Back to resultsPhase II Study of Teriflunomide as Adjunctive Therapy to Interferon-beta in Subjects With Multiple Sclerosis
Primary Purpose
Multiple Sclerosis
Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Teriflunomide
Placebo (for Teriflunomide)
Interferon-β
Sponsored by
About this trial
This is an interventional treatment trial for Multiple Sclerosis focused on measuring MS, interferon-beta, adjunctive therapy, relapses
Eligibility Criteria
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.
Sites / Locations
- Sanofi-Aventis Administrative Office
- Sanofi-Aventis Administrative Office
- Sanofi-Aventis Administrative Office
- Sanofi-Aventis Administrative Office
- Sanofi-Aventis Administrative Office
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Experimental
Placebo Comparator
Arm Label
Teriflunomide 7 mg + IFN-β
Teriflunomide 14 mg + IFN-β
Placebo + IFN-β
Arm Description
Teriflunomide 7 mg once daily concomitantly with Interferon-β (IFN-β) for 24 weeks
Teriflunomide 14 mg once daily concomitantly with Interferon-β (IFN-β) for 24 weeks
Placebo (for Teriflunomide) once daily concomitantly with Interferon-β (IFN-β) for 24 weeks
Outcomes
Primary Outcome Measures
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.
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.
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;
Secondary Outcome Measures
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).
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).
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.
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).
Pharmacokinetic [PK]: Teriflunomide Plasma Concentration
Plasma concentrations of teriflunomide were measured using validated liquid chromatography-tandem mass spectrometry methods.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT00489489
Brief Title
Phase II Study of Teriflunomide as Adjunctive Therapy to Interferon-beta in Subjects With Multiple Sclerosis
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.
Study Type
Interventional
2. Study Status
Record Verification Date
November 2012
Overall Recruitment Status
Completed
Study Start Date
May 2007 (undefined)
Primary Completion Date
June 2009 (Actual)
Study Completion Date
June 2009 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Sanofi
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief 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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Multiple Sclerosis
Keywords
MS, interferon-beta, adjunctive therapy, relapses
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
118 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Teriflunomide 7 mg + IFN-β
Arm Type
Experimental
Arm Description
Teriflunomide 7 mg once daily concomitantly with Interferon-β (IFN-β) for 24 weeks
Arm Title
Teriflunomide 14 mg + IFN-β
Arm Type
Experimental
Arm Description
Teriflunomide 14 mg once daily concomitantly with Interferon-β (IFN-β) for 24 weeks
Arm Title
Placebo + IFN-β
Arm Type
Placebo Comparator
Arm Description
Placebo (for Teriflunomide) once daily concomitantly with Interferon-β (IFN-β) for 24 weeks
Intervention Type
Drug
Intervention Name(s)
Teriflunomide
Other Intervention Name(s)
HMR1726
Intervention Description
Film-coated tablet
Oral administration
Intervention Type
Drug
Intervention Name(s)
Placebo (for Teriflunomide)
Intervention Description
Film-coated tablet
Oral administration
Intervention Type
Drug
Intervention Name(s)
Interferon-β
Other Intervention Name(s)
Avonex®, Rebif®, Betaseron®
Intervention Description
Powder for reconstitution, of any licensed strength for either intramuscular or subcutaneous injection
Primary Outcome Measure Information:
Title
Overview of Adverse Events [AE]
Description
AE are any unfavorable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study.
Time Frame
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)
Title
Overview of AE With Potential Risk of Occurrence
Description
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.
Time Frame
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)
Title
Liver Function: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA)
Description
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;
Time Frame
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 Measure Information:
Title
Cerebral Magnetic Resonance Imaging [MRI] Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease)
Description
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).
Time Frame
baseline (before randomization) and 24 weeks
Title
Cerebral MRI Assessment: Number of Gd-enhancing T1-lesions Per Scan (Poisson Regression Estimates)
Description
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).
Time Frame
24 weeks
Title
Cerebral MRI Assessment: Volume of Gd-enhancing T1-lesions Per Scan
Description
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.
Time Frame
24 weeks
Title
Annualized Relapse Rate [ARR]: Poisson Regression Estimates
Description
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).
Time Frame
24 weeks
Title
Pharmacokinetic [PK]: Teriflunomide Plasma Concentration
Description
Plasma concentrations of teriflunomide were measured using validated liquid chromatography-tandem mass spectrometry methods.
Time Frame
24 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
ICD
Organizational Affiliation
Sanofi
Official's Role
Study Director
Facility Information:
Facility Name
Sanofi-Aventis Administrative Office
City
Bridgewater
State/Province
New Jersey
ZIP/Postal Code
08807
Country
United States
Facility Name
Sanofi-Aventis Administrative Office
City
Laval
Country
Canada
Facility Name
Sanofi-Aventis Administrative Office
City
Berlin
Country
Germany
Facility Name
Sanofi-Aventis Administrative Office
City
Milan
Country
Italy
Facility Name
Sanofi-Aventis Administrative Office
City
Barcelona
Country
Spain
12. IPD Sharing Statement
Citations:
PubMed Identifier
22622860
Citation
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.
Results Reference
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Phase II Study of Teriflunomide as Adjunctive Therapy to Interferon-beta in Subjects With Multiple Sclerosis
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