Abstracts

Individuals with severe neurodevelopmental conditions live with profoundly impacted functional impairments along with co-occurring medical conditions. This group includes many developmental and epileptic encephalopathy (DEE) conditions. Characteristics usually include seizures and severe to profound impairment in neurodevelopment. Skill acquisition is slow and takes small steps, called “inchstones”. Available clinical outcome assessments (COAs) do not capture growth and regression of skills within this band of abilities. Established in 2022, the Inchstone project ensures that important domains can be adequately measured for upcoming precision therapy trials. We present a summary of the key learnings from the first 3 years.

The Inchstone Project is a team-science initiative bringing together researchers, clinicians, industry, and patient advocates to develop/adapt measurements that accurately reflect the subtle yet meaningful progress of profoundly impaired individuals. The research team is supported by regular consultation with a Steering Committee, an Industry Advisory Committee and close relationships with many Patient Advocacy Groups. Validation studies have been conducted on measures of functional impairments, associated neurological conditions and quality of life, and to understand meaningful improvement and goal attainment scaling. Clinical assessment data (n=10) and community survey data (n=267) have informed validation of clinical outcome assessments. Community engagement and advocacy underpin all projects.

This work demonstrates a systematic approach to achieving fit-for-purpose measures for clinical trials, consistent with FDA guidance, and applied to a broad community of individuals where floor effects in standardised measures are common. Initially we conducted a clinical assessment study was conducted with 10 individuals with SCN2A-DEE at the FamilieSCN2A conference in 2022, providing preliminary validity for adapted measures of awareness, the feasibility of individual goal setting and insights into how parents perceive meaningful change for their child’s functional abilities. Second, a survey was administered to the DEE community yielding 267 responses across 25+ etiologies. Family priorities were described, data further informed the concept of meaningful change, and validation for the Developmental Profile – 4^th Edition was conducted. Data enabled development of a draft concept model for alertness and awareness, along with a caregiver reported cortical visual impairment measure. The most important predictor of quality of life was cognition, items for awareness and responsiveness distinguished between high and low quality of life scores.

Ongoing development and validation of COAs should be informed by family priorities and the components of meaningful change. There is evidence for a transdiagnostic approach when validating COAs for individuals with severe to profound functional impairments. Ongoing work will continue validation of COAs and collect longitudinal data to inform trajectories of COA scores and factors associated with change in COA scores.