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Long Term Safety and Efficacy Study of Teriflunomide 7 mg or 14 mg in Patients With Relapsing-Remitting Multiple Sclerosis

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ClinicalTrials.gov Identifier: NCT00803049
Recruitment Status : Completed
First Posted : December 5, 2008
Results First Posted : January 30, 2017
Last Update Posted : January 30, 2017
Sponsor:
Information provided by (Responsible Party):
Sanofi

Tracking Information
First Submitted Date  ICMJE December 1, 2008
First Posted Date  ICMJE December 5, 2008
Results First Submitted Date  ICMJE December 5, 2016
Results First Posted Date  ICMJE January 30, 2017
Last Update Posted Date January 30, 2017
Study Start Date  ICMJE October 2006
Actual Primary Completion Date December 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 5, 2016)
Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: Baseline (LTS6050) up to 28 days after last dose of study drug up to 450 weeks ]
Adverse event (AE) was defined as any untoward medical occurrence in a participant who received investigational medicinal product (IMP) without regard to possibility of causal relationship with this treatment. TEAEs: AEs that developed or worsened or became serious during on-treatment period which was defined as the period from the time of first dose of study drug (in LTS6050) up to 4 weeks (28 days) after last dose of study drug. Serious adverse event (SAE) was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. Any TEAE included both serious and non-serious AEs.
Original Primary Outcome Measures  ICMJE
 (submitted: December 4, 2008)
Safety: adverse events, physical examinations, vital signs, blood and urine laboratory parameters, ultra-sound image of pancreas [ Time Frame: up to a maximum of 4 years ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 5, 2016)
  • Time to 12 Week Sustained Disability Progression (DP): Kaplan-Meier Estimates of the Rate of DP [ Time Frame: Up to 10.8 years (EFC6049: 108 weeks + LTS6050: 450 weeks) ]
    Sustained DP defined as sustained increase of at least 1 point from baseline (EFC6049) expanded disability status scale (EDSS) score (0.5 point for participants with baseline EDSS>5.5) persisting for at least 12 weeks. EDSS: an ordinal scale qualifies disability in participants with MS. EDSS total score range: 0 (normal neurological examination) to 10 (death due to Multiple Sclerosis [MS]). Probability of DP at 12 weeks was estimated using Kaplan-Meier method on time to DP defined as date of first DP minus (-) date of randomization in EFC6049 study +1 day. Participants free of DP (no DP observed on treatment) were censored at the date of last on-treatment EDSS evaluation in LTS6050. 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.
  • Time to 24 Week Sustained Disability Progression (DP): Kaplan-Meier Estimates of the Rate of DP [ Time Frame: Up to 10.8 years (EFC6049: 108 weeks + LTS6050: 450 weeks) ]
    Sustained DP was defined as sustained increase of at least 1 point from baseline (EFC6049) EDSS score (0.5 point for participants with baseline EDSS>5.5) persisting for at least 24 weeks. EDSS: an ordinal scale qualifies disability in participants with MS. EDSS total score range: 0 (normal neurological examination) to 10 (death due to MS). Probability of DP at 24 weeks was estimated using Kaplan-Meier method on time to DP defined as date of first DP minus (-) date of randomization in EFC6049 study +1 day. Participants free of DP (no DP observed on treatment) were censored at the date of last on-treatment EDSS evaluation in LTS6050. 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.
  • Percentage of Participants Free of Sustained Disability Progression (DP) [ Time Frame: Up to 10.8 years since EFC6049 randomization (EFC6049: 108 weeks + LTS6050: 450 weeks) ]
    Sustained DP was defined as sustained increase of at least 1 point from baseline (EFC6049) EDSS score (0.5 point for participants with baseline EDSS>5.5) persisting for at least 12 weeks and 24 weeks. EDSS is an ordinal scale in half-point increments that qualifies disability in participants with MS. It consists of 8 ordinal rating scales assessing seven functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder, cerebral) as well as ambulation. EDSS total score ranges from 0 (normal neurological examination) to 10 (death due to MS), where higher scores indicates worse neurological function. Percentage of participants who were considered as free of disability progression confirmed after 12 week sustained progression and 24 week sustained progression were reported. Analysis for this outcome measure was performed on combined data of EFC6049 and LTS6050 study, as pre-specified in protocol.
  • Annualized MS Relapse Rate (ARR): Poisson Regression Estimates [ Time Frame: Up to 8 years since LTS6050 randomization ]
    ARR was obtained from total number of confirmed relapses that occurred during treatment period divided by sum of treatment durations in LTS6050 study only. 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 EDSS score or Functional System (FS) scores. EDSS: an ordinal scale qualifies disability. EDSS total score range: 0 (normal neurological examination) to 10 (death due to MS). FSS: to assess the neurological function. Total score range: 0 (normal) - 6(worse), higher scores = worse neurological function. To account for the different treatment duration 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 enrolment and baseline EDSS stratum as covariates).
  • Magnetic Resonance Imaging (MRI) Assessment: Change From Baseline in Total Volume of Abnormal Lesions (Burden of Disease [BOD]) at Week 192 Since LTS6050 Randomization [ Time Frame: Baseline, Week 192 ]
    BOD was assessed by cerebral MRI and defined as the total volume of all abnormal brain tissue (calculated as the sum of the total volume of T2-lesion component and T1-hypointense lesion component).
Original Secondary Outcome Measures  ICMJE
 (submitted: December 4, 2008)
  • Expanded Disability Status Scores [ Time Frame: up to a maximum of 4 years ]
  • Annualized MS relapse rate [ Time Frame: up to a maximum of 4 years ]
  • MRI variables [ Time Frame: up to a maximum of 4 years ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Long Term Safety and Efficacy Study of Teriflunomide 7 mg or 14 mg in Patients With Relapsing-Remitting Multiple Sclerosis
Official Title  ICMJE Long-term Extension of the Multinational, Double-blind, Placebo Controlled Study EFC6049 (HMR1726D/3001) to Document the Safety of Two Doses of Teriflunomide (7 and 14 mg) in Patients With Multiple Sclerosis With Relapses
Brief Summary

The primary objective of this study was to document the long-term safety and tolerability of teriflunomide in Multiple Sclerosis (MS) participants with relapse.

The secondary objective was to document the long-term efficacy on disability progression, relapse rate and Magnetic Resonance Imaging (MRI) parameters.

Detailed Description

Participants completing the EFC6049 (HMR1726D/3001) study were given the opportunity to continue in the extension study;

  • participants receiving teriflunomide 7 mg or 14 mg were blindly maintained on the same dose of teriflunomide.
  • participants receiving placebo were randomized at a 1:1 ratio to teriflunomide 7 mg or 14 mg.

The study period per participant was broken down as follows:

  • Double-blind treatment: up to a maximum of 288 weeks or until teriflunomide was commercially available in the country where participant lived,
  • Post-washout follow-up: 4 weeks after last treatment intake. No post-washout follow up if participant continued on teriflunomide treatment by obtaining its commercial form after end of the study.

The total duration of the extension was 292 weeks (about 6 years) from the first participant enrolled or until teriflunomide is commercially available in the country where participant lived.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Multiple Sclerosis
Intervention  ICMJE Drug: Teriflunomide (HMR1726)
Tablet, oral administration QD.
Other Name: Aubagio
Study Arms  ICMJE
  • Experimental: Placebo/Teriflunomide 7 mg
    Participants who completed treatment of placebo (for teriflunomide) tablet once daily (QD) for 108 weeks in EFC6049 study, received teriflunomide tablet 7 mg QD for 288 weeks in this extension study.
    Intervention: Drug: Teriflunomide (HMR1726)
  • Experimental: Teriflunomide 7 mg/7 mg
    Participants who completed treatment of teriflunomide 7 mg tablet QD for 108 weeks in EFC6049 study, continued their treatment with teriflunomide 7 mg tablet QD for 288 weeks in this extension study.
    Intervention: Drug: Teriflunomide (HMR1726)
  • Experimental: Placebo/Teriflunomide 14 mg
    Participants who completed treatment of placebo (for teriflunomide) tablet QD for 108 weeks in EFC6049, study received teriflunomide 14 mg tablet QD for 288 weeks in this extension study.
    Intervention: Drug: Teriflunomide (HMR1726)
  • Experimental: Teriflunomide 14 mg/14 mg
    Participants who completed treatment of teriflunomide 14 mg tablet QD for 108 weeks in EFC6049 study, continued their treatment with teriflunomide 14 mg tablet QD for 288 weeks in this extension study.
    Intervention: Drug: Teriflunomide (HMR1726)
Publications *

*   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: January 26, 2016)
742
Original Estimated Enrollment  ICMJE
 (submitted: December 4, 2008)
1080
Actual Study Completion Date  ICMJE December 2015
Actual Primary Completion Date December 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Participant who completed the previous double-blind placebo-controlled study EFC6049 and who did not meet criteria for treatment withdrawal.
  • Willingness to participate in a long-term safety/efficacy trial.

Exclusion Criteria:

  • 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 participant'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 Austria,   Canada,   Chile,   Czech Republic,   Denmark,   Estonia,   Finland,   France,   Germany,   Italy,   Netherlands,   Norway,   Poland,   Portugal,   Russian Federation,   Sweden,   Switzerland,   Turkey,   Ukraine,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00803049
Other Study ID Numbers  ICMJE LTS6050
2006-003361-14 ( EudraCT Number )
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: Clinical Sciences & Operations Sanofi
PRS Account Sanofi
Verification Date December 2016

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