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An Efficacy Study of Teriflunomide in Patients With Relapsing Multiple Sclerosis (TOWER)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Sanofi
ClinicalTrials.gov Identifier:
NCT00751881
First received: May 7, 2008
Last updated: October 16, 2014
Last verified: October 2014
  Purpose

The primary objective of the study is to assess the effect of two doses of Teriflunomide, in comparison to placebo, on the frequency of multiple sclerosis (MS) relapses in patients with relapsing MS.

Key secondary objective is to assess the effect of the two doses of teriflunomide, in comparison to placebo, on disability progression.

Other secondary objectives are:

  • To assess the effect of the two doses of teriflunomide in comparison to placebo on:

    • Fatigue;
    • Health-related quality of life, a measure of the impact of the patient's health on his or her overall well being.
  • To evaluate the safety and tolerability of teriflunomide.

Condition Intervention Phase
Multiple Sclerosis
Drug: Placebo (for teriflunomide)
Drug: Teriflunomide
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Multi-center Double-blind Parallel-group Placebo-controlled Study of the Efficacy and Safety of Teriflunomide in Patients With Relapsing Multiple Sclerosis

Resource links provided by NLM:


Further study details as provided by Sanofi:

Primary Outcome Measures:
  • Annualized Relapse Rate (ARR): Poisson Regression Estimate [ Time Frame: Core treatment period between 48 - 152 weeks depending on time of enrollment ] [ Designated as safety issue: No ]

    ARR is obtained from the total number of confirmed relapses that occurred during the treatment period divided by the sum of 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 baseline EDSS stratum as covariates).



Secondary Outcome Measures:
  • Time to Disability Progression [ Time Frame: Core treatment period between 48 - 152 weeks depending on time of enrollment ] [ Designated as safety issue: No ]

    Probability of disability progression at 24, 48, 108 and 132 weeks was estimated using Kaplan-Meier method on the time to disability progression defined as the time from randomization to first 12-week sustained disability progression [i.e. 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].

    Participants free of disability progression (no disability progression observed on treatment) 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.


  • Time Without Relapse [ Time Frame: Core treatment period between 48 - 152 weeks depending on time of enrollment ] [ Designated as safety issue: No ]

    Probability of no relapse at 24, 48, 108 and 132 weeks was estimated using Kaplan-Meier method on the time to relapse defined as the time from randomization to first EDSS confirmed relapse.

    Participants free of confirmed relapse (no EDSS confirmed relapse observed on treatment) were censored at the date of the last study drug intake.


  • Change From Baseline to Week 48 in EDSS Total Score [ Time Frame: Baseline (before randomization), Week 12, Week 24, Week 36 and Week 48 ] [ Designated as safety issue: No ]

    EDSS is an ordinal scale in half-point increments that qualifies disability in patients with MS. It consists of 8 ordinal rating scales assessing 7 functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder and cerebral) as well as ambulation.

    EDSS total score ranges from 0 (normal neurological examination) to 10 (death due to MS).

    Baseline adjusted least-squares means at Week 48 were estimated using a Mixed-effect model with repeated measures (MMRM) on EDSS score data (treatment group, region of enrollment, baseline EDSS stratum, visit, treatment-by-visit interaction, baseline value, and baseline-by-visit interaction as factors). All the timepoints from randomization up to Week 48 were included in the model.


  • Change From Baseline to Week 48 in Fatigue Impact Scale (FIS) Total Score [ Time Frame: Baseline (before randomization), Week 12, Week 24 and Week 48 ] [ Designated as safety issue: No ]

    FIS is a subject-reported scale that qualifies the impact of fatigue on daily life in patients with MS. It consists of 40 statements that measure fatigue in 3 areas; physical, cognitive, and social.

    FIS total score ranges from 0 (no problem) to 160 (extreme problem).

    Baseline adjusted least-squares means at week 48 were estimated using a Mixed-effect model with repeated measures (MMRM) on FIS total score data (treatment group, region of enrollment, baseline EDSS stratum, visit, treatment-by-visit interaction, baseline value, and baseline-by-visit interaction as factors). All the timepoints from randomization up to Week 48 were included in the model.


  • Change From Baseline to Last Visit in Fatigue Impact Scale (FIS) Total Score [ Time Frame: Baseline (before randomization) and up to Week 152 ] [ Designated as safety issue: No ]
    Baseline adjusted least-squares means at last visit were estimated using an analysis of covariance (ANCOVA) model on collected data for FIS total score (treatment group, region of enrollment, baseline EDSS stratum, visit number for the last visit and baseline value as factors).

  • Change From Baseline to Week 48 in Short Form Generic Health Survey - 36 Items (SF-36) Summary Scores [ Time Frame: Baseline (before randomization), Week 12, Week 24 and Week 48 ] [ Designated as safety issue: No ]

    SF-36 scale is a generic, self-administered, health-related quality-of-life (QOL) instrument. It is constructed such that the 36 questions represent 8 of the most important health concepts: physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health.

    Two summary scores are obtained:

    • the physical health component summary score,
    • the mental health component summary score.

    Both scores range from 0 to 100 and a high score indicates a more favorable health state.

    Baseline adjusted least-squares means at week 48 were estimated using a Mixed-effect model with repeated measures [MMRM] on each summary score data (treatment group, region of enrollment, baseline EDSS stratum, visit, treatment-by-visit interaction, baseline value, and baseline-by-visit interaction as factors). All the timepoints from randomization up to Week 48 were included in the model.


  • Change From Baseline to Last Visit in Short Form Generic Health Survey - 36 Items (SF-36) Summary Scores [ Time Frame: Baseline (before randomization) and up to Week 152 ] [ Designated as safety issue: No ]
    Baseline adjusted least-squares means at last visit were estimated using an analysis of covariance (ANCOVA) model on collected data for each summary score (treatment group, region of enrollment, baseline EDSS stratum, visit number for the last visit and baseline value as factors).

  • Overview of Adverse Events [ Time Frame: From first study drug intake up to 112 days after last intake in the core treatment period or up to first intake in the extension treatment period, whichever occurred first ] [ Designated as safety issue: Yes ]
    Adverse Events (AE) are any unfavorable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study.


Other Outcome Measures:
  • 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 in the core treatment period or up to first intake in the extension treatment period, whichever occurred first ] [ 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 limit of normal(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.


Enrollment: 1169
Study Start Date: August 2008
Estimated Study Completion Date: March 2015
Primary Completion Date: April 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Teriflunomide 7 mg

Teriflunomide 7 mg once daily for 48 to 152 weeks depending on time of enrollment (core treatment period),

then optional,

Teriflunomide 14 mg once daily until teriflunomide is commercially available in the country the participant lives (extension treatment period).

Drug: Teriflunomide

Film-coated tablet

Oral administration

Other Name: HMR1726
Experimental: Teriflunomide 14 mg

Teriflunomide 14 mg once daily for 48 to 152 weeks depending on time of enrollment (core treatment period),

then optional,

Teriflunomide 14 mg once daily until teriflunomide is commercially available in the country the participant lives (extension treatment period).

Drug: Teriflunomide

Film-coated tablet

Oral administration

Other Name: HMR1726
Placebo Comparator: Placebo

Placebo (for teriflunomide) once daily for 48 to 152 weeks depending on time of enrollment (core treatment period),

then optional,

Teriflunomide 14 mg once daily until teriflunomide is commercially available in the country the participant lives (extension treatment period).

Drug: Placebo (for teriflunomide)

Film-coated tablet

Oral administration

Drug: Teriflunomide

Film-coated tablet

Oral administration

Other Name: HMR1726

Detailed Description:

The study consists in:

  • A core treatment period: Teriflunomide 7 mg or Teriflunomide 14 mg or placebo is administered in double-blind fashion until a fixed common end date which is approximately 48 weeks after randomization of the last participant.
  • An extension treatment period: the highest dose of teriflunomide is administered in open-label fashion to participants who successfully complete the core treatment period and wish to continue.

The overall treatment period is followed by a 4-week 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:

  • Relapsing multiple sclerosis,
  • Two relapses in prior 2 years or one relapse in prior year.

Exclusion Criteria:

  • Clinically relevant cardiovascular, hepatic, neurological, endocrine or other major systemic disease,
  • Significantly impaired bone marrow function or, significant anemia, leukopenia or thrombocytopenia,
  • Pregnant or nursing woman,
  • Alcohol or drug abuse,
  • Prior or concomitant use of cladribine, mitoxantrone, or other immunosuppressant agents such as azathioprine, cyclophosphamide, cyclosporin, methotrexate or mycophenolate,
  • Human immunodeficiency virus (HIV) positive,
  • 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: NCT00751881

  Show 193 Study Locations
Sponsors and Collaborators
Sanofi
Investigators
Study Director: Clinical Sciences & Operations Sanofi
  More Information

No publications provided by Sanofi

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Sanofi
ClinicalTrials.gov Identifier: NCT00751881     History of Changes
Other Study ID Numbers: EFC10531, 2007-004452-36
Study First Received: May 7, 2008
Results First Received: April 16, 2013
Last Updated: October 16, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Sanofi:
relapsing multiple sclerosis

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

ClinicalTrials.gov processed this record on November 24, 2014