A Trial of Metformin in Individuals With Fragile X Syndrome (Met)

NCT03862950 | Completed Phase 2 DMC

• 1 other identifier: FXSMET-2018 Version 16
• Study Type: interventional
• Target: 125
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Fragile X Mental Retardation Syndrome; Fragile X Syndrome; Mental Retardation, X-Linked; Genetic Diseases, X-Linked; Trinucleotide Repeat Expansion; Fra(X) Syndrome; Intellectual Disability; FXS; Neurobehavioral Manifestations; Sex Chromosome Disorders

Keywords

Congenital Abnormalities; Metformin; Nervous System Diseases; Chromosome Disorders

Outcome Measures

Primary Outcomes (1)

• Change from baseline in the Expressive Language Sampling (ELS) mean Number of Different Words (NDW) score

  The ELS is collected from shared interactions around a wordless picture book involving the participant and the examiner. The primary outcome measure will be Number of Different Words (NDW) derived from transcripts of audiorecorded samples of spoken language taken from two sampling contexts (conversation and narration), according to procedures described by Abbeduto and colleagues (Abbeduto et al., 1995; Kover et al., 2012). Samples are collected pre- and post- treatment using different books on each occasion. The mean of NDW in conversation and NDW in narration will be computed, and statistically adjusted through analysis of covariance for differences in talkativeness as outlined in Conners et al., 2018. The mean NDW score ranges from 1 to infinite/unspecified. An increase (positive change) in score from baseline to follow-up indicates improvement. The greater the increase, the greater the improvement.

  Baseline, End of Treatment/Week 16

Secondary Outcomes (22)

• Change from baseline in the FXS-normed Aberrant Behavior Checklist - Community Edition (ABC-C)

  Baseline, Week 8, End of Treatment/Week 16

• Improvement of symptoms in FXS using the Clinical Impression - Improvement (CGI-I) scale

  Baseline, Week 8, End of Treatment/Week 16

• Change from baseline in the Visual Analog Scale (VAS)

  Baseline, Week 8, End of Treatment/Week 16

• Change from baseline in the Vineland Adaptive Behavior Scales-Third Edition (VABS-III) Adaptive Behavior Composite Score

  Baseline, End of Treatment/Week 16

• Change from baseline in the Anxiety Depression and Mood Screen (ADAMS) overall score

  Baseline, Week 8, End of Treatment/Week 16

Study Arms (2)

Placebo Medication

PLACEBO COMPARATOR

The placebo will be dosed in a weight-dependent manner. For participants under 50kg at baseline, the initial dose will be 250mg once per day, and if this dose is well tolerated, they will increase each week by 250mg until a maximum dose of 1000mg daily is reached. For participants at and above 50kg at baseline, the initial dose will be 500mg once per day, and if this dose is well tolerated, they will increase each week by 500mg until a maximum dose of 2000mg daily is reached. After the 4-week titration period, each participant will continue dosing at his or her maximum tolerated dose daily for the remaining 12 weeks of the study.

Drug: Placebo Medication

Active Metformin Medication

ACTIVE COMPARATOR

The active metformin medication will be dosed in a weight-dependent manner. For participants under 50kg at baseline, the initial dose will be 250mg once per day, and if this dose is well tolerated, they will increase each week by 250mg until a maximum dose of 1000mg daily is reached. For participants at and above 50kg at baseline, the initial dose will be 500mg once per day, and if this dose is well tolerated, they will increase each week by 500mg until a maximum dose of 2000mg daily is reached. After the 4-week titration period, each participant will continue dosing at his or her maximum tolerated dose daily for the remaining 12 weeks of the study.

Drug: Metformin

Interventions

Metformin DRUG

Active medication

Also known as: Glumetza, Glucophage, Fortamet

Active Metformin Medication

Placebo Medication DRUG

Placebo liquid or capsules given in parallel to active medication.

Also known as: Placebo

Placebo Medication

Eligibility Criteria

• Age: 6 Years - 35 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Alberta: lead
• St. Justine's Hospital: collaborator

Study Sites (2)

University of Alberta

Edmonton, Alberta, T6G 2E1, Canada

Location

CHU Sainte-Justine

Montreal, Quebec, H3T 1C5, Canada

Location

Related Publications (3)

• Dy ABC, Tassone F, Eldeeb M, Salcedo-Arellano MJ, Tartaglia N, Hagerman R. Metformin as targeted treatment in fragile X syndrome. Clin Genet. 2018 Feb;93(2):216-222. doi: 10.1111/cge.13039. Epub 2017 Sep 25.

  PMID: 28436599 BACKGROUND

• Monyak RE, Emerson D, Schoenfeld BP, Zheng X, Chambers DB, Rosenfelt C, Langer S, Hinchey P, Choi CH, McDonald TV, Bolduc FV, Sehgal A, McBride SMJ, Jongens TA. Insulin signaling misregulation underlies circadian and cognitive deficits in a Drosophila fragile X model. Mol Psychiatry. 2017 Aug;22(8):1140-1148. doi: 10.1038/mp.2016.51. Epub 2016 Apr 19.

  PMID: 27090306 BACKGROUND

• Gantois I, Khoutorsky A, Popic J, Aguilar-Valles A, Freemantle E, Cao R, Sharma V, Pooters T, Nagpal A, Skalecka A, Truong VT, Wiebe S, Groves IA, Jafarnejad SM, Chapat C, McCullagh EA, Gamache K, Nader K, Lacaille JC, Gkogkas CG, Sonenberg N. Metformin ameliorates core deficits in a mouse model of fragile X syndrome. Nat Med. 2017 Jun;23(6):674-677. doi: 10.1038/nm.4335. Epub 2017 May 15.

  PMID: 28504725 BACKGROUND

MeSH Terms

Conditions

Fragile X Syndrome; X-Linked Intellectual Disability; Genetic Diseases, X-Linked; Intellectual Disability; Neurobehavioral Manifestations; Sex Chromosome Disorders; Congenital Abnormalities; Nervous System Diseases; Chromosome Disorders

Interventions

Metformin

Condition Hierarchy (Ancestors)

Neurologic Manifestations; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn; Heredodegenerative Disorders, Nervous System; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Neurodevelopmental Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Study Officials

• Francois Bolduc, MD

  University of Alberta

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 26, 2019
• First Posted: March 5, 2019
• Study Start: May 24, 2019
• Primary Completion: December 16, 2025
• Study Completion: December 16, 2025
• Last Updated: January 8, 2026

Record last verified: 2026-01

Locations

CA (2)