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

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ClinicalTrials.gov Identifier: NCT00489489
Recruitment Status : Completed
First Posted : June 21, 2007
Results First Posted : November 2, 2012
Last Update Posted : November 6, 2012
Sponsor:
Information provided by (Responsible Party):
Sanofi

Tracking Information
First Submitted Date  ICMJE June 20, 2007
First Posted Date  ICMJE June 21, 2007
Results First Submitted Date  ICMJE October 3, 2012
Results First Posted Date  ICMJE November 2, 2012
Last Update Posted Date November 6, 2012
Study Start Date  ICMJE May 2007
Actual Primary Completion Date June 2009   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 3, 2012)
  • 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) ]
    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) ]
    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) ]
    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;
Original Primary Outcome Measures  ICMJE
 (submitted: June 20, 2007)
Tolerability and safety data based on adverse event reports, physical examinations, laboratory evaluations, electrocardiograms and abdominal ultrasound of the pancreas.
Change History Complete list of historical versions of study NCT00489489 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 3, 2012)
  • Cerebral Magnetic Resonance Imaging [MRI] Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease) [ Time Frame: baseline (before randomization) and 24 weeks ]
    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 ]
    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 ]
    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 ]
    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 ]
    Plasma concentrations of teriflunomide were measured using validated liquid chromatography-tandem mass spectrometry methods.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 20, 2007)
Total number of gadolinium enhancing T1-lesions per MRI (Magnetic Resonance Imaging) scan over the study period, Percentage change from baseline at end of study in burden of disease (based on T2-lesions per MRI), Annualized relapse rate.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase II Study of Teriflunomide as Adjunctive Therapy to Interferon-beta in Subjects With Multiple Sclerosis
Official Title  ICMJE 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.
Brief Summary

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.
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Multiple Sclerosis
Intervention  ICMJE
  • Drug: Teriflunomide

    Film-coated tablet

    Oral administration

    Other Name: HMR1726
  • 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®
Study Arms  ICMJE
  • Experimental: Teriflunomide 7 mg + IFN-β
    Teriflunomide 7 mg once daily concomitantly with Interferon-β (IFN-β) for 24 weeks
    Interventions:
    • Drug: Teriflunomide
    • Drug: Interferon-β
  • Experimental: Teriflunomide 14 mg + IFN-β
    Teriflunomide 14 mg once daily concomitantly with Interferon-β (IFN-β) for 24 weeks
    Interventions:
    • Drug: Teriflunomide
    • Drug: Interferon-β
  • Placebo Comparator: Placebo + IFN-β
    Placebo (for Teriflunomide) once daily concomitantly with Interferon-β (IFN-β) for 24 weeks
    Interventions:
    • Drug: Placebo (for Teriflunomide)
    • Drug: Interferon-β
Publications * 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-β in relapsing multiple sclerosis: a randomized phase II trial. Neurology. 2012 Jun 5;78(23):1877-85. doi: 10.1212/WNL.0b013e318258f7d4. Epub 2012 May 23.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 5, 2012)
118
Original Estimated Enrollment  ICMJE
 (submitted: June 20, 2007)
120
Actual Study Completion Date  ICMJE June 2009
Actual Primary Completion Date June 2009   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 55 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   Germany,   Italy,   Spain,   United States
Removed Location Countries Poland
 
Administrative Information
NCT Number  ICMJE NCT00489489
Other Study ID Numbers  ICMJE PDY6045
2006-003134-14 ( EudraCT Number )
HMR1726D-2003 ( Other Identifier: HMR )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Sanofi
Study Sponsor  ICMJE Sanofi
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: ICD Sanofi
PRS Account Sanofi
Verification Date November 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP