A Trial of Metformin in Individuals With Fragile X Syndrome

NCT03479476 | Completed Phase 2 DMC FDA Drug

• 1 other identifier: 1068417
• Study Type: interventional
• Target: 120
• Locations: 2 countries
• Sites: 3

Brief Summary

This study is a controlled trial of metformin in individuals with fragile X syndrome between the ages of 6 and 25 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 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

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 (8)

• 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. Liquid placebo will be provided to any participants unable to swallow the placebo capsules. 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. Liquid metformin (100mg/cc) will be provided to any participants unable to swallow the metformin capsules. 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

Placebo Medication DRUG

Placebo liquid or capsules given in parallel to active medication.

Also known as: Placebo

Placebo Medication

Metformin DRUG

Active medication.

Also known as: Glumetza, Glucophage, Fortamet, Riomet

Active Metformin Medication

Eligibility Criteria

• Age: 6 Years - 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Molecular genetic confirmation of the full FMR1 mutation or mosaicism.
• Males and non-pregnant, non-lactating females age 6 to 25 years, inclusive.
• Ability of subject and/or caregiver to understand, read, write, and speak English fluently to complete study-related materials.
• IQ ≤ 79 as measured by the Leiter-III at screening.
• Participant is able to speak at least occasional 3-word phrases.
• Participant and parent/caregiver are willing to participate in the protocol and able to attend the clinic regularly and reliably.
• Stable concomitant medication dose and dosing regimen for at least 4 weeks prior to the screening/baseline visit, and the intention to maintain a stable regimen of allowed concomitant medications for the full duration of the study.
• Stable behavioral/educational treatments for at least 4 weeks prior to the screening/baseline visit.
• Sexually active women of childbearing potential must be using a medically acceptable method of birth control for the duration of the study and have a negative urine pregnancy test collected at the initial screening/baseline visit.
• For participants who are not their own legal guardian, the parent/legal authorized representative is able to understand and sign an informed consent to participate in the study.

You may not qualify if:

• Non-cooperation or inability to follow through with the study protocol.
• Life-threatening medical problem or other major systemic illness that compromises health or safety and/or would interfere with the study.
• History of intolerable adverse events with metformin.
• Current or recent metformin treatment (within the past year).
• Body mass index (BMI) less than 2 standard deviations for age.
• Serum creatinine \> 1.4 mg/dl (female) or \> 1.5 mg/dl (male) at screening.
• History of metabolic acidosis or a condition with lactic acidosis.
• Severe B12 deficiency.
• Pregnancy at screening or unwillingness to use acceptable method of birth control, if applicable.

Sponsors & Collaborators

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

Study Sites (3)

UC Davis MIND Institute

Sacramento, California, 95817, United States

Location

University of Alberta

Edmonton, Alberta, T6G2R3, Canada

Location

St Justine Hospital

Montreal, Quebec, H3T 1C5, Canada

Location

Related Links

• Learn more or sign up for the study here!

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

• Randi J Hagerman, MD

  University of California, Davis

  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: March 20, 2018
• First Posted: March 27, 2018
• Study Start: April 30, 2018
• Primary Completion: May 22, 2024
• Study Completion: May 22, 2024
• Last Updated: January 17, 2025

Record last verified: 2025-01

Locations

CA (2); US (1)