Metformin in Children and Adults With Fragile X Syndrome

• ClinicalTrials.gov Identifier: NCT03722290
• Recruitment Status: Completed
• First Posted: October 26, 2018
• Last Update Posted: February 4, 2021
• Sponsor: Université de Sherbrooke
• Collaborator: FRAXA Research Foundation
• Information provided by (Responsible Party): Çaku, Université de Sherbrooke

Study Description

Brief Summary:

Fragile X Syndrome (FXS) is caused by loss of FMR1 expression on the X chromosome that leads to increased mRNA translation, which results in hyperactivation of ERK (extracellular signal-regulated kinase) and mTORC1 (mechanistic target of rifampicin complex 1) signalling and consequently in synaptic dysfunction and neurological development. There is presently no cure for FXS. Recent studies suggest that metformin (a widely prescribed drug for type II diabetes in children and adults) which crosses the blood-brain barrier, corrects various neurological and behavioral FXS phenotypes by normalizing ERK signaling, EIF4E phosphorylation and lowering expression of MMP9 to normal. Since this drug has not been previously used specifically for treatment of FXS (only few cases reported), the investigators propose an open-label trial of metformin in children and adults with FXS to better understand the safety and efficacy in both behavior and cognition.

Condition or disease	Intervention/treatment	Phase
Fragile X Syndrome	Drug: Metformin	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 15 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Open-label trial
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Evaluate the Efficacy and Safety of Metformin in Children and Adults With Fragile X Syndrome: an Open-label Study
• Actual Study Start Date: September 1, 2018
• Actual Primary Completion Date: October 24, 2019
• Actual Study Completion Date: November 1, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Metformin; Metformin 500mg twice a day per os for 9 weeks	Drug: Metformin; Oral administration of metformin 250mg (twice a day) for the 1st week followed by metformin 500mg (twice a day) for the next 8 weeks.; Other Name: Glucophage

Outcome Measures

Primary Outcome Measures :

1. Incidence of adverses events reported during the study [ Time Frame: 9 weeks ]
   Number and severity of adverse events related to metformin treatment
2. Change from baseline in the total score of the FX-normed Aberrant Behavior Checklist-Community after 9 weeks of metformin treatment [ Time Frame: Baseline, Week 9 ]
   The ABC-C is a 58-item caregiver-rated behavior scale where each item ranges from 0 (not a problem) to 3 (severe problem).

Secondary Outcome Measures :

1. Level of cortical excitability using Transcranial Magnetic Stimulation (TMS) [ Time Frame: Baseline, Week 9 ]
   The effects of metformin on cortical excitability will be measured using a magnetic stimulation on the primary motor cortex to assess intracortical facilitation and inhibition
2. Level of synaptic plasticity using Electroencephalography (EEG) [ Time Frame: Baseline, Week 9 ]
   The effects of metformin on synaptic plasticity will be measured using the changes in amplitude of EEG waves
3. Changes from baseline in the score of each subscale of the Aberrant Behavior Checklist-Community (ABC-C) [ Time Frame: Baseline, Week 9 ]
   Determining if metformin lowers the score of each subscale of the ABC-C: Irritability (18 items), hyperactivity (10 items), lethargy (16 items), social avoidance (4 items), stereotypy (6 items) and inappropriate speech (4 items). Each item is scored from 0 (not a problem) to 3 (severe problem).
4. Changes from baseline in the Global Executive Composite (GEC) baseline score of the Behavior Rating Inventory of Executive Function (BRIEF) [ Time Frame: Baseline, Week 9 ]
   The BRIEF is a 86-item questionary evaluating executive functions rated on a 3-point Likert scale: 1 (never), 2 (sometimes) and 3 (often).
5. Changes from baseline in the score of 4 subtests of the computerized cognitive Test of Attentional Performance for Children [ Time Frame: Baseline, Week 9 ]
   KiTAP is a computerized continuous test of attention assessing the ability to maintain attention in the presence of distractors. The 4 subtests used are Alertness reaction time, Distractibility commission errors, Go/No-Go commission errors and Flexibility errors.

Eligibility Criteria

• Ages Eligible for Study: 10 Years to 45 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Aged between 10 et 45 years old
• BMI > 18.3
• Molecular diagnosis of FXS
• Accompanied by his legal tutor

Exclusion Criteria:

• Pregnancy/Breastfeeding
• Intolerance to metformin
• History of lactic acidosis
• Gastric/renal/hepatic pathology
• Acute medical condition
• Concomitant use of ACE inhibitors
• Modification of antipsychotic treatments in the last 6 weeks

Contacts and Locations

Locations

Canada, Quebec

Université de Sherbrooke

Sherbrooke, Quebec, Canada, J1H 5H3

Sponsors and Collaborators

Université de Sherbrooke

FRAXA Research Foundation

More Information

• Responsible Party: Çaku, Principal Investigator, Université de Sherbrooke
• ClinicalTrials.gov Identifier: NCT03722290
• Other Study ID Numbers: 2019-2797
• First Posted: October 26, 2018
• Last Update Posted: February 4, 2021
• Last Verified: February 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Çaku, Université de Sherbrooke:

Metformin; Insulin signalisation

Additional relevant MeSH terms:

Fragile X Syndrome; Metformin; Syndrome; Disease; Pathologic Processes; Mental Retardation, X-Linked; Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Sex Chromosome Disorders; Chromosome Disorders; Congenital Abnormalities; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Heredodegenerative Disorders, Nervous System; Hypoglycemic Agents; Physiological Effects of Drugs