Clinical Outcomes and Selection Criteria for Prodromal Huntington's Disease Trials.

ABSTRACT:

Background

Huntington's disease (HD) develops in individuals with extended cytosine-adenine-guanine (CAG) repeats within the huntingtin (HTT) gene, causing neurodegeneration and progressive motor and cognitive symptoms. The inclusion of mutant HTT carriers in whom overt symptoms are not yet fully manifest in therapeutic trials would enable the development of treatments that delay or halt the accumulation of significant disability.

Objectives

The present analyses assess whether screening prediagnosis (preHD) individuals based on a normalized prognostic index (PIN) score would enable the selection of prodromal preHD subjects in whom longitudinal changes in established outcome measures might provide robust signals. It also compares the relative statistical effect size of longitudinal change for these measures.

Methods

Individual participant data from 2 studies were used to develop mixed effect linear models to assess longitudinal changes in clinical metrics for participants with preHD and PIN-stratified subcohorts. Relative effect sizes were calculated in 5 preHD studies and internally normalized to evaluate the strength and consistency of each metric across cohorts.

Results

Longitudinal modeling data demonstrate the amplification of effect sizes when preHD subcohorts were selected by PIN score thresholds of >0.0 and?>0.4. These models and relative effect sizes across 5 studies consistently indicate that the Unified Huntington's Disease Rating Scale total motor score exhibits the greatest change in preHD.

Conclusions

These analyses suggest that the employment of PIN scores to homogenize and stratify preHD cohorts could improve the efficiency of current outcome measures, the most robust of which is the total motor score. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

SUBMITTER: Langbehn DR 

PROVIDER: S-EPMC7818458 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature