Effect of CANnabidiol on Anxiety and GABAergic Function in Individuals With Fragile-X Syndrome

Fragile X Syndrome Clinical Trial

— CANAX  

Official title:

Effect of CANnabidiol on Anxiety and GABAergic Function in Individuals With Fragile-X Syndrome

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06261502
• Other study ID #: 2023-4527
• Secondary ID: 275882202010PJT-
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: July 1, 2024
• Est. completion date: August 1, 2027

Study information

• Verified date: June 2024
• Source: Université de Sherbrooke
• Contact: François Corbin, MD, Ph.D.
• Phone: 819-346-1110
• Email: Francois.Corbin[@]USherbrooke.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 40
• Est. completion date: August 1, 2027
• Est. primary completion date: May 1, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 7 Years to 40 Years

Eligibility

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.

Related Conditions & MeSH terms

• Fragile X Syndrome
• Syndrome

Intervention

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.
• 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.

Locations

Country	Name	City	State
n/a

Sponsors (4)

Lead Sponsor	Collaborator
Université de Sherbrooke	Canadian Institutes of Health Research (CIHR), Centre de recherche du Centre hospitalier universitaire de Sherbrooke, Jazz Pharmaceuticals

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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