A prospective natural history study protocol for clinical trial readiness in synaptic disorders.
TL;DR
A feasible natural history protocol with prospective data for two complex neurodevelopmental disorders with natural histories that have previously been incompletely characterized is presented, within a regulatory framework that will support the use of these data to expedite clinical trial development.
Abstract
Objective
STXBP1-related disorder (STXBP1-RD) and SYNGAP1-related disorder (SYNGAP1-RD) are two common genetic synaptopathies that are associated with epilepsy, developmental delay, intellectual developmental disorder, and behavioral problems. Both STXBP1-RD and SYNGAP1-RD are potential targets for disease-modifying therapies, but there is limited information in the literature describing the natural history of either disorder, which impedes outcome selection for future clinical trials. The objective of this study is to develop a framework to better define and outline the clinical spectrum and longitudinal trajectories of STXBP1-RD and SYNGAP1-RD natural history, including development, behavior, seizure histories, and electrophysiology.
Methods
Here, we describe a protocol, regulatory structure, and supportive preliminary data for multicenter, prospective natural history studies of STXBP1-RD (STARR) and SYNGAP1-RD (ProMMiS). The protocols incorporate gold standard clinician-administered outcome measures including the Bayley Scales of Infant and Toddler Development 4th edition, Gross Motor Function Measure-66, fine motor domains of the Peabody Developmental Motor Scales 3rd edition, parent-reported outcome measures, epilepsy histories, and biomarker exploration. To date, the study has enrolled 164 individuals with STXBP1-RD and 159 with SYNGAP1-RD, with ongoing longitudinal assessments every 6 months in a subset of approximately 200 total individuals across both disorders.
Results
Our data support that existing developmental measures are feasible, informative, and show minimal floor or ceiling effects. Furthermore, we demonstrate that medical record-based seizure history reconstruction reveals unique epilepsy trajectories while minimizing burden to families. We observe disease-specific patterns of developmental performance and distinct longitudinal seizure dynamics, highlighting the need for data generation in a gene/disorder-specific manner for clinical trial readiness.
Significance
In summary, we present a feasible natural history protocol with prospective data for two complex neurodevelopmental disorders with natural histories that have previously been incompletely characterized, within a regulatory framework that will support the use of these data to expedite clinical trial development.