Effects of Metformin on children with Fragile X Syndrome: a randomized, double-blind, placebo-controlled trial
Yiting Zhu1, Dongyun Li1, Chunchun Hu1
1Department of Child Health Care, Children's Hospital of Fudan University, Shanghai, China.
Insights
Metformin showed no significant improvement in the overall Aberrant Behavior Checklist (ABC) score for Fragile X Syndrome (FXS). However, it improved hyperactivity and sleep issues in FXS patients, warranting further research.
Area of Science:
- Neuroscience
- Pharmacology
- Genetics
Background:
- Fragile X Syndrome (FXS) is a leading inherited intellectual disability with no approved treatments.
- Metformin's potential therapeutic role in FXS is suggested by preclinical and clinical findings.
- FXS pathophysiology involves mechanisms that may be targeted by metformin.
Purpose of the Study:
- To evaluate the efficacy and safety of metformin in treating FXS.
- To assess metformin's impact on behavioral, developmental, and sleep outcomes in FXS patients.
Main Methods:
- A 6-month, randomized, double-blind, placebo-controlled trial involving 34 participants (aged 2-16) with confirmed FXS.
- Participants received weight-adjusted metformin or placebo, with outcomes measured by ABC, GDS-C, ADOS-2, CSHQ, and RBS-R.
- Primary outcome was change in Aberrant Behavior Checklist (ABC) total score.
Main Results:
- Metformin significantly improved hyperactivity (p=0.016) and sleep disturbances (p=0.013), especially bedtime resistance (p=0.004).
- No significant differences were found in cognitive, social, or repetitive behavior measures between groups.
- Adverse events were comparable, with most side effects in the metformin group resolving spontaneously.
Conclusions:
- Metformin did not significantly improve the primary ABC total score outcome in FXS.
- Secondary outcomes showed significant benefits in hyperactivity and sleep, supporting further investigation.
- The study's modest sample size and duration limit definitive conclusions on long-term effects.
Background:
Fragile X Syndrome (FXS) is the most prevalent inherited intellectual disability disorder linked to the X chromosome, and currently lacks an approved specific treatment. Preclinical and some clinical studies have suggested metformin may have therapeutic potential for FXS based on its mechanisms related to the disorder's pathophysiology.
Methods:
We conducted a 6-month, randomized, double-blind, placebo-controlled trial at the Children's Hospital of Fudan University. Thirty-four participants aged 2-16 years with genetically confirmed FXS were randomized 1:1 to receive weight-adjusted metformin (250-1000 mg/day) or placebo. Primary outcomes were changes in Aberrant Behavior Checklist (ABC); secondary outcomes included Griffiths Development Scale-Chinese (GDS-C), Autism Diagnostic Observation Program Second Edition (ADOS-2), Children's Sleep Habits Questionnaire (CSHQ), Repetitive Behavior Scale-Revised Chinese version (RBS-R), and Clinical Global Impression (CGI).
Results:
Among 34 randomized participants, 30 completed the trial (15 per group). Metformin demonstrated significant improvements in hyperactivity (ABC-Hyperactivity: -7.86 ± 6.97 vs. -0.80 ± 8.09, p = 0.016) and sleep disturbances (CSHQ-Total: -0.73 ± 5.14 vs. + 5.13 ± 6.85, p = 0.013), particularly bedtime resistance (p = 0.004). Total ABC score reductions favored metformin (-16.60 ± 15.31 vs. -4.00 ± 23.67) but did not reach significance (p = 0.095). No significant between-group differences were observed in cognitive, social, or repetitive behavior measures (GDS-C, ADOS-2, RBS-R). Adverse event rates were comparable, with IGF-1 reduced (6.7%, p = 1), transient appetite loss (13.3%, p = 0.483) and lactic acidosis (26.7%, p = 0.330) resolving spontaneously in metformin group.
Limitation:
This study was constrained by its modest sample size (n = 30), and absence of objective neurophysiological measures. The 6-month duration precluded assessment of long-term therapeutic effects.
Conclusions:
In this controlled trial, metformin did not significantly improve the primary outcome of ABC total score. However, significant improvements were observed in the hyperactivity subscale and key secondary outcomes, including sleep parameters, while maintaining a favorable safety profile. Although the primary endpoint was not met, these secondary findings support further investigation of metformin for targeted behavioral domains in individuals with FXS.
Trial Registration:
This trial was prospectively registered on ClinicalTrials.gov (Registration No. NCT05120505, first posted November 03, 2021). The full protocol can be accessed at https://register.
Clinicaltrials:
gov/ .
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