Effects of Metformin on children with Fragile X Syndrome: a randomized, double-blind, placebo-controlled trial

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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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