Phase III Study With Teriflunomide Versus Placebo in Patients With First Clinical Symptom of Multiple Sclerosis
- Registration Number
- NCT00622700
- Lead Sponsor
- Sanofi
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 618
- 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
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo/Teriflunomide 7 mg or Teriflunomide 14 mg Placebo 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. Teriflunomide 14 mg/14 mg Teriflunomide Core treatment period: Teriflunomide 14 mg tablet once daily orally. Extension treatment period: Teriflunomide 14 mg tablet once daily orally. Placebo/Teriflunomide 7 mg or Teriflunomide 14 mg Teriflunomide 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. Teriflunomide 7 mg/7 mg Teriflunomide Core treatment period: Teriflunomide 7 mg tablet once daily orally. Extension treatment period: Teriflunomide 7 mg tablet once daily orally.
- Primary Outcome Measures
Name Time Method Core Treatment Period: Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS) Up to a maximum of 108 weeks depending on time of enrollment 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
Name Time Method Core Treatment Period: Time to Conversion to Definite Multiple Sclerosis (DMS) Up to a maximum of 108 weeks depending on time of enrollment 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: Brain MRI Assessment: Number of Gadolinium Enhancing (Gd-enhancing) T1-lesions Per MRI Scan (Poisson Regression Estimates) Up to a maximum of 108 weeks depending on time of enrollment 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 Up to a maximum of 108 weeks depending on time of enrollment 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 Baseline, Week 108 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 Magnetic Resonance Imaging (MRI) Assessment: Change From Baseline in Total Lesion Volume at Week 108 Baseline, 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: Change From Baseline in Volume of T2 Lesion Component Baseline, Week 108 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: Time to 12-Week Sustained Disability Progression Up to a maximum of 108 weeks depending on time of enrollment 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 Baseline, 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: Overview of Adverse Events (AEs) 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 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) From randomization in the core period up to 390 Weeks (Extension treatment period [maximum exposure: 283 Weeks]) 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.
Core Treatment Period: Annualized Relapse Rate (ARR) Up to a maximum of 108 weeks depending on time of enrollment 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 MRI Assessment: Percent Change From Baseline in Atrophy Baseline, Week 108 Atrophy was measured by MRI scan.
Core Treatment Period: Change From Baseline in Fatigue Impact Scale (FIS) Total Score at Week 108 Baseline, 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.
Extension Treatment Period: Overview of Adverse Events (AEs) From re-randomization up to 283 Weeks 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.
Trial Locations
- Locations (131)
Investigational Site Number 5307
🇧🇬Sofia, Bulgaria
Investigational Site Number 1405
🇦🇺Geelong, Australia
Investigational Site Number 8953
🇺🇸St. Petersburg, Florida, United States
Investigational Site Number 1404
🇦🇺Heidelberg, Australia
Investigational Site Number 5404
🇨🇦Toronto, Canada
Investigational Site Number 8937
🇺🇸St Louis, Missouri, United States
Investigational Site Number 1401
🇦🇺Parkville, Australia
Investigational Site Number 8941
🇺🇸Charlotte, North Carolina, United States
Investigational Site Number 1407
🇦🇺Hobart, Australia
Investigational Site Number 5410
🇨🇦Toronto, Canada
Investigational Site Number 8965
🇺🇸Cullman, Alabama, United States
Investigational Site Number 8914
🇺🇸Ft. Wayne, Indiana, United States
Investigational Site Number 8925
🇺🇸New York, New York, United States
Investigational Site Number 6611
🇫🇷Besancon, France
Investigational Site Number 6803
🇩🇪Essen, Germany
Investigational Site Number 5401
🇨🇦Ottawa, Canada
Investigational Site Number 6614
🇫🇷Nimes, France
Investigational Site Number 5402
🇨🇦Greenfield Park, Canada
Investigational Site Number 6807
🇩🇪Erbach, Germany
Investigational Site Number 6612
🇫🇷Nancy Cedex, France
Investigational Site Number 6607
🇫🇷Strasbourg Cedex, France
Investigational Site Number 5409
🇨🇦Montreal, Canada
Investigational Site Number 6806
🇩🇪Wiesbaden, Germany
Investigational Site Number 6605
🇫🇷Nantes Cedex 01, France
Investigational Site Number 6809
🇩🇪Hannover, Germany
Investigational Site Number 6201
🇪🇪Tallinn, Estonia
Investigational Site Number 6804
🇩🇪Ludwigshafen, Germany
Investigational Site Number 6801
🇩🇪Bayreuth, Germany
Investigational Site Number 8704
🇬🇧London, United Kingdom
Investigational Site Number 6810
🇩🇪Berlin, Germany
Investigational Site Number 6815
🇩🇪Minden, Germany
Investigational Site Number 6802
🇩🇪Münster, Germany
Investigational Site Number 8709
🇬🇧Liverpool, United Kingdom
Investigational Site Number 7909
🇷🇺Nizhny Novgorod, Russian Federation
Investigational Site Number 8705
🇬🇧Nottingham, United Kingdom
Investigational Site Number 8940
🇺🇸Indianapolis, Indiana, United States
Investigational Site Number 8962
🇺🇸Fort Collins, Colorado, United States
Investigational Site Number 6002
🇩🇰Aarhus C, Denmark
Investigational Site Number 6004
🇩🇰Esbjerg, Denmark
Investigational Site Number 6601
🇫🇷Clermont Ferrand Cedex 1, France
Investigational Site Number 6609
🇫🇷Lille Cedex, France
Investigational Site Number 6604
🇫🇷Montpellier Cedex 05, France
Investigational Site Number 6602
🇫🇷Nice Cedex, France
Investigational Site Number 8707
🇬🇧Salford, United Kingdom
Investigational Site Number 8702
🇬🇧Sheffield, United Kingdom
Investigational Site Number 8920
🇺🇸Maitland, Florida, United States
Investigational Site Number 8955
🇺🇸Grand Rapids, Michigan, United States
Investigational Site Number 8951
🇺🇸Albuquerque, New Mexico, United States
Investigational Site Number 8924
🇺🇸Dayton, Ohio, United States
Investigational Site Number 8963
🇺🇸Seattle, Washington, United States
Investigational Site Number 5403
🇨🇦London, Canada
Investigational Site Number 5408
🇨🇦Sherbrooke, Canada
Investigational Site Number 5406
🇨🇦Quebec, Canada
Investigational Site Number 6203
🇪🇪Tartu, Estonia
Investigational Site Number 5805
🇨🇿Ostrava - Poruba, Czech Republic
Investigational Site Number 6401
🇫🇮Turku, Finland
Investigational Site Number 6805
🇩🇪Berlin, Germany
Investigational Site Number 7502
🇲🇽Guadalajara, Mexico
Investigational Site Number 7501
🇲🇽Chihuahua, Mexico
Investigational Site Number 7707
🇵🇱Warszawa 44, Poland
Investigational Site Number 7912
🇷🇺Novosibirsk, Russian Federation
Investigational Site Number 8508
🇺🇦Kiev, Ukraine
Investigational Site Number 8511
🇺🇦Donets'K, Ukraine
Investigational Site Number 8505
🇺🇦Lviv, Ukraine
Investigational Site Number 8706
🇬🇧Newcastle Upon Tyne, United Kingdom
Investigational Site Number 8708
🇬🇧Plymouth, United Kingdom
Investigational Site Number 8949
🇺🇸Traverse City, Michigan, United States
Investigational Site Number 8930
🇺🇸Burlington, Vermont, United States
Investigational Site Number 8905
🇺🇸Round Rock, Tennessee, United States
Investigational Site Number 4005
🇦🇹Linz, Austria
Investigational Site Number 5309
🇧🇬Sofia, Bulgaria
Investigational Site Number 5801
🇨🇿Brno, Czech Republic
Investigational Site Number 5804
🇨🇿Olomouc, Czech Republic
Investigational Site Number 8954
🇺🇸Phoenix, Arizona, United States
Investigational Site Number 8946
🇺🇸Phoenix, Arizona, United States
Investigational Site Number 8922
🇺🇸Shreveport, Louisiana, United States
Investigational Site Number 4001
🇦🇹Wien, Austria
Investigational Site Number 5304
🇧🇬Sofia, Bulgaria
Investigational Site Number 5303
🇧🇬Sofia, Bulgaria
Investigational Site Number 4004
🇦🇹Innsbruck, Austria
Investigational Site Number 5312
🇧🇬Pleven, Bulgaria
Investigational Site Number 5601
🇨🇱Santiago, Chile
Investigational Site Number 5606
🇨🇱Santiago, Chile
Investigational Site Number 5306
🇧🇬Sofia, Bulgaria
Investigational Site Number 6405
🇫🇮Helsinki, Finland
Investigational Site Number 6403
🇫🇮Kuopio, Finland
Investigational Site Number 5602
🇨🇱Santiago, Chile
Investigational Site Number 5803
🇨🇿Hradec Kralove, Czech Republic
Investigational Site Number 5605
🇨🇱Viña Del Mar, Chile
Investigational Site Number 7101
🇭🇺Budapest, Hungary
Investigational Site Number 7105
🇭🇺Veszprém, Hungary
Investigational Site Number 7402
🇱🇹Klaipeda, Lithuania
Investigational Site Number 7401
🇱🇹Vilnius, Lithuania
Investigational Site Number 7710
🇵🇱Lodz, Poland
Investigational Site Number 7701
🇵🇱Warszawa, Poland
Investigational Site Number 7803
🇷🇴Bucuresti, Romania
Investigational Site Number 7108
🇭🇺Esztergom, Hungary
Investigational Site Number 7403
🇱🇹Siauliai, Lithuania
Investigational Site Number 7906
🇷🇺Nizhny Novgorod, Russian Federation
Investigational Site Number 7911
🇷🇺St-Petersburg, Russian Federation
Investigational Site Number 8312
🇹🇷Istanbul, Turkey
Investigational Site Number 8507
🇺🇦Chernihiv, Ukraine
Investigational Site Number 7703
🇵🇱Warszawa, Poland
Investigational Site Number 7103
🇭🇺Budapest, Hungary
Investigational Site Number 7709
🇵🇱Gdansk, Poland
Investigational Site Number 7805
🇷🇴Cluj-Napoca, Romania
Investigational Site Number 7806
🇷🇴Bucuresti, Romania
Investigational Site Number 7808
🇷🇴Timisoara, Romania
Investigational Site Number 7807
🇷🇴Cluj-Napoca, Romania
Investigational Site Number 7907
🇷🇺Kazan, Russian Federation
Investigational Site Number 8308
🇹🇷Istanbul, Turkey
Investigational Site Number 8512
🇺🇦Lutsk, Ukraine
Investigational Site Number 7910
🇷🇺Rostov-On-Don, Russian Federation
Investigational Site Number 7905
🇷🇺Smolensk, Russian Federation
Investigational Site Number 8304
🇹🇷Edirne, Turkey
Investigational Site Number 8309
🇹🇷Istanbul, Turkey
Investigational Site Number 8315
🇹🇷Istanbul, Turkey
Investigational Site Number 8301
🇹🇷Izmir, Turkey
Investigational Site Number 8303
🇹🇷Izmir, Turkey
Investigational Site Number 8314
🇹🇷Trabzon, Turkey
Investigational Site Number 8501
🇺🇦Dnipropetrovsk, Ukraine
Investigational Site Number 8504
🇺🇦Kharkiv, Ukraine
Investigational Site Number 8503
🇺🇦Vinnytsya, Ukraine
Investigational Site Number 7904
🇷🇺Nizhny Novgorod, Russian Federation
Investigational Site Number 8310
🇹🇷Istanbul, Turkey
Investigational Site Number 8305
🇹🇷Izmir, Turkey
Investigational Site Number 8302
🇹🇷Izmit, Turkey
Investigational Site Number 8506
🇺🇦Kharkiv, Ukraine
Investigational Site Number 8510
🇺🇦Poltava, Ukraine
Investigational Site Number 8502
🇺🇦Zaporizhzhya, Ukraine
Investigational Site Number 8701
🇬🇧London, United Kingdom