A Trial of Metformin in Individuals With Fragile X Syndrome

This is a single-center study at the UC Davis MIND Institute for fragile X syndrome (FXS)
patients aged 6 to 25 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. The 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 the UC Davis MIND Institute 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.

Study record updated 9/26/2018 to reflect the following IRB-approved protocol modifications:
Erroneous references to "digital" books for primary outcome measure were removed, as this
measure is administered using print (non-digital) materials. Eligibility criteria were
updated to include subjects with IQ of up to and including 79 on the Leiter-III at screening.
The Hyperphagia Questionnaire (HQ-CT) was replaced by the Anxiety Depression and Mood Screen
(ADAMS) as a secondary outcome measure.

Inclusion Criteria:

- 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.

Exclusion Criteria:

- 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.