Pre-specified subgroup analyses of a placebo-controlled phase III trial (TEMSO) of oral teriflunomide in relapsing multiple sclerosis

Abstract

Background: The Teriflunomide Multiple Sclerosis Oral (TEMSO) trial, a randomized, double-blind, placebo-controlled phase III study, demonstrated that teriflunomide significantly reduced annualized relapse rate (ARR), disease progression and magnetic resonance imaging (MRI) activity, with a favorable safety profile in relapsing multiple sclerosis (RMS) patients.

Objective: The purpose of this study was to report the effects of teriflunomide on ARR and disability progression in pre-specified subgroups.

Methods: RMS patients (n=1088) were randomized to placebo or teriflunomide, 7 mg or 14 mg, once daily, for 108 weeks. Subgroup analyses were performed for ARR and disability progression by baseline demographics (gender, race, age), disease characteristics (Expanded Disability Status Scale (EDSS) strata, relapse history, multiple sclerosis (MS) subtype), MRI parameters (gadolinium-enhancing lesions, total lesion volume) and prior use of MS drugs. A generalized estimating equation method and Cox regression model were used to assess consistency of the treatment effect across subgroups, utilizing a treatment-by-subgroup interaction test for each factor separately.

Results: Reductions in ARR and disability progression were consistent across subgroups in favor of teriflunomide, with no treatment-by-subgroup interaction test reaching statistical significance.

Conclusion: The positive effects of teriflunomide were demonstrated consistently across subgroups in TEMSO.

Trial registration: ClinicalTrials.gov NCT00134563.

Conflict of interest statement

Conflicts of interest: Aaron E Miller has received research support from Acorda Therapeutics, Biogen Idec, Genentech, Genzyme, sanofi-aventis, Novartis, Roche and Teva, and consulting fees from Acorda Therapeutics, Avanir, Biogen Idec, BioMarin, Chelsea Therapeutics, Daiichi-Sankyo, EMD Serono, GlaxoSmithKline, La-Ser, Merck Serono, Novartis, Nuron Biotech, ONO, and sanofi-aventis.

Paul O’Connor has received consulting fees and/or research support for MS trials from Actelion, Bayer, Biogen Idec, BioMS, Cognosci, Daiichi Sankyo, EMD Serono, Genentech, Genmab, Novartis, Roche, sanofi-aventis, Teva, and Warburg Pincus.

Jerry S Wolinsky, within the past two years, has had consulting agreements with, or served as a speaker for, Astellas, Bayer HealthCare, Celgene, Consortium of MS Clinics, Eli Lilly, Medscape CME, Novartis, PRIME, sanofi-aventis, Serono Symposia International Foundation, Teva and Teva Neurosciences, the National MS Society; has received royalties from Millipore (Chemicon International Corporation); and has research or contractual support from Clayton Foundation for Research, National Institutes of Health, and sanofi-aventis.

Christian Confavreux has received consulting fees from Biogen Dompé, Biogen Idec, Gemacbio, Genzyme Corporation, Hertie Foundation, Novartis, sanofi-aventis, Teva Pharma and UCB Pharma; lecture fees from Bayer Schering, Biogen Idec, Merck Serono, Novartis, sanofi-aventis, and Teva Pharma; research support from Bayer Schering, Biogen Idec, Merck Serono, Novartis, sanofi-aventis, and Teva Pharma; and fees for membership of Company Advisory Boards from Biogen Idec, Genzyme, Novartis, sanofi-sventis, Teva Pharma, and UCB Pharma.

Ludwig Kappos has received research support from Actelion, Advancell, Allozyne, BaroFold, Bayer Health Care Pharmaceuticals, Bayer Schering Pharma, Bayhill, Biogen Idec, BioMarin, CLC Behring, Elan, Genmab, Genmark, GeNeuro SA, Glaxo-SmithKline, Lilly, Merck Serono, MediciNova, Novartis, Novonordisk, Peptimmune, sanofi-aventis, Santhera, Roche, Teva, UCB, and Wyeth, and from the Swiss MS Society, the Swiss National Research Foundation, the European Union, and the Gianni Rubatto, Novartis, and Roche Research Foundations.

Tomas P Olsson has received consulting fees and/or research support for MS trials from Biogen Idec, Merck Serono, and sanofi-aventis, and for participation in scientific advisory boards and/or speaking activities from Merck Serono, Biogen Idec, and sanofi-aventis.

Philippe Truffinet and Lin Wang are employees of sanofi-aventis.

Laura D’Castro is an employee of Fishawack Communications Ltd, which has been contracted to provide editorial services for sanofi-aventis.

Giancarlo Comi has received, in the past year, consulting fees for participating on advisory boards from Novartis, Teva Pharmaceutical Ind. Ltd, sanofi-aventis, Merck Serono, Actelion and Bayer Schering, and lecture fess from Novartis, Teva Pharmaceutical Ind. Ltd, sanofi-aventis, Merck Serono, Biogen Dompè, Bayer Schering, and Serono Symposia International Foundation.

Mark S Freedman has received research or educational grant support from Bayer Healthcare and Genzyme; he has received honoraria or consultation fees from Bayer Healthcare, Biogen Idec, EMD Canada, Novartis, sanofi-aventis, Teva Canada Innovation, and is a member of Company Advisory Board/Board of Directors/or other similar group for: Bayer Healthcare, Biogen Idec, Merck Serono, Novartis, sanofi-aventis, and Celgene.

Figures

Figure 1.

Adjusted annualized relapse rate by patient subgroup. DMT: disease-modifying therapy; EDSS: Expanded Disability Status Scale; MS: multiple sclerosis.

Figure 2.

Twelve-week confirmed disability progression by patient subgroup. DMT: disease-modifying therapy; EDSS: Expanded Disability Status Scale; MS: multiple sclerosis.