Time-to-event analyses of motor examination and functional outcomes in early Parkinson’s disease clinical trials

Clinical trials in early untreated Parkinson’s Disease risk confounding due to treatment initiation. Milder clinical features, functional preservation, and slow progression raise questions as to how meaningful benefit can be demonstrated before treatment begins. Time-to-event (TTE) outcomes may be valuable to detect benefit before treatment. To explore the feasibility of detecting large, potentially more meaningful exam changes before treatment and how they correlate to functional outcomes, we analyzed four early interventional studies and one observational study over a 12-month period. Exam and functional worsening were assessed at varying thresholds using the Unified Parkinson’s Disease Rating Scale (UPDRS) or its Movement Disorders Society revision (MDS-UPDRS) Parts 2 and 3, respectively. At large thresholds, the percentage of persons achieving untreated worsening ranged from 32–42% on Part 2 ( ≥ 4 points) and 27–34% on Part 3 ( ≥ 7 points). As thresholds were relaxed on Part 2 and Part 3, the proportion of participants achieving worsening increased across all cohorts. Many participants at each Part III threshold experienced simultaneous Part 2 worsening, with higher Part 3 thresholds generally associated with greater functional worsening. These TTE analyses in early PD trials support the feasibility of 12-month studies powered for large worsening thresholds in exam scores.