The vanishing white matter registry: a case study of historical controls in clinical trial design

Background: Therapy development in ultra-rare, progressive and fatal diseases like vanishing white matter (VWM) is hampered by very low patient numbers and ethical constraints regarding placebo-controlled studies. Under such conditions, standard randomized controlled trials may not be feasible. The use of historical control information could be part of a solution, but would require extra considerations regarding selection of patients and choice of endpoints. We used the VWM registry as a case study to outline key methodological considerations for informing trial design in ultra-rare disease. Methods: The study included 462 patients, available in the VWM registry. Prospective clinical data were collected since 2004 using VWM-specific questionnaire and Health Utility Index (HUI) assessments, while retrospective data from clinical charts were available from 1988 on. We evaluated methodological aspects relevant to trial design, including patient selection, drift in the disease course over time, endpoint selection, and clinically relevant stratification into subgroups. Results: Regarding patient selection, patients with comorbidities impacting disease course, and pre-symptomatic individuals without clinical onset were considered not suitable as historical controls. After excluding patients before 1991, we found no evidence of drift in the disease course from 1991 onwards. Regarding choice of endpoints, episodes of rapid decline were relatively infrequent and occurred mostly at disease onset, limiting their usefulness as trial endpoint. Multi-state modelling and clinical evaluation showed ambulation as preferable endpoint over survival. For longitudinal HUI multiscores, baseline imputation allowed modelling of early disease. The scores showed a distinct ordering, reflecting the association between multi-domain function and disease progression. Regarding stratification, the combination of data-driven analyses and clinical expertise informed revised age of onset groups. Females showed later onset and milder disease; adjustment for age of onset eliminated the effect of sex. Conclusion: This case study provides key considerations for evaluating registry data as historical control and demonstrates how these considerations can inform clinical trial design in ultra-rare diseases.