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

Area of Science:

• Neurology
• Clinical Trials
• Multiple Sclerosis Research

Background:

• Composite progression independent of relapse activity (cPIRA) is an emerging endpoint in multiple sclerosis (MS) research.
• Evaluating cPIRA's characteristics and utility is crucial for refining clinical trial designs in relapsing MS (RMS).

Purpose of the Study:

• To assess the characteristics and utility of cPIRA as a clinical trial endpoint in RMS.
• To investigate the impact of different cPIRA definitions and rebaselining strategies.
• To explore the relationship between cPIRA, biomarkers, and future clinical outcomes.

Main Methods:

• Analysis of data from the ENSEMBLE and pooled OPERA I/II studies in RMS patients.
• Evaluation of various cPIRA definitions and the effect of post-relapse rebaselining.
• Correlation of cPIRA events with MRI activity and serum neurofilament light (sNfL) levels.
• Assessment of cPIRA event sustainability and association with future disability progression (EDSS, SDMT, MSIS-29).

Main Results:

• Rebaselining was unnecessary for cPIRA in over 95% of ocrelizumab-treated patients due to low disease activity.
• cPIRA events were largely independent of MRI activity and associated with lower sNfL levels in ocrelizumab arms.
• Interferon β-1a treatment showed higher sustainability of cPIRA events compared to ocrelizumab.
• cPIRA was significantly associated with an increased risk of subsequent worsening on EDSS, SDMT, and MSIS-29 physical scale.

Conclusions:

• cPIRA demonstrates clinical relevance and utility as a sensitive endpoint in multiple sclerosis clinical trials.
• cPIRA can effectively capture disability progression independent of relapses, offering valuable insights into treatment effects.
• Further validation of cPIRA as a composite endpoint is warranted for its broader application in MS research.