ArticlesSimvastatin for cognitive deficits and behavioural problems in patients with neurofibromatosis type 1 (NF1-SIMCODA): a randomised, placebo-controlled trial
Introduction
Neurofibromatosis type 1 is a common autosomal-dominant disorder, with a prevalence of 1 in every 2500–3000 births.1 It is caused by loss-of-function mutations in the NF1 gene, which encodes neurofibromin, a negative regulator of rat-sarcoma viral oncogene homologue (Ras). Neurofibromatosis type 1 is characterised by cutaneous café-au-lait spots, neurofibromas, and cognitive and behavioural problems.2 Up to 80% of children aged 6–18 years with neurofibromatosis type 1 present with moderate to severe impairment in one or more areas of cognitive functioning, and 40% attend special education.3, 4 Moreover, 30–40% of children with neurofibromatosis type 1 fulfil criteria for attention deficit hyperactivity disorder and up to 60% have problems with executive functioning.3, 5 The average intelligence quotient (IQ) is 10–15 points lower in these children than in population or sibling control groups.3, 6 Parents of children with neurofibromatosis type 1 frequently report difficulties in their child's social daily life activities and a high rate of internalising behavioural problems, such as anxiety or mood disorders.7 Taken together, cognitive and behavioural deficits lead to lower academic achievement and loss of quality of life,4, 8, 9 persisting into adulthood.10
The learning and attention deficits noted in patients with neurofibromatosis type 1 are reported in the Nf1 +/− mouse model,11, 12, 13 accompanied by a decrease in synaptic plasticity.11, 12, 13 These animal studies have shown that the plasticity and behavioural deficits are reversed by reducing Ras activity.11, 14 Ras activity requires farnesylation, which allows Ras to anchor to the plasma membrane where it can be activated by growth-factor receptors and their adaptor proteins. Since cholesterol is an obligate precursor of farnesyl, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase have been suggested as a potential therapy for neurofibromatosis type 1. Indeed, lovastatin normalised Ras activity, rescued synaptic plasticity deficits, and restored learning and attention deficits in the Nf1 +/− mouse model.14 Results of a small, open-label, single-arm study of lovastatin in children with neurofibromatosis type 1 suggested that lovastatin improved memory and attention, and normalised default network functional connectivity measured with resting state functional MRI.15, 16
However, lovastatin is not approved or marketed in many parts of the world, including the European Union. The closest approved alternative, simvastatin, is similar in structure, pharmacokinetics, and blood–brain barrier permeability. Moreover, simvastatin is a slightly more potent inhibitor of HMG-CoA reductase and is better at reducing HMG-CoA reductase activity in neurons than is lovastatin.17, 18 Although findings of a randomised controlled trial reporting the short-term effect of simvastatin in children with neurofibromatosis type 1 showed no effect after 12 weeks on a set of primary outcome measures,6 a significant improvement was reported for a secondary outcome measure, the object assembly subtask of the Dutch translation of the third edition of the Wechsler intelligence scale for children (WISC-III-NL).6 Although this trial had an overall negative outcome, it had some limitations that might have affected its results: children on stimulant-medication were not excluded, and 12 week treatment was short, with only 4 weeks at the highest target dose. A longer treatment duration would have allowed the assessment of the effects on global cognitive functioning, daily life functioning, and behaviour, and might have been necessary to show clinical benefits.
Given the large amount of safety data in children6, 19 and worldwide marketing authorisation of simvastatin, we aimed to improve upon the limitations of this previous trial by assessing the use of simvastatin for the treatment of cognitive and behavioural deficits in children with neurofibromatosis type 1 for 12 months.
Section snippets
Study design and participants
We undertook this randomised, parallel-group, placebo-controlled trial in two national referral centres: Erasmus MC (Rotterdam, Netherlands) and UZ Leuven (Leuven, Belgium). We screened patients aged 8–16 years with genetically confirmed neurofibromatosis type 1 for eligibility. Genetic counselling and testing for neurofibromatosis type 1 is part of routine care and was done independently of this trial. The rationale for genetic confirmation was the substantial overlap in phenotypes between
Results
We screened 343 patients for eligibility, of whom 221 were eligible. Between March 9, 2010, and March 6, 2012, we obtained informed consent from 84 patients or their parents. They were randomly assigned to 12 months of treatment with simvastatin (n=43) or placebo (n=41). Two patients in the placebo group were lost to follow-up before outcome could be assessed because they had behavioural problems that required drug therapy. Two participants in the placebo group discontinued study medication,
Discussion
Here we present the outcome of our randomised, double-masked, placebo-controlled trial aimed at improving cognitive deficits in children with neurofibromatosis type 1. Our results showed that simvastatin treatment for 12 months had no effect on full-scale intelligence, attention problems, or internalising behavioural problems. Moreover, we found no indications of efficacy on a carefully selected range of predefined secondary outcome measures. Hence, this trial refutes a role for simvastatin in
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