A Double-Blind, Placebo-Controlled Trial of Metformin in Individuals With Fragile X Syndrome (FXS)

  • End date
    Jun 12, 2026
  • participants needed
  • sponsor
    University of Alberta
Updated on 12 October 2022
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This study is a controlled trial of metformin in individuals with fragile X syndrome between the ages of 6 and 35 years. Participants will be randomized in a double-blind design to either drug or placebo and will attend three visits to the study site in a 4-month period for a series of tests. The primary objectives are to assess safety, tolerability, and efficacy of metformin in the treatment of language deficits, behavior problems, and obesity/excessive appetite in individuals with fragile X syndrome.


This is a multi-center study at the University of Alberta and CHU Sainte-Justine for fragile X syndrome (FXS) patients aged 6 to 35 years inclusive. It is a randomized, double-blind, placebo-controlled trial of metformin (also known as Glumetza, Glucophage, Fortamet), a type 2 diabetes medication that can also improve obesity and excessive appetite.

Metformin has emerged as a candidate drug for the targeted treatment of FXS based on animal studies showing rescue of multiple phenotypes in the FXS model. Metformin may contribute to normalizing signaling pathways in FXS in the central nervous system, which may include activities of mTOR and PI3K, both of which have shown to be pathogenically overactive in FXS. In addition, metformin inhibits phosphodiesterase, which would lead to correction of cAMP levels, and MMP9 production, which is also elevated in FXS. Looking at the potential signaling pathways, metformin appears to be a good candidate for targeting several of the intracellular functions in neurons disrupted in FXS and, therefore, has potential to rescue several types of symptoms in individuals with FXS. Researchers have utilized metformin in the clinical treatment of over 20 individuals with FXS between the ages of 4 and 58 years and have found the medication to be well tolerated and to provide benefits not only in lowering weight gain and normalizing appetite but also in language and behavior. In this controlled trial, the researchers hope to further assess metformin's safety and benefits in the areas of language and cognition, eating and weight loss, and overall behavior.

Each participant will be involved in this trial for a period of 4 months. This will include 3 visits to one of the sites and 5 phone calls. At each visit, the researchers will assess behavioral, cognitive, and language development. The researchers will also assess the side effects of the study medication throughout the trial.

Condition Fragile X Syndrome, Fragile X Mental Retardation Syndrome, Mental Retardation, X-Linked, Genetic Diseases, X-Linked, Trinucleotide Repeat Expansion, Fra(X) Syndrome, Intellectual Disability, FXS, Neurobehavioral Manifestations, Sex Chromosome Disorders
Treatment Metformin, Placebo medication
Clinical Study IdentifierNCT03862950
SponsorUniversity of Alberta
Last Modified on12 October 2022


Yes No Not Sure

Inclusion Criteria

Subject has Fragile X syndrome with a molecular genetic confirmation of the full FMR1 mutation (>200 CGG repeats) or the other loss of function mutations of the FMR1 gene (SNVs and deletions of the gene)
Subject is a male or non-pregnant, non-lactating female age 6 through 35 years, inclusive
Subjects who are capable of becoming pregnant must use an acceptable method of birth control for the duration of the study. Acceptable forms of birth control include abstinence (only for subjects who are not sexually active), intrauterine devices in place for at least 3 months, oral contraceptives, surgical sterilization, or adequate barrier methods
Subject must have a caregiver (parent, guardian, or other legally authorized representative) who is willing to participate in the whole study
Subject and caregiver are able to attend the clinic regularly and reliably
Subject and/or subject's caregiver is able to understand, read, write and speak English or French fluently to complete study-related materials
For subjects who are not their own legal guardian, subject's caregiver is able to understand and sign an informed consent to participate in the study
The use of concomitant medication must be stable, in terms of dose and dosing regimen, for at least 4 weeks prior to Screening and must remain stable during the period between first visit (Screening) and the commencement of the study; every effort should be made to maintain stable regimens of allowed concomitant medications from the time of commencement of double-blind study medication until the last study assessment
Behavioral/educational treatments must be stable for 4 weeks prior to first visit (Screening) and must remain stable during the period between Screening and the commencement of randomized double-blind study medication
\. Overall age equivalent is not higher than 13 and IQ is not higher than 85, as assessed at Screening on the Leiter-III, and subject must speak at least occasional 3-word phrases

Exclusion Criteria

Families that are not cooperative and will not follow through with the demands of this study
Subject has a life-threatening medical problem or other major systemic illness that compromises health or safety and/or would interfere with this study
Age younger than 6 or older than 35 years
History of intolerable adverse events with metformin
Current or recent metformin treatment (within the past 4-months)
BMI inferior to 2 standard deviations below the mean for age using the World Health Organization scale
Serum creatinine > 1.4 mg/dl (female) or > 1.5 mg/dl (male)
History of metabolic acidosis or a condition with lactic acidosis
Severe Vitamin B12 deficiency
Pregnancy at screening or unwillingness to use acceptable method of birth control, if applicable
Age equivalent higher than 13 or IQ higher than 85 on the Leiter-III at Screening
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