Impact of Primary Endpoint Definitions and Patient Baseline Characteristics on Study Outcomes in Progressive Multiple Sclerosis
ECTRIMS Online Library. Gold R. Oct 27, 2017; 200894; P1239
Ralf Gold
Ralf Gold
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Abstract

Abstract: P1239

Type: Poster

Abstract Category: Therapy - disease modifying - 31 Treatment of progressive MS

Background: EXPAND is a randomised, double-blind, parallel-group, placebo-controlled trial evaluating siponimod in secondary progressive MS (SPMS). EXPAND met its primary endpoint (PEP) of reducing the risk of confirmed disability progression (CDP). In the past 2 years, results from three other studies in progressive MS have become available: INFORMS on fingolimod in primary progressive MS (PPMS), ASCEND on natalizumab in SPMS, and ORATORIO on ocrelizumab in PPMS. The four studies used different PEPs. Expanded Disability Status Scale (EDSS)-based CDP was used as a sole PEP or as a component of composite PEPs in all four trials. Other components of composite PEPs were confirmed increases in timed 25-foot walk (T25FW) and 9-hole peg test (9HPT).
Objective: To provide sensitivity analyses for EXPAND by investigating the impact of different PEP definitions and to model the hazard ratio (HR) of 3-month CDP (3mCDP) for siponimod in study populations comparable to INFORMS, ASCEND or ORATORIO.
Methods: EXPAND data on EDSS, T25FW, and 9HPT were re-analysed using the PEP definitions of INFORMS, ASCEND, and ORATORIO. The second objective was addressed by building a Cox regression model on EXPAND individual patient data, using variable selection methods to identify covariates most predictive of outcome. Candidate covariates were baseline characteristics reported for INFORMS, ASCEND and ORATORIO: age, EDSS, brain volume, T2 lesion volume, disease duration, presence of gadolinium-enhancing lesions, and sex. Treatment was always included in the model. Model performance and stability was assessed by cross-validation and resampling. Model-based HRs with 95% confidence intervals (95%CI) were computed for the average patient in the respective trials.
Results: The observed HR in EXPAND was 0.79 (95%CI 0.65; 0.95). When using the PEP definitions of the three other trials for the EXPAND population, calculated HRs and 95%CIs were similar to the observed ones in EXPAND, e.g., for ORATORIO, the HR is 0.76 (95%CI 0.63; 0.91). Outcomes for composite endpoints were largely driven by effects on EDSS. Model-based HR predictions of 3mCDP for siponimod in other study populations were slightly lower than the one reported for EXPAND, with largely overlapping 95%CI.
Conclusion: The exploratory analyses on different PEP definitions in progressive MS trials and the model predictions for different baseline characteristics corroborate the observed beneficial effects of siponimod on disability progression.
Disclosure: This study was funded by Novartis Pharma AG, Basel, Switzerland. Ralf Gold has received compensation for serving as a consultant or speaker from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis and Teva Neuroscience, and he or the institution he works for has received research support from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis and Teva Neuroscience; he has also received honoraria as a Journal Editor from SAGE and Thieme Verlag.
Gavin Giovannoni is a steering committee member on the daclizumab trials for AbbVie, the BG12 and daclizumab trials for Biogen-Idec, the fingolimod and siponimod trials for Novartis, the laquinimod trials for Teva and the ocrelizumab trials for Roche. He has also received consultancy fees for advisory board meetings for oral cladribine trials for Merck-Serono, Genzyme-Sanofi, and in relation to DSMB activities for Synthon BV, as well as honoraria for speaking at the Physicians' summit and several medical education meetings. He is also the co-chief editor of Multiple Sclerosis and Related Disorders (Elsevier).
Bruce Cree has received personal compensation for consulting from Abbvie, Biogen Idec, EMD Serono, and Novartis.
Patrick Vermersch has received honoraria and consulting fees from Biogen Idec, Genzyme-Sanofi, Bayer, Novartis, Merck Serono, GSK, Almirall, and Servier; research support from Biogen Idec, Genzyme-Sanofi, Bayer, and Merck Serono.
Robert Fox has received compensation for serving as consultant or speaker from Allozyne, Avanir, Biogen Idec, Novartis, Questcor and Teva Pharmaceutical Industries. He or the institution he works for has received research support from Novartis.
Amit Bar-Or has received personal compensation for consulting; serving on scientific advisory boards; and/or speaking activities from Bayer, Bayhill Therapeutics, Berlex, Biogen Idec, BioMS, Diogenix, Eli Lilly, F. Hoffmann-La Roche Ltd, Genentech, GlaxoSmithKline (GSK), Guthy-Jackson/GGF, Merck Serono, Novartis, Ono Pharmacia, Sanofi-Aventis, Teva Neuroscience and Wyeth
Baldur Magnusson, Nicolas Rouyrre, Davorka Tomic, Frank Dahlke, and David Leppert are employees of Novartis.
Christian Wolf is a partner at Lycalis sprl. He is serving as a consultant to Novartis and has also received compensation for serving as a consultant for to-BBB, Desitin, Investitionsbank Berlin, Keyrus, Synthon, Mylan, ICON, and Teva.
Ludwig Kappos has received no personal compensation. Ludwig Kappos' institution (University Hospital Basel) has received in the last 3 years and used exclusively for research support: steering committee, advisory board and consultancy fees from Actelion, Addex, Bayer HealthCare, Biogen Idec, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi, Santhera, Siemens, Teva, UCB and Xenoport; speaker fees from Bayer HealthCare, Biogen Idec, Merck, Novartis, Sanofi and Teva; support of educational activities from Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi and Teva; license fees for Neurostatus products and grants from Bayer HealthCare, Biogen Idec, European Union, Merck, Novartis, Roche Research Foundation, Swiss MS Society and the Swiss National Research Foundation.

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