Clinical trial NCT06261502: Effect of CANnabidiol on Anxiety and GABAergic Function in Individuals with Fragile-X Syndrome
Official title: Effect of CANnabidiol on Anxiety and GABAergic Function in Individuals with Fragile-X Syndrome
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Fragile X Syndrome
Keywords: FXS
CBD
TMS
MRI
eCB
Lead sponsor: Université de Sherbrooke
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
name: Jazz Pharmaceuticals
name: Centre de recherche du Centre hospitalier universitaire de Sherbrooke
First posted: 2024-02-15
Enrollment: 40
Sex: ALL
Minimum age (years): 7
Maximum age (years): 40
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Randomized, Double-blind, placebo-controlled, single center, cross-over trial
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Impact of Oral CBD Solution anxiety.
timeFrame: At baseline, 12 weeks, 20 weeks, and 32 weeks
measure: Impact of Oral CBD Solution on disruptive behavior
timeFrame: At baseline, 12 weeks, 20 weeks, and 32 weeks
measure: Impact of Oral CBD Solution on Behavioral Inhibition
timeFrame: At baseline, 12 weeks, 20 weeks, and 32 weeks
Secondary outcomes:
measure: Impact of Oral CBD Solution on intracortical inhibition
timeFrame: At baseline, 12 weeks, 20 weeks, and 32 weeks
measure: Impact of Oral CBD Solution on intracortical facilitation
timeFrame: At baseline, 12 weeks, 20 weeks, and 32 weeks
measure: Impact of Oral CBD Solution on
timeFrame: At baseline, 12 weeks, 20 weeks, and 32 weeks
Other outcomes:
Locations:
Study officials:
References: