Phase II Study of Teriflunomide as Adjunctive Therapy to Interferon-beta in Subjects With Multiple Sclerosis

Multiple Sclerosis Clinical Trial

Official title:

A Randomized, Multinational, Double-Blind, Placebo-Controlled, Parallel-Group Design Pilot Study to Estimate the Tolerability, Safety, Pharmacokinetics, and Pharmacodynamic Effects of Teriflunomide for 24 Weeks When Added to Treatment With Interferon-beta in Subjects With Multiple Sclerosis.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00489489
• Other study ID #: PDY6045
• Secondary ID: 2006-003134-14HM
• Status: Completed
• Phase: Phase 2
• First received: June 20, 2007
• Last updated: November 5, 2012
• Start date: May 2007
• Est. completion date: June 2009

Study information

• Verified date: November 2012
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Health authority: Canada: Health CanadaGermany: Paul-Ehrlich-InstitutSpain: Spanish Agency of MedicinesUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

The primary objective was to estimate the tolerability and safety of 2 doses of teriflunomide administered once daily for 24 weeks, compared with placebo, in patients with multiple sclerosis [MS] with relapses who were on a stable dose of interferon-β [IFN-β].

Secondary objectives were:

• to estimate the effects of the 2 doses of teriflunomide, compared to placebo, in combination with a stable dose of IFN-β on Magnetic Resonance Imaging [MRI] parameters, relapse rate and patient-reported fatigue;

• to perform pharmacokinetic analyses of the 2 doses of teriflunomide in combination with a stable dose of IFN-β.

Description:

The study period per participant was approximatively 44 weeks broken down as follows:

• Screening period up to 4 weeks,

• 24-week double-blind treatment period*,

• 16-week post-treatment elimination follow-up period.

'*' participants successfully completing the week 24 visit were offered the opportunity to enter the optional long-term extension study LTS6047 - NCT00811395.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 118
• Est. completion date: June 2009
• Est. primary completion date: June 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 55 Years

Eligibility

Inclusion Criteria:

• Definite MS diagnosis according to McDonald's criteria;

• Relapsing clinical course, with or without progression;

• Expanded Disability Status Scale [EDSS] less or equal to 5.5 (ambulatory);

• Stable dose of IFN-ß for at least 26 weeks prior to the screening visit;

• No onset of MS relapse in the preceding 60 days prior to randomization;

• Clinically stable for 4 weeks prior to randomization.

Exclusion Criteria:

• Other chronic disease of the immune system, liver function impairment or chronic pancreatic disease;

• Pregnant or nursing woman;

• Alcohol or drug abuse;

• Use of cladribine, mitoxantrone, or other immunosuppressant agents such as azathioprine, cyclophosphamide, cyclosporin, methotrexate or mycophenolate before enrollment;

• Human immunodeficiency virus [HIV] positive status;

• 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 patient's potential participation in a clinical trial.

Study Design

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

Related Conditions & MeSH terms

• Multiple Sclerosis
• Sclerosis

Intervention

Drug:
• Teriflunomide
Film-coated tablet Oral administration
• Placebo (for Teriflunomide)
Film-coated tablet Oral administration
• Interferon-ß
Powder for reconstitution, of any licensed strength for either intramuscular or subcutaneous injection

Locations

Country	Name	City	State
Canada	Sanofi-Aventis Administrative Office	Laval
Germany	Sanofi-Aventis Administrative Office	Berlin
Italy	Sanofi-Aventis Administrative Office	Milan
Spain	Sanofi-Aventis Administrative Office	Barcelona
United States	Sanofi-Aventis Administrative Office	Bridgewater	New Jersey

Sponsors (1)

Lead Sponsor	Collaborator
Sanofi

Countries where clinical trial is conducted

United States,  Canada,  Germany,  Italy,  Spain, 

References & Publications (1)

Freedman MS, Wolinsky JS, Wamil B, Confavreux C, Comi G, Kappos L, Olsson TP, Miller A, Benzerdjeb H, Li H, Simonson C, O'Connor PW; Teriflunomide Multiple Sclerosis Trial Group and the MRI Analysis Center. Teriflunomide added to interferon-ß in relapsing — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overview of Adverse Events [AE]	AE 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 or up to the first intake in the extension study LTS6047, whichever occured first (40 weeks max)	Yes
Primary	Overview of AE With Potential Risk of Occurrence	AE with potential risk of occurrence were defined as follows: Hepatic disorders; Immune effects, mainly effects on bone marrow and infection; Pancreatic disorders; Malignancy; Skin disorders, mainly Hair loss and Hair thinning; Pulmonary disorders; Hypertension; Peripheral neuropathy; Psychiatric disorders; Hypersensitivity.	from first study drug intake up to 112 days after last intake or up to the first intake in the extension study LTS6047, whichever occured first (40 weeks max)	Yes
Primary	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 Normal Limit [ULN]; Aspartate aminotransferase [AST] >3, 5, 10 or 20 ULN; Alkaline Phosphatase >1.5 ULN; Total Bilirubin [TB] >1.5 or 2 ULN; ALT >3 ULN and TB >2 ULN;	from first study drug intake up to 112 days after last intake or up to the first intake in the extension study LTS6047, whichever occured first (40 weeks max)	Yes
Secondary	Cerebral Magnetic Resonance Imaging [MRI] Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease)	Total lesion volume is the sum of the total volume of all T2-lesions and the total volume of all T1-hypointense post-gadolinium lesions measured through T2/proton density scan analysis and gadolinium-enhanced T1 scan analysis.; Least-square means were estimated using a Mixed-effect model with repeated measures [MMRM] on cubic root transformed volume data (treatment group, region of enrollment, IFN-ß dose level, visit, treatment-by-visit interaction, baseline value (cubic root transformed), and baseline-by-visit interaction as factors).	baseline (before randomization) and 24 weeks	No
Secondary	Cerebral MRI Assessment: Number of Gd-enhancing T1-lesions Per Scan (Poisson Regression Estimates)	Number of Gd-enhancing T1-lesions per scan is obtained from the total number of Gd-enhancing T1-lesions observed during the study divided by the total number of scans performed during the study.; 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-ß dose level and baseline number of Gd-enhancing T1-lesions as covariates).	24 weeks	No
Secondary	Cerebral MRI Assessment: Volume of Gd-enhancing T1-lesions Per Scan	Total volume of Gd-enhancing T1-lesions per scan is obtained from the sum of the volumes of Gd-enhancing T1-lesions observed during the study divided by the total number of scans performed during the study.	24 weeks	No
Secondary	Annualized Relapse Rate [ARR]: Poisson Regression Estimates	ARR is obtained from the total number of confirmed relapses that occured during the treatment period divided by the sum of the treatment durations.; 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-ß dose level as covariates).	24 weeks	No
Secondary	Pharmacokinetic [PK]: Teriflunomide Plasma Concentration	Plasma concentrations of teriflunomide were measured using validated liquid chromatography-tandem mass spectrometry methods.	24 weeks	No