Randomized placebo-controlled study of lovastatin in children with neurofibromatosis type 1

Objective: To assess the efficacy of lovastatin on visuospatial learning and attention for treating cognitive and behavioral deficits in children with neurofibromatosis type 1 (NF1). Methods: A multicenter, international, randomized, double-blind, placebo-controlled trial was conducted between July 2009 and May 2014 as part of the NF Clinical Trials Consortium. Children with NF1 aged 8–15 years were screened for visuospatial learning or attention deficits (n = 272); 146 children demonstrated deficits at baseline and were randomly assigned to lovastatin (n = 74; 40 mg/d) or placebo (n = 70). Treatment was administered once daily for 16 weeks. Primary outcomes were total errors on the Cambridge Neuropsychological Test Automated Battery Paired Associate Learning task (visuospatial learning) and the Score subtest from the Test of Everyday Attention for Children (sustained attention). Secondary outcomes measured executive function, attention, visuospatial skills, behavior, and quality of life. Primary analyses were performed on the intention-to-treat population. Results: Lovastatin had no significant effect on primary outcomes after 16 weeks of treatment: visuospatial learning (Cohen d = −0.15, 95% confidence interval −0.47 to 0.18) or sustained attention (Cohen d = 0.19, 95% confidence interval −0.14 to 0.53). Lovastatin was well tolerated, with no increase in reported adverse events compared to placebo. Conclusions: Lovastatin administered once daily for 16 weeks did not improve visuospatial learning or attention in children with NF1 and is not recommended for amelioration of cognitive deficits in this population. ClinicalTrials.gov identifier: This study was registered at ClinicalTrials.gov (NCT00853580) and Australian New Zealand Clinical Trials Registry (ACTRN12607000560493). Classification of evidence: This study provides Class I evidence that for children with NF1, lovastatin does not improve visuospatial learning or attention deficits.

[1]  F. Irani,et al.  Judgment of Line Orientation , 2017 .

[2]  Alcino J. Silva,et al.  A randomized placebo‐controlled lovastatin trial for neurobehavioral function in neurofibromatosis I , 2016, Annals of clinical and translational neurology.

[3]  C. Gerloff,et al.  Impairment of Procedural Learning and Motor Intracortical Inhibition in Neurofibromatosis Type 1 Patients , 2015, EBioMedicine.

[4]  M. Castelo‐Branco,et al.  Abnormal relationship between GABA, neurophysiology and impulsive behavior in neurofibromatosis type 1 , 2015, Cortex.

[5]  C. Catsman-Berrevoets,et al.  Simvastatin for cognitive deficits and behavioural problems in patients with neurofibromatosis type 1 (NF1-SIMCODA): a randomised, placebo-controlled trial , 2013, The Lancet Neurology.

[6]  Long-Sheng Chang,et al.  ERK Inhibition Rescues Defects in Fate Specification of Nf1-Deficient Neural Progenitors and Brain Abnormalities , 2012, Cell.

[7]  Michael P. Milham,et al.  Lovastatin regulates brain spontaneous low-frequency brain activity in Neurofibromatosis type 1 , 2012, Neuroscience Letters.

[8]  K. North,et al.  Paired associate learning in children with neurofibromatosis type 1: implications for clinical trials , 2012, Journal of Neurology.

[9]  G. Gioia,et al.  Lovastatin as treatment for neurocognitive deficits in neurofibromatosis type 1: phase I study. , 2011, Pediatric neurology.

[10]  W. Brown.  Framingham Heart Study. , 2011, Journal of clinical lipidology.

[11]  Kathryn N North,et al.  Brain structure and function in neurofibromatosis type 1: current concepts and future directions , 2010, Journal of Neurology, Neurosurgery & Psychiatry.

[12]  S. Huson,et al.  Birth incidence and prevalence of tumor‐prone syndromes: Estimates from a UK family genetic register service , 2010, American journal of medical genetics. Part A.

[13]  Cecil R. Reynolds,et al.  Behavior Assessment System for Children , 2010 .

[14]  Alcino J. Silva,et al.  Effect of Simvastatin on Cognitive Functioning in Children with Neurofibromatosis Type 1 a Randomized Controlled Trial , 2022 .

[15]  Alcino J. Silva,et al.  The HMG-CoA Reductase Inhibitor Lovastatin Reverses the Learning and Attention Deficits in a Mouse Model of Neurofibromatosis Type 1 , 2005, Current Biology.

[16]  Kathryn N North,et al.  The nature and frequency of cognitive deficits in children with neurofibromatosis type 1 , 2005, Neurology.

[17]  R. D'Agostino,et al.  Serum Cholesterol and Cognitive Performance in the Framingham Heart Study , 2005, Psychosomatic medicine.

[18]  Sharlene D. Newman,et al.  Frontal and parietal participation in problem solving in the Tower of London: fMRI and computational modeling of planning and high-level perception , 2003, Neuropsychologia.

[19]  D. Altman,et al.  Analysing controlled trials with baseline and follow up measurements , 2001, BMJ : British Medical Journal.

[20]  I. Baron.  Test of Everyday Attention for Children; The Thames Valley Test Company, Bury St. Edmunds, Suffolk, UK , 2001 .

[21]  Michael Seid,et al.  PedsQL™ 4.0: Reliability and Validity of the Pediatric Quality of Life Inventory™ Version 4.0 Generic Core Scales in Healthy and Patient Populations , 2001, Medical care.

[22]  I. Baron,et al.  Test of Everyday Attention for Children; The Thames Valley Test Company, Bury St. Edmunds, Suffolk, UK , 2001, Child neuropsychology : a journal on normal and abnormal development in childhood and adolescence.

[23]  N. Jacobson,et al.  Clinical significance: a statistical approach to defining meaningful change in psychotherapy research. , 1991, Journal of consulting and clinical psychology.

[24]  Neurofibromatosis. Conference statement. National Institutes of Health Consensus Development Conference. , 1988, Archives of neurology.