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

Multiple Sclerosis Relapse Clinical Trial

— TERACLES  

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01252355
• Other study ID #: EFC6058
• Secondary ID: 2010-023172-12U1
• Status: Terminated
• Phase: Phase 3
• First received: November 30, 2010
• Last updated: May 30, 2014
• Start date: January 2011
• Est. completion date: April 2013

Study information

• Verified date: May 2014
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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)

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 534
• Est. completion date: April 2013
• Est. primary completion date: April 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 55 Years

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Multiple Sclerosis
• Multiple Sclerosis Relapse
• Sclerosis

Intervention

Drug:
• Teriflunomide
Film-coated tablet Oral administration
• Placebo (for teriflunomide)
Film-coated tablet Oral administration
• Interferon-beta (IFN-beta)
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.

Locations

Country	Name	City	State
Argentina	Investigational Site Number 032002	Argentina
Argentina	Investigational Site Number 032003	Buenos Aires
Argentina	Investigational Site Number 032004	Caba
Australia	Investigational Site Number 036008	Bedford Park
Australia	Investigational Site Number 036005	Chatswood
Australia	Investigational Site Number 036001	Heidelberg West
Australia	Investigational Site Number 036004	Kogarah
Australia	Investigational Site Number 036010	New Lambton
Austria	Investigational Site Number 040001	Graz
Austria	Investigational Site Number 040004	Linz
Belgium	Investigational Site Number 056005	Charleroi
Belgium	Investigational Site Number 056004	Gent
Belgium	Investigational Site Number 056003	Hasselt
Belgium	Investigational Site Number 056006	La Louvière
Belgium	Investigational Site Number 056002	Leuven
Belgium	Investigational Site Number 056001	Sijsele-Damme
Belgium	Investigational Site Number 056007	Wilrijk
Brazil	Investigational Site Number 076009	Joinville
Brazil	Investigational Site Number 076012	Passo Fundo
Brazil	Investigational Site Number 076003	Porto Alegre
Brazil	Investigational Site Number 076007	Sao Paulo
Brazil	Investigational Site Number 076013	Sao Paulo
Canada	Investigational Site Number 124005	Calgary
Canada	Investigational Site Number 124004	Edmonton
Canada	Investigational Site Number 124003	Gatineau
Canada	Investigational Site Number 124006	Kingston
Canada	Investigational Site Number 124007	Montreal
Canada	Investigational Site Number 124008	Ottawa
Canada	Investigational Site Number 124002	Regina
Canada	Investigational Site Number 124001	Sherbrooke
Canada	Investigational Site Number 124009	Winnipeg
Chile	Investigational Site Number 152003	Santiago
Chile	Investigational Site Number 152004	Santiago
Chile	Investigational Site Number 152005	Viña Del Mar
Colombia	Investigational Site Number 170001	Barranquilla
Colombia	Investigational Site Number 170005	Bogota
Colombia	Investigational Site Number 170007	Bogota
Colombia	Investigational Site Number 170009	Medellin
Denmark	Investigational Site Number 208002	Aarhus C
Estonia	Investigational Site Number 233002	Tallinn
Estonia	Investigational Site Number 233001	Tartu
Finland	Investigational Site Number 246003	Helsinki
Finland	Investigational Site Number 246006	Hyvinkää
Finland	Investigational Site Number 246004	Oulu
Finland	Investigational Site Number 246002	Pori
Finland	Investigational Site Number 246001	Turku
France	Investigational Site Number 250003	Besancon
France	Investigational Site Number 250010	Clermont Ferrand Cedex 1
France	Investigational Site Number 250002	Lyon Cedex 03
France	Investigational Site Number 250004	Montpellier Cedex 5
France	Investigational Site Number 250001	Nancy Cedex
France	Investigational Site Number 250006	Nantes Cedex 01
Germany	Investigational Site Number 276009	Bad Mergentheim
Germany	Investigational Site Number 276020	Bamberg
Germany	Investigational Site Number 276003	Bayreuth
Germany	Investigational Site Number 276015	Berlin
Germany	Investigational Site Number 276016	Berlin
Germany	Investigational Site Number 276021	Berlin
Germany	Investigational Site Number 276012	Bonn
Germany	Investigational Site Number 276005	Dresden
Germany	Investigational Site Number 276032	Düsseldorf
Germany	Investigational Site Number 276018	Erbach
Germany	Investigational Site Number 276004	Erlangen
Germany	Investigational Site Number 276028	Freiburg
Germany	Investigational Site Number 276006	Gießen
Germany	Investigational Site Number 276010	Hamburg
Germany	Investigational Site Number 276022	Hennigsdorf
Germany	Investigational Site Number 276024	Kassel
Germany	Investigational Site Number 276001	Leipzig
Germany	Investigational Site Number 276013	Mainz
Germany	Investigational Site Number 276023	Minden
Germany	Investigational Site Number 276002	Münster
Germany	Investigational Site Number 276031	Rostock
Germany	Investigational Site Number 276008	Wiesbaden
Germany	Investigational Site Number 276026	Wuppertal
Greece	Investigational Site Number 300001	Athens
Greece	Investigational Site Number 300002	Athens
Greece	Investigational Site Number 300003	Heraklion
Greece	Investigational Site Number 300006	Thessaloniki
Hungary	Investigational Site Number 348002	Budapest
Hungary	Investigational Site Number 348006	Budapest
Hungary	Investigational Site Number 348010	Budapest
Hungary	Investigational Site Number 348009	Eger
Hungary	Investigational Site Number 348003	Esztergom
Hungary	Investigational Site Number 348001	Szeged
Hungary	Investigational Site Number 348005	Szekesfehervar
Hungary	Investigational Site Number 348007	Zalaegerszeg
Italy	Investigational Site Number 380009	Catania
Italy	Investigational Site Number 380002	Cefalù
Italy	Investigational Site Number 380003	Fidenza
Italy	Investigational Site Number 380004	Gallarate
Italy	Investigational Site Number 380012	Montichiari
Italy	Investigational Site Number 380010	Napoli
Italy	Investigational Site Number 380011	Napoli
Italy	Investigational Site Number 380006	Padova
Italy	Investigational Site Number 380005	Roma
Italy	Investigational Site Number 380008	Roma
Italy	Investigational Site Number 380014	Verona
Korea, Republic of	Investigational Site Number 410002	Goyang-Si
Korea, Republic of	Investigational Site Number 410001	Seoul
Korea, Republic of	Investigational Site Number 410004	Seoul
Lithuania	Investigational Site Number 440002	Kaunas
Lithuania	Investigational Site Number 440004	Klaipeda
Lithuania	Investigational Site Number 440003	Siauliai
Netherlands	Investigational Site Number 528001	Breda
Netherlands	Investigational Site Number 528005	Nieuwegein
Netherlands	Investigational Site Number 528002	Sittard-Geleen
Netherlands	Investigational Site Number 528006	Venray
Norway	Investigational Site Number 578002	Tønsberg
Portugal	Investigational Site Number 620001	Amadora
Portugal	Investigational Site Number 620002	Coimbra
Portugal	Investigational Site Number 620004	Coimbra
Portugal	Investigational Site Number 620003	Setubal
Russian Federation	Investigational Site Number 643012	Kaluga
Russian Federation	Investigational Site Number 643007	Kazan
Russian Federation	Investigational Site Number 643001	Kemerovo
Russian Federation	Investigational Site Number 643013	Moscow
Russian Federation	Investigational Site Number 643004	Nizhny Novgorod
Russian Federation	Investigational Site Number 643006	Nizhny Novgorod
Russian Federation	Investigational Site Number 643015	Novosibirsk
Russian Federation	Investigational Site Number 643009	Rostov-On-Don
Russian Federation	Investigational Site Number 643010	Rostov-On-Don
Russian Federation	Investigational Site Number 643016	Samara
Russian Federation	Investigational Site Number 643005	Smolensk
Russian Federation	Investigational Site Number 643002	St-Petersburg
Russian Federation	Investigational Site Number 643003	St-Petersburg
Russian Federation	Investigational Site Number 643011	St-Petersburg
Russian Federation	Investigational Site Number 643017	St-Petersburg
Russian Federation	Investigational Site Number 643018	St-Petersburg
Russian Federation	Investigational Site Number 643014	Yaroslavl
Slovakia	Investigational Site Number 703002	Martin
Slovakia	Investigational Site Number 703001	Trnava
Spain	Investigational Site Number 724001	Barcelona
Spain	Investigational Site Number 724002	Barcelona
Spain	Investigational Site Number 724009	Córdoba
Spain	Investigational Site Number 724003	Girona
Spain	Investigational Site Number 724004	Madrid
Spain	Investigational Site Number 724005	Madrid
Spain	Investigational Site Number 724007	Murcia
Spain	Investigational Site Number 724008	Sevilla
Sweden	Investigational Site Number 752004	Göteborg
Sweden	Investigational Site Number 752001	Stockholm
Sweden	Investigational Site Number 752003	Stockholm
Tunisia	Investigational Site Number 788002	Manouba
Tunisia	Investigational Site Number 788005	Monastir
Tunisia	Investigational Site Number 788004	Sfax
Tunisia	Investigational Site Number 788006	Tunis
United Kingdom	Investigational Site Number 826008	Birmingham
United Kingdom	Investigational Site Number 826005	Leeds
United Kingdom	Investigational Site Number 826006	Liverpool
United Kingdom	Investigational Site Number 826003	London
United Kingdom	Investigational Site Number 826004	Plymouth
United Kingdom	Investigational Site Number 826001	Salford
United States	Investigational Site Number 840023	Albuquerque	New Mexico
United States	Investigational Site Number 840028	Baltimore	Maryland
United States	Investigational Site Number 840041	Baltimore	Maryland
United States	Investigational Site Number 840006	Bismark	North Dakota
United States	Investigational Site Number 840027	Charlotte	North Carolina
United States	Investigational Site Number 840034	Chicago	Illinois
United States	Investigational Site Number 840016	Clinton Township	Michigan
United States	Investigational Site Number 840005	Cordova	Alaska
United States	Investigational Site Number 840049	Cullman	Alabama
United States	Investigational Site Number 840046	Dayton	Ohio
United States	Investigational Site Number 840037	Elk Grove Village	Illinois
United States	Investigational Site Number 840007	Fargo	North Dakota
United States	Investigational Site Number 840036	Fort Collins	Colorado
United States	Investigational Site Number 840033	Louisville	Kentucky
United States	Investigational Site Number 840012	Maitland	Florida
United States	Investigational Site Number 840009	Missoula	Montana
United States	Investigational Site Number 840002	Nashville	Tennessee
United States	Investigational Site Number 840015	New York	New York
United States	Investigational Site Number 840011	Oceanside	California
United States	Investigational Site Number 840013	Ormond Beach	Florida
United States	Investigational Site Number 840003	Phoenix	Arizona
United States	Investigational Site Number 840055	Pompano Beach	Florida
United States	Investigational Site Number 840040	Round Rock	Texas
United States	Investigational Site Number 840020	San Antonio	Texas
United States	Investigational Site Number 840030	St Louis	Missouri
United States	Investigational Site Number 840031	St Louis	Missouri
United States	Investigational Site Number 840021	St. Petersburg	Florida
United States	Investigational Site Number 840004	Tampa	Florida
United States	Investigational Site Number 840047	Tampa	Florida
United States	Investigational Site Number 840017	Toledo	Ohio
United States	Investigational Site Number 840043	Tulsa	Oklahoma
United States	Investigational Site Number 840032	Vienna	Virginia

Sponsors (1)

Lead Sponsor	Collaborator
Sanofi

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  Brazil,  Canada,  Chile,  Colombia,  Denmark,  Estonia,  Finland,  France,  Germany,  Greece,  Hungary,  Italy,  Korea, Republic of,  Lithuania,  Netherlands,  Norway,  Portugal,  Russian Federation,  Slovakia,  Spain,  Sweden,  Tunisia,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA)	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 or 10 Upper Limit of Normal (ULN); Aspartate Aminotransferase (AST) >3, 5 or 10 ULN; Alkaline Phosphatase >1.5 ULN; Total Bilirubin (TB) >1.5 ULN; and ALT >3 ULN and TB >2 ULN.	First study drug intake up to 28 days after last study drug intake, for up to 112 weeks	Yes
Primary	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	No
Secondary	Brain Magnetic Resonance Imaging (MRI) Assessment: Number of Gadolinium Enhancing (Gd-enhancing) T1-lesions Per Scan (Poisson Regression Estimates)	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 number of scans among participants, a Poisson regression model with robust error variance was used (total number of Gd-enhancing T1-lesions as response variable; log-transformed number of scans as offset variable; treatment group, region of enrollment, IFN-beta dose stratum and baseline number of Gd-enhancing T1-lesions as covariates).	Up to a maximum of 108 weeks depending on time of enrollment	No
Secondary	Time to 12-Week Sustained Disability Progression	The 12-week sustained disability progression was defined as an increase from baseline of at least 1-point in EDSS score (at least 0.5-point for participants with baseline EDSS score >5.5) that persisted for at least 12 weeks. Probability of disability progression was to be estimated using Kaplan-Meier method.	Up to a maximum of 108 weeks depending on time of enrollment	No
Secondary	Brain MRI Assessment: Volume of Gd-enhancing T1-lesions Per MRI Scan	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.	Up to a maximum of 108 weeks depending on time of enrollment	No
Secondary	Brain MRI Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease) at Week 24	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, region, IFN-beta dose stratum, visit, treatment-by-visit interaction, cubic root transformed baseline burden of disease, and baseline-by-visit interaction.	Baseline, Week 24	No
Secondary	Time to Relapse: Kaplan-Meier Estimates of the Probability of no Relapse at Week 24, 48, and 72	Probability of no relapse at 24, 48 and 72 weeks was estimated using Kaplan-Meier method on the time to relapse defined as the time from randomization to first EDSS confirmed relapse. Participants free of confirmed relapse (no EDSS confirmed relapse observed on treatment) were censored at the date of the last study drug intake. Kaplan-Meier method consists in computing probabilities of non-occurrence of event at any observed time of event and multiplying successive probabilities for time <=t by any earlier computed probabilities to estimate the probability of being event-free for the amount of time t.	Up to a maximum of 108 weeks depending on time of enrollment	No
Secondary	Change From Baseline in Fatigue Impact Scale (FIS) Total Score at Week 24	FIS is a participant-reported scale that qualifies the impact of fatigue on daily life in participants with MS.	Baseline, Week 24	No
Secondary	Change From Baseline in Short Form Generic Health Survey - 36 Items, Version 2 (SF-36v2) Summary Scores at Week 24	SF-36 scale is a generic, self-administered, health-related quality-of-life (QOL) instrument.	Baseline, Week 24	No
Secondary	Resource Utilization When Relapse	Resource utilization each time a participant experiences an MS relapse, specifically the number of hospitalizations, the number of over night spent in the hospital and number of intensive care admissions if hospitalized were to be reported.	Up to a maximum of 108 weeks depending on time of enrollment	No
Secondary	Overview of Adverse Events (AEs)	AEs are any unfavorable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study.	First study drug intake up to 28 days after last study drug intake, for up to 112 weeks	Yes