Phase II Study of Teriflunomide as Adjunctive Therapy to Interferon-beta in Subjects With Multiple Sclerosis

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Sanofi
ClinicalTrials.gov Identifier:
NCT00489489
First received: June 20, 2007
Last updated: November 5, 2012
Last verified: November 2012
  Purpose

The primary objective was to estimate the tolerability and safety of 2 doses of teriflunomide administered once daily for 24 weeks, compared with placebo, in patients with multiple sclerosis [MS] with relapses who were on a stable dose of interferon-β [IFN-β].

Secondary objectives were:

  • to estimate the effects of the 2 doses of teriflunomide, compared to placebo, in combination with a stable dose of IFN-β 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 IFN-β.

Condition Intervention Phase
Multiple Sclerosis
Drug: Teriflunomide
Drug: Placebo (for Teriflunomide)
Drug: Interferon-β
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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 Interferon-beta in Subjects With Multiple Sclerosis.

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 up to 112 days after last intake or up to the first intake in the extension study LTS6047, whichever occured first (40 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 Occurrence [ Time Frame: 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) ] [ 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 up to 112 days after last intake or up to the first intake in the extension study LTS6047, whichever occured first (40 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:
  • Cerebral Magnetic Resonance Imaging [MRI] Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease) [ Time Frame: baseline (before randomization) and 24 weeks ] [ Designated as safety issue: No ]

    Total lesion volume is the sum of the total volume of all T2-lesions and the total volume of 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, IFN-β dose level, 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: 24 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, 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, IFN-β dose level and baseline number of Gd-enhancing T1-lesions as covariates).


  • Cerebral MRI Assessment: Volume of Gd-enhancing T1-lesions Per Scan [ Time Frame: 24 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.

  • Annualized Relapse Rate [ARR]: Poisson Regression Estimates [ Time Frame: 24 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, 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, region of enrollment and IFN-β dose level as covariates).


  • Pharmacokinetic [PK]: Teriflunomide Plasma Concentration [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    Plasma concentrations of teriflunomide were measured using validated liquid chromatography-tandem mass spectrometry methods.


Enrollment: 118
Study Start Date: May 2007
Study Completion Date: June 2009
Primary Completion Date: June 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Teriflunomide 7 mg + IFN-β
Teriflunomide 7 mg once daily concomitantly with Interferon-β (IFN-β) for 24 weeks
Drug: Teriflunomide

Film-coated tablet

Oral administration

Other Name: HMR1726
Drug: Interferon-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 weeks
Drug: Teriflunomide

Film-coated tablet

Oral administration

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

Film-coated tablet

Oral administration

Drug: Interferon-β
Powder for reconstitution, of any licensed strength for either intramuscular or subcutaneous injection
Other Names:
  • Avonex®
  • Rebif®
  • Betaseron®

Detailed Description:

The study period per 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.

  Eligibility

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

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 IFN-β 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.

  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00489489

Locations
United States, New Jersey
Sanofi-Aventis Administrative Office
Bridgewater, New Jersey, United States, 08807
Canada
Sanofi-Aventis Administrative Office
Laval, Canada
Germany
Sanofi-Aventis Administrative Office
Berlin, Germany
Italy
Sanofi-Aventis Administrative Office
Milan, Italy
Spain
Sanofi-Aventis Administrative Office
Barcelona, Spain
Sponsors and Collaborators
Sanofi
Investigators
Study Director: ICD Sanofi
  More Information

Publications:
Responsible Party: Sanofi
ClinicalTrials.gov Identifier: NCT00489489     History of Changes
Other Study ID Numbers: PDY6045, 2006-003134-14, HMR1726D-2003
Study First Received: June 20, 2007
Results First Received: October 3, 2012
Last Updated: November 5, 2012
Health Authority: Canada: Health Canada
Germany: Paul-Ehrlich-Institut
Spain: Spanish Agency of Medicines
United States: Food and Drug Administration

Keywords provided by Sanofi:
MS
interferon-beta
adjunctive therapy
relapses

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

ClinicalTrials.gov processed this record on April 22, 2014