Metformin in Children and Adults With Fragile X Syndrome

Evaluate the Efficacy and Safety of Metformin in Children and Adults With Fragile X Syndrome: an Open-label Study

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.

Study Overview

• Status: Completed
• Conditions: Fragile X Syndrome
• Intervention / Treatment: Drug: Metformin

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Sherbrooke, Quebec, Canada, J1H 5H3
      • Université de Sherbrooke

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 41 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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 Names: Glucophage

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Level of cortical excitability using Transcranial Magnetic Stimulation (TMS)	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	Baseline, Week 9
Level of synaptic plasticity using Electroencephalography (EEG)	The effects of metformin on synaptic plasticity will be measured using the changes in amplitude of EEG waves	Baseline, Week 9
Changes from baseline in the score of each subscale of the Aberrant Behavior Checklist-Community (ABC-C)	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).	Baseline, Week 9
Changes from baseline in the Global Executive Composite (GEC) baseline score of the Behavior Rating Inventory of Executive Function (BRIEF)	The BRIEF is a 86-item questionary evaluating executive functions rated on a 3-point Likert scale: 1 (never), 2 (sometimes) and 3 (often).	Baseline, Week 9
Changes from baseline in the score of 4 subtests of the computerized cognitive Test of Attentional Performance for Children	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.	Baseline, Week 9

Collaborators and Investigators

• Sponsor: Université de Sherbrooke
• Collaborators: FRAXA Research Foundation

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2018
• Primary Completion (Actual): October 24, 2019
• Study Completion (Actual): November 1, 2020

Study Registration Dates

• First Submitted: October 24, 2018
• First Submitted That Met QC Criteria: October 25, 2018
• First Posted (Actual): October 26, 2018

Study Record Updates

• Last Update Posted (Actual): February 4, 2021
• Last Update Submitted That Met QC Criteria: February 1, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: Metformin; Insulin signalisation
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Disease; Congenital Abnormalities; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Mental Retardation, X-Linked; Intellectual Disability; Heredodegenerative Disorders, Nervous System; Chromosome Disorders; Sex Chromosome Disorders; Syndrome; Fragile X Syndrome; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: 2019-2797

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