Abstracts

Rationale: Establishing treatment benefit for non-seizure outcomes in rare epileptic diseases, such as Dravet syndrome (DS), is challenging due to a rarity of disease-specific clinical outcome assessments. The Vineland Adaptive Behavior-Scale Third Edition (Vineland-3) commonly assesses these outcomes in DS; however, meaningful change thresholds (MCTs) have not been established. This qualitative study aimed to bridge this gap.

Methods: Data were collected in two stages (Figure 1). Stage 1 included semi-structured interviews with 18 caregivers of children and adolescents with DS from the United States, who discussed their child’s DS experience and spontaneously reported signs/symptoms. Caregivers then completed eight Vineland-3 subdomains and reported which items they would consider meaningful to change, why and by how much, from a list of items reportedly sometimes or never performed by their child. Caregivers also ranked the subdomains in order of importance for improvement. Stage 2 included a two-hour meeting to discuss the caregiver results with seven clinical experts in DS.

Results: Stage 1: Caregivers spontaneously reported 35 DS signs/symptoms: seizures were the most frequently reported (n=16). Caregivers also reported disruptive behavior, developmental delay and impaired communication as some of the most important signs/symptoms to change with treatment, consistent with the DSF Voice of the Patient report. Across the Vineland-3 subdomains, raw score improvements of 1 to 3 points (equating to 2 to 3 growth scale values) were considered meaningful to at least 50% of caregivers. Meaningful changes were mostly associated with greater independence and safety. Of the eight Vineland-3 subdomains evaluated, expressive and receptive communication were ranked as most important to change.

Stage 2: Overall, clinical experts aligned with caregiver feedback and reported additional caregiver impacts including fear of Sudden Unexpected Death in Epilepsy, sleep disturbances, grief, inability to work, spousal conflict and feeding difficulties. Clinical experts supported caregiver-reported meaningful change, noting that this may be individual and dependent upon the age and severity of the child. Additional considerations included the child’s underlying intellectual and developmental ability, heterogeneity of DS, presence of Autism Spectrum Disorder, seizure frequency, and caregiver comprehension of the Vineland-3. Clinical experts generally agreed with caregivers’ rankings of subdomains while noting a potential shift in caregiver priorities as the child ages.


Conclusions: Overall, small changes were considered meaningful to caregivers and clinical experts on the Vineland-3 and were associated with important impacts for patients and families. This study provides novel insights to support the selection of MCTs for the Vineland-3 and provides support for its meaningfulness and validity to DS caregivers and its use to explore cognitive and behavioral treatment benefit in a clinical trial setting as a secondary outcome assessment. Follow-up psychometric evaluation of Vineland-3 MCTs may be considered.

Funding: AAdelphi Values were provided funding from Stoke Therapeutics for the conduct of this study.