Clinical Study Of caNNabidiol in childrEn and adolesCenTs With Fragile X (CONNECT-FX) (CONNECT-FX)

A Randomized, Double-Blind, Placebo-Controlled Multiple-Center, Efficacy and Safety Study of ZYN002 Administered as a Transdermal Gel to Children and Adolescents With Fragile X Syndrome

This trial will evaluate the efficacy and safety of ZYN002, a clear cannabidiol gel that can be applied to the skin (called transdermal application) twice a day for the treatment of behavioral symptoms of Fragile X Syndrome (FXS). Eligible participants will then participate in up to a 14 week treatment period, where all participants will receive placebo or active study drug. Patients ages 3 to < 18 years, will be eligible to participate.

Study Overview

• Status: Completed
• Conditions: Fragile X Syndrome
• Intervention / Treatment: Drug: ZYN002 - Cannabidiol Transdermal Gel; Other: Placebo Transdermal Gel

Detailed Description

This is a randomized, double-blind, placebo-controlled, multiple-center study, to assess the efficacy and safety of ZYN002, a pharmaceutically manufactured cannabidiol, formulated as a transdermal gel, for the treatment of children and adolescent with FXS. Approximately 204 male and female patients, ages 3 to < 18 years, will undergo a screening process. Eligible participants will be randomized 1:1 to either trial drug or placebo and will undergo a 14-week treatment period. Randomization will be stratified by gender, weight category and geographic region. All participants may receive placebo during the trial. Participants who are taking anti-seizure drugs may undergo an additional 1-2 weeks of blinded treatment to taper off study drug treatment. The assignment will be done by a computer generated system and neither the trial doctor or the participant or their caregivers will know which treatment is being given to them. The dose of the treatment will depend on the weight of the participants. If the participants weigh less than or equal to 35 kg, they will receive 2 sachets of the gel twice a day (1 sachet approximately every 12 hours) and if they weigh more than 35 kg, they will receive 4 sachets of gel per day (2 sachets approximately every 12 hours). Parents/ caregivers will be instructed on proper application of the gel. The gel will be applied to clean, dry, intact skin of the upper arms/ shoulders.

Blood samples will be collected for safety analysis of ZYN002. An independent analytical laboratory will also perform CGG repeat and methylation status analyses. Additionally, the parents/caregivers will be asked to complete some questionnaires. There will be other questionnaires and scales that will be completed at the site by the trial doctor.

After the final dose, patients will be followed weekly for 4 weeks by telephone, prior to discharge from the study.

• Study Type: Interventional
• Enrollment (Actual): 212
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2145
      • Westmead Children's Hospital
  • Queensland
    • Brisbane, Queensland, Australia, 4101
      • Lady Cilento Children's Hospital - South Brisbane
  • Victoria
    • Melbourne, Victoria, Australia, 3161
      • Genetics Clinics Australia
• New Zealand
  • Wellington, New Zealand, 6021
    • Wellington Hospital
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85006
      • Southwest Autism Research and Resource Center
    • Phoenix, Arizona, United States, 85016
      • Phoenix Children's Hospital
  • California
    • Sacramento, California, United States, 95817
      • UC Davis Health System, MIND Institute
  • Colorado
    • Denver, Colorado, United States, 80045
      • Children's Hospital of Colorado
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University School of Medicine
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Kennedy Krieger Institute
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • New Jersey
    • Morristown, New Jersey, United States, 07960
      • Fragile X Center of Atlantic Health System
  • New York
    • New York, New York, United States, 10029
      • The Fragile X Spectrum Disorder Clinic at Icahn School of Medicine at Mount Sinai, Division of Medical Genetics
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27510
      • University of North Carolina
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Cleveland Medical Center
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74136
      • Central States Research
  • Pennsylvania
    • Media, Pennsylvania, United States, 19063
      • Suburban Research Associates
  • South Carolina
    • Greenville, South Carolina, United States, 29605
      • Greenwood Genetic Center
  • Washington
    • Seattle, Washington, United States, 98198
      • University of Washington Center for Human Development and Disability

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female children and adolescents aged 3 to less than 18 years, at the time of Screening.
• Diagnosis of FXS through molecular documentation of FMR1 full mutation.
• Judged to be in good health based on physical exam, 12-lead ECG and clinical laboratory test results.
• Patients must be assessed by the Investigator as being moderately to severely impacted due to FXS.
• Patients taking psychotropic medication(s) should be on a stable regimen of not more than two such medications for at least fours weeks preceding Screening and must maintain that regimen throughout the study.
• If patients are receiving non-pharmacological, behavioral and/or dietary interventions, they must be stable and have been doing so for three months prior to screening.
• Patients and parents/caregivers must be adequately informed of the nature and risks of the study and given written informed consent prior to Screening.
• In the Investigator's opinion, patients and parents/caregivers are reliable and willing and able to comply with all protocol requirements and procedures.

Exclusion Criteria:

• Females who are pregnant, nursing or planning a pregnancy.
• Alanine aminotransferase (ALT), aspartate aminotransferase (AST) or total bilirubin levels greater than or equal to 2 times the upper limit of normal or alkaline phosphatase levels greater than or equal to 3 times the upper limit of normal.
• Use of a strong inhibitor/inducer of CYP3A4 or sensitive substrate of CYP3A4.
• Use of minocycline for 30 days prior to screening or throughout the study.
• Use of any benzodiazepine at screening or throughout the study.
• Use of THC or CBD-containing product within three months of Screening Visit or during the study.
• Change in pharmacologic or non-pharmacologic intervention during the course of the study.
• Any skin disease or condition including eczema, psoriasis, melanoma, acne, contact dermatitis, scarring, imperfections, lesions, tattoos, or discoloration that may affect treatment application, application site assessments or absorption of the trial drug.
• Patient is using the following ASMs: clobazam, phenobarbital, ethosuximide, felbamate or vigabatrin.
• Patients has an advanced, severe or unstable disease that may interfere with the study outcome evaluations.
• Patient has acute or progressive neurological disease, psychosis, schizophrenia or any other psychiatric disorder or severe mental abnormalities (other than FXS) that are likely to require changes in drug therapy or interfere with the study objectives or ability to adhere to protocol requirements.
• Patient has suspected or confirmed cardiovascular disease, advanced arteriosclerosis, structural cardiac abnormality, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, cardiac conduction problems, exercise-related cardiac events including syncope and pre-syncope, risk factors for Torsades de pointes (e.g. heart failure, hypokalemia, family history of Long QT Syndrome) or other serious cardiac problems.
• History of treatment for, or evidence of drug abuse within the past year.
• Patient responds "yes" to Question 4 or 5 on the C-SSRS (Children) during Screening or at any time on study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ZYN002 - Cannabidiol transdermal gel; ZYN002 supplied as a transdermal gel. Patients weighing less than or equal to 35 kg will be randomized to receive either 125 mg cannabidiol Q12H or placebo. Patients weighing greater than 35 kg will be randomized to receive 250 mg cannabidiol Q12H or placebo.	Drug: ZYN002 - Cannabidiol Transdermal Gel; Pharmaceutically manufactured. Cannabidiol formulated as a clear gel (transdermal delivery)
Placebo Comparator: Placebo transdermal gel; Matching ZYN002 placebo supplied as a transdermal gel.	Other: Placebo Transdermal Gel; Placebo formulated as a clear gel (transdermal delivery); Other Names: Matching Placebo; Placebo Comparator

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Aberrant Behavior Checklist-Community Fragile X Factor Structure (ABC-C FXS) Social Avoidance Subscale - Full Analysis Set	The Aberrant Behavior Checklist-Community is a standard parent/caregiver reported behavioral outcome measure for use in developmental disability clinical trials. The range for score for the subscale is from 0 to 12, and a higher value indicates a worse outcome.	Change from Baseline to end of treatment (Week 12)
Aberrant Behavior Checklist-Community Fragile X Factor Structure (ABC-C FXS) Social Avoidance Subscale - Ad Hoc Analysis	The Aberrant Behavior Checklist-Community is a standard parent/caregiver reported behavioral outcome measure for use in developmental disability clinical trials. The range for score for the subscale is from 0 and 12, and the higher score means a worse outcome.	Change from baseline to end of treatment (Week 12)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Aberrant Behavior Checklist-Community Fragile X Factor Structure (ABC-C FXS) Irritability Subscale - Full Analysis Set	The Aberrant Behavior Checklist-Community is a standard parent/caregiver reported behavioral outcome measure for use in developmental disability clinical trials. The range for score for the subscale is between 0 and 54, and the higher score means a worse outcome.	Change from baseline to end of treatment (Week 12)
Aberrant Behavior Checklist-Community, Fragile X Factor Structure (ABC-C FXS) Socially Unresponsive/Lethargic Subscale - Full Analysis Set	The Aberrant Behavior Checklist-Community is a standard parent/caregiver reported behavioral outcome measure for use in developmental disability clinical trials. The range for score for the subscale is from 0 and 39, and a higher mean indicates a worse outcome.	Change from baseline to end of treatment (Week 12)
Number of Participants With Any Improvement - Clinical Global Impressions- Improvement (CGI-I) - Full Analysis Set	The Clinical Global Impressions- Improvement global improvement item is a 7-point Likert scale designed to measure behavioral symptomatic change at a specific time compared to baseline. CGI-I is a standard global measure of potential change with treatment in placebo-controlled pharmacotherapy trials in developmental disabilities. The score ranges form 1-very much improved to 7-very much worse. The percentage of patients with any improvement (minimally, much, very much improved) was assessed.	Change in CGI-I at end of treatment (Week 12)
Aberrant Behavior Checklist-Community Fragile X Factor Structure (ABC-C FXS) Irritability Subscale - Ad Hoc Analysis	The Aberrant Behavior Checklist-Community is a standard parent/caregiver reported behavioral outcome measure for use in developmental disability clinical trials. The range for score for the subscale is between 0 and 54, and the higher score means a worse outcome.	Change from baseline in ABC-C to end of treatment (Week 12)
Aberrant Behavior Checklist-Community Fragile X Factor Structure (ABC-C FXS) Socially Unresponsive/Lethargic Subscale - Ad Hoc Analysis	The Aberrant Behavior Checklist-Community is a standard parent/caregiver reported behavioral outcome measure for use in developmental disability clinical trials. The range for score for the subscale is from 0 to 39 , and the higher score means a worse outcome.	Change from baseline in ABC-C to end of treatment (Week 12)
Number of Participants With Any Improvement - Clinical Global Impressions- Improvement (CGI-I) - Ad Hoc Analysis	The Clinical Global Impressions- Improvement global improvement item is a 7-point Likert scale designed to measure behavioral symptomatic change at a specific time compared to baseline. CGI-I is a standard global measure of potential change with treatment in placebo-controlled pharmacotherapy trials in developmental disabilities. The score ranges form 1-very much improved to 7-very much worse. The percentage of patients with any improvement (minimally, much, very much improved) was assessed.	Change in CGI-I at end of treatment (Week 12)

Collaborators and Investigators

• Sponsor: Zynerba Pharmaceuticals, Inc.

Publications and helpful links

General Publications

• Heussler HS. Emerging Therapies and challenges for individuals with Angelman syndrome. Curr Opin Psychiatry. 2021 Mar 1;34(2):123-128. doi: 10.1097/YCO.0000000000000674. Erratum In: Curr Opin Psychiatry. 2021 Sep 1;34(5):514.

Study record dates

Study Major Dates

• Study Start (Actual): June 12, 2018
• Primary Completion (Actual): June 14, 2020
• Study Completion (Actual): June 14, 2020

Study Registration Dates

• First Submitted: July 10, 2018
• First Submitted That Met QC Criteria: August 2, 2018
• First Posted (Actual): August 3, 2018

Study Record Updates

• Last Update Posted (Actual): July 6, 2022
• Last Update Submitted That Met QC Criteria: June 15, 2022
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Disease; Congenital Abnormalities; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Mental Retardation, X-Linked; Intellectual Disability; Heredodegenerative Disorders, Nervous System; Chromosome Disorders; Sex Chromosome Disorders; Syndrome; Fragile X Syndrome; Anticonvulsants; Cannabidiol
• Other Study ID Numbers: ZYN2-CL-016

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No