{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T06:21:27Z","timestamp":1780467687189,"version":"3.54.1"},"reference-count":44,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T00:00:00Z","timestamp":1751932800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>The characteristics and utility of composite progression independent of relapse activity (cPIRA; worsening on the Expanded Disability Status Scale [EDSS], or 9\u2010Hole Peg Test, or Timed 25\u2010Foot Walk Test) were evaluated as an endpoint in relapsing multiple sclerosis (RMS) trials using the ENSEMBLE (NCT03085810) and pooled OPERA I\/II (NCT01247324\/NCT01412333) studies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We evaluated: (i) different definitions and the impact of rebaselining post\u2010relapse on cPIRA, (ii) cPIRA and biomarkers (MRI activity and serum neurofilament light [sNfL] levels), (iii) sustainability of cPIRA events, and (iv) cPIRA impact on future outcomes, in patients treated with ocrelizumab (600\u2009mg, OPERA I\/II [<jats:italic>n<\/jats:italic>\u2009=\u2009827] and ENSEMBLE [<jats:italic>n<\/jats:italic>\u2009=\u20091225]) or interferon \u03b2\u20101a (44\u2009\u03bcg, OPERA I\/II [<jats:italic>n<\/jats:italic>\u2009=\u2009829]).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Low disease activity (relapses\/new MRI lesions) rendered rebaselining unnecessary for cPIRA status in &gt;\u200995% of ocrelizumab\u2010treated participants, and variations of cPIRA definitions yielded similar event rates. In OPERA I\/II and ENSEMBLE ocrelizumab arms, cPIRA events were independent of MRI activity (86.5% and 95.5%, respectively), and occurred when sNfL was low (risk of cPIRA, hazard ratio [HR]: 0.67; <jats:italic>p<\/jats:italic>\u2009=\u20090.11 and 0.57; <jats:italic>p<\/jats:italic>\u2009=\u20090.003); more cPIRA events were sustained until study end with interferon \u03b2\u20101a (80.3% OPERA I\/II) vs. ocrelizumab (63.2% OPERA I\/II, 56.6% ENSEMBLE). Across studies and treatments, cPIRA was associated with an increased risk of subsequent worsening on the EDSS (HR, 1.62\u20131.74; <jats:italic>p<\/jats:italic>\u2009=\u20090.121\u20130.037), Symbol Digit Modalities Test (HR, 1.16\u20132.62; <jats:italic>p<\/jats:italic>\u2009=\u20090.54\u20130.009), and Multiple Sclerosis Impact Scale\u201029 physical scale (HR, 1.76; <jats:italic>p<\/jats:italic>\u2009=\u20090.064).<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>cPIRA is clinically relevant and demonstrates utility as a sensitive endpoint in MS clinical trials.<\/jats:p><\/jats:sec><jats:sec><jats:title>Trial Registration<\/jats:title><jats:p><jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/clinicaltrials.gov\">ClinicalTrials.gov<\/jats:ext-link> identifiers: OPERA I (NCT01247324; <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/clinicaltrials.gov\/study\/NCT01247324\">https:\/\/clinicaltrials.gov\/study\/NCT01247324<\/jats:ext-link>); OPERA II (NCT01412333; <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/clinicaltrials.gov\/study\/NCT01412333\">https:\/\/clinicaltrials.gov\/study\/NCT01412333<\/jats:ext-link>); ENSEMBLE (NCT03085810; <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/clinicaltrials.gov\/study\/NCT03085810\">https:\/\/clinicaltrials.gov\/study\/NCT03085810<\/jats:ext-link>)<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.70111","type":"journal-article","created":{"date-parts":[[2025,7,9]],"date-time":"2025-07-09T13:58:39Z","timestamp":1752069519000},"page":"1805-1812","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Performance of Composite Endpoints Defining Progression Independent of Relapse Activity in Multiple Sclerosis"],"prefix":"10.1002","volume":"12","author":[{"given":"Ludwig","family":"Kappos","sequence":"first","affiliation":[{"name":"Research Center for Clinical Neuroimmunology and Neuroscience (RC2NB) University Hospital Basel, University of Basel  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean","family":"Yiu","sequence":"additional","affiliation":[{"name":"Roche Products Ltd.  Welwyn Garden City UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Reucassel","sequence":"additional","affiliation":[{"name":"Roche Products Ltd.  Welwyn Garden City UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiwon","family":"Oh","sequence":"additional","affiliation":[{"name":"Division of Neurology, Department of Medicine, St. Michael's Hospital University of Toronto  Ontario Canada"},{"name":"Department of Neurology Johns Hopkins University  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Granziera","sequence":"additional","affiliation":[{"name":"Research Center for Clinical Neuroimmunology and Neuroscience (RC2NB) University Hospital Basel, University of Basel  Basel Switzerland"},{"name":"Translational Imaging in Neurology (ThINk) Basel Group, Department of Biomedical Engineering, Faculty of Medicine University Hospital Basel and University of Basel  Basel Switzerland"},{"name":"Department of Neurology University Hospital Basel  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joep","family":"Killestein","sequence":"additional","affiliation":[{"name":"Department of Neurology Amsterdam University Medical Centers, Vrije Universiteit Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Bermel","sequence":"additional","affiliation":[{"name":"Mellen Center for Multiple Sclerosis Treatment and Research Neurological Institute, Cleveland Clinic Foundation  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claude","family":"Berge","sequence":"additional","affiliation":[{"name":"F. 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