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A Randomized Double-Blind, Placebo-Controlled Trial of Minocycline in Children and Adolescents with Fragile X Syndrome

Leigh, Mary Jacena S. MD*,†; Nguyen, Danh V. PhD; Mu, Yi MS; Winarni, Tri I. MD§; Schneider, Andrea PhD*,†; Chechi, Tasleem BS*,†; Polussa, Jonathan BS*,†; Doucet, Paul BA; Tassone, Flora PhD†,‖; Rivera, Susan M. PhD†,¶; Hessl, David PhD†,**; Hagerman, Randi J. MD*,†

Journal of Developmental & Behavioral Pediatrics: April 2013 - Volume 34 - Issue 3 - p 147–155
doi: 10.1097/DBP.0b013e318287cd17
Original Article

Objective: Minocycline rescued synaptic abnormalities and improved behavior in the fragile X mouse model. Previous open-label human studies demonstrated benefits in individuals with fragile X syndrome (FXS); however, its efficacy in patients with FXS has not been assessed in a controlled trial.

Method: Randomized, double-blind, placebo-controlled, crossover trial in individuals with FXS, aged 3.5 years to 16 years (n = 55, mean age 9.2 [SD, 3.6] years). Participants were randomized to minocycline or placebo for 3 months and then switched to the other treatment.

Results: Sixty-nine subjects were screened and 66 were randomized. Fifty-five subjects (83.3%) completed at least the first period and 48 (72.7%) completed the full trial. Intention-to-treat analysis demonstrated significantly greater improvements in one primary outcome, Clinical Global Impression Scale—Improvement after minocycline compared with placebo (2.49 ± 0.13 and 2.97 ± 0.13, respectively, p = .0173) and greater improvement in ad hoc analysis of anxiety and mood-related behaviors on the Visual Analog Scale (minocycline: 5.26 cm ± 0.46 cm, placebo: 4.05 cm ± 0.46 cm; p = .0488). Side effects were not significantly different during the minocycline and placebo treatments. No serious adverse events occurred on minocycline. Results may be potentially biased by study design weaknesses, including unblinding of subjects when they completed the study, drug-related side effects unblinding, and preliminary efficacy analysis results known to investigators.

Conclusions: Minocycline treatment for 3 months in children with FXS resulted in greater global improvement than placebo. Treatment for 3 months appears safe; however, longer trials are indicated to further assess benefits, side effects, and factors associated with a clinical response to minocycline.

*Department of Pediatrics, University of California Davis Medical Center, Sacramento, CA;

MIND Institute, University of California Davis, Sacramento, CA;

Department of Biostatistics, University of California Davis, Davis, CA;

§Department of Human Genetics, CEBIOR Diponegoro University, Semarang, Central Java, Indonesia;

Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, CA;

Department of Psychology, Center for Mind and Brain, University of California Davis, Davis, CA;

**Department of Psychiatry and Behavioral Sciences, University of California Davis, Sacramento, CA.

Address for reprints: Mary Jacena Leigh, MD, Department of Developmental and Behavioral Pediatrics, MIND Institute, University of California, 2825 50th Street, Sacramento, CA 95817; e-mail: maryjacena.leigh@ucdmc.ucdavis.edu.

Disclosure: Dr. Hagerman has received funding from Hoffman LaRoche, Novartis, Seaside Therapeutics, Forest, and Curemark for treatment trials in patients with fragile X syndrome, autism, and fragile X-associated tremor ataxia syndrome. She is also on the Treatment Advisory Board for Novartis regarding fragile X syndrome treatment studies. Dr. Hessl has received financial support from Hoffman LaRoche, Novartis, and Seaside Therapeutics for clinical trials of patients with fragile X syndrome. The other authors report no financial interests or conflicts of interest.

The authors thank the National Fragile X Foundation for their funding of this project. This study was also partially supported by grant UL1 TR000002 from the National Center for Advancing Translational Sciences (D.V.N.), Interdisciplinary Training for Autism Researchers 5T32MH073124 (M.J.L.), A Toolbox of Outcome Measures for Targeted Treatment Trials in Children 3UL1 RR024146-04S4, and the Fragile X Research Center grant HD02274. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Trial Registration: Clinicaltrials.gov http://www.clinicaltrials.gov/ct2/show/NCT01053156.

Received October , 2012

Accepted January , 2013

© 2013 Lippincott Williams & Wilkins, Inc.