Phase III Study With Teriflunomide Versus Placebo in Patients With First Clinical Symptom of Multiple Sclerosis (TOPIC)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Sanofi
ClinicalTrials.gov Identifier:
NCT00622700
First received: February 14, 2008
Last updated: December 17, 2014
Last verified: December 2014
  Purpose

The primary objective is to demonstrate the effect of teriflunomide (HMR1726) (14 milligram per day [mg/day] and 7 mg/day), in comparison to placebo, for reducing conversion of participants presenting with their first clinical episode consistent with multiple sclerosis (MS) to clinically definite multiple sclerosis (CDMS).

The secondary objectives are:

  • To demonstrate the effect of teriflunomide, in comparison to placebo, on:

    • Reducing conversion to definite multiple sclerosis (DMS)
    • Reducing annualized relapse rate (ARR)
    • Reducing disease activity/progression as measured by Magnetic Resonance Imaging (MRI)
    • Reducing accumulation of disability for at least 12 weeks as measured by the Expanded Disability Status Scale (EDSS)
    • Proportion of disability-free participants as assessed by the EDSS
    • Reducing participant-reported fatigue
  • To evaluate the safety and tolerability of teriflunomide
  • To evaluate the pharmacokinetics (PK) of teriflunomide
  • Optional pharmacogenomic testing aimed at assessing the association between the main enzyme systems of teriflunomide metabolism and hepatic safety, and other potential associations between gene variations and clinical outcomes

Condition Intervention Phase
Multiple Sclerosis
Drug: Teriflunomide
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: An International, Multi-center, Randomized, Double-blind, Placebo-controlled, Parallel Group Study to Evaluate the Efficacy and Safety of Two Year Treatment With Teriflunomide 7 mg Once Daily and 14 mg Once Daily Versus Placebo in Patients With a First Clinical Episode Suggestive of Multiple Sclerosis Plus a Long Term Extension Period

Resource links provided by NLM:


Further study details as provided by Sanofi:

Primary Outcome Measures:
  • Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS) [ Time Frame: Up to a maximum of 108 weeks depending on time of enrollment ] [ Designated as safety issue: No ]
    Conversion to CDMS was defined by the occurrence of a relapse, which was defined as a new neurological abnormality separated by at least 30 days from onset of a preceding clinical event, presented for at least 24 hours and occurred in the absence of fever or known infection. Percent probability of conversion at 24, 48, and 108 weeks was estimated using Kaplan-Meier method.


Secondary Outcome Measures:
  • Time to Conversion to Definite Multiple Sclerosis (DMS) [ Time Frame: Up to a maximum of 108 weeks depending on time of enrollment ] [ Designated as safety issue: No ]
    Conversion to DMS was demonstrated by dissemination of MRI lesions in time (as per McDonald criteria) or a relapse, whichever occurs first. MRI Imaging criteria were detection of Gadolinium (Gd) enhancement at least 3 months after onset of initial clinical event, if not at site corresponding to initial event; detection of new T2 lesion if it appears at any time compared with reference scan (done at time of screening) done at least 30 days after onset of the initial clinical event. Occurrence of relapse was defined as new neurological abnormality separated by at least 30 days from onset of preceding clinical event, present for at least 24 hours and occurring in absence of fever or known infection. New clinical abnormality (neurological sign) that is consistent with participant's symptoms with increase in at least one Functional System (FS) or EDSS score compared to last EDSS assessment. Percent probability of conversion at 24, 48, and 108 weeks was estimated using Kaplan-Meier method.

  • Annualized Relapse Rate (ARR) [ Time Frame: Up to a maximum of 108 weeks depending on time of enrollment ] [ Designated as safety issue: No ]
    ARR is the total number of confirmed relapses that occurred during the treatment period divided by the total number of patient-years treated. 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 scores. ARR was assessed using Poisson regression model with robust error variance. To account for the different treatment durations among participants, a Poisson regression model with robust error variance was used (total number of confirmed relapses onset between randomization date and last dose date as the response variable, treatment, region and baseline monofocal/multifocal status as covariates, and log-transformed treatment duration as an offset variable).

  • Brain Magnetic Resonance Imaging (MRI) Assessment: Change From Baseline in Total Lesion Volume at Week 108 [ Time Frame: Baseline, Week 108 ] [ Designated as safety issue: No ]
    The total lesion volume (burden of disease) is the total volumes of hyperintense on T2 plus hypointense on T1 as measured by MRI scan. Least-square means were estimated using a Mixed-effect model with repeated measures (MMRM) on cubic root transformed volume data with factors for treatment, baseline monofocal/multifocal status, region, visit, treatment-by-visit interaction, cubic root transformed baseline burden of disease, and baseline-by-visit interaction.

  • Brain MRI Assessment: Number of Gadolinium Enhancing (Gd-enhancing) T1-lesions Per MRI Scan (Poisson Regression Estimates) [ Time Frame: Up to a maximum of 108 weeks depending on time of enrollment ] [ Designated as safety issue: No ]
    Number of Gd-enhancing T1-lesions per scan is the total number of Gd-enhancing T1-lesions that occurred during the treatment period divided by the total number of scans performed during the treatment period. To account for the different numbers of scans performed among the participants, a Poisson regression model with robust error variance was used (total number of Gd-enhancing T1-lesions as response variable, treatment, baseline monofocal/multifocal status, region and baseline number of Gd-enhancing T1-lesions as covariates, and log-transformed number of scans as an offset variable).

  • Brain MRI Assessment: Volume of Gadolinium Enhancing (Gd-enhancing) T1-lesions Per MRI Scan [ Time Frame: Up to a maximum of 108 weeks depending on time of enrollment ] [ Designated as safety issue: No ]
    Total volume of Gd-enhancing T1-lesions per scan is the sum of the volumes of Gd-enhancing T1-lesions observed during the treatment period divided by the total number of scans performed during the treatment period. To account for the different numbers of scans performed among the participants, a Poisson regression model with robust error variance was used (total number of Gd-enhancing T1-lesions as response variable, treatment, baseline monofocal/multifocal status, region and baseline number of Gd-enhancing T1-lesions as covariates, and log-transformed number of scans as an offset variable).

  • Brain MRI Assessment: Change From Baseline in Volume of Hypointense Post-Gadolinium T1 Lesion Component [ Time Frame: Baseline, Week 108 ] [ Designated as safety issue: No ]
    Volume of hypointense post-gadolinium T1 lesion component was measured by MRI scan. Least-square means were estimated using a Mixed-effect model with repeated measures (MMRM) on cubic root transformed volume data adjusted for baseline monofocal/multifocal status, region, visit, treatment-by-visit interaction, cubic root transformed baseline value, and baseline-by-visit interaction

  • Brain MRI Assessment: Change From Baseline in Volume of T2 Lesion Component [ Time Frame: Baseline, Week 108 ] [ Designated as safety issue: Yes ]
    Volume of T2 lesion component was measured by MRI scan. Least-square means were estimated using a Mixed-effect model with repeated measures (MMRM) on cubic root transformed volume data adjusted for baseline monofocal/multifocal status, region, visit, treatment-by-visit interaction, cubic root transformed baseline value, and baseline-by-visit interaction.

  • Brain MRI Assessment: Percent Change From Baseline in Atrophy [ Time Frame: Baseline, Week 108 ] [ Designated as safety issue: No ]
    Atrophy was measured by MRI scan.

  • Time to 12-Week Sustained Disability Progression [ Time Frame: Up to a maximum of 108 weeks depending on time of enrollment ] [ Designated as safety issue: No ]
    The 12-week sustained disability progression was defined as increase from baseline of at least 1-point in EDSS score (at least 0.5-point for participants with baseline EDSS score of greater than [>] 5.5) that persisted for at least 12 weeks. Percent probability of participants free of 12-week sustained disability progression at 24, 48, and 108 weeks was estimated using Kaplan-Meier method.

  • Change From Baseline in EDSS at Week 108 [ Time Frame: Baseline, Week 108 ] [ Designated as safety issue: No ]
    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 and cerebral) as well as ambulation. EDSS total score ranges from 0 (normal neurological examination) to 10 (death due to MS). Least-square means were estimated using a Mixed-effect model with repeated measures (MMRM) on cubic root transformed volume data adjusted for baseline monofocal/multifocal status, region, visit, treatment-by-visit interaction, baseline value and baseline-by-visit interaction

  • Change From Baseline in Fatigue Impact Scale (FIS) Total Score at Week 108 [ Time Frame: Baseline, Week 108 ] [ Designated as safety issue: No ]
    FIS is a participant-reported scale that qualifies the impact of fatigue on daily life in participants with MS. It consists of 40 statements that measure fatigue in three areas; physical, cognitive, and social. FIS total score ranges from 0 (no problem) to 160 (extreme problem). Least-square means were estimated using a Mixed-effect model with repeated measures [MMRM] on FIS total score data adjusted for or baseline monofocal/multifocal status, region, visit, treatment-by-visit interaction, baseline value and baseline-by-visit interaction.

  • Overview of Adverse Events (AEs) [ Time Frame: From first study drug intake up to 112 days after last intake in the placebo-controlled period or up to first intake in the extension treatment period, whichever occurred first ] [ Designated as safety issue: Yes ]
    AEs 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 placebo-controlled 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, 2, or 3 ULN;
    • ALT >3 ULN and TB >2 ULN.


Enrollment: 618
Study Start Date: February 2008
Estimated Study Completion Date: December 2015
Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Placebo
Placebo matched to teriflunomide tablet once daily orally.
Drug: Placebo
Film-coated tablet Oral administration
Experimental: Teriflunomide 7 mg
Teriflunomide 7 mg tablet once daily orally.
Drug: Teriflunomide
Film-coated tablet Oral administration
Other Names:
  • HMR1726
  • Aubagio
Experimental: Teriflunomide 14 mg
Teriflunomide 14 mg tablet once daily orally.
Drug: Teriflunomide
Film-coated tablet Oral administration
Other Names:
  • HMR1726
  • Aubagio

Detailed Description:

The study consists of 4 periods:

  • Screening period: up to 4 weeks,
  • Placebo-controlled treatment period: up to 108 weeks (at least 24 weeks for participants who experienced conversion to CDMS),
  • Extension treatment period (without placebo-control): the extension period will continue until teriflunomide is commercially available in participant's country of residence.
  • Post-treatment washout period: 4 weeks after last treatment intake.

The maximal duration of the study period per participant is expected to be 116 weeks if he/she does not continue in the extension treatment period.

  Eligibility

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

Inclusion Criteria:

  • First acute or subacute, well-defined neurological event consistent with demyelination (that is, optic neuritis confirmed by an ophthalmologist, spinal cord syndrome, brainstem/cerebellar syndromes)
  • Onset of MS symptoms occurring within 90 days of randomization
  • A screening MRI scan with 2 or more T2 lesions at least 3 millimeter (mm) in diameter that are characteristic of MS

Exclusion Criteria:

  • Clinically relevant cardiovascular, hepatic, neurological, endocrine or other major systemic disease
  • Significantly impaired bone marrow function
  • Pregnancy or nursing
  • Alcohol or drug abuse
  • Use of cladribine, mitoxantrone, or other immunosuppressant agents such as azathioprine, cyclophosphamide, cyclosporin, methotrexate or mycophenolate before enrollment
  • 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.

  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: NCT00622700

  Show 131 Study Locations
Sponsors and Collaborators
Sanofi
Investigators
Study Director: Clinical Sciences & Operations Sanofi
  More Information

No publications provided

Responsible Party: Sanofi
ClinicalTrials.gov Identifier: NCT00622700     History of Changes
Other Study ID Numbers: EFC6260, HMR1726D-3005, 2006-001152-12
Study First Received: February 14, 2008
Results First Received: November 7, 2014
Last Updated: December 17, 2014
Health Authority: United States: Food and Drug Administration
Canada: Health Canada
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Germany: Paul-Ehrlich-Institut

Keywords provided by Sanofi:
MS
Clinically Isolated Syndrome
CIS
CDMS
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

ClinicalTrials.gov processed this record on July 30, 2015