DMT05
Benefits of Repeated Confirmed Disability Progressions Analyses in MS Clinical Trials: A Case Study Using the Opera and Oratorio Trials and Their Open-Label Extensions

Thursday, June 2, 2022: 3:50 PM
Woodrow Wilson D (Gaylord National Resort & Convention Center)
Jerry S Wolinsky, MD , McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX
Hans-Peter Hartung, MD , Department of Neurology, UKD, Center of Neurology and Neuropsychiatry and LVR-Klinikum, Heinrich Heine University Düsseldorf, Düsseldorf, Germany, Brain and Mind Centre, University of Sydney, Sydney, Australia
Stephen L. Hauser, MD , UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA
Robert T. Naismith, MD , Washington University School of Medicine, St. Louis, MO
Hans-Martin Schneble, MD , F. Hoffmann-La Roche Ltd, Basel, Switzerland
Ben Townsend, PhD , F. Hoffmann-La Roche Ltd, Basel, Switzerland
Qing Wang, PhD , F. Hoffmann-La Roche Ltd, Basel, Switzerland
Ludwig Kappos, PhD , Research Center for Clinical Neuroimmunology and Neuroscience, University Hospital Basel, University of Basel, Basel, Switzerland



Background:

In multiple sclerosis (MS), reaching irreversible key clinical milestones such as requiring a walking aid or wheelchair (and the associated personal and societal burdens, e.g. decreased employment rates; physical, emotional and financial challenges) is usually the result of repeated progression events. The current gold standard to assess disability accumulation in MS clinical trials (time-to-first confirmed disability progression; CDP) neglects subsequent on-trial progression events thereby requiring larger study sizes and longer follow-up to detect treatment effects, and potentially missing the full effect of a disease-modifying therapy (DMT). Repeated event analyses provide more comprehensive assessments of disability trajectories during long-term follow-up.

Objectives:

To report the rate of repeated 48-week (48W) CDPs during OPERA (NCT01247324/NCT01412333) and ORATORIO (NCT01194570) and their ongoing open-label extensions (OLE).

Methods:

In the double-blind period (DBP) patients were randomized to ocrelizumab (OCR) or placebo (PBO; ORATORIO)/interferon-beta 1a (IFN; OPERA) for =>120/96 weeks. OLE patients continued OCR (OCR–OCR) or switched to OCR (PBO–OCR)/(IFN–OCR). Repeated 48W-CDP rates were defined as for prior first CDP event analyses, and for Expanded Disability Status Scale (EDSS), Nine-Hole Peg Test (9HPT) or Timed 25-Foot Walk Test (T25FW), following rebaselining after the respective initial progression of the previous event.

Results:

In PPMS, after 7 years, continuous OCR treatment reduced the rate of repeated 48W-CDP–EDSS, repeated 48W-CDP–9HPT and repeated 48W-CDP–T25FW vs PBO–OCR (24%, p=0.005; 36%, p=0.005; 27%, p=0.003). Annualized repeated event rate ratios (ARER: 48W-CDP–EDSS) for OCR–OCR/PBO–OCR were: 0.52 at Week (W) 48 DBP, 0.64 at W144 DBP, 1.24 at W240 and 1.04 at W384; CDP trajectories were similar for 48W-CDP–9HPT and 48W-CDP–T25FW. In RMS, after 7 years, continuous OCR reduced the rate of repeated 48W-CDP–EDSS vs IFN–OCR by 26% (p=0.017). ARER: 48W-CDP–EDSS for OCR–OCR/IFN–OCR was: 0.41 at W48 DBP, 0.45 at W96 DBP, 0.84 at OLE W48 and 0.92 at OLE W288.

Conclusions:

Repeated CDP analyses better capture treatment effects after first disability progression events, providing further insights into the trajectory of disease progression, including response to DMT.

See more of: Disease Modifying Therapies
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