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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Sanofi
ClinicalTrials.gov Identifier:
NCT00622700
First received: February 14, 2008
Last updated: February 25, 2016
Last verified: February 2016

February 14, 2008
February 25, 2016
February 2008
December 2012   (final data collection date for primary outcome measure)
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.
Conversion to clinically definite MS [ Time Frame: up to 2 years ]
Complete list of historical versions of study NCT00622700 on ClinicalTrials.gov Archive Site
  • 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.
  • Conversion to definite MS based on MRI data as defined by the demonstration of dissemination of MRI lesions in time
  • Annualized relapse rate
  • Burden of disease and other MRI variables
  • Proportion of disability-free patients, reported fatigue and Quality of Life
  • Safety and tolerability of teriflunomide
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.
Not Provided
 
Phase III Study With Teriflunomide Versus Placebo in Patients With First Clinical Symptom of Multiple Sclerosis
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

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

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.

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Multiple Sclerosis
  • Drug: Teriflunomide
    Film-coated tablet Oral administration
    Other Names:
    • HMR1726
    • Aubagio
  • Drug: Placebo
    Film-coated tablet Oral administration
  • Placebo Comparator: Placebo
    Placebo matched to teriflunomide tablet once daily orally.
    Intervention: Drug: Placebo
  • Experimental: Teriflunomide 7 mg
    Teriflunomide 7 mg tablet once daily orally.
    Intervention: Drug: Teriflunomide
  • Experimental: Teriflunomide 14 mg
    Teriflunomide 14 mg tablet once daily orally.
    Intervention: Drug: Teriflunomide
Miller AE, Wolinsky JS, Kappos L, Comi G, Freedman MS, Olsson TP, Bauer D, Benamor M, Truffinet P, O'Connor PW; TOPIC Study Group. Oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis (TOPIC): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2014 Oct;13(10):977-86. doi: 10.1016/S1474-4422(14)70191-7. Epub 2014 Sep 2.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
618
February 2016
December 2012   (final data collection date for primary outcome measure)

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.

Both
18 Years to 55 Years   (Adult)
No
Contact information is only displayed when the study is recruiting subjects
United States,   Australia,   Austria,   Bulgaria,   Canada,   Chile,   Czech Republic,   Denmark,   Estonia,   Finland,   France,   Germany,   Hungary,   Lithuania,   Mexico,   Poland,   Romania,   Russian Federation,   Turkey,   Ukraine,   United Kingdom
Brazil,   Italy,   Slovakia
 
NCT00622700
EFC6260, HMR1726D-3005, 2006-001152-12
Yes
Not Provided
Not Provided
Sanofi
Sanofi
Not Provided
Study Director: Clinical Sciences & Operations Sanofi
Sanofi
February 2016

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