Objective: The Roche Natural History (NH) study in Huntington’s disease (HD) (NCT03664804) is a prospective, longitudinal cohort study designed to provide further clinical validation of mutant huntingtin (mHTT) protein as a prognostic biomarker of disease outcome in early stages of manifest HD. The NH study will also be used as an external comparator group for the ongoing HD open-label extension study (OLE) (NCT03342053) to aid the interpretation of treatment effects of RG6042. Here, we describe the baseline demographic and clinical characteristics of both cohorts (NH and OLE), and test for comparability on key demographic and clinical features.

Background: To reduce the potential for confounding from baseline cohort differences on clinical outcomes observed when using an external comparator group, the NH study has been designed to match participants to OLE participants on key demographic and clinical variables. The study design is comparable in terms of clinical, digital clinical, fluid biomarker and imaging outcomes utilised. Length of follow-up and assessment schedule for measures common to both studies is identical.

Method: Up to n=100 individuals with stage I or II HD are being enrolled and matched on parameters of disease stage (I or II), age (+/- 5 years), sex (M/F) 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 was developed using the Almac IxRS system to facilitate enrolment of “matched” patients by constantly updating the list of unmatched OLE patients.

Results: The comparability of patients in the NH study to the OLE cohort at baseline on disease stage, sex, age and CAG repeat length at both a group and individual matching level will be presented. Baseline symptom severity on key outcomes of the UHDRS including the Total Functional Capacity Scale, Total Motor Score, Symbol Digit Modality Test and Stroop Word Test, and the composite UHDRS (cUHDRS) will also be presented.

Conclusion: The Roche HD NH study will provide important longitudinal data on the relationship between mHTT and specific measures of HD disease progression. By prospectively assembling an external control group through selective matching criteria in an NH study protocol, a comparison of outcome data between the NH and OLE studies will allow consideration of RG6042 effects versus natural disease progression.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-roche-hd-natural-history-study-an-external-comparator-by-design/