Contribution of Relapse-Independent Progression vs Relapse-Associated Worsening to Overall Confirmed Disability Accumulation in Typical Relapsing Multiple Sclerosis in a Pooled Analysis of 2 Randomized Clinical Trials

Abstract

Importance: Accumulation of disability in multiple sclerosis may occur as relapse-associated worsening (RAW) or steady progression independent of relapse activity (PIRA), with PIRA regarded as a feature of primary and secondary progressive multiple sclerosis.

Objective: To investigate the contributions of relapse-associated worsening vs relapse-independent progression to overall confirmed disability accumulation (CDA) and assess respective baseline prognostic factors and outcomes of 2 treatments.

Design, setting, and participants: Analyses occurred from July 2015 to February 2020 on pooled data from the intention-to-treat population of 2 identical, phase 3, multicenter, double-blind, double-dummy, parallel-group randomized clinical trials (OPERA I and II) conducted between August 2011 and April 2015. In the trials, patients with relapsing multiple sclerosis (RMS), diagnosed using the 2010 revised McDonald criteria, were randomized from 307 trial sites in 56 countries; resulting data were analyzed in the pooled data set.

Interventions: Participants were randomized 1:1 to receive 600 mg of ocrelizumab by intravenous infusion every 24 weeks or subcutaneous interferon β-1a 3 times a week at a dose of 44 μg throughout a 96-week treatment period.

Main outcomes and measures: Confirmed disability accumulation was defined by an increase in 1 or more of 3 measures (Expanded Disability Status Scale, timed 25-ft walk, or 9-hole peg test), confirmed after 3 or 6 months, and classified per temporal association with confirmed clinical relapses (PIRA or RAW).

Results: In the pooled OPERA I and II population (1656 of 2096 eligible participants), baseline demographics and disease characteristics were similar for patients randomized to interferon β-1a vs ocrelizumab (mean [SD] age, 37.2 [9.2] vs 37.1 [9.2] years; 552 [66.6%] vs 541 women [65.4%]). After 96 weeks, 12-week composite CDA had occurred in 223 (29.6% by Kaplan-Meier estimate) randomized to interferon β-1a and 167 (21.1%) randomized to ocrelizumab; 24-week composite CDA had occurred in 170 (22.7%) taking interferon β-1a and 129 (16.2%) taking ocrelizumab. The PIRA events were the main contributors to 12-week and 24-week composite CDA after 96 weeks in patients treated with interferon β-1a (174 of 223 [78.0%] and 137 of 170 [80.6%], respectively) and ocrelizumab (147 of 167 [88.0%] and 115 of 129 [89.1%], respectively); a minority had CDA explained by RAW events (69 of 390 [17.7%] and 52 of 299 [17.4%], respectively). Very few patients with composite CDA experienced both RAW and PIRA events (17 of 390 [4.4%] for 12-week and 15 of 299 [5.0%] for 24-week composite CDA). Ocrelizumab (vs interferon β-1a) was associated with reduced risk of composite CDA (hazard ratio [HR], 0.67) and confirmed PIRA (HR, 0.78) and RAW (HR, 0.47) events.

Conclusions and relevance: Most disability accumulation in RMS is not associated with overt relapses. This indicates an underlying progression in this typical RMS population and challenges the current clinical distinction of relapsing and progressive forms of multiple sclerosis. Ocrelizumab was superior to interferon β-1a in preventing both RAW and PIRA.

Trial registration: ClinicalTrials.gov Identifiers: OPERA I (NCT01247324) and OPERA II (NCT01412333).

Conflict of interest statement

Conflict of Interest Disclosures: Dr Kappos’ institution, the University Hospital Basel, has received research support and payments that were used exclusively for research support for Dr Kappos’ activities as principal investigator and a member or chair of planning and steering committees or advisory boards for trials sponsored by Actelion, Addex, Almirall, Bayer HealthCare Pharmaceuticals, CSL Behring, df-mp, Excemed, F. Hoffmann–La Roche Ltd, Genentech Inc, GeNeuro SA, Genzyme, Japan Tobacco, Merck, Minoryx, Mitsubishi Pharma, Novartis, Octapharma, Ono Pharmaceutical, Pfizer, Celgene/Receptos, Sanofi, Santhera, Siemens, Teva, UCB, and XenoPort; has received license fees for Neurostatus products; and has received research grants from the European Union, Novartis Research Foundation, Roche Research Foundation, Swiss Multiple Sclerosis Society, Innosuisse, and Swiss National Research Foundation. Dr Kappos also reported receiving fees for educational activities from Baxalta, Allergan, CSL Behring, and Desitin and royalties from Neurostatus UHB. Dr Wolinsky has served on advisory boards, data monitoring committees, or steering committees or has consulting agreements from AbbVie, Acorda Therapeutics, Actelion, Alkermes, Biogen, Bionest, Brainstorm Cell Therapeutics, Celgene, Clene Nanomedicine, EMD Serono, Forward Pharma A/S, GeNeuro, GW Pharma Ltd, MedDay Pharmaceuticals, NervGen Pharma Corp, Novartis Pharmaceuticals, Otsuka, PTC Therapeutics, Roche/Genentech, and Sanofi Genzyme; royalties are received for out-licensed monoclonal antibodies through University of Texas Health from Millipore Corporation; and Dr Wolinsky has a patent to licensing agreement with royalties paid and a patent (US010363245B2) issued. Dr Giovannoni has received honoraria from AbbVie, Atara Biotherapeutics, Bayer HealthCare, Biogen, Canbex Therapeutics, F. Hoffmann–La Roche Ltd, Five Prime Therapeutics, Genentech, Genzyme, GlaxoSmithKline, GW Pharmaceuticals, Merck, Merck Serono, Novartis, Protein Discovery Laboratories, Synthon, Teva, UCB, and Vertex; research grant support from Biogen, Ironwood, Merck Serono, Merz, and Novartis; compensation from Elsevier; and personal fees and grants from Roche. Dr Arnold has received personal fees for consulting from Acorda, Albert Charitable Trust, Biogen, Celgene, F. Hoffmann–La Roche Ltd, Frequency Therapeutics, GeNeuro, MedDay, MedImmune, Merck Serono, Mitsubishi, Novartis, Receptos, and Sanofi-Aventis; grants from Biogen and Novartis; an equity interest in NeuroRx Research; and personal fees from Wave Life Sciences. Dr Wang is an employee of F. Hoffmann–La Roche Ltd. Dr Bernasconi is a contractor for F. Hoffmann–La Roche Ltd. Dr Model is an employee and shareholder of F. Hoffmann–La Roche Ltd. Dr Koendgen is an employee and shareholder of F. Hoffmann–La Roche Ltd. Dr Manfrini is an employee of F. Hoffmann–La Roche Ltd. Dr Belachew was an employee of F. Hoffmann–La Roche Ltd. during the completion of the work associated with this article. Dr Hauser serves on the board of trustees for Neurona and scientific advisory boards for Alector, Annexon, Bionure, Molecular Stethoscope, and Symbiotix, and has received travel reimbursement and writing assistance from F. Hoffmann–La Roche Ltd for meetings and presentations on CD20. No other disclosures were reported.

Figures

Figure 1.. Schematic Representations of Composite Relapse-Associated Worsening (RAW) and Composite Progression Independent of Relapse Activity (PIRA) Definitions

A, Composite RAW and B, composite PIRA are the 2 nonmutually exclusive components (or drivers) of overall accumulation of disability, as measured by composite confirmed disability accumulation (CDA) in relapsing and progressive forms of MS. Study baseline is the reference point for disability changes measured over time; in the context of the studies, this is the time of randomization to study treatment, but in the context of the clinic, this would be the reference disability assessment visit from which subsequent changes are measured over time. The shaded areas represent the intervals around the neurological assessments that had to remain free of relapses to fulfill the criterion of independence from relapses (at initial event and confirmation points). Neurological assessments were scheduled to occur every 12 weeks, according to the protocol of the study; if a relapse occurred, there was 1 neurological assessment outside of the schedule, at a point corresponding to the leftmost point on the relapse triangle. EDSS indicates Expanded Disability Status Scale; IID indicates initial increase of disability; MS, multiple sclerosis.

Figure 2.. Relative Contributions of Composite Relapse-Associated Worsening (RAW) and Progression Independent of Relapse Activity (PIRA) vs Overall Composite Confirmed Disability Accumulation (CDA) in Treatment Groups

The graphs compare the 12-week confirmed (A and B) and 24-week confirmed (C and D) overall composite CDA. All percentages indicate Kaplan-Meier proportions of patients with confirmed disability accumulation at week 96 in the pooled OPERA I and OPERA II intention-to-treat population.

Figure 3.. Proportions of Patients With All Respective Combinations for 12-Week Composite Confirmed Disability Accumulation (CDA), Composite Relapse-Associated Worsening (RAW), and Composite Progression Independent of Relapse Activity (PIRA)

The graphs compare the pooled OPERA I and OPERA II population, analyzed by intention to treat. Surface-proportional Venn diagrams for patients receiving interferon β-1a (A) and ocrelizumab (B). For patients with protocol-defined relapses, composite CDA, composite RAW, and composite PIRA, all numbers embedded in these surface-proportional Venn diagrams represent the percentage of patients who experienced these specific types of events, alone or in combination. All values weremeasured by an increase in Expanded Disability Status Scale score (≥1.0 if the baseline score was ≤5.5, or ≥0.5 if the baseline score was >5.5) or an increase of 20% or more in the timed 25-ft walk or 20% or more in the 9-hole peg test. The segment indicating patients with relapses corresponds to the triangular shapes indicating relapse on each panel in Figure 1; the composite RAW and composite PIRA segments correspond to the shaded segments labeled RAW and PIRA in Figure 1A and B, respectively.