Metformin for Fragile X Syndrome

No longer recruiting at 1 trial location

Overseen By Maryse Thibeault

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Alberta

Must not be taking: Metformin

Disqualifiers: Non-cooperative, Major illness, Metabolic acidosis, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 6 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: 16 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether metformin, a common diabetes medication, can improve language skills, behavior, and weight management in people with fragile X syndrome. Fragile X syndrome is a genetic condition affecting learning and behavior. The study compares the effects of metformin to a placebo (a non-active lookalike pill) to determine if it makes a significant difference. People with fragile X syndrome, diagnosed through genetic testing and possessing some language ability, might be suitable for this study. Participants will attend three study visits over four months. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial requires that any medications you are currently taking must be stable in terms of dose and schedule for at least 4 weeks before the screening and must remain stable throughout the study. You won't need to stop taking your current medications, but you should not change them during the trial.

Is there any evidence suggesting that metformin is likely to be safe for individuals with fragile X syndrome?

Research has shown that metformin is generally safe for people with fragile X syndrome. Previous studies found no increase in negative side effects, indicating participants did not experience more problems than expected. Participants in these studies took metformin without major issues, suggesting its safety. Additionally, metformin is an FDA-approved medication commonly used to treat type 2 diabetes, which further reassures its safety for other conditions. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for fragile X syndrome?

Researchers are excited about using metformin for Fragile X Syndrome because it represents a novel approach to managing this genetic condition. While most treatments for Fragile X focus on behavioral therapies and medications that manage symptoms like anxiety or hyperactivity, metformin, a drug commonly used for diabetes, may address underlying biological pathways. Metformin is thought to improve cellular signaling and reduce inflammation, which could lead to cognitive and behavioral improvements for individuals with Fragile X. This potential to target the root causes of symptoms makes metformin a promising candidate for offering more comprehensive benefits compared to current symptom-focused treatments.

What evidence suggests that metformin might be an effective treatment for fragile X syndrome?

Research has shown that metformin might help treat fragile X syndrome. Animal studies have found that metformin can correct certain brain cell problems associated with fragile X syndrome. In human case studies, children with fragile X syndrome who took metformin demonstrated improvements in speech and thinking skills. Additionally, metformin is generally well tolerated, causing few side effects. In this trial, participants will receive either the active metformin medication or a placebo. These findings suggest that metformin could help manage symptoms such as language difficulties and behavior problems in individuals with fragile X syndrome. ^{1 2 3 6 7}

Who Is on the Research Team?

Francois Bolduc, MD

Principal Investigator

University of Alberta

Are You a Good Fit for This Trial?

This trial is for males and non-pregnant females aged 6-35 with Fragile X syndrome confirmed by genetic testing. Participants must be able to attend clinic visits, have a caregiver involved, speak English or French, and use birth control if applicable. Exclusions include pregnancy, severe vitamin B12 deficiency, certain medical conditions, history of adverse reactions to metformin or recent treatment with it.

Inclusion Criteria

I have Fragile X syndrome confirmed by genetic testing.

I am using or willing to use an approved birth control method during the study.

Subject must have a caregiver (parent, guardian, or other legally authorized representative) who is willing to participate in the whole study.

Exclusion Criteria

You have a very low level of Vitamin B12.

My BMI is much lower than average for my age.

Your blood test shows high levels of creatinine, a waste product from your muscles, above a certain level. For females, it's above 1.4 mg/dl, and for males, it's above 1.5 mg/dl.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive metformin or placebo in a double-blind design, with dosage titration over 4 weeks followed by 12 weeks at maximum tolerated dose

16 weeks

3 visits (in-person), 5 phone calls

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Metformin
• Placebo Medication

Trial Overview

The study tests the safety and effectiveness of metformin compared to a placebo in treating language deficits, behavioral issues, and obesity/excessive appetite in individuals with Fragile X syndrome. It's a double-blind trial where participants are randomly assigned to receive either metformin or placebo over four months.

How Is the Trial Designed?

Group I: Active Metformin Medication Active Control 1 Intervention

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.

Group II: Placebo Medication Placebo Group 1 Intervention

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.

Metformin is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as Glucophage for:

• Type 2 diabetes

Approved in United States as Glucophage for:

• Type 2 diabetes

Approved in Canada as Glucophage for:

• Type 2 diabetes

Approved in Japan as Glucophage for:

• Type 2 diabetes

Approved in China as Glucophage for:

• Type 2 diabetes

Approved in Switzerland as Glucophage for:

• Type 2 diabetes

Who Is Running the Clinical Trial?

University of Alberta

Lead Sponsor

Trials

957

Recruited

437,000+

St. Justine's Hospital

Collaborator

Trials

205

Recruited

87,300+

Published Research Related to This Trial

Despite the success of hydroxyurea in increasing fetal hemoglobin levels for sickle cell disease, attempts to find a similar effective treatment for thalassemia have largely failed, with small-scale studies showing disappointing results.

The report highlights the need for further investigation into the factors hindering the development of effective fetal hemoglobin induction therapies for thalassemia, suggesting that understanding these factors is crucial for future treatment advancements.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacological induction of fetal hemoglobin: Why haven't we been more successful in thalassemia? Fathallah, H., Sutton, M., Atweh, GF.[2017]

In a study evaluating the effectiveness of traditional and novel antifols in treating childhood acute leukemias and lymphomas, talotrexin and aminopterin showed greater cytotoxicity than methotrexate and pemetrexed, with lower IC50 values indicating they are more effective at lower concentrations.

While aminopterin did not demonstrate any advantage over methotrexate, pemetrexed showed significantly better clinical potency, suggesting it could be a promising candidate for further research in treating childhood leukemias.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical potency of methotrexate, aminopterin, talotrexin and pemetrexed in childhood leukemias. Norris, RE., Adamson, PC.[2022]

Trofinetide is the first FDA-approved drug for Rett syndrome (RTT), a rare genetic disorder affecting girls, and has shown favorable safety and efficacy in improving core symptoms during Phase II clinical trials.

The drug is well-tolerated with no known drug interactions, making it a promising treatment option for managing RTT symptoms and enhancing the quality of life for affected individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trofinetide in Rett syndrome: A brief review of safety and efficacy. Singh, A., Balasundaram, MK., Gupta, D.[2023]

Fenfluramine demonstrated long-term safety and effectiveness in reducing drop seizure frequency in patients with Lennox-Gastaut syndrome (LGS), with a median reduction of 28.6% over the treatment period and a notable 50.5% reduction at Month 15.

The treatment was well tolerated, with no cases of serious side effects like valvular heart disease or pulmonary arterial hypertension reported, making fenfluramine a promising long-term option for managing seizures in LGS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fenfluramine provides clinically meaningful reduction in frequency of drop seizures in patients with Lennox-Gastaut syndrome: Interim analysis of an open-label extension study. Knupp, KG., Scheffer, IE., Ceulemans, B., et al.[2023]

In a small study of five patients with Dravet syndrome under 2 years old, fenfluramine (FFA) was found to be safe and well-tolerated, with no significant adverse effects on body mass index or heart function.

FFA significantly reduced the monthly convulsive seizure frequency by about 54% after 6 months, and two patients showed improvements in their developmental scores, suggesting it may help protect neurodevelopment in young children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fenfluramine below the age of 2 years in Dravet Syndrome: what about safety and efficacy? Pietrafusa, N., Trivisano, M., Casellato, S., et al.[2023]

In a real-world study involving 149 patients with Dravet syndrome, fenfluramine treatment led to a significant reduction in monthly convulsive seizure frequency, with 62% of patients under 6 years, 53% aged 6-17, and 50% aged 18 and older achieving a ≥75% reduction after 3 months.

Fenfluramine was generally well-tolerated, with the most common side effects being loss of appetite (21%) and somnolence (16%), and no serious cardiovascular issues like valvular heart disease or pulmonary artery hypertension were reported, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An examination of the efficacy and safety of fenfluramine in adults, children, and adolescents with Dravet syndrome in a real-world practice setting: A report from the Fenfluramine European Early Access Program. Guerrini, R., Specchio, N., Aledo-Serrano, Á., et al.[2022]

Metformin, a drug commonly used to treat diabetes, shows potential for repurposing as a treatment for fragile X syndrome, a genetic condition that can cause developmental issues.

This finding suggests that metformin may have effects beyond its original use, potentially benefiting patients with fragile X syndrome, although further research is needed to confirm its efficacy in this new context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A therapy for FXS? Ferrarelli, LK.[2018]

Metformin, a drug commonly used to treat diabetes, shows promise in addressing core symptoms of Fragile X syndrome (FXS) and other neurological disorders, based on findings from various animal and cellular models.

The review highlights the mechanisms of action of metformin, suggesting it could be a potential therapeutic option for improving cognitive and behavioral deficits associated with FXS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin for Treatment of Fragile X Syndrome and Other Neurological Disorders. Gantois, I., Popic, J., Khoutorsky, A., et al.[2021]

Metformin was found to be safe for use in 15 normoglycemic individuals with Fragile X syndrome (FXS) over a 9-week treatment period, with no significant adverse events reported.

The treatment showed potential in modifying GABA-mediated inhibition, which is a key feature of FXS, suggesting that metformin could be beneficial in addressing some behavioral and attentional issues associated with the disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety and efficacy of metformin in fragile X syndrome: An open-label study. Proteau-Lemieux, M., Lacroix, A., Galarneau, L., et al.[2022]

In a clinical study involving two individuals with fragile X syndrome (FXS) treated with metformin for one year, both patients showed significant cognitive and behavioral improvements.

Metformin also led to better eating habits and normalization of weight percentiles, suggesting it may be a promising treatment option for various symptoms associated with FXS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cognitive and behavioral improvement in adults with fragile X syndrome treated with metformin-two cases. Protic, D., Aydin, EY., Tassone, F., et al.[2021]

This study involved 17 participants with Fragile X syndrome (FXS) who were treated with metformin, and it aimed to identify molecular biomarkers that could predict treatment response and symptom severity.

The research found that specific proteins (hexokinase 1, RAS, and MMP9) were dysregulated in FXS and their normalized expression correlated with significant improvements in clinical symptoms, suggesting these proteins could serve as useful biomarkers for patient stratification in future treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Blood-Based Biomarkers Predictive of Metformin Target Engagement in Fragile X Syndrome. Jasoliya, M., Bowling, H., Petrasic, IC., et al.[2021]

Voxelotor (Oxbryta) has been granted accelerated approval for treating sickle cell disease in children aged 4 to 11 years, marking a new treatment option for this age group.

The drug works by preventing red blood cells from sickling, which helps reduce tissue and red blood cell damage associated with sickle cell disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sickle Cell Drug Approved for Children Ages Four to 11. Aschenbrenner, DS.[2023]

Hydroxyurea significantly increases fetal hemoglobin (HbF) production and reduces the frequency of painful vasoocclusive crises in most pediatric sickle cell anemia patients, with a mean effective dosage of 20 mg/kg/day.

While short- and medium-term safety profiles are acceptable, with manageable side effects, the long-term safety of hydroxyurea remains uncertain, and its use should be limited to patients with severe symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Hydroxyurea and other agents stimulating synthesis of fetal hemoglobin]. de Montalembert, M.[2013]

In a phase I clinical trial involving two patients with high-grade myelodysplastic syndrome (MDS) or oligoblastic acute myeloid leukemia (O-AML), the IGF-MTX treatment was well tolerated with no dose-limiting toxicity observed.

Both patients showed stable or improved blood cell counts and lived significantly longer than their expected life expectancy, indicating potential efficacy of IGF-MTX in treating MDS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1b Study of IGF-Methotrexate Conjugate in the Treatment of High-grade Myelodysplastic Syndromes. Alkhateeb, HB., Patnaik, MM., Al-Kali, A., et al.[2020]

Brivaracetam (BRV) is effective and well tolerated in treating epilepsy in patients with intellectual disability (ID), with over half of the 116 patients experiencing seizure reduction and minimal side effects after 12 months.

The study showed that BRV's efficacy and tolerability were consistent regardless of whether patients had previously been treated with levetiracetam (LEV), indicating it can be a suitable option even for those who did not respond to LEV.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and tolerability of brivaracetam in patients with intellectual disability and epilepsy. Gillis, RME., Wammes-van der Heijden, EA., Schelhaas, HJ., et al.[2021]

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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.

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