Abstract Details

Title Repeated Confirmed Disability Progressions Analyses of the OPERA and ORATORIO Studies and Their Open-Label Extensions

Topic Multiple Sclerosis

Presentation(s) P7 - Poster Session 7 (8:00 AM-9:00 AM)

Poster/Presentation
Number 12-002

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.

Authors/Disclosures
Ludwig Kappos, MD, FAAN (RC2NB, University Hospital Basel) PRESENTER	Dr. Kappos has nothing to disclose.
Hans-Peter Hartung, MD, FAAN (Heinrich Heine University Medical Faculty)	Dr. Hartung has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BMS Celgene. Dr. Hartung has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Geneuro. Dr. Hartung has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Hartung has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Hartung has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck. Dr. Hartung has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Bayer. Dr. Hartung has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for TG Therapeutics. Dr. Hartung has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Hartung has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Frontiers Neurology.
Stephen L. Hauser, MD (UCSF Weill Institute for Neurosciences)	Dr. Hauser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for NGM Bio. Dr. Hauser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Moderna. Dr. Hauser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BD. Dr. Hauser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Pheno Therapeutics. Dr. Hauser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Nurix Therapeutics. Dr. Hauser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Gilead. Dr. Hauser has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Accure. Dr. Hauser has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alector. Dr. Hauser has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Hinge Therapeutics. Dr. Hauser has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Neurona. Dr. Hauser has a non-compensated relationship as a Clinical Trial/Primary Investigator with Roche that is relevant to AAN interests or activities. Dr. Hauser has a non-compensated relationship as a Clinical Trial/Primary Investigator with Novartis that is relevant to AAN interests or activities.
Robert T. Naismith, MD, FAAN (Washington University)	Dr. Naismith has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Naismith has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bristol Myers Squib. Dr. Naismith has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genentech. Dr. Naismith has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Genzyme. Dr. Naismith has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Lundbeck. Dr. Naismith has received personal compensation in the range of $500-$4,999 for serving as a Consultant for TG Therapeutics. Dr. Naismith has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Celltrion. Dr. Naismith has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion. Dr. Naismith has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for EMD Serono. Dr. Naismith has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sandoz. Dr. Naismith has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Astoria. Dr. Naismith has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Impaact-Bio. Dr. Naismith has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Kyverna. Dr. Naismith has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Horizon. Dr. Naismith has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for NEJM Journal Watch.
Hans-Martin Schneble, MD (Roche)	Dr. Schneble has received personal compensation for serving as an employee of F. Hoffmann-La Roche Ltd.. Dr. Schneble has received stock or an ownership interest from F. Hoffmann-La Roche, Ltd..
Ben Townsend (F. Hoffmann-La Roche AG)	No disclosure on file
Qing Wang	Qing Wang has nothing to disclose.
Jerry S. Wolinsky, MD, FAAN (McGovern Medical School, UTHealth)	Dr. Wolinsky has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Avotres. Dr. Wolinsky has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Brainstorm Cell Therapeutics. Dr. Wolinsky has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Cleveland Clinic Foundation. Dr. Wolinsky has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for EMD Serono. Dr. Wolinsky has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Inmagene. Dr. Wolinsky has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis/Sandoz. Dr. Wolinsky has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche/Genentech. Dr. Wolinsky has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi/Genzyme. Dr. Wolinsky has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for University of Alabama Birmingham. Dr. Wolinsky has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Dr. Wolinsky has received intellectual property interests from a discovery or technology relating to health care. Dr. Wolinsky has received intellectual property interests from a discovery or technology relating to health care.

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