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

Area of Science:

• Neurology
• Clinical Trials
• Biostatistics

Background:

• Clinical trial design can be informed by observational data, with the Huntington's Disease Integrated Staging System (HD-ISS) modeling disease progression.
• Enrichment strategies applied to HD-ISS can identify patient subgroups needing smaller sample sizes for trials aimed at delaying disease progression.

Purpose of the Study:

• To evaluate time to functional decline (HD-ISS Stage 3) as a clinical endpoint in Huntington's disease (HD) trials.
• To present sample size estimates for HD trials utilizing enrichment methods based on the prognostic index normed (PIN).

Main Methods:

• Individuals from observational studies were classified using the HD-ISS.
• The prognostic index normed (PIN) and its components were assessed for their ability to predict time to HD-ISS Stage 3.
• Enrichment subgroups were created from deciles of baseline PIN for HD-ISS Stage 2 participants, focusing on those nearer to Stage 3 transition.

Main Results:

• The PIN demonstrated superior predictive ability for time to HD-ISS Stage 3 compared to its individual components.
• Survival analysis revealed that PIN deciles from 1.48 to 2.74 corresponded to a median time of approximately 2 years to Stage 3.
• Sample size estimates were calculated for these selected enrichment subgroups.

Conclusions:

• The prognostic index normed (PIN) is a reliable predictor of functional decline in Huntington's disease.
• Achieving a 9-month or greater delay in transition to Stage 3 within an enriched sample provides feasible sample size estimates.
• This enrichment approach using PIN can significantly aid in the planning and efficiency of future Huntington's disease clinical trials.