eligibility

Ages Eligible for Study:   18 Years to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00811395

Locations
United States, New Jersey
Sanofi-Aventis Administrative Office
Bridgewater, New Jersey, United States, 08807
Austria
Sanofi-Aventis Administrative Office
Wien, Austria
Canada
Sanofi-Aventis Administrative Office
Laval, Canada
Germany
Sanofi-Aventis Administrative Office
Berlin, Germany
Italy
Sanofi-Aventis Administrative Office
Milano, Italy
Spain
Sanofi-Aventis Administrative Office
Barcelona, Spain
United Kingdom
Sanofi-Aventis Administrative Office
Guildford, United Kingdom
Sponsors and Collaborators
Sanofi
Investigators
Study Director: Clinical Sciences & Operations Sanofi
  More Information

Publications:
Responsible Party: Sanofi
ClinicalTrials.gov Identifier: NCT00811395     History of Changes
Other Study ID Numbers: LTS6047, HMR1726D/2005, 2007-003997-24
Study First Received: December 18, 2008
Results First Received: October 3, 2012
Last Updated: December 18, 2012
Health Authority: Canada: Health Canada
United States: Food and Drug Administration

Additional relevant MeSH terms:
Multiple Sclerosis
Sclerosis
Autoimmune Diseases
Autoimmune Diseases of the Nervous System
Demyelinating Autoimmune Diseases, CNS
Demyelinating Diseases
Immune System Diseases
Nervous System Diseases
Pathologic Processes
Copolymer 1
Interferon-beta
Interferons
Adjuvants, Immunologic
Anti-Infective Agents
Antineoplastic Agents
Antiviral Agents
Immunologic Factors
Immunosuppressive Agents
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on November 24, 2014