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. 2024 Oct;39(10):1809-1816.
doi: 10.1002/mds.29963. Epub 2024 Aug 5.

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

James A Mills  1 , Jeffrey D Long  1   2 , Jatin G Vaidya  1 , Emily C Gantman  3 , Swati Sathe  3 , Sarah J Tabrizi  4 , Cristina Sampaio  3
Affiliations

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

James A Mills et al. Mov Disord. 2024 Oct.

Abstract

Background: Clinical 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.

Objective: Investigate 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.

Methods: We 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.

Results: In 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.

Conclusions: PIN 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.

Keywords: Huntington's disease; clinical trials; enrichment; sample size.

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