OBJECTIVES: The ABC-C is an observer-reported outcome measure that has been validated in individuals with intellectual disabilities and autism spectrum disorders. An FXS-specific domain structure of the ABC-C (henceforth the ABC-C_FXS), which is more representative of the FXS phenotype, has been established. To aid score interpretation, a responder threshold (RT) representing individual patient-level change indicative of treatment benefit was established for three ABC-C_FXS subscales (Social Avoidance [SA], Irritability, and Socially Unresponsive/Lethargic [SUL]) measuring the primary and key secondary endpoints in ZYN2-CL-016 (CONNECT-FX), a Phase 3 study of ZYN002 (transdermal cannabidiol) in FXS (NCT03614663).

METHODS: Anchor-based methods supplemented with visual plots were used to estimate the RT for change from Baseline to Week 12 in the three ABC-C_FXS subscales. Anchors included domain-specific (DS) Caregiver Global Impression of Severity and Change (CaGI-S/C) items for DS behavioral problems as well as CaGI-S/C items for overall behavior (OB). Higher scores on the ABC-C_FXS indicate more severe behavior problems. Identification of the amount of change on the CaGI-S/C representing meaningful change was informed by qualitative interviews with 25 caregivers of children with FXS.

RESULTS: Caregivers of children with FXS reported that even small improvements in their child’s behavior would be meaningful. In the analyses (n=193), patients with a 1-category improvement on the CaGI-S DS and OB items had a mean (SD) change of -3.0 (2.96) and -3.6 (2.64), -9.8 (9.65) and -8.9 (9.43), and -5.4 (6.46) and -6.8 (6.92) points on the ABC-C_FXS SA, Irritability, and SUL subscales, respectively. A similar pattern of mean change was observed for the CaGI-C DS and OB items.

CONCLUSIONS: A change from Baseline to Week 12 of 3, 9, and 5 points on the ABC-C_FXS SA, Irritability, and SUL subscales can be interpreted as a meaningful change indicative of treatment benefit for an individual patient with FXS.