Objective: To replicate a composite milestone(CM) approach in a range of Parkinson Disease(PD) studies(observational, clinical trials) over a long time period(up to 12 years). To assess its performance in different subgroups, aiming to identify fast-progressing populations which could be used to enrich future clinical trial arms.

Background: Traditional outcome measures(OMs) in PD are suboptimal for the detection of disease modification in clinical trials, especially in L-dopa-treated cohorts.To address this, a CM of PD progression was proposed, including 5-year clinical data on various domains(Walking/balance, Motor complications, Cognition, Autonomic dysfunction, Functional dependence, Activities of daily living) derived from clinical scales.Data on CM performance in different populations and over longer time periods are lacking.

Method: The CM approach was replicated in the original cohort (Parkinson’s Progression Markers Initiative(PPMI)) up to 12 years, then applied to a pooled cohort of observational and interventional studies, extracted from the Critical Path for Parkinson’s (CPP) consortium integrated dataset. Time-to-event(i.e. first CM occurrence) analyses – whole cohort and subgroups(log-rank test) – were performed. Sample size was calculated (log-rank test,power = 80%,⍺ = 0.05)for a two-trial arm based on the CPP dataset(whole cohort and specific subgroups).

Results: The median CM-free time was 6 years in the whole PPMI cohort(n = 372), 5 years in the baseline Hoehn & Yahr(H&Y)≥2 subgroup(n = 207).In the CPP cohort(n = 3491), median CM-free time was 4.5 years.Age > 65(p < 0.001), longer PD duration(p < 0.001), H&Y ≥ 2(p < 0.001), postural instability-gait disorder phenotype(p < 0.001), type 2 diabetes mellitus(p = 0.01) and REM sleep behaviour disorder(p = 0.04) subgroups had shorter times to CM.For a 3-year trial with a hazard ratio of 0.70, a total sample of 1328(whole cohort), 1166(baseline H&Y  ≥ 2) or 1122(baseline age > 65 years) would be required.

Conclusion: A CM approach represents a promising endpoint for disease-modifying PD trials.This work provides novel evidence that CM behaviour aligns with the existing knowledge on factors influencing PD natural history,and supplies sample size estimates for future trials.Enrichment of trial populations can achieve higher efficiency through smaller sample sizes.Work on refinement of CM items and its stability and patient relevance is underway.

References: 1. Brumm MC, Siderowf A, Simuni T, Burghardt E, Choi SH, Caspell-Garcia C, et al. Parkinson’s Progression Markers Initiative. Parkinson’s Progression Markers Initiative: A Milestone-Based Strategy to Monitor Parkinson’s Disease Progression. J Parkinsons Dis. 2023;13(6):899-916. doi: 10.3233/JPD-223433.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/exploring-a-milestone-based-approach-as-an-outcome-measure-for-disease-modifying-parkinson-disease-trials/