PRO1 Meaningful Change Thresholds for the Aberrant Behavior Checklist-Community Fragile X Syndrome (ABC-CFXS) in Children and Adolescents with FXS

Abstract

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-CFXS), 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-CFXS 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). Anchor-based methods supplemented with visual plots were used to estimate the RT for change from Baseline to Week 12 in the three ABC-CFXS 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-CFXS 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. 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-CFXS SA, Irritability, and SUL subscales, respectively. A similar pattern of mean change was observed for the CaGI-C DS and OB items. A change from Baseline to Week 12 of 3, 9, and 5 points on the ABC-CFXS SA, Irritability, and SUL subscales can be interpreted as a meaningful change indicative of treatment benefit for an individual patient with FXS.