Effect of CANnabidiol on Anxiety and GABAergic Function in Individuals with Fragile-X Syndrome (CANAX)

This study focuses on the therapeutic relevance of the endocannabinoid (eCB) system for the treatment of Fragile-X syndrome (FXS), the primary hereditary cause of autism spectrum disorder (ASD). Most individuals with FXS have moderate to severe intellectual disability (ID), and caregivers are mainly concerned about aggressive behavior and anxiety problems. Since FXS individuals have a normal lifespan, the overall lifetime cost for the Canadian society of a single case is estimated at $1.2 to $4.7 millions reaching $18 billions for all FXS cases. There is no cure for FXS, as all clinical trials so far have been unsuccessful.FXS is caused by transcriptional silencing of the Fragile X mental retardation protein (FMR1) gene, making FXS a simple model to study ASD and ID pathophysiological mechanisms. Of those, neuronal hyperexcitability is largely recognized as a core deficit in FXS, and a critical therapeutic target for the disorder. Using transcranial magnetic stimulation (TMS) in FXS patients, our team provided the first direct evidence of Gamma-aminobutyric acid (GABA) receptor a (GABAa) dysfunctions in humans with this disorder and showed that this inhibitory deficit is linked with cortical hyperexcitability (PMID: 31748507). Concurrent lines of evidence suggest that stimulation of the endocannabinoid (eCB) system with the administration of Cannabidiol (CBD) could upregulate GABAergic function and correct inhibitory deficits presumed responsible for the neuropsychiatric phenotype of FXS. CBD has been shown to increase GABA concentration levels in the brains of healthy individuals, an effect that could help correct the hyperexcitability typically found in FXS. Thus, this trial aims to define the therapeutic potential of the eCB system for FXS, by measuring the impacts of oral CBD administration on the principal inhibitory neurotransmitter system of FXS patients, and the severity of the clinical phenotype.

Study Overview

• Status: Not yet recruiting
• Conditions: Fragile X Syndrome
• Intervention / Treatment: Drug: CBD Oral Solution; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: François Corbin, MD, Ph.D.; Phone Number: 15801 819-346-1110; Email: Francois.Corbin@USherbrooke.ca
• Study Contact Backup: Name: Samantha Cote, Ph.D.; Phone Number: 70184 819-346-1110; Email: Samantha.cote@usherbrooke.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Molecular diagnosis of FXS
• Age 7 to 40 inclusively
• Overall ABC-C score > 20
• Taking up to 3 psychoactive drugs
• No therapeutic change for the last 3 months

Exclusion Criteria:

• Taking valproic acid
• Taking clobazam
• History of liver problems
• aspartate aminotransferase (AST) or alanine transaminase (ALT), > 3 times the reference values
• Bilirubin > 2 times the reference values
• Absolute contraindication to the use of TMS and MRI (e.g. presence of metal in the body), will also be considered as an exclusion criterion.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CBD First; Participants will start with CBD to stimulate the eCB for 12 weeks, undergo an 8-week washout period, and then receive a 12-week placebo.	Drug: CBD Oral Solution; Participants will start with oral CBD dose of 5 mg/kg/day for two weeks and then increase to 10 mg/kg/day.; Drug: Placebo; Participants will receive a dose of a placebo composed of the inactive ingredients of CBD of the same volume as the CBD Oral Solution.
Experimental: Placebo First; Participants will start with a placebo for 12 weeks, undergo an 8-week washout period, and then receive a 12-week CBD to stimulate the eCB system.	Drug: CBD Oral Solution; Participants will start with oral CBD dose of 5 mg/kg/day for two weeks and then increase to 10 mg/kg/day.; Drug: Placebo; Participants will receive a dose of a placebo composed of the inactive ingredients of CBD of the same volume as the CBD Oral Solution.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Impact of Oral CBD Solution anxiety.	Caregivers will complete The Anxiety, Depression, and Mood Scale (ADAMS). The ADAMS consists of 29 items on a 4-point scale from 0 (behavior have not occurred or is not a problem) to 3 (behavior occurs a lot, or is a severe problem). It evaluates emotional disturbances along five dimensions: mania/hyperactivity, depressed mood, social avoidance, general anxiety, and obsessive behavior.	At baseline, 12 weeks, 20 weeks, and 32 weeks
Impact of Oral CBD Solution on disruptive behavior	Caregivers will complete the Aberrant Behavior Checklist-Community Fragile-X (ABC-C FX). The ABC-C FX has 55 items and is subdivided into explores 6 subdomains: irritability, hyperactivity, lethargy/withdrawal, stereotypy, inappropriate speech, and social avoidance. Higher scores reflect higher aberrant behavior. ABC-C FX is considered the gold standard for assessing behavioral changes in clinical trials in FXS.	At baseline, 12 weeks, 20 weeks, and 32 weeks
Impact of Oral CBD Solution on Behavioral Inhibition	Participants will complete the NIH Toolbox Cognitive Battery Flanker Task, a behavioral inhibition task validated in FXS. Global scores range from 0 to 10 and are algorithmically defined using accuracy and reaction time. Higher scores reflect better performance.	At baseline, 12 weeks, 20 weeks, and 32 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Impact of Oral CBD Solution on intracortical inhibition	TMS-derived measure of Intracortical inhibition: The degree of decrease of peak-to-peak motor evoked potential (MEP) amplitude induced by the administration of a conditioning stimulus (set at 70% of resting motor threshold) 2-4 ms before the test stimulus (stimulation intensity required to produce an MEP of 1 millivolt (mV), approximately 120% of resting motor threshold)	At baseline, 12 weeks, 20 weeks, and 32 weeks
Impact of Oral CBD Solution on intracortical facilitation	Transcranial magnetic stimulation (TMS) -derived measure of Intracortical facilitation: The degree of increase of peak-to-peak motor evoked potential (MEP) amplitude induced by the administration of a conditioning stimulus (set at 80% of resting motor threshold) 12-24 ms before the test stimulus (stimulation intensity required to produce an MEP of 1 mV, approximately 120% of resting motor threshold).	At baseline, 12 weeks, 20 weeks, and 32 weeks
Impact of Oral CBD Solution on	Estimation of GABA concentrations in the brain from magnetic resonance spectroscopy	At baseline, 12 weeks, 20 weeks, and 32 weeks

Collaborators and Investigators

• Sponsor: Université de Sherbrooke
• Collaborators: Canadian Institutes of Health Research (CIHR); Centre de recherche du Centre hospitalier universitaire de Sherbrooke; Jazz Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2025
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: January 26, 2024
• First Submitted That Met QC Criteria: February 7, 2024
• First Posted (Actual): February 15, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 13, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: MRI; CBD; TMS; FXS; eCB
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Pathologic Processes; Genetic Diseases, Inborn; Disease; Neurobehavioral Manifestations; Congenital Abnormalities; Heredodegenerative Disorders, Nervous System; Mental Retardation, X-Linked; Intellectual Disability; Genetic Diseases, X-Linked; Sex Chromosome Disorders; Chromosome Disorders; Syndrome; Fragile X Syndrome
• Other Study ID Numbers: 2023-4527; 202010PJT-451514 (Other Grant/Funding Number: Canadian Institutes of Health Research); 275882 (Other Identifier: Health Canada)

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: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No