Social Pediatrics, School of Medicine, Technical University of Munich, Munich, Germany.
Münchner Studienzentrum, School of Medicine, Technical University of Munich, Munich, Germany.
Trials. 2023 Jun 6;24(1):383. doi: 10.1186/s13063-023-07392-z.
Cognitive impairment is a common medical issue in rat sarcoma (RAS) pathway disorders, so-called RASopathies, like Neurofibromatosis type 1 (NF1) or Noonan syndrome (NS). It is presumed to be caused by impaired synaptic plasticity. In animal studies, pathway-specific pharmacological interventions with lovastatin (LOV) and lamotrigine (LTG) have been shown to improve synaptic plasticity as well as cognitive function. The aim of this clinical trial is to translate the findings of animal studies to humans and to probe the effect of lovastatin (NS) and lamotrigine (NS and NF1) on synaptic plasticity and cognitive function/alertness in RASopathies.
Within this phase IIa, monocentre, randomized, double-blind, parallel-group, placebo-controlled, cross-over clinical trial (syn. SynCoRAS), three approaches (approaches I-III) will be carried out. In patients with NS, the effect of LTG (approach I) and of LOV (approach II) is investigated on synaptic plasticity and alertness. LTG is tested in patients with NF1 (approach III). Trial participants receive a single dose of 300 mg LTG or placebo (I and III) and 200 mg LOV or placebo (II) daily for 4 days with a cross-over after at least 7 days. Synaptic plasticity is investigated using a repetitive high-frequency transcranial magnetic stimulation (TMS) protocol called quadri-pulse theta burst stimulation (qTBS). Attention is examined by using the test of attentional performance (TAP). Twenty-eight patients are randomized in groups NS and NF1 with n = 24 intended to reach the primary endpoint (change in synaptic plasticity). Secondary endpoints are attention (TAP) and differences in short interval cortical inhibition (SICI) between placebo and trial medication (LTG and LOV).
The study is targeting impairments in synaptic plasticity and cognitive impairment, one of the main health problems of patients with RASopathies. Recent first results with LOV in patients with NF1 have shown an improvement in synaptic plasticity and cognition. Within this clinical trial, it is investigated if these findings can be transferred to patients with NS. LTG is most likely a more effective and promising substance improving synaptic plasticity and, consecutively, cognitive function. It is expected that both substances are improving synaptic plasticity as well as alertness. Changes in alertness may be a precondition for improvement of cognition.
The clinical trial is registered in ClinicalTrials.gov (NCT03504501; https://www.
gov ; date of registration: 04/11/2018) and in EudraCT (number 2016-005022-10).
认知障碍是大鼠肉瘤（RAS）通路疾病（所谓的 RAS 病）中的常见医学问题，如神经纤维瘤病 1 型（NF1）或努南综合征（NS）。据推测，它是由突触可塑性受损引起的。在动物研究中，已显示洛伐他汀（LOV）和拉莫三嗪（LTG）的通路特异性药理学干预可改善突触可塑性和认知功能。本临床试验的目的是将动物研究的发现转化为人类，并探究洛伐他汀（NS）和拉莫三嗪（NS 和 NF1）对 RAS 病中突触可塑性和认知功能/警觉性的影响。
在这项 IIa 期、单中心、随机、双盲、平行组、安慰剂对照、交叉临床试验（SynCoRAS）中，将进行三种方法（方法 I-III）。在 NS 患者中，研究 LTG（方法 I）和 LOV（方法 II）对突触可塑性和警觉性的影响。在 NF1 患者中测试 LTG（方法 III）。试验参与者每天接受 300mg LTG 或安慰剂（I 和 III）和 200mg LOV 或安慰剂（II）单次剂量，至少 7 天后进行交叉。使用称为四脉冲θ爆发刺激（qTBS）的重复高频经颅磁刺激（TMS）方案来研究突触可塑性。使用注意力表现测试（TAP）来检查注意力。将 28 名患者随机分为 NS 和 NF1 组，每组 24 名患者，旨在达到主要终点（突触可塑性变化）。次要终点是注意力（TAP）和安慰剂与试验药物（LTG 和 LOV）之间的短间隔皮质抑制（SICI）差异。
该研究针对的是 RAS 病患者的主要健康问题之一，即突触可塑性和认知障碍。最近在 NF1 患者中进行的 LOV 初步研究结果表明，突触可塑性和认知能力有所改善。在这项临床试验中，研究了这些发现是否可以转移到 NS 患者身上。LTG 很可能是一种更有效和更有前途的改善突触可塑性并随之改善认知功能的物质。预计这两种物质都能改善突触可塑性和警觉性。警觉性的变化可能是认知改善的前提。
该临床试验在 ClinicalTrials.gov 注册（NCT03504501；https://www.clinicaltrials.gov；注册日期：2018 年 11 月 4 日）和 EudraCT（编号 2016-005022-10）。
