Elsevier

The Lancet Neurology

Volume 12, Issue 11, November 2013, Pages 1076-1083
The Lancet Neurology

Articles
Simvastatin for cognitive deficits and behavioural problems in patients with neurofibromatosis type 1 (NF1-SIMCODA): a randomised, placebo-controlled trial

https://doi.org/10.1016/S1474-4422(13)70227-8Get rights and content

Summary

Background

Neurofibromatosis type 1 is a common genetic disorder characterised by neurocutaneous manifestations and cognitive and behavioural problems. Statins were shown to reduce analogous learning deficits in a mouse model of the disease, but a short-term trial in humans was inconclusive. We aimed to assess the use of simvastatin for the improvement of cognitive and behavioural deficits in children with neurofibromatosis type 1 for 12 months.

Methods

In this randomised, double-masked, placebo-controlled trial, we recruited children with genetically confirmed neurofibromatosis type 1 aged 8–16 years from two national referral centres in the Netherlands and Belgium. Those with symptomatic CNS abnormalities or on neurotropic medication, including stimulants, were excluded. Eligible patients were randomly assigned (1:1) via a computer-generated, permuted-block list to simvastatin (10 mg per day in month 1, 20 mg per day in month 2, and 20–40 mg per day in months 3–12) or placebo for 12 months. Investigators, participants, and parents were masked to treatment assignment. Primary outcome measures were full-scale intelligence (Wechsler intelligence scale for children), attention problems (child behaviour checklist, parent-rated [CBCL]), and internalising behavioural problems (CBCL). We did intention-to-treat analyses (of all patients who had outcome data) using linear regression of the 12 month outcome scores, adjusted for baseline performance. This trial is registered with the Netherlands Trial Register, number NTR2150.

Findings

We randomly assigned 84 children to a treatment group (43 to simvastatin, 41 to placebo) between March 9, 2010, and March 6, 2012. We did not assess outcomes in two patients in the placebo group because they needed additional drug therapy. Simvastatin for 12 months had no effect on full-scale intelligence (treatment effect compared with placebo −1·3 IQ points [95% CI −3·8 to 1·3]; p=0·33), attention problems (–1·6 T-score points [–4·3 to 1·0]; p=0·23), and internalising behavioural problems (–0·1 T-score points [–3·3 to 3·1]; p=0·96). 38 (88%) of 43 patients on simvastatin and 39 (95%) of 41 patients on placebo reported adverse events, which were serious in two and four patients, respectively.

Interpretation

12 month simvastatin treatment did not ameliorate cognitive deficits or behavioural problems in children with neurofibromatosis type 1. The use of 20–40 mg simvastatin per day for cognitive enhancement in children with neurofibromatosis type 1 is not recommended.

Funding

The Netherlands Organization for Health Research and Development (ZonMw), Research Foundation Flanders (FWO-Vlaanderen), Marguerite-Marie Delacroix Foundation, and the Dutch Neurofibromatosis Association (NFVN).

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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