Repeated Confirmed Disability Progressions Analyses of the OPERA and ORATORIO Studies and Their Open-Label Extensions
Ludwig Kappos1, Hans-Peter Hartung2,3, Stephen L Hauser4, Robert Naismith5, Hans-Martin Schneble6, Ben Townsend6, Qing Wang6, Jerry Wolinsky7
1Research Center for Clinical Neuroimmunology and Neuroscience, University Hospital Basel, University of Basel, 2Department of Neurology, UKD, Center of Neurology and Neuropsychiatry and LVR-Klinikum, Heinrich Heine University Düsseldorf, 3Brain and Mind Centre, University of Sydney, University of Sydney, 4UCSF Weill Institute for Neurosciences, University of California, San Francisco, 5Washington University School of Medicine, 6F. Hoffmann-La Roche Ltd, 7McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth)
Objective:

To report the rate of repeated 48-week (48W) confirmed disability progressions (CDP) during OPERA and ORATORIO and their ongoing open-label extensions (OLE).

 

Background:

Time-to-first event analyses neglect relevant information about subsequent progression. Repeated event analyses provide more comprehensive assessments of disability trajectories during long-term follow-up.

Design/Methods:

In the double-blind period (DBP) patients were randomized to ocrelizumab (OCR) or placebo (PBO; ORATORIO)/interferon β-1a (IFN; OPERA) for ≥120/96 weeks. OLE patients continued OCR (OCR-OCR) or switched to OCR (PBO-OCR)/(IFN-OCR). Rates of repeated 48W-CDP were defined as for prior first event CDP analyses and then following rebaselining EDSS, 9HPT or T25FW after the respective last progression confirmation.

Results:

In PPMS, after 7 years, continuous OCR treatment reduced the rate of repeated 48W-CDP-EDSS by 24% (rate ratio, RR [95% CI]: 0.76 [0.62–0.92]; p=0.005), repeated 48W-CDP-9HPT by 36% (0.64 [0.47–0.88]; p=0.005) and repeated 48W-CDP-T25FW by 27% (0.73 [0.59–0.90]; p=0.003), vs PBO-OCR. Annualized repeated event rate ratios (ARER) OCR-OCR/PBO-OCR RR (95% CI) were: 48W-CDP-EDSS: Week 48 (DBP) 0.52 (0.33–0.84) p=0.008, Week 144 (start of extended control phase/switching) 0.64 (0.44–0.94) p=0.022, Week 240 (end of switching/OLE start) 1.24 (0.71–2.17) p=0.451, Week 384 (OLE) 1.04 (0.45–2.42) p=0.919; similar CDP trajectories were obtained for 48W-CDP-9HPT and 48W-CDP-T25FW. In RMS, after 7 years, continuous OCR vs IFN-OCR reduced the rate of repeated 48W-CDP-EDSS by 26% (RR [95% CI]: 0.74 [0.58–0.95]; p=0.017). ARER (95% CI) for OCR-OCR/IFN-OCR were: 48W-CDP-EDSS: DBP Week 48 0.41 (0.21–0.79) p=0.007, Week 96 (DBP end/OLE start) 0.45 (0.26–0.78) p=0.004, OLE Week 48 0.84 (0.43–1.64) p=0.610, OLE Week 288 0.92 (0.44–1.94) p=0.833.

Conclusions:

Repeated progression event analyses more comprehensively capture treatment effects after a first disability progression event. Analyses of annualized repeated CDP provide better insight into the longer trajectory of clinical disease progression, including response to treatment changes.