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

ClinicalTrials.gov processed this record on October 30, 2014