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
  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
Study Completion Date: February 2016
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   (Adult)
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

  Hide Study Locations
Locations
United States, Alabama
Investigational Site Number 8965
Cullman, Alabama, United States, 35058
United States, Arizona
Investigational Site Number 8954
Phoenix, Arizona, United States, 85013-4496
Investigational Site Number 8946
Phoenix, Arizona, United States, 85060
United States, Colorado
Investigational Site Number 8962
Fort Collins, Colorado, United States, 80528
United States, Florida
Investigational Site Number 8920
Maitland, Florida, United States, 32761
Investigational Site Number 8953
St. Petersburg, Florida, United States, 33701
United States, Indiana
Investigational Site Number 8914
Ft. Wayne, Indiana, United States, 63104
Investigational Site Number 8940
Indianapolis, Indiana, United States, 46256
United States, Louisiana
Investigational Site Number 8922
Shreveport, Louisiana, United States, 71103
United States, Michigan
Investigational Site Number 8955
Grand Rapids, Michigan, United States, 49503
Investigational Site Number 8949
Traverse City, Michigan, United States, 49684
United States, Missouri
Investigational Site Number 8937
St Louis, Missouri, United States, 63104
United States, New Mexico
Investigational Site Number 8951
Albuquerque, New Mexico, United States, 87131
United States, New York
Investigational Site Number 8925
New York, New York, United States, 10029-6574
United States, North Carolina
Investigational Site Number 8941
Charlotte, North Carolina, United States, 28204
United States, Ohio
Investigational Site Number 8924
Dayton, Ohio, United States, 45409
United States, Tennessee
Investigational Site Number 8905
Round Rock, Tennessee, United States, 78681
United States, Vermont
Investigational Site Number 8930
Burlington, Vermont, United States, 05401
United States, Washington
Investigational Site Number 8963
Seattle, Washington, United States, 98122
Australia
Investigational Site Number 1405
Geelong, Australia, 3220
Investigational Site Number 1404
Heidelberg, Australia, 3081
Investigational Site Number 1407
Hobart, Australia, 7001
Investigational Site Number 1401
Parkville, Australia, 3050
Austria
Investigational Site Number 4004
Innsbruck, Austria, 6020
Investigational Site Number 4005
Linz, Austria, 4020
Investigational Site Number 4001
Wien, Austria, 1010
Bulgaria
Investigational Site Number 5312
Pleven, Bulgaria, 5800
Investigational Site Number 5307
Sofia, Bulgaria, 1000
Investigational Site Number 5304
Sofia, Bulgaria, 1407
Investigational Site Number 5309
Sofia, Bulgaria, 1431
Investigational Site Number 5306
Sofia, Bulgaria, 1606
Investigational Site Number 5303
Sofia, Bulgaria, 1527
Canada
Investigational Site Number 5402
Greenfield Park, Canada, J4V 2J2
Investigational Site Number 5403
London, Canada, N6A 5A5
Investigational Site Number 5409
Montreal, Canada, H1T 2M4
Investigational Site Number 5401
Ottawa, Canada, K1H 8L6
Investigational Site Number 5406
Quebec, Canada, G1J 1Z4
Investigational Site Number 5408
Sherbrooke, Canada, J1H 5N4
Investigational Site Number 5410
Toronto, Canada, M4N 3M5
Investigational Site Number 5404
Toronto, Canada, M5B 1W8
Chile
Investigational Site Number 5602
Santiago, Chile, 760-0746
Investigational Site Number 5601
Santiago, Chile
Investigational Site Number 5606
Santiago, Chile
Investigational Site Number 5605
Viña Del Mar, Chile, 2520997
Czech Republic
Investigational Site Number 5801
Brno, Czech Republic, 65691
Investigational Site Number 5803
Hradec Kralove, Czech Republic, 50005
Investigational Site Number 5804
Olomouc, Czech Republic, 77520
Investigational Site Number 5805
Ostrava - Poruba, Czech Republic, 70852
Denmark
Investigational Site Number 6002
Aarhus C, Denmark, 8000
Investigational Site Number 6004
Esbjerg, Denmark, 6700
Estonia
Investigational Site Number 6201
Tallinn, Estonia, 10617
Investigational Site Number 6203
Tartu, Estonia, 50406
Finland
Investigational Site Number 6405
Helsinki, Finland, 00100
Investigational Site Number 6403
Kuopio, Finland, 70210
Investigational Site Number 6401
Turku, Finland, 20100
France
Investigational Site Number 6611
Besancon, France, 25030
Investigational Site Number 6601
Clermont Ferrand Cedex 1, France, 63003
Investigational Site Number 6609
Lille Cedex, France, 59037
Investigational Site Number 6604
Montpellier Cedex 05, France, 34295
Investigational Site Number 6612
Nancy Cedex, France, 54036
Investigational Site Number 6605
Nantes Cedex 01, France, 44093
Investigational Site Number 6602
Nice Cedex, France, 06002
Investigational Site Number 6614
Nimes, France, 30029
Investigational Site Number 6607
Strasbourg Cedex, France, 67091
Germany
Investigational Site Number 6801
Bayreuth, Germany, 95445
Investigational Site Number 6810
Berlin, Germany, 10713
Investigational Site Number 6805
Berlin, Germany, 10785
Investigational Site Number 6807
Erbach, Germany, 64711
Investigational Site Number 6803
Essen, Germany, 45122
Investigational Site Number 6809
Hannover, Germany, 30625
Investigational Site Number 6804
Ludwigshafen, Germany, 67063
Investigational Site Number 6815
Minden, Germany, 32429
Investigational Site Number 6802
Münster, Germany, 48149
Investigational Site Number 6806
Wiesbaden, Germany, 65191
Hungary
Investigational Site Number 7101
Budapest, Hungary, 1076
Investigational Site Number 7103
Budapest, Hungary, 1145
Investigational Site Number 7108
Esztergom, Hungary, 2500
Investigational Site Number 7105
Veszprém, Hungary, 8200
Lithuania
Investigational Site Number 7402
Klaipeda, Lithuania, LT-92288
Investigational Site Number 7403
Siauliai, Lithuania, LT-76231
Investigational Site Number 7401
Vilnius, Lithuania, LT-08661
Mexico
Investigational Site Number 7501
Chihuahua, Mexico, 31203
Investigational Site Number 7502
Guadalajara, Mexico, 45110
Poland
Investigational Site Number 7709
Gdansk, Poland, 80-803
Investigational Site Number 7710
Lodz, Poland, 93-513
Investigational Site Number 7703
Warszawa, Poland, 02-957
Investigational Site Number 7701
Warszawa, Poland, 02-097
Investigational Site Number 7707
Warszawa 44, Poland, 04-141
Romania
Investigational Site Number 7803
Bucuresti, Romania, 020125
Investigational Site Number 7806
Bucuresti, Romania, 050098
Investigational Site Number 7805
Cluj-Napoca, Romania, 400012
Investigational Site Number 7807
Cluj-Napoca, Romania, 400012
Investigational Site Number 7808
Timisoara, Romania, 300736
Russian Federation
Investigational Site Number 7907
Kazan, Russian Federation, 420021
Investigational Site Number 7909
Nizhny Novgorod, Russian Federation, 603000
Investigational Site Number 7904
Nizhny Novgorod, Russian Federation, 603126
Investigational Site Number 7906
Nizhny Novgorod, Russian Federation, 603076
Investigational Site Number 7912
Novosibirsk, Russian Federation, 630007
Investigational Site Number 7910
Rostov-On-Don, Russian Federation, 344085
Investigational Site Number 7905
Smolensk, Russian Federation, 214019
Investigational Site Number 7911
St-Petersburg, Russian Federation, 194044
Turkey
Investigational Site Number 8304
Edirne, Turkey
Investigational Site Number 8312
Istanbul, Turkey
Investigational Site Number 8309
Istanbul, Turkey, 34390
Investigational Site Number 8315
Istanbul, Turkey, 34400
Investigational Site Number 8310
Istanbul, Turkey
Investigational Site Number 8308
Istanbul, Turkey
Investigational Site Number 8305
Izmir, Turkey, 35100
Investigational Site Number 8301
Izmir, Turkey, 35340
Investigational Site Number 8303
Izmir, Turkey, 35380
Investigational Site Number 8302
Izmit, Turkey, 41380
Investigational Site Number 8314
Trabzon, Turkey, 61080
Ukraine
Investigational Site Number 8507
Chernihiv, Ukraine, 14029
Investigational Site Number 8501
Dnipropetrovsk, Ukraine, 49027
Investigational Site Number 8511
Donets'K, Ukraine, 83099
Investigational Site Number 8504
Kharkiv, Ukraine, 61178
Investigational Site Number 8506
Kharkiv, Ukraine, 61018
Investigational Site Number 8508
Kiev, Ukraine, 03110
Investigational Site Number 8512
Lutsk, Ukraine, 43005
Investigational Site Number 8505
Lviv, Ukraine, 79010
Investigational Site Number 8510
Poltava, Ukraine, 36011
Investigational Site Number 8503
Vinnytsya, Ukraine, 21005
Investigational Site Number 8502
Zaporizhzhya, Ukraine, 69000
United Kingdom
Investigational Site Number 8709
Liverpool, United Kingdom, L9 7LJ
Investigational Site Number 8701
London, United Kingdom, E1 1BB
Investigational Site Number 8704
London, United Kingdom, SW17 0QT
Investigational Site Number 8706
Newcastle Upon Tyne, United Kingdom, NE1 4LP
Investigational Site Number 8705
Nottingham, United Kingdom, NG7 2UH
Investigational Site Number 8708
Plymouth, United Kingdom, PL6 5BX
Investigational Site Number 8707
Salford, United Kingdom, M6 8HD
Investigational Site Number 8702
Sheffield, United Kingdom, S10 2JF
Sponsors and Collaborators
Sanofi
Investigators
Study Director: Clinical Sciences & Operations Sanofi
  More Information

Publications:
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: February 25, 2016
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:
Sclerosis
Multiple Sclerosis
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases

ClinicalTrials.gov processed this record on July 21, 2016