A randomized, controlled trial of ZYN002 cannabidiol transdermal gel in children and adolescents with fragile X syndrome (CONNECT-FX)

Elizabeth Berry-Kravis; Randi Hagerman; Dejan Budimirovic; Craig Erickson; Helen Heussler; Nicole Tartaglia; Jonathan Cohen; Flora Tassone; Thomas Dobbins; Elizabeth Merikle; Terri Sebree; Nancy Tich; Joseph M. Palumbo; Stephen O’Quinn

doi:10.1186/s11689-022-09466-6

A randomized, controlled trial of ZYN002 cannabidiol transdermal gel in children and adolescents with fragile X syndrome (CONNECT-FX)

Elizabeth Berry-Kravis, Randi Hagerman, Dejan Budimirovic, Craig Erickson, Helen Heussler, Nicole Tartaglia, Jonathan Cohen, Flora Tassone, Thomas Dobbins, Elizabeth Merikle, Terri Sebree, Nancy Tich, Joseph M. Palumbo, Stephen O’Quinn

Kennedy Krieger Institute

Research output: Contribution to journal › Article › peer-review

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: Patients were randomized to 12 weeks of ZYN002 (250 mg or 500 mg daily [weight-based]) or placebo, as add-on to standard of care. The primary endpoint assessed change in social avoidance (SA) measured by the Aberrant Behavior Checklist–Community Edition FXS (ABC-C_FXS) 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).

Original language	English (US)
Article number	56
Journal	Journal of Neurodevelopmental Disorders
Volume	14
Issue number	1
DOIs	https://doi.org/10.1186/s11689-022-09466-6
State	Published - Dec 2022

Keywords

Cannabidiol
Clinical trial
Endocannabinoid system
Fragile X syndrome

ASJC Scopus subject areas

Clinical Neurology
Cognitive Neuroscience
Pediatrics, Perinatology, and Child Health
Pathology and Forensic Medicine

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10.1186/s11689-022-09466-6

Cite this

Berry-Kravis, E., Hagerman, R., Budimirovic, D., Erickson, C., Heussler, H., Tartaglia, N., Cohen, J., Tassone, F., Dobbins, T., Merikle, E., Sebree, T., Tich, N., Palumbo, J. M., & O’Quinn, S. (2022). A randomized, controlled trial of ZYN002 cannabidiol transdermal gel in children and adolescents with fragile X syndrome (CONNECT-FX). Journal of Neurodevelopmental Disorders, 14(1), Article 56. https://doi.org/10.1186/s11689-022-09466-6

Berry-Kravis, E, Hagerman, R, Budimirovic, D, Erickson, C, Heussler, H, Tartaglia, N, Cohen, J, Tassone, F, Dobbins, T, Merikle, E, Sebree, T, Tich, N, Palumbo, JM & O’Quinn, S 2022, 'A randomized, controlled trial of ZYN002 cannabidiol transdermal gel in children and adolescents with fragile X syndrome (CONNECT-FX)', Journal of Neurodevelopmental Disorders, vol. 14, no. 1, 56. https://doi.org/10.1186/s11689-022-09466-6

@article{e144249e03ba470d96a2bb77b4f042d3,

title = "A randomized, controlled trial of ZYN002 cannabidiol transdermal gel in children and adolescents with fragile X syndrome (CONNECT-FX)",

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: Patients were randomized to 12 weeks of ZYN002 (250 mg or 500 mg daily [weight-based]) or placebo, as add-on to standard of care. The primary endpoint assessed change in social avoidance (SA) measured by the Aberrant Behavior Checklist–Community Edition FXS (ABC-CFXS) 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).",

keywords = "Cannabidiol, Clinical trial, Endocannabinoid system, Fragile X syndrome",

author = "Elizabeth Berry-Kravis and Randi Hagerman and Dejan Budimirovic and Craig Erickson and Helen Heussler and Nicole Tartaglia and Jonathan Cohen and Flora Tassone and Thomas Dobbins and Elizabeth Merikle and Terri Sebree and Nancy Tich and Palumbo, {Joseph M.} and Stephen O{\textquoteright}Quinn",

note = "Funding Information: The CONNECT-FX trial was funded by Zynerba Pharmaceuticals Inc. Devon, PA, USA. We would like to thank p -value communications for providing support for technical writing, editing, and publication assistance; this support was funded by Zynerba Pharmaceuticals Inc. Devon, PA, USA. EB-K, RA, CE, and NTartaglia are members of the Scientific Advisory Board for Zynerba Pharmaceuticals Inc. We thank the clinical site principal investigators who participated in the CONNECT-FX trial: Darius Adams, Jacobs Levy Personalized Genomic Medicine and Research Program, Morristown, NJ, USA; Elizabeth Berry-Kravis, Rush University Medical Center, Department of Pediatrics, Neurological Sciences and Biochemistry, Chicago, IL, USA; Caroline Buchanan, Greenwood Genetic Center, Greenville Clinic, Greenville, SC, USA; Dejan Budimirovic, Department of Psychiatry & Behavioral Sciences-Child Psychiatry, Fragile X Clinic and Clinical Trials Unit, Kennedy Krieger Institute/the Johns Hopkins Medical Institutions, Baltimore, MD, USA; Diana Cejas, University of North Carolina & Translational Research Center, Chapel Hill, NC, USA; Jonathan Cohen, Genetic Clinics Australia, Melbourne, Victoria, Australia; Craig Erickson, Cincinnati Children's Hospital Medical Center, Department of Psychiatry, Cincinnati, OH, USA; Richard Frye, Phoenix Children's Hospital, Phoenix, AZ, USA; Randi Hagerman, UC Davis Health System, MIND Institute, Department of Pediatrics, Sacramento, CA, USA; Shivkumar Hatti, Suburban Research Associates, Media, PA, USA; Helen Heussler, Queensland Childrens{\textquoteright} Hospital, South Brisbane, Queensland, Australia; Soo-Jeong Kim, Bernier Lab, University of Washington, Seattle, WA, USA; Sarah Land, Central States Research, Tulsa, OK, USA; Reymundo Lozano, Seaver Autism Center for Research and Treatment, Departments of Genetics and Genomic Sciences, Psychiatry and Pediatrics at Icahn School of Medicine at Mount Sinai, New York, NY, USA; Andrew Marshall, Wellington Hospital, Wellington, New Zealand; Nora McNamara, University Hospitals Cleveland Medical Center, Cleveland, OH, USA; Raun Melmed, Southwest Autism Research and Resource Center, Department of Research, Phoenix, AZ, USA; Lisa Prock, Boston Children's Hospital, Boston, MA, USA; Natalie Silove, Westmead Children{\textquoteright}s Hospital, Sydney, New South Wales, Australia; Amy Talboy, Emory University School of Medicine, Atlanta, GA, USA; Nicole Tartaglia, Children's Clinical Research Organization, Research Institute, Children{\textquoteright}s Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA. Funding Information: EB-K, RH, CE, and NTartaglia have received funding from Zynerba Pharmaceuticals for the conduct of the study as investigators and are on scientific advisory board for fragile X syndrome for Zynerba Pharmaceuticals. DB, HH, JC, and FT have received funding from Zynerba Pharmaceuticals for the conduct of the study as investigators. TD and EM are paid consultants for Zynerba Pharmaceuticals. TS, NTich, and SO{\textquoteright}Q are employees of Zynerba Pharmaceuticals. JMP was an employee of Zynerba Pharmaceuticals at the time of the study. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1186/s11689-022-09466-6",

language = "English (US)",

volume = "14",

journal = "Journal of Neurodevelopmental Disorders",

issn = "1866-1947",

publisher = "Springer New York",

number = "1",

}

TY - JOUR

T1 - A randomized, controlled trial of ZYN002 cannabidiol transdermal gel in children and adolescents with fragile X syndrome (CONNECT-FX)

AU - Berry-Kravis, Elizabeth

AU - Hagerman, Randi

AU - Budimirovic, Dejan

AU - Erickson, Craig

AU - Heussler, Helen

AU - Tartaglia, Nicole

AU - Cohen, Jonathan

AU - Tassone, Flora

AU - Dobbins, Thomas

AU - Merikle, Elizabeth

AU - Sebree, Terri

AU - Tich, Nancy

AU - Palumbo, Joseph M.

AU - O’Quinn, Stephen

N1 - Funding Information: The CONNECT-FX trial was funded by Zynerba Pharmaceuticals Inc. Devon, PA, USA. We would like to thank p -value communications for providing support for technical writing, editing, and publication assistance; this support was funded by Zynerba Pharmaceuticals Inc. Devon, PA, USA. EB-K, RA, CE, and NTartaglia are members of the Scientific Advisory Board for Zynerba Pharmaceuticals Inc. We thank the clinical site principal investigators who participated in the CONNECT-FX trial: Darius Adams, Jacobs Levy Personalized Genomic Medicine and Research Program, Morristown, NJ, USA; Elizabeth Berry-Kravis, Rush University Medical Center, Department of Pediatrics, Neurological Sciences and Biochemistry, Chicago, IL, USA; Caroline Buchanan, Greenwood Genetic Center, Greenville Clinic, Greenville, SC, USA; Dejan Budimirovic, Department of Psychiatry & Behavioral Sciences-Child Psychiatry, Fragile X Clinic and Clinical Trials Unit, Kennedy Krieger Institute/the Johns Hopkins Medical Institutions, Baltimore, MD, USA; Diana Cejas, University of North Carolina & Translational Research Center, Chapel Hill, NC, USA; Jonathan Cohen, Genetic Clinics Australia, Melbourne, Victoria, Australia; Craig Erickson, Cincinnati Children's Hospital Medical Center, Department of Psychiatry, Cincinnati, OH, USA; Richard Frye, Phoenix Children's Hospital, Phoenix, AZ, USA; Randi Hagerman, UC Davis Health System, MIND Institute, Department of Pediatrics, Sacramento, CA, USA; Shivkumar Hatti, Suburban Research Associates, Media, PA, USA; Helen Heussler, Queensland Childrens’ Hospital, South Brisbane, Queensland, Australia; Soo-Jeong Kim, Bernier Lab, University of Washington, Seattle, WA, USA; Sarah Land, Central States Research, Tulsa, OK, USA; Reymundo Lozano, Seaver Autism Center for Research and Treatment, Departments of Genetics and Genomic Sciences, Psychiatry and Pediatrics at Icahn School of Medicine at Mount Sinai, New York, NY, USA; Andrew Marshall, Wellington Hospital, Wellington, New Zealand; Nora McNamara, University Hospitals Cleveland Medical Center, Cleveland, OH, USA; Raun Melmed, Southwest Autism Research and Resource Center, Department of Research, Phoenix, AZ, USA; Lisa Prock, Boston Children's Hospital, Boston, MA, USA; Natalie Silove, Westmead Children’s Hospital, Sydney, New South Wales, Australia; Amy Talboy, Emory University School of Medicine, Atlanta, GA, USA; Nicole Tartaglia, Children's Clinical Research Organization, Research Institute, Children’s Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA. Funding Information: EB-K, RH, CE, and NTartaglia have received funding from Zynerba Pharmaceuticals for the conduct of the study as investigators and are on scientific advisory board for fragile X syndrome for Zynerba Pharmaceuticals. DB, HH, JC, and FT have received funding from Zynerba Pharmaceuticals for the conduct of the study as investigators. TD and EM are paid consultants for Zynerba Pharmaceuticals. TS, NTich, and SO’Q are employees of Zynerba Pharmaceuticals. JMP was an employee of Zynerba Pharmaceuticals at the time of the study. Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - 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: Patients were randomized to 12 weeks of ZYN002 (250 mg or 500 mg daily [weight-based]) or placebo, as add-on to standard of care. The primary endpoint assessed change in social avoidance (SA) measured by the Aberrant Behavior Checklist–Community Edition FXS (ABC-CFXS) 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).

AB - 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: Patients were randomized to 12 weeks of ZYN002 (250 mg or 500 mg daily [weight-based]) or placebo, as add-on to standard of care. The primary endpoint assessed change in social avoidance (SA) measured by the Aberrant Behavior Checklist–Community Edition FXS (ABC-CFXS) 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).

KW - Cannabidiol

KW - Clinical trial

KW - Endocannabinoid system

KW - Fragile X syndrome

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A randomized, controlled trial of ZYN002 cannabidiol transdermal gel in children and adolescents with fragile X syndrome (CONNECT-FX)

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Keywords

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