A randomized, controlled trial of ZYN002 cannabidiol transdermal gel in children and adolescents with fragile X syndrome (CONNECT-FX)
Year: 2022
Type: article
Study design: Clinical Trial
Abstract: BACKGROUND: Fragile X syndrome (FXS) is associated with dysregulated endocannabinoid signaling and may therefore respond to cannabidiol therapy. DESIGN: CONNECT-FX was a double-blind, randomized phase 3 trial assessing efficacy and safety of ZYN002, transdermal cannabidiol gel, for the treatment of behavioral symptoms in children and adolescents with FXS. METHODS: ) SA subscale in a full cohort of patients with a FXS full mutation, regardless of the FMR1 methylation status. Ad hoc analyses assessed efficacy in patients with ≥ 90% and 100% methylation of the promoter region of the FMR1 gene, in whom FMR1 gene silencing is most likely. RESULTS: A total of 212 patients, mean age 9.7 years, 75% males, were enrolled. A total of 169 (79.7%) patients presented with ≥ 90% methylation of the FMR1 promoter and full mutation of FMR1. Although statistical significance for the primary endpoint was not achieved in the full cohort, significant improvement was demonstrated in patients with ≥ 90% methylation of FMR1 (nominal P = 0.020). This group also achieved statistically significant improvements in Caregiver Global Impression-Change in SA and isolation, irritable and disruptive behaviors, and social interactions (nominal P-values: P = 0.038, P = 0.028, and P = 0.002). Similar results were seen in patients with 100% methylation of FMR1. ZYN002 was safe and well tolerated. All treatment-emergent adverse events (TEAEs) were mild or moderate. The most common treatment-related TEAE was application site pain (ZYN002: 6.4%; placebo: 1.0%). CONCLUSIONS: In CONNECT-FX, ZYN002 was well tolerated in patients with FXS and demonstrated evidence of efficacy with a favorable benefit risk relationship in patients with ≥ 90% methylation of the FMR1 gene, in whom gene silencing is most likely, and the impact of FXS is typically most severe. TRIAL REGISTRATION: The CONNECT-FX trial is registered on Clinicaltrials.gov (NCT03614663).
Institutions: Rush University Medical Center, University of California Davis Medical Center, University of California, Davis, Kennedy Krieger Institute, Johns Hopkins University, Johns Hopkins Medicine, Cincinnati Children's Hospital Medical Center, University of Cincinnati, The University of Queensland, Children's Health Queensland Hospital and Health Service, Children's Hospital Colorado, University of Colorado Anschutz, University of Colorado Denver, Monash University, LabCorp (United States), Zynerba Pharmaceuticals (United States)
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,690
Funders: Emory University, Cincinnati Children's Hospital Medical Center, Children's Hospital Colorado, University of Washington, Johns Hopkins University, Rush University, Zynerba Pharmaceuticals, School of Medicine, Emory University, University of California, Davis, University of Colorado School of Medicine, Anschutz Medical Campus
OpenAlex ID: W4310051511