Over a prodromal period of many years before clinical diagnosis of Huntington’s disease, subtle neurodegenerative motor, and cognitive deficits accrue (HD). Incorporating prodromal patients into clinical trials would allow for early testing of medicines and the development of remedies to prevent or delay impairment. The normalized prognostic index (PIN) score is evaluated as a premanifest trial participant selection technique. For a study, researchers investigated the expected PIN-based inclusion rates in the pre HD screening population and calculate sample-size needs depending on the PIN threshold, trial duration, and outcome measure.
Individual ENROLL-HD participant data were used to build mixed effect linear models to analyze longitudinal changes in clinical metrics for participants with early-manifest HD and PIN-stratified pre HD subcohorts. In ENROLL-HD, 40% of pre-HD patients passed the PIN criterion of 0.0; 39.4% and 55.2% advanced to new diagnoses of early-manifest HD within 2 and 3 years, respectively. For a premanifest experiment, different PIN criteria allowed for selecting specific ratios of prodromal pre HD to early manifest HD patients. According to the nature of the screening pool, the length of follow-up (1, 2, or 3 years), and the outcome measure, estimated sample sizes for a trial enrolling prodromal pre HD (PIN>0.0) and stage 1 and 2 motor-diagnosed patients differed. Predetermined PIN criteria can be used to define the composition of a premanifest clinical trial cohort, making it easier to examine prospective disease-modifying medications in HD.