Ofatumumab versus teriflunomide in relapsing MS: adaptive design of two Phase 3 studies (ASCLEPIOS I and ASCLEPIOS II) (S16.005)

Objective: To present the innovative adaptive design of two Phase 3 studies of the ofatumumab program in relapsing multiple sclerosis (RMS). Background: In Phase 2b, ofatumumab administered subcutaneously significantly reduced the cumulative number of new gadolinium-enhancing lesions in Weeks 4–12 by ≥90% vs placebo in patients with RMS. Design/Methods: ASCLEPIOS I (NCT02792218) and ASCLEPIOS II(NCT02792231) are phase 3, randomized, double-blind/double-dummy, active-controlled, multi-center trials of identical design conducted in parallel. Centers can only participate in one of the two trials. In each trial, 900 RMS patients aged 18–55 years will be randomized to ofatumumab 20 mg subcutaneous injections every 4 weeks or teriflunomide 14 mg orally once daily. This is considered sufficient to power each study for the demonstration of superiority of ofatumumab over teriflunomide on annualized relapse rates (ARR, primary endpoint). The sample size can be increased based on a pre-planned analysis of blinded data to a maximum of 1250 patients per trial. If both studies meet the primary endpoint, the data of the two studies will be combined to assess key-secondary endpoints (3 and 6-months confirmed disability worsening) and MRI-related outcomes. The study duration is flexible but capped at a maximum of 30 months in individual patients. ‘End of Study’ will be declared based on a pre-planned analysis of blinded data when each study is powered to 90% for the primary and to ≥80% for all key-secondary endpoints. Statistical analysis methods (e.g. Cox regression, negative binomial models with offset) are adequate for a study with flexible duration. Results: The sample size and study duration adapt according to the activity of the study population in order to provide sufficient power. Conclusions: An adaptive design with flexible study duration should limit the exposure of patients to double-dummy treatment to the minimum that is required to address the scientific objectives. Study Supported by: This study was funded by Novartis Pharma AG, Basel, Switzerland Disclosure: Dr. Hauser has received personal compensation for activities with Annexon, Symbiotix, Bionure as a scientific advisory board member and from F. Hoffmann-La Roche Ltd. Dr. Bar-Or has received personal compensation for activities with Bayer, Bayhill Therapeutics, Berlex, Biogen Idec, BioMS, Diogenix, and Eli Lilly for consulting, serving on scientific advisory boards and/or as a speaker. Dr. Cohen received personal compensation for activities with Genentech, Genzyme, Novartis, and Teva. Dr. Cohen has received personal compensation in an editorial capacity for the Multiple Sclerosis Journal. Dr. Comi has received personal compensation for activities with Novartis, Teva, Sanofi, Genzyme, Merck Serono, Biogen, Serono Symposia International Foundation, Excemed, Roche Almirall, Chugai, Receptos, and Forward Pharma. Dr. Correale has received personal compensation from Biogen Argentina, Teva Argentina, Novartis Argentina and MERCK Argentina for travel stipends and is a board member of Merck/Serono Argentina and Novartis Argentina. Dr. Coyle has received personal compensation for activities with AbbVie, Accordant, Acorda, Bayer, Biogen Idec, Genentech/Roche, Genzyme/Sanofi, Mallinckrodt, Novartis, Serono, and Teva as a consultant. Dr. Cross has received personal compensation for activities with AbbVie, Biogen, EMD Serono, Genentech/Roche, Genzyme/Sanofi, Novartis, and Teva Dr. De Seze has received personal compensation for activities with Alexion, Allergan, Almiral, Bayer, Biogen, Chugai, CSL Behring, F. Hoffmann-La Roche Ltd., Genzyme, LFB, Merck, Novartis, and Teva. Dr. Montalban has received personal compensation for activities with Almirall, Bayer, Biogen, Celgene, Sanofi Genzyme, Merck, Novartis, Roche, and Teva Pharmaceutical. Dr. Selmaj received personal compensation for activities with Biogen, Novartis, TEVA, Roche, Genzyme, Synthon, Receptos, and Bayer. Dr. Heinz has received personal compensation for activities with Bayer Healthcare, Biogen Idec, Fresenius Medical Care, and GlaxoSmithKline as a consultant. Dr. Kakarieka has received personal compensation for activities with Novartis Pharma AG as an employee. Dr. Karlsson has received personal compensation for activities with Novartis Pharma AG as an employee. Dr. Haering has received personal compensation for activities with Novartis as an employee. Dr. Wallstrom has nothing to disclose. Dr. Kappos has reveived personal compensation for activities with University Hospital Basel as an advisory board member. Dr. Kappos has received research support from Swiss Multiple Sclerosis Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis Research Foundation, and Roche Research Foundation.