A Placebo-Controlled, Double-Blinded Study of Minocycline in Children with Fragile X Syndrome

Background: Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and the most common known single gene cause of autism.  Minocycline has been found to decrease levels of matrix metalloproteinase 9 and normalize synaptic connections in the knock out mouse model of FXS.  Minocycline also normalized the behavioral phenotype of the fragile X mouse model.  Prior open label studies of minocycline in individuals with FXS suggest benefits for behavior. 

Objectives: To assess the efficacy and safety of minocycline as a targeted treatment for children with FXS with and without a pervasive developmental disorder.

Methods: Children with FXS 3.5-16 years of age were randomized to receive minocycline or placebo. After three months, participants were crossed over to minocycline or placebo for the following three months. Investigators and participants were blinded to the randomization. Outcome measures including the Clinical Global Impressions-Improvement scale (CGI-I), Visual Analogue Scale (VAS) for target behaviors, and the Aberrant Behavior Checklist (ABC) were administered at baseline, 3 months and 6 months. Appropriate Autism Diagnostic Observation Schedule (ADOS) modules and cognitive measures were administered to participants at baseline.

Results: This preliminary analysis focuses on 40 individuals, mean age 8.64 +/- 3.46 years. There was a significantly greater improvement in CGI-I scores after minocycline treatment compared to placebo (p=0.0274).  The VAS showed a trend for greater improvement after minocycline treatment for one of the target behaviors identified by caregivers.  No serious adverse events occurred and there was no significant difference in side effects during the minocycline period vs. the placebo period.

Conclusions: Preliminary analysis supports the potential efficacy of minocycline treatment for FXS, but evidence of a placebo effect is also seen. Treatment with minocycline for 3 months has been well tolerated. The trial is ongoing.  Although preliminary data has been presented before, further results will include updated data for 50 patients as well as an analysis of ABC composite scores and subscale scores including a revised subscale for FXS individuals.  Correlations of baseline ADOS scores and IQ scores with response to treatment and available data regarding anti-nuclear antibodies (ANA) post-treatment will be presented as well.  Larger, multi-center trials are indicated to further study this treatment.  Recommendations for patients on minocycline include close monitoring for side effects and obtaining pre- and post- treatment ANA levels when possible.