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

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.

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.

Study Overview

• Status: Completed
• Conditions: Multiple Sclerosis
• Intervention / Treatment: Drug: Teriflunomide; Drug: Interferon-β; Drug: Placebo (for Teriflunomide)

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 118
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Laval, Canada
    • Sanofi-Aventis Administrative Office
• Germany
  • Berlin, Germany
    • Sanofi-Aventis Administrative Office
• Italy
  • Milan, Italy
    • Sanofi-Aventis Administrative Office
• Spain
  • Barcelona, Spain
    • Sanofi-Aventis Administrative Office
• United States
  • New Jersey
    • Bridgewater, New Jersey, United States, 08807
      • Sanofi-Aventis Administrative Office

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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-β 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Teriflunomide 7 mg + IFN-β; Teriflunomide 7 mg once daily concomitantly with Interferon-β (IFN-β) for 24 weeks	Drug: Teriflunomide; Film-coated tablet Oral administration; Other Names: HMR1726; Drug: Interferon-β; Powder for reconstitution, of any licensed strength for either intramuscular or subcutaneous injection; Other Names: Rebif®; Avonex®; Betaseron®
Experimental: Teriflunomide 14 mg + IFN-β; Teriflunomide 14 mg once daily concomitantly with Interferon-β (IFN-β) for 24 weeks	Drug: Teriflunomide; Film-coated tablet Oral administration; Other Names: HMR1726; Drug: Interferon-β; Powder for reconstitution, of any licensed strength for either intramuscular or subcutaneous injection; Other Names: Rebif®; Avonex®; Betaseron®
Placebo Comparator: Placebo + IFN-β; Placebo (for Teriflunomide) once daily concomitantly with Interferon-β (IFN-β) for 24 weeks	Drug: Interferon-β; Powder for reconstitution, of any licensed strength for either intramuscular or subcutaneous injection; Other Names: Rebif®; Avonex®; Betaseron®; Drug: Placebo (for Teriflunomide); Film-coated tablet Oral administration

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)
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)
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)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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-β 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
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-β dose level and baseline number of Gd-enhancing T1-lesions as covariates).	24 weeks
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
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-β dose level as covariates).	24 weeks
Pharmacokinetic [PK]: Teriflunomide Plasma Concentration	Plasma concentrations of teriflunomide were measured using validated liquid chromatography-tandem mass spectrometry methods.	24 weeks

Collaborators and Investigators

• Sponsor: Sanofi

Publications and helpful links

General Publications

• 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-beta in relapsing multiple sclerosis: a randomized phase II trial. Neurology. 2012 Jun 5;78(23):1877-85. doi: 10.1212/WNL.0b013e318258f7d4. Epub 2012 May 23.

Study record dates

Study Major Dates

• Study Start: May 1, 2007
• Primary Completion (Actual): June 1, 2009
• Study Completion (Actual): June 1, 2009

Study Registration Dates

• First Submitted: June 20, 2007
• First Submitted That Met QC Criteria: June 20, 2007
• First Posted (Estimate): June 21, 2007

Study Record Updates

• Last Update Posted (Estimate): November 6, 2012
• Last Update Submitted That Met QC Criteria: November 5, 2012
• Last Verified: November 1, 2012

More Information

Terms related to this study

• Keywords: MS; adjunctive therapy; relapses; interferon-beta
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis; Physiological Effects of Drugs; Anti-Infective Agents; Peripheral Nervous System Agents; Antiviral Agents; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Adjuvants, Immunologic; Interferons; Interferon-beta; Interferon beta-1b; Teriflunomide
• Other Study ID Numbers: PDY6045; 2006-003134-14 (EudraCT Number); HMR1726D-2003 (Other Identifier: HMR)