The Roche HD natural history study – An external comparator by design

Abstract

The Roche Huntington’s disease (HD) Natural History Study (NHS) (NCT03664804) is a prospective, longitudinal cohort study designed to provide further clinical validation of mutant huntingtin protein (mHTT) as a prognostic biomarker of disease outcomes in early stages of manifest HD. The NHS will also be used as an external comparator group for the ongoing HD open-label extension (OLE) of the Phase I/IIa study (NCT03342053). The study designs are comparable in terms of clinical, digital clinical, fluid biomarker and imaging outcomes. Length of follow-up and assessment schedule for measures common to both studies are identical. Up to 100 Stage I or II HD individuals are being enrolled and matched on parameters of disease Stage (I or II), age (+/- 5 years), sex and CAG repeat length (+/- 2), and followed prospectively in the 15-month study, with key outcomes assessed at baseline, 3, 9 and 15 months. A matching algorithm has been developed using the Almac IxRS system to facilitate enrolment of "matched" patients by constantly updating the list of unmatched OLE patients. The comparability between the two cohorts, and baseline symptom severity on key outcomes of the Unified HD Rating Scale (UHDRS) and the composite UHDRS, will be presented. This study will provide important longitudinal data on the relationship between mHTT and measures of HD disease progression. A comparison of outcome data between the NHS and OLE studies will allow consideration of RG6042 effects versus natural disease progression.