The KCNT1-related epilepsy study: design and methods of a fully-decentralized prospective natural history study in a rare disease

ObjectiveKCNT1-related epilepsy is an ultra-rare pediatric onset epileptic encephalopathy with a broad clinical phenotype ranging from, most commonly, severe infantile-onset epilepsy and global developmental delay to, less commonly, milder phenotypes including nocturnal seizures, autism spectrum disorder, and learning disability. We initiated the first-ever prospective natural history study to comprehensively clinically phenotype individuals impacted by this disorder. MethodsThe primary study aim was to characterize seizures in individuals with KCNT1-related epilepsy. Secondary and exploratory aims included characterization of the full spectrum of disease symptoms, understanding caregiver burden, and collection of blood and urine samples for biomarker exploration. All study activities were conducted remotely (e.g., home-based assessments, telehealth visits). Results35 participants (n=20 males, 15 females) enrolled in this study. The average age at the baseline visit was 76.0 months old (s.d. = 75.5). This paper presents the study design and methods, presents several challenges that arose in its implementation, and discusses various solutions implemented in this medically complex population. SignificanceFuture work will apply the lessons from the current study in the planning and design of clinical trials for KCNT1-related epilepsy and possibly other developmental and epileptic encephalopathies. HighlightsO_LIKCNT1-related epilepsy is an ultra-rare pediatric onset epileptic encephalopathy with no disease-modifying therapy yet available. C_LIO_LIBecause of its rarity, little is known about the phenotypic range and natural history of symptoms in affected individuals. C_LIO_LITo inform clinical trial planning, we initiated the first ever prospective, longitudinal natural history study of KCNT1-related epilepsy. C_LIO_LIThe unique all-remote design of this study presented various challenges, opportunities, and learnings that will inform future studies. C_LI