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

NCT06261502 | Not Yet Recruiting Phase 2

• 3 other identifiers: 2023-4527275882202010PJT-451514
• Study Type: interventional
• Target: 40
• Locations: 0 countries
• Sites: N/A

Brief 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.

Conditions

Fragile X Syndrome

Keywords

FXS; CBD; TMS; MRI; eCB

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (3)

• Impact of Oral CBD Solution on intracortical inhibition

  At baseline, 12 weeks, 20 weeks, and 32 weeks

• Impact of Oral CBD Solution on intracortical facilitation

  At baseline, 12 weeks, 20 weeks, and 32 weeks

• Impact of Oral CBD Solution on

  At baseline, 12 weeks, 20 weeks, and 32 weeks

Study Arms (2)

CBD First

EXPERIMENTAL

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; Drug: Placebo

Placebo First

EXPERIMENTAL

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; Drug: Placebo

Interventions

CBD Oral Solution DRUG

Participants will start with oral CBD dose of 5 mg/kg/day for two weeks and then increase to 10 mg/kg/day.

CBD First; Placebo First

Placebo DRUG

Participants will receive a dose of a placebo composed of the inactive ingredients of CBD of the same volume as the CBD Oral Solution.

CBD First; Placebo First

Eligibility Criteria

• Age: 7 Years - 40 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

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

MeSH Terms

Conditions

Fragile X Syndrome

Condition Hierarchy (Ancestors)

X-Linked Intellectual Disability; Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Sex Chromosome Disorders; Chromosome Disorders; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Heredodegenerative Disorders, Nervous System

Central Study Contacts

François Corbin, MD, Ph.D.

CONTACT

819-346-1110; Francois.Corbin@USherbrooke.ca

Samantha Cote, Ph.D.

CONTACT

819-346-1110; Samantha.cote@usherbrooke.ca

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The randomization and participant code allocation process will be carried out by the Centre de recherche du Centre hospitalier universitaire de Sherbrooke (CRCHUS) pharmacy. The pharmacy will dispense the medication or placebo based on the randomization. The principal investigators, Drs. Lepage and Corbin and the research, as well as the participants and their caregivers, will never be aware of the randomization. To avoid any suspicions on the part of the investigators, Dr. Artuela Çaku, who is not part of the research team, will have access to the laboratory results. In the event of an adverse drug effect, Dr. Çaku may break the code to make a more informed decision for the patient's well-being, such as discontinuing participation or reducing the dose, etc.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Full professor, Department of biochemistry

Model Details: Randomized, Double-blind, placebo-controlled, single center, cross-over trial

Study Record Dates

• First Submitted: January 26, 2024
• First Posted: February 15, 2024
• Study Start: May 1, 2025
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2027
• Last Updated: February 17, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will not share