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

Primary Purpose

Multiple Sclerosis

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Teriflunomide
Placebo
Sponsored by
Sanofi
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Multiple Sclerosis focused on measuring MS, Clinically Isolated Syndrome, CIS, CDMS, relapses

Eligibility Criteria

18 Years - 55 Years (Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Investigational Site Number 8965
  • Investigational Site Number 8954
  • Investigational Site Number 8946
  • Investigational Site Number 8962
  • Investigational Site Number 8920
  • Investigational Site Number 8953
  • Investigational Site Number 8914
  • Investigational Site Number 8940
  • Investigational Site Number 8922
  • Investigational Site Number 8955
  • Investigational Site Number 8949
  • Investigational Site Number 8937
  • Investigational Site Number 8951
  • Investigational Site Number 8925
  • Investigational Site Number 8941
  • Investigational Site Number 8924
  • Investigational Site Number 8905
  • Investigational Site Number 8930
  • Investigational Site Number 8963
  • Investigational Site Number 1405
  • Investigational Site Number 1404
  • Investigational Site Number 1407
  • Investigational Site Number 1401
  • Investigational Site Number 4004
  • Investigational Site Number 4005
  • Investigational Site Number 4001
  • Investigational Site Number 5312
  • Investigational Site Number 5307
  • Investigational Site Number 5304
  • Investigational Site Number 5309
  • Investigational Site Number 5303
  • Investigational Site Number 5306
  • Investigational Site Number 5402
  • Investigational Site Number 5403
  • Investigational Site Number 5409
  • Investigational Site Number 5401
  • Investigational Site Number 5406
  • Investigational Site Number 5408
  • Investigational Site Number 5410
  • Investigational Site Number 5404
  • Investigational Site Number 5602
  • Investigational Site Number 5601
  • Investigational Site Number 5606
  • Investigational Site Number 5605
  • Investigational Site Number 5801
  • Investigational Site Number 5803
  • Investigational Site Number 5804
  • Investigational Site Number 5805
  • Investigational Site Number 6002
  • Investigational Site Number 6004
  • Investigational Site Number 6201
  • Investigational Site Number 6203
  • Investigational Site Number 6405
  • Investigational Site Number 6403
  • Investigational Site Number 6401
  • Investigational Site Number 6611
  • Investigational Site Number 6601
  • Investigational Site Number 6609
  • Investigational Site Number 6604
  • Investigational Site Number 6612
  • Investigational Site Number 6605
  • Investigational Site Number 6602
  • Investigational Site Number 6614
  • Investigational Site Number 6607
  • Investigational Site Number 6801
  • Investigational Site Number 6810
  • Investigational Site Number 6805
  • Investigational Site Number 6807
  • Investigational Site Number 6803
  • Investigational Site Number 6809
  • Investigational Site Number 6804
  • Investigational Site Number 6815
  • Investigational Site Number 6802
  • Investigational Site Number 6806
  • Investigational Site Number 7101
  • Investigational Site Number 7103
  • Investigational Site Number 7108
  • Investigational Site Number 7105
  • Investigational Site Number 7402
  • Investigational Site Number 7403
  • Investigational Site Number 7401
  • Investigational Site Number 7501
  • Investigational Site Number 7502
  • Investigational Site Number 7709
  • Investigational Site Number 7710
  • Investigational Site Number 7707
  • Investigational Site Number 7701
  • Investigational Site Number 7703
  • Investigational Site Number 7803
  • Investigational Site Number 7806
  • Investigational Site Number 7805
  • Investigational Site Number 7807
  • Investigational Site Number 7808
  • Investigational Site Number 7907
  • Investigational Site Number 7909
  • Investigational Site Number 7906
  • Investigational Site Number 7904
  • Investigational Site Number 7912
  • Investigational Site Number 7910
  • Investigational Site Number 7905
  • Investigational Site Number 7911
  • Investigational Site Number 8304
  • Investigational Site Number 8309
  • Investigational Site Number 8315
  • Investigational Site Number 8308
  • Investigational Site Number 8310
  • Investigational Site Number 8312
  • Investigational Site Number 8305
  • Investigational Site Number 8301
  • Investigational Site Number 8303
  • Investigational Site Number 8302
  • Investigational Site Number 8314
  • Investigational Site Number 8507
  • Investigational Site Number 8501
  • Investigational Site Number 8511
  • Investigational Site Number 8506
  • Investigational Site Number 8504
  • Investigational Site Number 8508
  • Investigational Site Number 8512
  • Investigational Site Number 8505
  • Investigational Site Number 8510
  • Investigational Site Number 8503
  • Investigational Site Number 8502
  • Investigational Site Number 8709
  • Investigational Site Number 8701
  • Investigational Site Number 8704
  • Investigational Site Number 8706
  • Investigational Site Number 8705
  • Investigational Site Number 8708
  • Investigational Site Number 8707
  • Investigational Site Number 8702

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Placebo Comparator

Experimental

Experimental

Arm Label

Placebo/Teriflunomide 7 mg or Teriflunomide 14 mg

Teriflunomide 7 mg/7 mg

Teriflunomide 14 mg/14 mg

Arm Description

Core treatment period: Placebo matched to teriflunomide tablet once daily orally. Extension treatment period: Re-randomized in 1:1 ratio to either teriflunomide 7 mg or 14 mg once daily orally.

Core treatment period: Teriflunomide 7 mg tablet once daily orally. Extension treatment period: Teriflunomide 7 mg tablet once daily orally.

Core treatment period: Teriflunomide 14 mg tablet once daily orally. Extension treatment period: Teriflunomide 14 mg tablet once daily orally.

Outcomes

Primary Outcome Measures

Core Treatment Period: Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS)
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

Core Treatment Period: Time to Conversion to Definite Multiple Sclerosis (DMS)
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.
Core Treatment Period: Annualized Relapse Rate (ARR)
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).
Core Treatment Period: Brain Magnetic Resonance Imaging (MRI) Assessment: Change From Baseline in Total Lesion Volume at Week 108
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.
Core Treatment Period: Brain MRI Assessment: Number of Gadolinium Enhancing (Gd-enhancing) T1-lesions Per MRI Scan (Poisson Regression Estimates)
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).
Core Treatment Period: Brain MRI Assessment: Volume of Gadolinium Enhancing (Gd-enhancing) T1-lesions Per MRI Scan
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).
Core Treatment Period: Brain MRI Assessment: Change From Baseline in Volume of Hypointense Post-Gadolinium T1 Lesion Component
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
Core Treatment Period: Brain MRI Assessment: Change From Baseline in Volume of T2 Lesion Component
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.
Core Treatment Period: Brain MRI Assessment: Percent Change From Baseline in Atrophy
Atrophy was measured by MRI scan.
Core Treatment Period: Time to 12-Week Sustained Disability Progression
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.
Core Treatment Period: Change From Baseline in EDSS at Week 108
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
Core Treatment Period: Change From Baseline in Fatigue Impact Scale (FIS) Total Score at Week 108
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.
Core Treatment Period: Overview of Adverse Events (AEs)
AEs are any unfavorable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study.
Extension Treatment Period: Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS)
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 was estimated using Kaplan-Meier method.
Extension Treatment Period: Overview of Adverse Events (AEs)
AEs are any unfavorable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study. Safety population included all randomized population who actually received at least 1 dose of the IMP in extension and analyzed according to the treatment actually received in core study followed by treatment actually received in the extension treatment period.

Full Information

First Posted
February 14, 2008
Last Updated
January 20, 2017
Sponsor
Sanofi
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1. Study Identification

Unique Protocol Identification Number
NCT00622700
Brief Title
Phase III Study With Teriflunomide Versus Placebo in Patients With First Clinical Symptom of Multiple Sclerosis
Acronym
TOPIC
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
Study Type
Interventional

2. Study Status

Record Verification Date
January 2017
Overall Recruitment Status
Completed
Study Start Date
February 2008 (undefined)
Primary Completion Date
December 2012 (Actual)
Study Completion Date
February 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Sanofi

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The primary objective was 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 were: 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
Detailed Description
The study consisted 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 continued until teriflunomide was 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 was expected to be 116 weeks if he/she did not continue in the extension treatment period.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Multiple Sclerosis
Keywords
MS, Clinically Isolated Syndrome, CIS, CDMS, relapses

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
618 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Placebo/Teriflunomide 7 mg or Teriflunomide 14 mg
Arm Type
Placebo Comparator
Arm Description
Core treatment period: Placebo matched to teriflunomide tablet once daily orally. Extension treatment period: Re-randomized in 1:1 ratio to either teriflunomide 7 mg or 14 mg once daily orally.
Arm Title
Teriflunomide 7 mg/7 mg
Arm Type
Experimental
Arm Description
Core treatment period: Teriflunomide 7 mg tablet once daily orally. Extension treatment period: Teriflunomide 7 mg tablet once daily orally.
Arm Title
Teriflunomide 14 mg/14 mg
Arm Type
Experimental
Arm Description
Core treatment period: Teriflunomide 14 mg tablet once daily orally. Extension treatment period: Teriflunomide 14 mg tablet once daily orally.
Intervention Type
Drug
Intervention Name(s)
Teriflunomide
Other Intervention Name(s)
HMR1726, Aubagio
Intervention Description
Film-coated tablet Oral administration
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Film-coated tablet Oral administration
Primary Outcome Measure Information:
Title
Core Treatment Period: Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS)
Description
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.
Time Frame
Up to a maximum of 108 weeks depending on time of enrollment
Secondary Outcome Measure Information:
Title
Core Treatment Period: Time to Conversion to Definite Multiple Sclerosis (DMS)
Description
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.
Time Frame
Up to a maximum of 108 weeks depending on time of enrollment
Title
Core Treatment Period: Annualized Relapse Rate (ARR)
Description
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).
Time Frame
Up to a maximum of 108 weeks depending on time of enrollment
Title
Core Treatment Period: Brain Magnetic Resonance Imaging (MRI) Assessment: Change From Baseline in Total Lesion Volume at Week 108
Description
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.
Time Frame
Baseline, Week 108
Title
Core Treatment Period: Brain MRI Assessment: Number of Gadolinium Enhancing (Gd-enhancing) T1-lesions Per MRI Scan (Poisson Regression Estimates)
Description
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).
Time Frame
Up to a maximum of 108 weeks depending on time of enrollment
Title
Core Treatment Period: Brain MRI Assessment: Volume of Gadolinium Enhancing (Gd-enhancing) T1-lesions Per MRI Scan
Description
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).
Time Frame
Up to a maximum of 108 weeks depending on time of enrollment
Title
Core Treatment Period: Brain MRI Assessment: Change From Baseline in Volume of Hypointense Post-Gadolinium T1 Lesion Component
Description
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
Time Frame
Baseline, Week 108
Title
Core Treatment Period: Brain MRI Assessment: Change From Baseline in Volume of T2 Lesion Component
Description
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.
Time Frame
Baseline, Week 108
Title
Core Treatment Period: Brain MRI Assessment: Percent Change From Baseline in Atrophy
Description
Atrophy was measured by MRI scan.
Time Frame
Baseline, Week 108
Title
Core Treatment Period: Time to 12-Week Sustained Disability Progression
Description
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.
Time Frame
Up to a maximum of 108 weeks depending on time of enrollment
Title
Core Treatment Period: Change From Baseline in EDSS at Week 108
Description
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
Time Frame
Baseline, Week 108
Title
Core Treatment Period: Change From Baseline in Fatigue Impact Scale (FIS) Total Score at Week 108
Description
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.
Time Frame
Baseline, Week 108
Title
Core Treatment Period: Overview of Adverse Events (AEs)
Description
AEs are any unfavorable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study.
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
Title
Extension Treatment Period: Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS)
Description
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 was estimated using Kaplan-Meier method.
Time Frame
From randomization in the core period up to 390 Weeks (Extension treatment period [maximum exposure: 283 Weeks])
Title
Extension Treatment Period: Overview of Adverse Events (AEs)
Description
AEs are any unfavorable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study. Safety population included all randomized population who actually received at least 1 dose of the IMP in extension and analyzed according to the treatment actually received in core study followed by treatment actually received in the extension treatment period.
Time Frame
From re-randomization up to 283 Weeks
Other Pre-specified Outcome Measures:
Title
Core Treatment Period: Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA)
Description
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.
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Clinical Sciences & Operations
Organizational Affiliation
Sanofi
Official's Role
Study Director
Facility Information:
Facility Name
Investigational Site Number 8965
City
Cullman
State/Province
Alabama
ZIP/Postal Code
35058
Country
United States
Facility Name
Investigational Site Number 8954
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85013-4496
Country
United States
Facility Name
Investigational Site Number 8946
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85060
Country
United States
Facility Name
Investigational Site Number 8962
City
Fort Collins
State/Province
Colorado
ZIP/Postal Code
80528
Country
United States
Facility Name
Investigational Site Number 8920
City
Maitland
State/Province
Florida
ZIP/Postal Code
32761
Country
United States
Facility Name
Investigational Site Number 8953
City
St. Petersburg
State/Province
Florida
ZIP/Postal Code
33701
Country
United States
Facility Name
Investigational Site Number 8914
City
Ft. Wayne
State/Province
Indiana
ZIP/Postal Code
63104
Country
United States
Facility Name
Investigational Site Number 8940
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46256
Country
United States
Facility Name
Investigational Site Number 8922
City
Shreveport
State/Province
Louisiana
ZIP/Postal Code
71103
Country
United States
Facility Name
Investigational Site Number 8955
City
Grand Rapids
State/Province
Michigan
ZIP/Postal Code
49503
Country
United States
Facility Name
Investigational Site Number 8949
City
Traverse City
State/Province
Michigan
ZIP/Postal Code
49684
Country
United States
Facility Name
Investigational Site Number 8937
City
St Louis
State/Province
Missouri
ZIP/Postal Code
63104
Country
United States
Facility Name
Investigational Site Number 8951
City
Albuquerque
State/Province
New Mexico
ZIP/Postal Code
87131
Country
United States
Facility Name
Investigational Site Number 8925
City
New York
State/Province
New York
ZIP/Postal Code
10029-6574
Country
United States
Facility Name
Investigational Site Number 8941
City
Charlotte
State/Province
North Carolina
ZIP/Postal Code
28204
Country
United States
Facility Name
Investigational Site Number 8924
City
Dayton
State/Province
Ohio
ZIP/Postal Code
45409
Country
United States
Facility Name
Investigational Site Number 8905
City
Round Rock
State/Province
Tennessee
ZIP/Postal Code
78681
Country
United States
Facility Name
Investigational Site Number 8930
City
Burlington
State/Province
Vermont
ZIP/Postal Code
05401
Country
United States
Facility Name
Investigational Site Number 8963
City
Seattle
State/Province
Washington
ZIP/Postal Code
98122
Country
United States
Facility Name
Investigational Site Number 1405
City
Geelong
ZIP/Postal Code
3220
Country
Australia
Facility Name
Investigational Site Number 1404
City
Heidelberg
ZIP/Postal Code
3081
Country
Australia
Facility Name
Investigational Site Number 1407
City
Hobart
ZIP/Postal Code
7001
Country
Australia
Facility Name
Investigational Site Number 1401
City
Parkville
ZIP/Postal Code
3050
Country
Australia
Facility Name
Investigational Site Number 4004
City
Innsbruck
ZIP/Postal Code
6020
Country
Austria
Facility Name
Investigational Site Number 4005
City
Linz
ZIP/Postal Code
4020
Country
Austria
Facility Name
Investigational Site Number 4001
City
Wien
ZIP/Postal Code
1010
Country
Austria
Facility Name
Investigational Site Number 5312
City
Pleven
ZIP/Postal Code
5800
Country
Bulgaria
Facility Name
Investigational Site Number 5307
City
Sofia
ZIP/Postal Code
1000
Country
Bulgaria
Facility Name
Investigational Site Number 5304
City
Sofia
ZIP/Postal Code
1407
Country
Bulgaria
Facility Name
Investigational Site Number 5309
City
Sofia
ZIP/Postal Code
1431
Country
Bulgaria
Facility Name
Investigational Site Number 5303
City
Sofia
ZIP/Postal Code
1527
Country
Bulgaria
Facility Name
Investigational Site Number 5306
City
Sofia
ZIP/Postal Code
1606
Country
Bulgaria
Facility Name
Investigational Site Number 5402
City
Greenfield Park
ZIP/Postal Code
J4V 2J2
Country
Canada
Facility Name
Investigational Site Number 5403
City
London
ZIP/Postal Code
N6A 5A5
Country
Canada
Facility Name
Investigational Site Number 5409
City
Montreal
ZIP/Postal Code
H1T 2M4
Country
Canada
Facility Name
Investigational Site Number 5401
City
Ottawa
ZIP/Postal Code
K1H 8L6
Country
Canada
Facility Name
Investigational Site Number 5406
City
Quebec
ZIP/Postal Code
G1J 1Z4
Country
Canada
Facility Name
Investigational Site Number 5408
City
Sherbrooke
ZIP/Postal Code
J1H 5N4
Country
Canada
Facility Name
Investigational Site Number 5410
City
Toronto
ZIP/Postal Code
M4N 3M5
Country
Canada
Facility Name
Investigational Site Number 5404
City
Toronto
ZIP/Postal Code
M5B 1W8
Country
Canada
Facility Name
Investigational Site Number 5602
City
Santiago
ZIP/Postal Code
760-0746
Country
Chile
Facility Name
Investigational Site Number 5601
City
Santiago
Country
Chile
Facility Name
Investigational Site Number 5606
City
Santiago
Country
Chile
Facility Name
Investigational Site Number 5605
City
Viña Del Mar
ZIP/Postal Code
2520997
Country
Chile
Facility Name
Investigational Site Number 5801
City
Brno
ZIP/Postal Code
65691
Country
Czech Republic
Facility Name
Investigational Site Number 5803
City
Hradec Kralove
ZIP/Postal Code
50005
Country
Czech Republic
Facility Name
Investigational Site Number 5804
City
Olomouc
ZIP/Postal Code
77520
Country
Czech Republic
Facility Name
Investigational Site Number 5805
City
Ostrava - Poruba
ZIP/Postal Code
70852
Country
Czech Republic
Facility Name
Investigational Site Number 6002
City
Aarhus C
ZIP/Postal Code
8000
Country
Denmark
Facility Name
Investigational Site Number 6004
City
Esbjerg
ZIP/Postal Code
6700
Country
Denmark
Facility Name
Investigational Site Number 6201
City
Tallinn
ZIP/Postal Code
10617
Country
Estonia
Facility Name
Investigational Site Number 6203
City
Tartu
ZIP/Postal Code
50406
Country
Estonia
Facility Name
Investigational Site Number 6405
City
Helsinki
ZIP/Postal Code
00100
Country
Finland
Facility Name
Investigational Site Number 6403
City
Kuopio
ZIP/Postal Code
70210
Country
Finland
Facility Name
Investigational Site Number 6401
City
Turku
ZIP/Postal Code
20100
Country
Finland
Facility Name
Investigational Site Number 6611
City
Besancon
ZIP/Postal Code
25030
Country
France
Facility Name
Investigational Site Number 6601
City
Clermont Ferrand Cedex 1
ZIP/Postal Code
63003
Country
France
Facility Name
Investigational Site Number 6609
City
Lille Cedex
ZIP/Postal Code
59037
Country
France
Facility Name
Investigational Site Number 6604
City
Montpellier Cedex 05
ZIP/Postal Code
34295
Country
France
Facility Name
Investigational Site Number 6612
City
Nancy Cedex
ZIP/Postal Code
54036
Country
France
Facility Name
Investigational Site Number 6605
City
Nantes Cedex 01
ZIP/Postal Code
44093
Country
France
Facility Name
Investigational Site Number 6602
City
Nice Cedex
ZIP/Postal Code
06002
Country
France
Facility Name
Investigational Site Number 6614
City
Nimes
ZIP/Postal Code
30029
Country
France
Facility Name
Investigational Site Number 6607
City
Strasbourg Cedex
ZIP/Postal Code
67091
Country
France
Facility Name
Investigational Site Number 6801
City
Bayreuth
ZIP/Postal Code
95445
Country
Germany
Facility Name
Investigational Site Number 6810
City
Berlin
ZIP/Postal Code
10713
Country
Germany
Facility Name
Investigational Site Number 6805
City
Berlin
ZIP/Postal Code
10785
Country
Germany
Facility Name
Investigational Site Number 6807
City
Erbach
ZIP/Postal Code
64711
Country
Germany
Facility Name
Investigational Site Number 6803
City
Essen
ZIP/Postal Code
45122
Country
Germany
Facility Name
Investigational Site Number 6809
City
Hannover
ZIP/Postal Code
30625
Country
Germany
Facility Name
Investigational Site Number 6804
City
Ludwigshafen
ZIP/Postal Code
67063
Country
Germany
Facility Name
Investigational Site Number 6815
City
Minden
ZIP/Postal Code
32429
Country
Germany
Facility Name
Investigational Site Number 6802
City
Münster
ZIP/Postal Code
48149
Country
Germany
Facility Name
Investigational Site Number 6806
City
Wiesbaden
ZIP/Postal Code
65191
Country
Germany
Facility Name
Investigational Site Number 7101
City
Budapest
ZIP/Postal Code
1076
Country
Hungary
Facility Name
Investigational Site Number 7103
City
Budapest
ZIP/Postal Code
1145
Country
Hungary
Facility Name
Investigational Site Number 7108
City
Esztergom
ZIP/Postal Code
2500
Country
Hungary
Facility Name
Investigational Site Number 7105
City
Veszprém
ZIP/Postal Code
8200
Country
Hungary
Facility Name
Investigational Site Number 7402
City
Klaipeda
ZIP/Postal Code
LT-92288
Country
Lithuania
Facility Name
Investigational Site Number 7403
City
Siauliai
ZIP/Postal Code
LT-76231
Country
Lithuania
Facility Name
Investigational Site Number 7401
City
Vilnius
ZIP/Postal Code
LT-08661
Country
Lithuania
Facility Name
Investigational Site Number 7501
City
Chihuahua
ZIP/Postal Code
31203
Country
Mexico
Facility Name
Investigational Site Number 7502
City
Guadalajara
ZIP/Postal Code
45110
Country
Mexico
Facility Name
Investigational Site Number 7709
City
Gdansk
ZIP/Postal Code
80-803
Country
Poland
Facility Name
Investigational Site Number 7710
City
Lodz
ZIP/Postal Code
93-513
Country
Poland
Facility Name
Investigational Site Number 7707
City
Warszawa 44
ZIP/Postal Code
04-141
Country
Poland
Facility Name
Investigational Site Number 7701
City
Warszawa
ZIP/Postal Code
02-097
Country
Poland
Facility Name
Investigational Site Number 7703
City
Warszawa
ZIP/Postal Code
02-957
Country
Poland
Facility Name
Investigational Site Number 7803
City
Bucuresti
ZIP/Postal Code
020125
Country
Romania
Facility Name
Investigational Site Number 7806
City
Bucuresti
ZIP/Postal Code
050098
Country
Romania
Facility Name
Investigational Site Number 7805
City
Cluj-Napoca
ZIP/Postal Code
400012
Country
Romania
Facility Name
Investigational Site Number 7807
City
Cluj-Napoca
ZIP/Postal Code
400012
Country
Romania
Facility Name
Investigational Site Number 7808
City
Timisoara
ZIP/Postal Code
300736
Country
Romania
Facility Name
Investigational Site Number 7907
City
Kazan
ZIP/Postal Code
420021
Country
Russian Federation
Facility Name
Investigational Site Number 7909
City
Nizhny Novgorod
ZIP/Postal Code
603000
Country
Russian Federation
Facility Name
Investigational Site Number 7906
City
Nizhny Novgorod
ZIP/Postal Code
603076
Country
Russian Federation
Facility Name
Investigational Site Number 7904
City
Nizhny Novgorod
ZIP/Postal Code
603126
Country
Russian Federation
Facility Name
Investigational Site Number 7912
City
Novosibirsk
ZIP/Postal Code
630007
Country
Russian Federation
Facility Name
Investigational Site Number 7910
City
Rostov-On-Don
ZIP/Postal Code
344085
Country
Russian Federation
Facility Name
Investigational Site Number 7905
City
Smolensk
ZIP/Postal Code
214019
Country
Russian Federation
Facility Name
Investigational Site Number 7911
City
St-Petersburg
ZIP/Postal Code
194044
Country
Russian Federation
Facility Name
Investigational Site Number 8304
City
Edirne
Country
Turkey
Facility Name
Investigational Site Number 8309
City
Istanbul
ZIP/Postal Code
34390
Country
Turkey
Facility Name
Investigational Site Number 8315
City
Istanbul
ZIP/Postal Code
34400
Country
Turkey
Facility Name
Investigational Site Number 8308
City
Istanbul
Country
Turkey
Facility Name
Investigational Site Number 8310
City
Istanbul
Country
Turkey
Facility Name
Investigational Site Number 8312
City
Istanbul
Country
Turkey
Facility Name
Investigational Site Number 8305
City
Izmir
ZIP/Postal Code
35100
Country
Turkey
Facility Name
Investigational Site Number 8301
City
Izmir
ZIP/Postal Code
35340
Country
Turkey
Facility Name
Investigational Site Number 8303
City
Izmir
ZIP/Postal Code
35380
Country
Turkey
Facility Name
Investigational Site Number 8302
City
Izmit
ZIP/Postal Code
41380
Country
Turkey
Facility Name
Investigational Site Number 8314
City
Trabzon
ZIP/Postal Code
61080
Country
Turkey
Facility Name
Investigational Site Number 8507
City
Chernihiv
ZIP/Postal Code
14029
Country
Ukraine
Facility Name
Investigational Site Number 8501
City
Dnipropetrovsk
ZIP/Postal Code
49027
Country
Ukraine
Facility Name
Investigational Site Number 8511
City
Donets'K
ZIP/Postal Code
83099
Country
Ukraine
Facility Name
Investigational Site Number 8506
City
Kharkiv
ZIP/Postal Code
61018
Country
Ukraine
Facility Name
Investigational Site Number 8504
City
Kharkiv
ZIP/Postal Code
61178
Country
Ukraine
Facility Name
Investigational Site Number 8508
City
Kiev
ZIP/Postal Code
03110
Country
Ukraine
Facility Name
Investigational Site Number 8512
City
Lutsk
ZIP/Postal Code
43005
Country
Ukraine
Facility Name
Investigational Site Number 8505
City
Lviv
ZIP/Postal Code
79010
Country
Ukraine
Facility Name
Investigational Site Number 8510
City
Poltava
ZIP/Postal Code
36011
Country
Ukraine
Facility Name
Investigational Site Number 8503
City
Vinnytsya
ZIP/Postal Code
21005
Country
Ukraine
Facility Name
Investigational Site Number 8502
City
Zaporizhzhya
ZIP/Postal Code
69000
Country
Ukraine
Facility Name
Investigational Site Number 8709
City
Liverpool
ZIP/Postal Code
L9 7LJ
Country
United Kingdom
Facility Name
Investigational Site Number 8701
City
London
ZIP/Postal Code
E1 1BB
Country
United Kingdom
Facility Name
Investigational Site Number 8704
City
London
ZIP/Postal Code
SW17 0QT
Country
United Kingdom
Facility Name
Investigational Site Number 8706
City
Newcastle Upon Tyne
ZIP/Postal Code
NE1 4LP
Country
United Kingdom
Facility Name
Investigational Site Number 8705
City
Nottingham
ZIP/Postal Code
NG7 2UH
Country
United Kingdom
Facility Name
Investigational Site Number 8708
City
Plymouth
ZIP/Postal Code
PL6 5BX
Country
United Kingdom
Facility Name
Investigational Site Number 8707
City
Salford
ZIP/Postal Code
M6 8HD
Country
United Kingdom
Facility Name
Investigational Site Number 8702
City
Sheffield
ZIP/Postal Code
S10 2JF
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
25192851
Citation
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.
Results Reference
background

Learn more about this trial

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

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