Efficacy and Safety of Teriflunomide in Patients With Relapsing Multiple Sclerosis and Treated With Interferon-beta

NCT01252355 | Terminated Phase 3 Results DMC

• 3 other identifiers: EFC60582010-023172-12U1111-1115-2414
• Study Type: interventional
• Target: 534
• Locations: 26 countries
• Sites: 172

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)

Conditions

Multiple Sclerosis Relapse

Outcome Measures

Primary Outcomes (1)

• Annualized Relapse Rate (ARR) (Poisson Regression Estimates)

  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 Expanded Disability Status Scale (EDSS) score or Functional System scores. To account for the different treatment durations among participants, a Poisson regression model with robust error variance was used (total number of confirmed relapses as response variable; log-transformed treatment duration as "offset" variable; treatment group, region of enrollment and IFN-beta dose stratum, and number of relapses in the year prior to randomization as covariates).

  Up to a maximum of 108 weeks depending on time of enrollment

Secondary Outcomes (9)

• Brain Magnetic Resonance Imaging (MRI) Assessment: Number of Gadolinium Enhancing (Gd-enhancing) T1-lesions Per Scan (Poisson Regression Estimates)

  Up to a maximum of 108 weeks depending on time of enrollment

• Time to 12-Week Sustained Disability Progression

  Up to a maximum of 108 weeks depending on time of enrollment

• Brain MRI Assessment: Volume of Gd-enhancing T1-lesions Per MRI Scan

  Up to a maximum of 108 weeks depending on time of enrollment

• Brain MRI Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease) at Week 24

  Baseline, Week 24

• Time to Relapse: Kaplan-Meier Estimates of the Probability of no Relapse at Week 24, 48, and 72

  Up to a maximum of 108 weeks depending on time of enrollment

Other Outcomes (1)

• Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA)

  First study drug intake up to 28 days after last study drug intake, for up to 112 weeks

Study Arms (3)

Teriflunomide 7 mg + IFN-beta

EXPERIMENTAL

Teriflunomide 7 milligram (mg) once a day concomitantly with IFN-beta therapy.

Drug: Teriflunomide; Drug: Interferon-beta (IFN-beta)

Teriflunomide 14 mg + IFN-beta

EXPERIMENTAL

Teriflunomide 14 mg once a day concomitantly with IFN-beta therapy.

Drug: Teriflunomide; Drug: Interferon-beta (IFN-beta)

Placebo + IFN-beta

PLACEBO COMPARATOR

Placebo (for teriflunomide) once a day concomitantly with IFN-beta therapy.

Drug: Placebo (for teriflunomide); Drug: Interferon-beta (IFN-beta)

Interventions

Teriflunomide DRUG

Film-coated tablet Oral administration

Also known as: HMR1726

Teriflunomide 14 mg + IFN-beta; Teriflunomide 7 mg + IFN-beta

Placebo (for teriflunomide) DRUG

Film-coated tablet Oral administration

Placebo + IFN-beta

Interferon-beta (IFN-beta) DRUG

Any of the IFN-beta which are approved for marketed use in the country where the patient is enrolled. Administration according to the package insert.

Placebo + IFN-beta; Teriflunomide 14 mg + IFN-beta; Teriflunomide 7 mg + IFN-beta

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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)

You may not qualify if:

• 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.

Sponsors & Collaborators

• Sanofi: lead

Study Sites (185)

Investigational Site Number 840049

Cullman, Alabama, 35058, United States

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Investigational Site Number 840005

Cordova, Alaska, 38018, United States

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Investigational Site Number 840003

Phoenix, Arizona, 85060, United States

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Investigational Site Number 840011

Oceanside, California, 92056, United States

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Investigational Site Number 840036

Fort Collins, Colorado, 80528, United States

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Investigational Site Number 840012

Maitland, Florida, 32761, United States

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Investigational Site Number 840013

Ormond Beach, Florida, 32174, United States

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Investigational Site Number 840055

Pompano Beach, Florida, 33060, United States

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Investigational Site Number 840021

St. Petersburg, Florida, 33713, United States

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Investigational Site Number 840004

Tampa, Florida, 33609-4052, United States

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Investigational Site Number 840047

Tampa, Florida, 33612, United States

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Investigational Site Number 840034

Chicago, Illinois, 60637, United States

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Investigational Site Number 840037

Elk Grove Village, Illinois, 60007, United States

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Investigational Site Number 840033

Louisville, Kentucky, 40217, United States

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Investigational Site Number 840041

Baltimore, Maryland, 21201, United States

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Investigational Site Number 840028

Baltimore, Maryland, 21287, United States

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Investigational Site Number 840016

Clinton Township, Michigan, 48035, United States

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Investigational Site Number 840031

St Louis, Missouri, 63104, United States

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Investigational Site Number 840030

St Louis, Missouri, 63110, United States

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Investigational Site Number 840009

Missoula, Montana, 59802, United States

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Investigational Site Number 840023

Albuquerque, New Mexico, 87131, United States

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Investigational Site Number 840015

New York, New York, 10029, United States

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Investigational Site Number 840027

Charlotte, North Carolina, 28204, United States

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Investigational Site Number 840006

Bismarck, North Dakota, 58501, United States

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Investigational Site Number 840007

Fargo, North Dakota, 58103, United States

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Investigational Site Number 840046

Dayton, Ohio, 45409, United States

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Investigational Site Number 840017

Toledo, Ohio, 43699, United States

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Investigational Site Number 840043

Tulsa, Oklahoma, 74137, United States

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Investigational Site Number 840002

Nashville, Tennessee, 37232, United States

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Investigational Site Number 840040

Round Rock, Texas, 78681, United States

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Investigational Site Number 840020

San Antonio, Texas, 78231, United States

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Investigational Site Number 840032

Vienna, Virginia, 22182, United States

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Investigational Site Number 032002

Argentina, 1426, Argentina

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Investigational Site Number 032003

Buenos Aires, Argentina

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Investigational Site Number 032004

Caba, Argentina

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Investigational Site Number 036008

Bedford Park, 5042, Australia

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Investigational Site Number 036005

Chatswood, 2067, Australia

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Investigational Site Number 036001

Heidelberg West, 3081, Australia

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Investigational Site Number 036004

Kogarah, 2217, Australia

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Investigational Site Number 036010

New Lambton, 2305, Australia

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Investigational Site Number 040001

Graz, 8036, Austria

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Investigational Site Number 040004

Linz, 4020, Austria

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Investigational Site Number 056005

Charleroi, 6000, Belgium

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Investigational Site Number 056004

Ghent, 9000, Belgium

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Investigational Site Number 056003

Hasselt, B-3590, Belgium

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Investigational Site Number 056006

La Louvière, 7100, Belgium

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Investigational Site Number 056002

Leuven, 3000, Belgium

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Investigational Site Number 056001

Sijsele-Damme, 8340, Belgium

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Investigational Site Number 056007

Wilrijk, 2610, Belgium

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Investigational Site Number 076009

Joinville, 89202-165, Brazil

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Investigational Site Number 076012

Passo Fundo, 99010-180, Brazil

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Investigational Site Number 076003

Porto Alegre, 90020-090, Brazil

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Investigational Site Number 076007

São Paulo, 04024-002, Brazil

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Investigational Site Number 076013

São Paulo, 08270-070, Brazil

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Investigational Site Number 124005

Calgary, T2N 2T9, Canada

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Investigational Site Number 124004

Edmonton, T6G 2G3, Canada

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Investigational Site Number 124003

Gatineau, J9J 0A5, Canada

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Investigational Site Number 124006

Kingston, K7L 2V7, Canada

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Investigational Site Number 124007

Montreal, H3A 2B4, Canada

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Investigational Site Number 124008

Ottawa, K1H 8L6, Canada

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Investigational Site Number 124002

Regina, S4T 1A5, Canada

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Investigational Site Number 124001

Sherbrooke, J1H 5N4, Canada

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Investigational Site Number 124009

Winnipeg, R3A 1R9, Canada

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Investigational Site Number 152003

Santiago, 7500710, Chile

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Investigational Site Number 152004

Santiago, 838-0456, Chile

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Investigational Site Number 152005

Viña del Mar, 2570017, Chile

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Investigational Site Number 170001

Barranquilla, Colombia

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Investigational Site Number 170005

Bogotá, Colombia

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Investigational Site Number 170007

Bogotá, Colombia

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Investigational Site Number 170009

Medellín, Colombia

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Investigational Site Number 208002

Aarhus C, 8000, Denmark

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Investigational Site Number 233002

Tallinn, 10617, Estonia

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Investigational Site Number 233001

Tartu, 50406, Estonia

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Investigational Site Number 246003

Helsinki, 00100, Finland

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Investigational Site Number 246006

Hyvinkää, 05800, Finland

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Investigational Site Number 246004

Oulu, 90220, Finland

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Investigational Site Number 246002

Pori, 28100, Finland

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Investigational Site Number 246001

Turku, 20100, Finland

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Investigational Site Number 250003

Besançon, 25030, France

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Investigational Site Number 250010

Clermont-Ferrand, 63003, France

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Investigational Site Number 250002

Lyon, 69394, France

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Investigational Site Number 250004

Montpellier, 34000, France

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Investigational Site Number 250001

Nancy, 54036, France

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Investigational Site Number 250006

Nantes, 44093, France

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Investigational Site Number 276009

Bad Mergentheim, 97980, Germany

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Investigational Site Number 276020

Bamberg, 96047, Germany

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Investigational Site Number 276003

Bayreuth, 95445, Germany

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Investigational Site Number 276015

Berlin, 10117, Germany

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Investigational Site Number 276016

Berlin, 10713, Germany

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Investigational Site Number 276021

Berlin, 12099, Germany

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Investigational Site Number 276012

Bonn, 53105, Germany

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Investigational Site Number 276005

Dresden, 01307, Germany

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Investigational Site Number 276032

Düsseldorf, 40211, Germany

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Investigational Site Number 276018

Erbach im Odenwald, 64711, Germany

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Investigational Site Number 276004

Erlangen, 91054, Germany

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Investigational Site Number 276028

Freiburg im Breisgau, 79098, Germany

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Investigational Site Number 276006

Giessen, 35385, Germany

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Investigational Site Number 276010

Hamburg, 20249, Germany

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Investigational Site Number 276022

Hennigsdorf, 16761, Germany

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Investigational Site Number 276024

Kassel, 34121, Germany

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Investigational Site Number 276001

Leipzig, 04103, Germany

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Investigational Site Number 276013

Mainz, 55131, Germany

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Investigational Site Number 276023

Minden, 32429, Germany

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Investigational Site Number 276002

Münster, 48149, Germany

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Investigational Site Number 276031

Rostock, 18055, Germany

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Investigational Site Number 276008

Wiesbaden, 65191, Germany

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Investigational Site Number 276026

Wuppertal, 42283, Germany

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Investigational Site Number 300002

Athens, 11527, Greece

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Investigational Site Number 300001

Athens, 11535, Greece

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Investigational Site Number 300003

Heraklion, 71110, Greece

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Investigational Site Number 300006

Thessaloniki, 57010, Greece

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Investigational Site Number 348002

Budapest, 1106, Hungary

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Investigational Site Number 348006

Budapest, 1145, Hungary

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Investigational Site Number 348010

Budapest, 1204, Hungary

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Investigational Site Number 348009

Eger, 3300, Hungary

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Investigational Site Number 348003

Esztergom, 2500, Hungary

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Investigational Site Number 348001

Szeged, 6720, Hungary

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Investigational Site Number 348005

Székesfehérvár, 8000, Hungary

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Investigational Site Number 348007

Zalaegerszeg, 8900, Hungary

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Investigational Site Number 380009

Catania, 95123, Italy

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Investigational Site Number 380002

Cefalù, 90015, Italy

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Investigational Site Number 380003

Fidenza, 43036, Italy

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Investigational Site Number 380004

Gallarate, 21013, Italy

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Investigational Site Number 380012

Montichiari, 25012, Italy

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Investigational Site Number 380010

Napoli, 80131, Italy

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Investigational Site Number 380011

Napoli, 80131, Italy

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Investigational Site Number 380006

Padua, 35128, Italy

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Investigational Site Number 380005

Roma, 00133, Italy

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Investigational Site Number 380008

Roma, 00161, Italy

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Investigational Site Number 380014

Verona, 37134, Italy

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Investigational Site Number 440002

Kaunas, LT-50009, Lithuania

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Investigational Site Number 440004

Klaipėda, LT-92288, Lithuania

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Investigational Site Number 440003

Šiauliai, LT-76231, Lithuania

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Investigational Site Number 528001

Breda, 4818 CK, Netherlands

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Investigational Site Number 528005

Nieuwegein, 3435 CM, Netherlands

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Investigational Site Number 528002

Sittard-Geleen, 6162 BG, Netherlands

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Investigational Site Number 528006

Venray, 5801 CE, Netherlands

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Investigational Site Number 578002

Tønsberg, 3116, Norway

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Investigational Site Number 620001

Amadora, 2720-276, Portugal

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Investigational Site Number 620002

Coimbra, 3000-075, Portugal

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Investigational Site Number 620004

Coimbra, 3041-801, Portugal

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Investigational Site Number 620003

Setúbal, 2910-446, Portugal

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Investigational Site Number 643012

Kaluga, 248007, Russia

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Investigational Site Number 643007

Kazan', 420021, Russia

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Investigational Site Number 643001

Kemerovo, 650066, Russia

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Investigational Site Number 643013

Moscow, 129110, Russia

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Investigational Site Number 643006

Nizhny Novgorod, 603076, Russia

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Investigational Site Number 643004

Nizhny Novgorod, 603126, Russia

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Investigational Site Number 643015

Novosibirsk, 630007, Russia

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Investigational Site Number 643010

Rostov-on-Don, 344015, Russia

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Investigational Site Number 643009

Rostov-on-Don, 344022, Russia

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Investigational Site Number 643011

Saint Petersburg, 194044, Russia

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Investigational Site Number 643018

Saint Petersburg, 194291, Russia

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Investigational Site Number 643003

Saint Petersburg, 194354, Russia

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Investigational Site Number 643017

Saint Petersburg, 197089, Russia

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Investigational Site Number 643002

Saint Petersburg, 197376, Russia

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Investigational Site Number 643016

Samara, 443095, Russia

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Investigational Site Number 643005

Smolensk, 214019, Russia

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Investigational Site Number 643014

Yaroslavl, 150030, Russia

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Investigational Site Number 703002

Martin, 03659, Slovakia

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Investigational Site Number 703001

Trnava, 91775, Slovakia

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Investigational Site Number 410002

Goyang-si, 410-760, South Korea

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Investigational Site Number 410004

Seoul, 110-744, South Korea

Location

Investigational Site Number 410001

Seoul, 136-705, South Korea

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Investigational Site Number 724001

Barcelona, 08035, Spain

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Investigational Site Number 724002

Barcelona, 08036, Spain

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Investigational Site Number 724009

Córdoba, 14004, Spain

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Investigational Site Number 724003

Girona, 17007, Spain

Location

Investigational Site Number 724004

Madrid, 28005, Spain

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Investigational Site Number 724005

Madrid, 28040, Spain

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Investigational Site Number 724007

Murcia, 30120, Spain

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Investigational Site Number 724008

Seville, 41008, Spain

Location

Investigational Site Number 752004

Gothenburg, 413 45, Sweden

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Investigational Site Number 752003

Stockholm, 14186, Sweden

Location

Investigational Site Number 752001

Stockholm, 171 76, Sweden

Location

Investigational Site Number 788002

Manouba, 2010, Tunisia

Location

Investigational Site Number 788005

Monastir, 5000, Tunisia

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Investigational Site Number 788004

Sfax, 3029, Tunisia

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Investigational Site Number 788006

Tunis, 1008, Tunisia

Location

Investigational Site Number 826008

Birmingham, B15 2TH, United Kingdom

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Investigational Site Number 826005

Leeds, LS1 3EX, United Kingdom

Location

Investigational Site Number 826006

Liverpool, L9 7LJ, United Kingdom

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Investigational Site Number 826003

London, SW17 0QT, United Kingdom

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Investigational Site Number 826004

Plymouth, PL6 8BX, United Kingdom

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Investigational Site Number 826001

Salford, M6 8HD, United Kingdom

Location

MeSH Terms

Interventions

teriflunomide; Interferon-beta

Intervention Hierarchy (Ancestors)

Interferon Type I; Interferons; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Limitations and Caveats

The early termination of study with reduced sample size and participant follow-up impacts the power and interpretability, and limits the ability to assess the overall benefit/risk of adjunctive therapy. Termination was not due to any safety concerns.

Results Point of Contact

• Title: Trial Transparency Team
• Organization: Sanofi

Contact-us@sanofi.com

Study Officials

• Clinical Sciences & Operations

  Sanofi

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 30, 2010
• First Posted: December 3, 2010
• Study Start: January 1, 2011
• Primary Completion: April 1, 2013
• Study Completion: April 1, 2013
• Last Updated: June 9, 2014
• Results First Posted: May 22, 2014

Record last verified: 2014-05

Locations

KR (3); DE (23); AU (2); ES (2); IT (11); CL (3); FR (6); PT (4); CA (9); AR (3); US (32); CO (4); HU (8); NL (4); LI (3); BR (5); BE (7); TU (4); NO (1); GR (4); RU (17); SL (2); SE (3); GB (6); FI (5); DK (1)