Abstracts

This is a Late Breaking abstract

Rationale: SCN2A-associated developmental and epileptic encephalopathy (DEE) is a condition with highly variable phenotype and extremely low prevalence. Outcomes targeting patient-important, core, common features of SCN2A-DEE are needed for future precision medicine trials (e.g., gene-targeted) to ensure eligibility of a maximum number of patients (FDA guidances 2009, 2019, 2022).

Methods: The SCN2A Clinical Trials Readiness Study (CTRS) recruited 66 families of children with pathogenic/likely pathogenic SCN2A variants for longitudinal assessment with validated parent-reported instruments, including the Vineland-3, and other measures of key functional abilities. In July 2022, as part of the Inchstone pilot study,10 of the families also participated in a Goal Attainment Scaling (GAS) process in which parents identified 3 critically important goals of their choice for their child.

Results: SCN2A-affected children had a median age of 6.4 years (Interquartile Range, 4.0 to 10.5, max=29), and 36 (44%) were female. Although substantial impairments were evident in all functional domains, communication was severely to profoundly affected for almost all subjects. Vineland V-scores for expressive (mean=2.5, SD=3) and receptive (mean=2.0, SD=2.7) communication indicated function 4-5 standard deviations below the population mean (population mean=15, SD=3). The median scores for both were 1.0, the floor of the measures. A score of 1 was obtained by >75% on the expressive scale.
_x000D_ The primary form of communication was speech (11, 17%), sign language (2, 3%), gestures (12, 18%), sounds (22, 33%), communication devices (10, 15%), gaze/eye-pointing (6, 9%), and other (5, 8%, mostly involuntary behaviors). Based on the mCHAT, only 5 (8%) used pointing with one finger to indicate something of interest. Of 56 subjects ≥2 years-old assessed on the Communication Function Classification System, 4 (7%) were considered “effective” communicators, 5 (8%) communicated only with very familiar people, and 47 (84%) did not communicate effectively even with familiar people. In the GAS pilot study, 9/10 parents identified 10 expressive communication goals, including rudimentary use of communication devices (N=5), making yes/no choices through eye gaze (N=1) or by hand with a yes/no button (N=2), and effective use of one single word (N=2).

Conclusions: Expressive communication is severely to profoundly impaired in almost all people affected by SCN2A-DEE and was identified by 9/10 parents in the GAS pilot as a critically important goal for improvement. As such, per FDA guidances, expressive communication should be considered a construct of interest for a clinical trial outcome. Use of Clinical Outcome Assessments (COA) standardized to the general population (e.g., Vineland) are inappropriate for SCN2A-DEE because of the severe floor effects. Robust, valid COAs appropriate for measuring expressive communication in the extremely low range of functioning that is typical of this disorder will be required to facilitate robust clinical trials for SCN2A-DEE.

Funding: FamilieSCN2A Foundation, GAS pilot work funded by The Inchstone Project