Objective: To develop and evaluate a time-to-event endpoint to measure disease progression in individuals with premanifest HD.

Background: HD is typically diagnosed between the ages of 30 and 50 years [1]. Subtle changes in cognitive, motor and behavioural symptoms can appear years before diagnosis of motor onset, during “premanifest HD”. Predictive testing identifies patients who will eventually develop HD symptoms, and who may benefit from early treatment to delay or prevent disease onset, once disease-modifying therapies are available. As signs and symptoms of premanifest HD vary across individuals in presentation and progression, defining a clinical efficacy endpoint in a premanifest HD population is challenging. This study aimed to develop a time-to-event endpoint, potentially permitting adequately powered trials with smaller participant numbers yet encompassing decline across relevant symptom domains.

Method: Components defining the progression events were selected from the Unified HD Rating Scale and studied in premanifest participants matching the target study population (age 18-55, Diagnostic Confidence Level [DCL]<4, Total Functional Capacity [TFC]>11 and CAG age-product 300-450) in the Enroll-HD (n=1,074) and Registry (n=402) cohorts.
Motor (DLC and Total Motor Score [TMS]), overarching functional ability (TFC), and cognitive measures (Symbol Digit Modality Test and Stroop Word Reading Test) were assessed. Qualitative anchor-based approaches were used to define meaningful change thresholds (Clinical Global Impression of Severity and DCL) and a distribution-based approach (Standard Error of Measurement). Estimates of progression rate, accounting for the stability of changes over time, assessed feasibility of a clinical study.

Results: Favourable metric properties emerged from a time-to-event endpoint approach where the progression event was defined as either reaching a DCL score of 4 OR experiencing an increase in DCL of ≥2 points OR  in TMS of  ≥5-point OR a decrease of  ≥1-point in TFC. With an estimated progression-free rate of 66% at 3 years and a possible target hazard ratio of 0.6, 0.65 or 0.7, a placebo-controlled clinical study could be executed with approximately 434, 594 or 842 patients respectively, with a maximum study duration of 4 years.

Conclusion: Use of a time-to-event outcome is a powerful and feasible approach to study the effect of interventions in individuals with premanifest HD.

References: 1. Roos RA. Huntington’s disease: A clinical review. Orphanet J Rare Dis. 2010; 5:40.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/development-of-a-time-to-event-endpoint-for-use-in-premanifest-huntingtons-disease-hd-clinical-trials/