Time to Functional Loss as an Endpoint in Huntington's Disease Trials: Enrichment and Sample Size

Abstract

AbstractBackgroundClinical trial scenarios can be modeled using data from observational studies, providing critical information for design of real‐world trials. The Huntington's Disease Integrated Staging System (HD‐ISS) characterizes disease progression over an individual's lifespan and allows for flexibility in the design of trials with the goal of delaying progression. Enrichment methods can be applied to the HD‐ISS to identify subgroups requiring smaller estimated sample sizes.ObjectiveInvestigate time to the event of functional decline (HD‐ISS Stage 3) as an endpoint for trials in HD and present sample size estimates after enrichment.MethodsWe classified individuals from observational studies according to the HD‐ISS. We assessed the ability of the prognostic index normed (PIN) and its components to predict time to HD‐ISS Stage 3. For enrichment, we formed groups from deciles of the baseline PIN distribution for HD‐ISS Stage 2 participants. We selected enrichment subgroups closer to Stage 3 transition and estimated sample sizes, using delay in the transition time as the effect size.ResultsIn predicting time to HD‐ISS Stage 3, PIN outperforms its components. Survival curves for each PIN decile show that groups with PIN from 1.48 to 2.74 have median time to Stage 3 of approximately 2 years and these are combined to create enrichment subgroups. Sample size estimates are presented by enrichment subgroup.ConclusionsPIN is predictive of functional decline. A delay of 9 months or more in the transition to Stage 3 for an enriched sample yields feasible sample size estimates, demonstrating that this approach can aid in planning future trials. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.