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A Randomized Controlled Trial

Lianne C. Krab, MSc; Arja de Goede-Bolder, MD; Femke K. Aarsen, MA; Saskia M. F. Pluijm, PhD; Marlies J. Bouman, MA; Jos N. van der Geest, PhD; Maarten Lequin, MD, PhD; Coriene E. Catsman, MD, PhD; Willem Frans M. Arts, MD, PhD; Steven A. Kushner, MD, PhD; Alcino J. Silva, PhD; Chris I. de Zeeuw, MD, PhD; Henriëtte A. Moll, MD, PhD; Ype Elgersma, PhD

JAMA. 2008;300(3):287-294.

Context  Neurofibromatosis type 1 (NF1) is among the most common genetic disorders that cause learning disabilities. Recently, it was shown that statin-mediated inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase restores the cognitive deficits in an NF1 mouse model.

Objective  To determine the effect of simvastatin on neuropsychological, neurophysiological, and neuroradiological outcome measures in children with NF1.

Design, Setting, and Participants  Sixty-two of 114 eligible children (54%) with NF1 participated in a randomized, double-blind, placebo-controlled trial conducted between January 20, 2006, and February 8, 2007, at an NF1 referral center at a Dutch university hospital.

Intervention  Simvastatin or placebo treatment once daily for 12 weeks.

Main Outcome Measures  Primary outcomes were scores on a Rey complex figure test (delayed recall), cancellation test (speed), prism adaptation, and the mean brain apparent diffusion coefficient based on magnetic resonance imaging. Secondary outcome measures were scores on the cancellation test (standard deviation), Stroop color word test, block design, object assembly, Rey complex figure test (copy), Beery developmental test of visual-motor integration, and judgment of line orientation. Scores were corrected for baseline performance, age, and sex.

Results  No significant differences were observed between the simvastatin and placebo groups on any primary outcome measure: Rey complex figure test (β = 0.10; 95% confidence interval [CI], –0.36 to 0.56); cancellation test (β = –0.19; 95% CI, –0.67 to 0.29); prism adaptation (odds ratio = 2.0; 95% CI, 0.55 to 7.37); and mean brain apparent diffusion coefficient (β = 0.06; 95% CI, –0.07 to 0.20). In the secondary outcome measures, we found a significant improvement in the simvastatin group in object assembly scores (β = 0.54; 95% CI, 0.08 to 1.01), which was specifically observed in children with poor baseline performance (β = 0.80; 95% CI, 0.29 to 1.30). Other secondary outcome measures revealed no significant effect of simvastatin treatment.

Conclusion  In this 12-week trial, simvastatin did not improve cognitive function in children with NF1.

Trial Registration  isrctn.org Identifier: ISRCTN14965707

Author Affiliations: NF1 Core (Cognitive Research) Team, Departments of General Pediatrics (Ms Krab and Drs De Goede-Bolder and Moll), Neuroscience (Ms Krab and Drs Van der Geest, De Zeeuw, and Elgersma), Pediatric Neurology (Mss Aarsen and Bouman and Drs Catsman-Berrevoets and Arts); Public Health (Dr Pluijm), Pediatric Radiology (Dr Lequin), and Psychiatry (Dr Kushner), Erasmus MC University Medical Center, Sophia Children's Hospital, Rotterdam, the Netherlands; Departments of Neurobiology, Psychiatry, and Psychology, Brain Research Institute, Los Angeles, California (Drs Kushner and Silva); and Netherlands Institute for Neuroscience, Royal Academy of Sciences (KNAW), Amsterdam, the Netherlands (Dr De Zeeuw).

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