Phase III Study With Teriflunomide Versus Placebo in Patients With First Clinical Symptom of Multiple Sclerosis

Multiple Sclerosis Clinical Trial

— TOPIC  

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00622700
• Other study ID #: EFC6260
• Secondary ID: HMR1726D-3005200
• Status: Active, not recruiting
• Phase: Phase 3
• First received: February 14, 2008
• Last updated: December 17, 2014
• Start date: February 2008
• Est. completion date: December 2015

Study information

• Verified date: December 2014
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationCanada: Health CanadaFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Germany: Paul-Ehrlich-Institut
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 618
• Est. completion date: December 2015
• Est. primary completion date: December 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 55 Years

Eligibility

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.

Study Design

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

Related Conditions & MeSH terms

• Multiple Sclerosis
• Sclerosis

Intervention

Drug:
• Teriflunomide
Film-coated tablet Oral administration
• Placebo
Film-coated tablet Oral administration

Locations

Country	Name	City	State
Australia	Investigational Site Number 1405	Geelong
Australia	Investigational Site Number 1404	Heidelberg
Australia	Investigational Site Number 1407	Hobart
Australia	Investigational Site Number 1401	Parkville
Austria	Investigational Site Number 4004	Innsbruck
Austria	Investigational Site Number 4005	Linz
Austria	Investigational Site Number 4001	Wien
Bulgaria	Investigational Site Number 5312	Pleven
Bulgaria	Investigational Site Number 5303	Sofia
Bulgaria	Investigational Site Number 5304	Sofia
Bulgaria	Investigational Site Number 5306	Sofia
Bulgaria	Investigational Site Number 5307	Sofia
Bulgaria	Investigational Site Number 5309	Sofia
Canada	Investigational Site Number 5402	Greenfield Park
Canada	Investigational Site Number 5403	London
Canada	Investigational Site Number 5409	Montreal
Canada	Investigational Site Number 5401	Ottawa
Canada	Investigational Site Number 5406	Quebec
Canada	Investigational Site Number 5408	Sherbrooke
Canada	Investigational Site Number 5404	Toronto
Canada	Investigational Site Number 5410	Toronto
Chile	Investigational Site Number 5601	Santiago
Chile	Investigational Site Number 5602	Santiago
Chile	Investigational Site Number 5606	Santiago
Chile	Investigational Site Number 5605	Viña Del Mar
Czech Republic	Investigational Site Number 5801	Brno
Czech Republic	Investigational Site Number 5803	Hradec Kralove
Czech Republic	Investigational Site Number 5804	Olomouc
Czech Republic	Investigational Site Number 5805	Ostrava - Poruba
Denmark	Investigational Site Number 6002	Aarhus C
Denmark	Investigational Site Number 6004	Esbjerg
Estonia	Investigational Site Number 6201	Tallinn
Estonia	Investigational Site Number 6203	Tartu
Finland	Investigational Site Number 6405	Helsinki
Finland	Investigational Site Number 6403	Kuopio
Finland	Investigational Site Number 6401	Turku
France	Investigational Site Number 6611	Besancon
France	Investigational Site Number 6601	Clermont Ferrand Cedex 1
France	Investigational Site Number 6609	Lille Cedex
France	Investigational Site Number 6604	Montpellier Cedex 05
France	Investigational Site Number 6612	Nancy Cedex
France	Investigational Site Number 6605	Nantes Cedex 01
France	Investigational Site Number 6602	Nice Cedex
France	Investigational Site Number 6614	Nimes
France	Investigational Site Number 6607	Strasbourg Cedex
Germany	Investigational Site Number 6801	Bayreuth
Germany	Investigational Site Number 6805	Berlin
Germany	Investigational Site Number 6810	Berlin
Germany	Investigational Site Number 6807	Erbach
Germany	Investigational Site Number 6803	Essen
Germany	Investigational Site Number 6809	Hannover
Germany	Investigational Site Number 6804	Ludwigshafen
Germany	Investigational Site Number 6815	Minden
Germany	Investigational Site Number 6802	Münster
Germany	Investigational Site Number 6806	Wiesbaden
Hungary	Investigational Site Number 7101	Budapest
Hungary	Investigational Site Number 7103	Budapest
Hungary	Investigational Site Number 7108	Esztergom
Hungary	Investigational Site Number 7105	Veszprém
Lithuania	Investigational Site Number 7402	Klaipeda
Lithuania	Investigational Site Number 7403	Siauliai
Lithuania	Investigational Site Number 7401	Vilnius
Mexico	Investigational Site Number 7501	Chihuahua
Mexico	Investigational Site Number 7502	Guadalajara
Poland	Investigational Site Number 7709	Gdansk
Poland	Investigational Site Number 7710	Lodz
Poland	Investigational Site Number 7701	Warszawa
Poland	Investigational Site Number 7703	Warszawa
Poland	Investigational Site Number 7707	Warszawa 44
Romania	Investigational Site Number 7803	Bucuresti
Romania	Investigational Site Number 7806	Bucuresti
Romania	Investigational Site Number 7805	Cluj-Napoca
Romania	Investigational Site Number 7807	Cluj-Napoca
Romania	Investigational Site Number 7808	Timisoara
Russian Federation	Investigational Site Number 7907	Kazan
Russian Federation	Investigational Site Number 7904	Nizhny Novgorod
Russian Federation	Investigational Site Number 7906	Nizhny Novgorod
Russian Federation	Investigational Site Number 7909	Nizhny Novgorod
Russian Federation	Investigational Site Number 7912	Novosibirsk
Russian Federation	Investigational Site Number 7910	Rostov-On-Don
Russian Federation	Investigational Site Number 7905	Smolensk
Russian Federation	Investigational Site Number 7911	St-Petersburg
Turkey	Investigational Site Number 8304	Edirne
Turkey	Investigational Site Number 8308	Istanbul
Turkey	Investigational Site Number 8309	Istanbul
Turkey	Investigational Site Number 8310	Istanbul
Turkey	Investigational Site Number 8312	Istanbul
Turkey	Investigational Site Number 8315	Istanbul
Turkey	Investigational Site Number 8301	Izmir
Turkey	Investigational Site Number 8303	Izmir
Turkey	Investigational Site Number 8305	Izmir
Turkey	Investigational Site Number 8302	Izmit
Turkey	Investigational Site Number 8314	Trabzon
Ukraine	Investigational Site Number 8507	Chernihiv
Ukraine	Investigational Site Number 8501	Dnipropetrovsk
Ukraine	Investigational Site Number 8511	Donets'K
Ukraine	Investigational Site Number 8504	Kharkiv
Ukraine	Investigational Site Number 8506	Kharkiv
Ukraine	Investigational Site Number 8508	Kiev
Ukraine	Investigational Site Number 8512	Lutsk
Ukraine	Investigational Site Number 8505	Lviv
Ukraine	Investigational Site Number 8510	Poltava
Ukraine	Investigational Site Number 8503	Vinnytsya
Ukraine	Investigational Site Number 8502	Zaporizhzhya
United Kingdom	Investigational Site Number 8709	Liverpool
United Kingdom	Investigational Site Number 8701	London
United Kingdom	Investigational Site Number 8704	London
United Kingdom	Investigational Site Number 8706	Newcastle Upon Tyne
United Kingdom	Investigational Site Number 8705	Nottingham
United Kingdom	Investigational Site Number 8708	Plymouth
United Kingdom	Investigational Site Number 8707	Salford
United Kingdom	Investigational Site Number 8702	Sheffield
United States	Investigational Site Number 8951	Albuquerque	New Mexico
United States	Investigational Site Number 8930	Burlington	Vermont
United States	Investigational Site Number 8941	Charlotte	North Carolina
United States	Investigational Site Number 8965	Cullman	Alabama
United States	Investigational Site Number 8924	Dayton	Ohio
United States	Investigational Site Number 8962	Fort Collins	Colorado
United States	Investigational Site Number 8914	Ft. Wayne	Indiana
United States	Investigational Site Number 8955	Grand Rapids	Michigan
United States	Investigational Site Number 8940	Indianapolis	Indiana
United States	Investigational Site Number 8920	Maitland	Florida
United States	Investigational Site Number 8925	New York	New York
United States	Investigational Site Number 8946	Phoenix	Arizona
United States	Investigational Site Number 8954	Phoenix	Arizona
United States	Investigational Site Number 8905	Round Rock	Tennessee
United States	Investigational Site Number 8963	Seattle	Washington
United States	Investigational Site Number 8922	Shreveport	Louisiana
United States	Investigational Site Number 8937	St Louis	Missouri
United States	Investigational Site Number 8953	St. Petersburg	Florida
United States	Investigational Site Number 8949	Traverse City	Michigan

Sponsors (1)

Lead Sponsor	Collaborator
Sanofi

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Bulgaria,  Canada,  Chile,  Czech Republic,  Denmark,  Estonia,  Finland,  France,  Germany,  Hungary,  Lithuania,  Mexico,  Poland,  Romania,  Russian Federation,  Turkey,  Ukraine,  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, 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.	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	Yes
Primary	Time to Conversion to Clinically De?nite Multiple Sclerosis (CDMS)	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.	Up to a maximum of 108 weeks depending on time of enrollment	No
Secondary	Time to Conversion to Definite Multiple Sclerosis (DMS)	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.	Up to a maximum of 108 weeks depending on time of enrollment	No
Secondary	Annualized Relapse Rate (ARR)	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).	Up to a maximum of 108 weeks depending on time of enrollment	No
Secondary	Brain Magnetic Resonance Imaging (MRI) Assessment: Change From Baseline in Total Lesion Volume at Week 108	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.	Baseline, Week 108	No
Secondary	Brain MRI Assessment: Number of Gadolinium Enhancing (Gd-enhancing) T1-lesions Per MRI 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 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).	Up to a maximum of 108 weeks depending on time of enrollment	No
Secondary	Brain MRI Assessment: Volume of Gadolinium Enhancing (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. 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).	Up to a maximum of 108 weeks depending on time of enrollment	No
Secondary	Brain MRI Assessment: Change From Baseline in Volume of Hypointense Post-Gadolinium T1 Lesion Component	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	Baseline, Week 108	No
Secondary	Brain MRI Assessment: Change From Baseline in Volume of T2 Lesion Component	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.	Baseline, Week 108	Yes
Secondary	Brain MRI Assessment: Percent Change From Baseline in Atrophy	Atrophy was measured by MRI scan.	Baseline, Week 108	No
Secondary	Time to 12-Week Sustained Disability Progression	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.	Up to a maximum of 108 weeks depending on time of enrollment	No
Secondary	Change From Baseline in EDSS at Week 108	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	Baseline, Week 108	No
Secondary	Change From Baseline in Fatigue Impact Scale (FIS) Total Score at Week 108	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.	Baseline, Week 108	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.	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	Yes