Recurrent disability progression endpoints in multiple sclerosis clinical trials

Area of Science:

• Clinical Trials Methodology
• Biostatistics
• Neurology

Background:

• Current multiple sclerosis (MS) trials use time-to-first disability progression, ignoring subsequent events.
• This standard endpoint may limit comprehensive assessment of treatment effects on disability accumulation.

Purpose of the Study:

• To define recurrent disability progression events in MS.
• To compare the efficacy of time-to-first event analysis versus recurrent event analysis.

Main Methods:

• Defined recurrent disability progression events by extending the first event definition.
• Compared marginal recurrent event models (negative binomial, Lin-Wei-Yang-Ying) with Cox regression.
• Utilized data from relapsing MS (RMS) and primary progressive MS (PPMS) randomized controlled trials and simulated data.

Main Results:

• Recurrent event analyses captured more progression events (+7.5-9.9% in RMS, +22.7% in PPMS) than time-to-first analyses.
• This increased event count led to more precise treatment effect estimates.
• Statistical power was enhanced by incorporating recurrent events.

Conclusions:

• Recurrent event data analysis is recommended for progressive MS trials.
• This approach improves treatment effect estimation and statistical power.
• It provides a better understanding of long-term disability progression in MS.