Time-to-event analysis mitigates the impact of symptomatic therapy on therapeutic benefit in Parkinson's disease trials

Abstract

The use of symptomatic medications represents a challenge for clinical trials of novel medicines designed to slow Parkinson's disease progression. A time-to-event (TTE) approach using a defined motor progression milestone may mitigate the confounding effect of symptomatic therapy on the Movement Disorders Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS). This analysis uses prasinezumab- and placebo-treated groups from the PASADENA study to evaluate the impact of symptomatic medications on treatment effects by comparing a TTE approach to a change-from-baseline approach with and without censoring the population upon starting symptomatic therapy. While the TTE approach yielded consistent hazard ratios between censored and non-censored analyses, the estimated difference between treatment arms using the change-from-baseline approach was lower without censoring than with censoring, suggesting a potential masking of prasinezumab treatment effects by symptomatic therapy. Thus, the TTE approach may mitigate the potential confounding effect of symptomatic therapy on MDS-UPDRS Part III.

Fig. 1. PASADENA Part 1 MDS-UPDRS Part III results.

a MMRM hypothetical strategy, b MMRM treatment policy strategy, c TTE ( + 5 points on MDS-UPDRS Part III) hypothetical strategy (Kaplan‒Meier curve), d TTE ( + 5 points on MDS-UPDRS Part III) treatment policy strategy (Kaplan‒Meier curve). CI confidence interval, MDS-UPDRS Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale, MMRM Mixed-effect Model for Repeated Measures, TTE time-to event.