Clinical trial NCT01252355: Efficacy and Safety of Teriflunomide in Patients With Relapsing Multiple Sclerosis and Treated With Interferon-beta
Official title: A Multi-center Double-blind Parallel-group Placebo-controlled Study of the Efficacy and Safety of Teriflunomide in Patients With Relapsing Multiple Sclerosis Who Are Treated With Interferon-beta
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Multiple Sclerosis Relapse
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2010-12-03
Enrollment: 534
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, in comparison to placebo, on frequency of Multiple Sclerosis (MS) relapses in patients with relapsing forms of MS who are treated with Interferon-beta (IFN-beta).

The secondary objectives were:

* Assess the effect of teriflunomide, in comparison to placebo, when added to IFN-beta on:

  * Disease activity as measured by brain Magnetic Resonance Imaging (MRI)
  * Disability progression
  * Burden of disease and disease progression as measured by brain MRI
* Evaluate the safety and tolerability of teriflunomide when added to IFN-beta therapy
* Assess the pharmacokinetics of teriflunomide in use in addition to baseline IFN-beta therapy
* Assess associations between variations in genes and clinical outcomes (safety and efficacy)
* Assess other measures of efficacy of teriflunomide such as fatigue and health-related quality of life
* Assess measures of health economics (hospitalization due to relapse, including the length of stay and any admission to intensive care unit)

Detailed description: The study period per patient was expected to be between 56 and 160 weeks depending on when the patient was randomized and this included the following:

* a screening period up to 4 weeks,
* a treatment period expected to be between 48 and 152 weeks,
* 4-week post rapid elimination follow-up period.

Patients were to continue on treatment until a fixed common end date which was approximately 48 weeks after randomization of the last patient.

For those patients who completed the treatment period, a long term extension study of approximately 1 year (including teriflunomide alone) was initially planned to be proposed.

Eligibility criteria: Inclusion criteria :

* Patient with relapsing forms of MS treated with IFN-beta
* Stable dose of IFN-beta (approved brand) for at least 6 months prior to randomization
* Disease activity in the 12 months prior to randomization and after first 3 months of IFN-beta treatment (defined by at least 1 relapse supported by EDSS or equivalent neurological examination, or, at least 1 brain or spinal cord MRI with at least one T1 gadolinium enhancing lesion)

Exclusion criteria:

* McDonald criteria for MS diagnosis not met at time of screening visit
* EDSS score greater than (\>) 5.5 at randomization visit
* A relapse within 30 days prior randomization
* Persistent significant or severe infection
* Patients must not have used adrenocorticotrophic hormone or systemic corticosteroids for 2 weeks prior to randomization
* Prior or concomitant use of cytokine therapy (except baseline interferons), glatiramer acetate or intravenous immunoglobulins in the 3 months preceding randomization
* Liver function impairment or persisting elevations (confirmed by retest) of alanine aminotransferase (ALT), aspartate aminotransferase (AST), or direct bilirubin greater than 2 times the upper limit of normal range (ULN)
* Active hepatitis or hepatobiliary disease or known history of severe hepatitis
* Pregnant or breast-feeding women or those who were planning to become pregnant during the study
* Significantly impaired bone marrow function or significant anemia, leukopenia, or thrombocytopenia
* Human Immunodeficiency Virus (HIV) positive
* Known history of active tuberculosis not adequately treated
* Prior use within 2 years preceding randomization or concomitant use of cladribine and mitoxantrone
* Prior use within 6 months preceding randomization or concomitant use of natalizumab, or any other immunosuppressive agents such as azathioprine, cyclophosphamide, cyclosporine, methotrexate, mycophenolate, or fingolimod

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Primary outcomes:
measure: Annualized Relapse Rate (ARR) (Poisson Regression Estimates)
timeFrame: Up to a maximum of 108 weeks depending on time of enrollment
Secondary outcomes:
measure: Brain Magnetic Resonance Imaging (MRI) Assessment: Number of Gadolinium Enhancing (Gd-enhancing) T1-lesions Per Scan (Poisson Regression Estimates)
timeFrame: Up to a maximum of 108 weeks depending on time of enrollment
measure: Time to 12-Week Sustained Disability Progression
timeFrame: Up to a maximum of 108 weeks depending on time of enrollment
measure: Brain MRI Assessment: Volume of Gd-enhancing T1-lesions Per MRI Scan
timeFrame: Up to a maximum of 108 weeks depending on time of enrollment
measure: Brain MRI Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease) at Week 24
timeFrame: Baseline, Week 24
measure: Time to Relapse: Kaplan-Meier Estimates of the Probability of no Relapse at Week 24, 48, and 72
timeFrame: Up to a maximum of 108 weeks depending on time of enrollment
measure: Change From Baseline in Fatigue Impact Scale (FIS) Total Score at Week 24
timeFrame: Baseline, Week 24
measure: Change From Baseline in Short Form Generic Health Survey - 36 Items, Version 2 (SF-36v2) Summary Scores at Week 24
timeFrame: Baseline, Week 24
measure: Resource Utilization When Relapse
timeFrame: Up to a maximum of 108 weeks depending on time of enrollment
measure: Overview of Adverse Events (AEs)
timeFrame: First study drug intake up to 28 days after last study drug intake, for up to 112 weeks
Other outcomes:
measure: Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA)
timeFrame: First study drug intake up to 28 days after last study drug intake, for up to 112 weeks
Locations:
city: Cullman
country: United States
facility: Investigational Site Number 840049
state: Alabama
city: Cordova
country: United States
facility: Investigational Site Number 840005
state: Alaska
city: Phoenix
country: United States
facility: Investigational Site Number 840003
state: Arizona
city: Oceanside
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state: California
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city: Ormond Beach
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state: Florida
city: Pompano Beach
country: United States
facility: Investigational Site Number 840055
state: Florida
city: St. Petersburg
country: United States
facility: Investigational Site Number 840021
state: Florida
city: Tampa
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facility: Investigational Site Number 840004
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city: Tampa
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facility: Investigational Site Number 840047
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city: Chicago
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state: Illinois
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state: Maryland
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city: Clinton Township
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facility: Investigational Site Number 840016
state: Michigan
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facility: Investigational Site Number 840031
state: Missouri
city: St Louis
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facility: Investigational Site Number 840030
state: Missouri
city: Missoula
country: United States
facility: Investigational Site Number 840009
state: Montana
city: Albuquerque
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facility: Investigational Site Number 840023
state: New Mexico
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city: Charlotte
country: United States
facility: Investigational Site Number 840027
state: North Carolina
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facility: Investigational Site Number 840006
state: North Dakota
city: Fargo
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facility: Investigational Site Number 840007
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city: Dayton
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facility: Investigational Site Number 840046
state: Ohio
city: Toledo
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facility: Investigational Site Number 840017
state: Ohio
city: Tulsa
country: United States
facility: Investigational Site Number 840043
state: Oklahoma
city: Nashville
country: United States
facility: Investigational Site Number 840002
state: Tennessee
city: Round Rock
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facility: Investigational Site Number 840040
state: Texas
city: San Antonio
country: United States
facility: Investigational Site Number 840020
state: Texas
city: Vienna
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country: Argentina
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country: Belgium
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country: Belgium
facility: Investigational Site Number 056006
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country: Belgium
facility: Investigational Site Number 056002
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facility: Investigational Site Number 056001
city: Wilrijk
country: Belgium
facility: Investigational Site Number 056007
city: Joinville
country: Brazil
facility: Investigational Site Number 076009
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country: Brazil
facility: Investigational Site Number 076012
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country: Brazil
facility: Investigational Site Number 076003
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country: Brazil
facility: Investigational Site Number 076007
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country: Brazil
facility: Investigational Site Number 076013
city: Calgary
country: Canada
facility: Investigational Site Number 124005
city: Edmonton
country: Canada
facility: Investigational Site Number 124004
city: Gatineau
country: Canada
facility: Investigational Site Number 124003
city: Kingston
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country: Canada
facility: Investigational Site Number 124007
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facility: Investigational Site Number 124008
city: Regina
country: Canada
facility: Investigational Site Number 124002
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country: Canada
facility: Investigational Site Number 124001
city: Winnipeg
country: Canada
facility: Investigational Site Number 124009
city: Santiago
country: Chile
facility: Investigational Site Number 152003
city: Santiago
country: Chile
facility: Investigational Site Number 152004
city: Viña Del Mar
country: Chile
facility: Investigational Site Number 152005
city: Barranquilla
country: Colombia
facility: Investigational Site Number 170001
city: Bogota
country: Colombia
facility: Investigational Site Number 170005
city: Bogota
country: Colombia
facility: Investigational Site Number 170007
city: Medellin
country: Colombia
facility: Investigational Site Number 170009
city: Aarhus C
country: Denmark
facility: Investigational Site Number 208002
city: Tallinn
country: Estonia
facility: Investigational Site Number 233002
city: Tartu
country: Estonia
facility: Investigational Site Number 233001
city: Helsinki
country: Finland
facility: Investigational Site Number 246003
city: Hyvinkää
country: Finland
facility: Investigational Site Number 246006
city: Oulu
country: Finland
facility: Investigational Site Number 246004
city: Pori
country: Finland
facility: Investigational Site Number 246002
city: Turku
country: Finland
facility: Investigational Site Number 246001
city: Besancon
country: France
facility: Investigational Site Number 250003
city: Clermont Ferrand Cedex 1
country: France
facility: Investigational Site Number 250010
city: Lyon Cedex 03
country: France
facility: Investigational Site Number 250002
city: Montpellier Cedex 5
country: France
facility: Investigational Site Number 250004
city: Nancy Cedex
country: France
facility: Investigational Site Number 250001
city: Nantes Cedex 01
country: France
facility: Investigational Site Number 250006
city: Bad Mergentheim
country: Germany
facility: Investigational Site Number 276009
city: Bamberg
country: Germany
facility: Investigational Site Number 276020
city: Bayreuth
country: Germany
facility: Investigational Site Number 276003
city: Berlin
country: Germany
facility: Investigational Site Number 276015
city: Berlin
country: Germany
facility: Investigational Site Number 276016
city: Berlin
country: Germany
facility: Investigational Site Number 276021
city: Bonn
country: Germany
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city: Dresden
country: Germany
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city: Düsseldorf
country: Germany
facility: Investigational Site Number 276032
city: Erbach
country: Germany
facility: Investigational Site Number 276018
city: Erlangen
country: Germany
facility: Investigational Site Number 276004
city: Freiburg
country: Germany
facility: Investigational Site Number 276028
city: Gießen
country: Germany
facility: Investigational Site Number 276006
city: Hamburg
country: Germany
facility: Investigational Site Number 276010
city: Hennigsdorf
country: Germany
facility: Investigational Site Number 276022
city: Kassel
country: Germany
facility: Investigational Site Number 276024
city: Leipzig
country: Germany
facility: Investigational Site Number 276001
city: Mainz
country: Germany
facility: Investigational Site Number 276013
city: Minden
country: Germany
facility: Investigational Site Number 276023
city: Münster
country: Germany
facility: Investigational Site Number 276002
city: Rostock
country: Germany
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city: Wiesbaden
country: Germany
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city: Wuppertal
country: Germany
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city: Athens
country: Greece
facility: Investigational Site Number 300002
city: Athens
country: Greece
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city: Heraklion
country: Greece
facility: Investigational Site Number 300003
city: Thessaloniki
country: Greece
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city: Budapest
country: Hungary
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city: Budapest
country: Hungary
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country: Hungary
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country: Hungary
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country: Hungary
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country: Hungary
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country: Hungary
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country: Hungary
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city: Catania
country: Italy
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country: Italy
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country: Italy
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city: Gallarate
country: Italy
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country: Italy
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city: Napoli
country: Italy
facility: Investigational Site Number 380010
city: Napoli
country: Italy
facility: Investigational Site Number 380011
city: Padova
country: Italy
facility: Investigational Site Number 380006
city: Roma
country: Italy
facility: Investigational Site Number 380005
city: Roma
country: Italy
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city: Verona
country: Italy
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city: Goyang-Si
country: Korea, Republic of
facility: Investigational Site Number 410002
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number 410004
city: Seoul
country: Korea, Republic of
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country: Lithuania
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country: Lithuania
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country: Lithuania
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country: Netherlands
facility: Investigational Site Number 528001
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country: Netherlands
facility: Investigational Site Number 528005
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country: Netherlands
facility: Investigational Site Number 528002
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country: Netherlands
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city: Tønsberg
country: Norway
facility: Investigational Site Number 578002
city: Amadora
country: Portugal
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city: Coimbra
country: Portugal
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city: Coimbra
country: Portugal
facility: Investigational Site Number 620004
city: Setubal
country: Portugal
facility: Investigational Site Number 620003
city: Kaluga
country: Russian Federation
facility: Investigational Site Number 643012
city: Kazan
country: Russian Federation
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city: Kemerovo
country: Russian Federation
facility: Investigational Site Number 643001
city: Moscow
country: Russian Federation
facility: Investigational Site Number 643013
city: Nizhny Novgorod
country: Russian Federation
facility: Investigational Site Number 643006
city: Nizhny Novgorod
country: Russian Federation
facility: Investigational Site Number 643004
city: Novosibirsk
country: Russian Federation
facility: Investigational Site Number 643015
city: Rostov-On-Don
country: Russian Federation
facility: Investigational Site Number 643010
city: Rostov-On-Don
country: Russian Federation
facility: Investigational Site Number 643009
city: Samara
country: Russian Federation
facility: Investigational Site Number 643016
city: Smolensk
country: Russian Federation
facility: Investigational Site Number 643005
city: St-Petersburg
country: Russian Federation
facility: Investigational Site Number 643011
city: St-Petersburg
country: Russian Federation
facility: Investigational Site Number 643018
city: St-Petersburg
country: Russian Federation
facility: Investigational Site Number 643003
city: St-Petersburg
country: Russian Federation
facility: Investigational Site Number 643017
city: St-Petersburg
country: Russian Federation
facility: Investigational Site Number 643002
city: Yaroslavl
country: Russian Federation
facility: Investigational Site Number 643014
city: Martin
country: Slovakia
facility: Investigational Site Number 703002
city: Trnava
country: Slovakia
facility: Investigational Site Number 703001
city: Barcelona
country: Spain
facility: Investigational Site Number 724001
city: Barcelona
country: Spain
facility: Investigational Site Number 724002
city: Córdoba
country: Spain
facility: Investigational Site Number 724009
city: Girona
country: Spain
facility: Investigational Site Number 724003
city: Madrid
country: Spain
facility: Investigational Site Number 724004
city: Madrid
country: Spain
facility: Investigational Site Number 724005
city: Murcia
country: Spain
facility: Investigational Site Number 724007
city: Sevilla
country: Spain
facility: Investigational Site Number 724008
city: Göteborg
country: Sweden
facility: Investigational Site Number 752004
city: Stockholm
country: Sweden
facility: Investigational Site Number 752003
city: Stockholm
country: Sweden
facility: Investigational Site Number 752001
city: Manouba
country: Tunisia
facility: Investigational Site Number 788002
city: Monastir
country: Tunisia
facility: Investigational Site Number 788005
city: Sfax
country: Tunisia
facility: Investigational Site Number 788004
city: Tunis
country: Tunisia
facility: Investigational Site Number 788006
city: Birmingham
country: United Kingdom
facility: Investigational Site Number 826008
city: Leeds
country: United Kingdom
facility: Investigational Site Number 826005
city: Liverpool
country: United Kingdom
facility: Investigational Site Number 826006
city: London
country: United Kingdom
facility: Investigational Site Number 826003
city: Plymouth
country: United Kingdom
facility: Investigational Site Number 826004
city: Salford
country: United Kingdom
facility: Investigational Site Number 826001
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References: