Clinical trial NCT00622700: Phase III Study With Teriflunomide Versus Placebo in Patients With First Clinical Symptom of Multiple Sclerosis
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
Overall status: COMPLETED
Phase: PHASE3
Conditions: Multiple Sclerosis
Keywords: MS
Clinically Isolated Syndrome
CIS
CDMS
relapses
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2008-02-25
Enrollment: 618
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

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