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

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).