Abstract
Objective:
Using global MSBase registry, this study establishes 6-month confirmed disability progression events as indicators of long-term disability worsening suitable for use in randomized clinical trials in multiple sclerosis (MS).
Background:
Randomized clinical trials evaluate short-term treatment effect on disability in the form of 3–6-month confirmed disability progression, but whether these translate into long-term disability outcomes is unknown.
Design/Methods:
A Cox proportional hazards model identified associations between patients’ demographic and clinical characteristics and the probability of recovery from disability progression events. The coefficients from this model were used to calculate a sustained progression score, which was evaluated in a validation cohort and applied to a trial cohort.
Results:
902 patients (development cohort), patient characteristics at the time of progression associated with lower probability of subsequent improvement were age (hazard ratio (HR)=0.98), primary progressive (HR=0.37) and progressive-relapsing (HR=0.36) MS, expanded disability status scale score >=6 (HR=0.71) and its change from baseline (HR=0.67), number of affected functional system scores (HR=0.92) and pyramidal (HR=0.79) functional system score (p<0.05). The strength of the association with pyramidal score decreased with time (HR=1.01). A relapse within previous month (HR=1.46) and worsening in sensory functional system score (HR=1.17) were associated with higher probability of improvement after progression. The sustained progression score (range 0.39–4.79) in the validation cohort with 1,271 progression events, estimated a 53% lower chance of improvement for each unit increase in the score (HR=0.47). The proportions of progression events sustained at 5 years stratified by the score were 1: 68%, 2: 79%, 3: 94%, 4: 100%. The progression scores were then applied to the CLARITY trial data.
Conclusions:
Estimate of the probability of disability progression events being sustained over the long term will enable future trials to establish the effect of therapy not only on the short-term but also on long-term disability accrual.