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NCT Number: NCT03722290

Metformin in Children and Adults With Fragile X Syndrome

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.

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Key information

Conditions

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

Age range

10 year–45 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Université de Sherbrooke

Sherbrooke, Quebec, J1H 5H3, Canada

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

metformin

Drug

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

Primary outcomes

  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 outcomes

  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.

Sponsors and collaborators

Lead sponsor

Université de Sherbrooke

Other

Collaborators

  • FRAXA Research Foundation

Registry information

Official study title

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

Important dates

Study start
2018
Primary completion
2019
Study completion
2020
First posted
Oct 26, 2018
Registry last updated
Feb 4, 2021

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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