Department of Neuroscience, Erasmus University Medical Centre, Rotterdam, Netherlands; Department of Paediatrics, Erasmus University Medical Centre, Rotterdam, Netherlands; ENCORE Expertise Centre For Neurodevelopmental Disorders, Erasmus University Medical Centre, Rotterdam, Netherlands.
Lancet Neurol. 2013 Nov;12(11):1076-83. doi: 10.1016/S1474-4422(13)70227-8. Epub 2013 Oct 1.
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.
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.
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.
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.
The Netherlands Organization for Health Research and Development (ZonMw), Research Foundation Flanders (FWO-Vlaanderen), Marguerite-Marie Delacroix Foundation, and the Dutch Neurofibromatosis Association (NFVN).
1 型神经纤维瘤病是一种常见的遗传疾病，其特征为神经皮肤表现以及认知和行为问题。他汀类药物已被证明可减少疾病小鼠模型中的类似学习缺陷，但人类的短期试验尚无定论。我们旨在评估辛伐他汀在改善 1 型神经纤维瘤病儿童认知和行为缺陷方面的作用，为期 12 个月。
在这项随机、双盲、安慰剂对照试验中，我们从荷兰和比利时的两个国家转诊中心招募了经基因确认患有 1 型神经纤维瘤病的 8-16 岁儿童。有症状性中枢神经系统异常或正在接受神经毒性药物治疗（包括兴奋剂）的患者被排除在外。合格的患者通过计算机生成的、随机块列表以 1:1 的比例随机分配至辛伐他汀（第 1 个月每天 10mg，第 2 个月每天 20mg，第 3 至 12 个月每天 20-40mg）或安慰剂治疗 12 个月。研究者、参与者和家长对治疗分配均不知情。主要结局测量指标为全量表智力（儿童韦氏智力量表）、注意力问题（儿童行为检查表，家长评定[CBCL]）和内化行为问题（CBCL）。我们使用线性回归对 12 个月的结局评分进行意向治疗分析（对所有有结局数据的患者），并根据基线表现进行了调整。本试验在荷兰试验注册中心（NTR2150）注册。
我们于 2010 年 3 月 9 日至 2012 年 3 月 6 日之间将 84 名儿童随机分配至治疗组（43 名接受辛伐他汀治疗，41 名接受安慰剂治疗）。由于另外两名接受安慰剂治疗的患者需要接受额外的药物治疗，因此我们没有评估他们的结局。辛伐他汀治疗 12 个月对全量表智力（与安慰剂相比的治疗效果为 -1.3 个智商点[95%CI -3.8 至 1.3]；p=0.33）、注意力问题（-1.6 个 T 分数[4.3 至 1.0]；p=0.23）和内化行为问题（-0.1 个 T 分数[-3.3 至 3.1]；p=0.96）均无影响。43 名接受辛伐他汀治疗的患者中有 38 名（88%）和 41 名接受安慰剂治疗的患者中有 39 名（95%）报告了不良事件，分别有 2 名和 4 名患者的不良事件为严重不良事件。
辛伐他汀治疗 12 个月并未改善神经纤维瘤病 1 型儿童的认知缺陷或行为问题。不建议每天使用 20-40mg 辛伐他汀来增强神经纤维瘤病 1 型儿童的认知能力。
荷兰健康研究与发展组织（ZonMw）、佛兰德研究基金会（FWO-Vlaanderen）、玛格丽特-玛丽·德拉罗克基金会（Marguerite-Marie Delacroix Foundation）和荷兰神经纤维瘤病协会（NFVN）。
