Sample enrichment for clinical trials to show delay of onset in huntington disease

Abstract

Background: Disease-modifying clinical trials in persons without symptoms are often limited in methods to assess the impact associated with experimental therapeutics. This study suggests sample enrichment approaches to facilitate preventive trials to delay disease onset in individuals with the dominant gene for Huntington disease.

Methods: Using published onset prediction indexes, we conducted the receiver operating curve analysis for diagnosis within a 3-year clinical trial time frame. We determined optimal cut points on the indexes for participant recruitment and then conducted sample size and power calculations to detect varying effect sizes for treatment efficacy in reducing 3-year rates of disease onset (or diagnosis).

Results: Area under the curve for 3 onset prediction indexes all demonstrated excellent value in sample enrichment methodology, with the best-performing index being the multivariate risk score (MRS).

Conclusions: This study showed that conducting an intervention trial in premanifest and prodromal individuals with the gene expansion for Huntington disease is highly feasible using sample enrichment recruitment methods. Ongoing natural history studies are highly likely to indicate additional markers of disease prior to diagnosis. Statistical modeling of identified markers can facilitate participant enrichment to increase the likelihood of detecting a difference between treatment arms in a cost-effective and efficient manner. Such variations may expedite translation of emerging therapies to persons in an earlier phase of the disease.

Trial registration: PREDICT-HD is registered with www.clinicaltrials.gov, number NCT00051324. © 2019 International Parkinson and Movement Disorder Society.

Keywords: Clinical trials methodology/study design; genetics; huntington disease; movement disorders; prevention.

Figure 1.

Age of HD onset by CAG repeat length for 225 prospectively diagnosed individuals in the 12-year natural history study entitled PREDICT-HD.

Figure 2.

The ROC curve for the three-year HD diagnosis based on the prognostic marker MRS.

Figure 3.

Sample size required in each arm for a randomized treatment-control clinical trial equipped with two-sided test for proportions at significance level 0.05 and powered at 0.9.