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. 2025 Sep;12(9):1805-1812.
doi: 10.1002/acn3.70111. Epub 2025 Jul 8.

Performance of Composite Endpoints Defining Progression Independent of Relapse Activity in Multiple Sclerosis

Ludwig Kappos  1 , Sean Yiu  2 , Jason Reucassel  2 , Jiwon Oh  3   4 , Cristina Granziera  1   5   6 , Joep Killestein  7 , Robert A Bermel  8 , Claude Berge  9 , Agne Kazlauskaite  9 , Hans-Martin Schneble  9 , Frank Dahlke  10 , Bruce A C Cree  11
Affiliations

Performance of Composite Endpoints Defining Progression Independent of Relapse Activity in Multiple Sclerosis

Ludwig Kappos et al. Ann Clin Transl Neurol. 2025 Sep.

Abstract

Objective: The characteristics and utility of composite progression independent of relapse activity (cPIRA; worsening on the Expanded Disability Status Scale [EDSS], or 9-Hole Peg Test, or Timed 25-Foot 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.

Methods: We evaluated: (i) different definitions and the impact of rebaselining post-relapse 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 mg, OPERA I/II [n = 827] and ENSEMBLE [n = 1225]) or interferon β-1a (44 μg, OPERA I/II [n = 829]).

Results: Low disease activity (relapses/new MRI lesions) rendered rebaselining unnecessary for cPIRA status in > 95% of ocrelizumab-treated 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; p = 0.11 and 0.57; p = 0.003); more cPIRA events were sustained until study end with interferon β-1a (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, 1.62-1.74; p = 0.121-0.037), Symbol Digit Modalities Test (HR, 1.16-2.62; p = 0.54-0.009), and Multiple Sclerosis Impact Scale-29 physical scale (HR, 1.76; p = 0.064).

Interpretation: cPIRA is clinically relevant and demonstrates utility as a sensitive endpoint in MS clinical trials.

Trial registration: ClinicalTrials.gov identifiers: OPERA I (NCT01247324; https://clinicaltrials.gov/study/NCT01247324); OPERA II (NCT01412333; https://clinicaltrials.gov/study/NCT01412333); ENSEMBLE (NCT03085810; https://clinicaltrials.gov/study/NCT03085810).

Keywords: clinical trial; disability progression; multiple sclerosis; progression independent of relapse activity.

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Conflict of interest statement

Commercial firms whose product (ocrelizumab) was used in this study are F. Hoffmann‐La Roche Ltd. and Genentech Inc. The following authors disclosed financial relationships with these companies. L.K. research support for activities as principal investigator and member or chair of planning and steering committees or advisory boards for trials sponsored by F. Hoffmann‐La Roche Ltd. S.Y. and J.R. were employees of Roche Products Ltd., Welwyn Garden City, United Kingdom. J.O. research funding F. Hoffmann‐La Roche Ltd. C.G. reported The University Hospital Basel (USB), as the employer of C.G., has received the following fees which were used exclusively for research support: (1) advisory boards and consultancy fees from Hoffmann‐La Roche Ltd.; (2) speaker fees from F. Hoffmann‐La Roche Ltd.; and (3) research grants from F. Hoffmann‐La Roche Ltd. J.K. research funding F. Hoffmann‐La Roche Ltd. R.A.B. institutional research funding and consultation fees F. Hoffmann‐La Roche Ltd. and Genentech Inc. C.B., A.G., and H.‐M.S. were employees of and shareholders in F. Hoffmann‐La Roche Ltd. F.D. as an employee of impulze GmbH Zürich, Zürich, Switzerland, consulting fees from F. Hoffmann‐La Roche Ltd. B.A.C.C. research support from Genentech Inc.

Figures

FIGURE 1
FIGURE 1
Approach to Examine Subclinical MRI Activity Close to cPIRA Events. The approach to examining subclinical MRI activity close to cPIRA events consisted of defining a 60‐day window around cPIRA events and then applying approaches 1 and 2 in sequence to identify subclinical MRI activity within the 60‐day window. cPIRA, composite progression independent of relapse activity; MRI, magnetic resonance imaging.
FIGURE 2
FIGURE 2
Kaplan–Meier Estimates of the Proportions of cCDW/cCDP and cPIRA Events Using Four Different Definitions in OPERA I/II and ENSEMBLE. cCDP, composite confirmed disability progression; cCDW, composite confirmed disability worsening; cPIRA, composite progression independent of relapse activity; d, day; IFN, interferon β‐1a; PDR, protocol‐defined relapse. Kappos L, et al. JAMA Neurology 77 (2020): 1132–1140.
See this image and copyright information in PMC

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