Ph 2 Study of Dextromethorphan in the Treatment of Rett Syndrome

描述（由申请人提供）： 本次重新提交是一项在Kennedy Krieger研究所（KKI）/约翰霍普金斯医疗机构（JHMI）进行的安慰剂对照试验，研究美沙芬治疗Rett综合征（RTT）。 RTT是一种神经发育障碍，对大脑和 系统神经元患有RTT的女孩有癫痫发作和多动运动， 过度的兴奋性神经元活动，以及兴奋性神经递质的水平， 脑脊液中谷氨酸的含量升高脑磁共振波谱（MRS） 也显示出高水平的谷氨酸盐死后额叶神经递质放射自显影 来自8岁以下女孩的RTT皮质显示NMDA型显著增加， （N-甲基-D-天冬氨酸）谷氨酸受体，尽管其数量减少了50%， 突触此外，在体外研究培养的神经元从小鼠与突变， MECP 2基因对缺氧和谷氨酸介导的细胞凋亡异常敏感 兴奋性毒性 对这些小鼠的电生理学研究表明， 海马和皮层节律性放电。由于美沙芬（DM）竞争性阻断NMDA受体通道，申请人提出其将通过减少兴奋性突触活性从而拯救脑组织免于兴奋性毒性来改善RTT的临床表现（异常行为、认知缺陷、神经生理学异常和癫痫发作）。目前，RTT没有治愈方法。目的是测试糖尿病在RTT中改善沟通和减轻行为和身体症状的有效性和安全性。为了实现这一目标，结果测量是：主要结果：马伦量表上的接受语言年龄等效分数的改善;次要结果：a）马伦量表的其他子量表的改善; B）葡萄园适应行为的社会化和沟通量表的改善; c）社会互动的Ghuman-Folstein筛查的改善。探索性变量为a）异常行为检查表评分的变化; B）Rett综合征行为问卷; c）EEG和不匹配负波; d）生活质量问卷。共有60名受试者是DM的快代谢者，具有RTT的临床特征和MECP 2基因中的已知突变，将在双盲试验中使用区组和分层（针对年龄和癫痫发作的存在）随机化均等地随机分配至安慰剂或5 mg美沙芬/kg/天治疗12周。将在意向治疗基础上进行分析。

DESCRIPTION (provided by applicant): This resubmission is a Placebo controlled trial of dextromethorphan in Rett syndrome (RTT) to be conducted at the Kennedy Krieger Institute (KKI)/Johns Hopkins Medical Institutions (JHMI). RTT is a neurodevelopmental disorder with devastating consequences on both brain and systemic neurons. Girls with RTT have seizures and hyperkinetic movements suggesting excessive excitatory neuronal activity, and the levels of the excitatory neurotransmitter, glutamate, in cerebrospinal fluid are elevated. Brain magnetic resonance spectroscopy (MRS) also shows high levels of glutamate. Neurotransmitter autoradiography of postmortem frontal cortex from girls less than 8 years of age with RTT showed a significant increase in NMDA-type (N-methyl-D-aspartate) glutamate receptors despite a 50% reduction in the number of synapses. Additionally, in vitro studies of cultured neurons from mice with a mutation in the MECP2 gene show that they are abnormally sensitive to hypoxia and glutamate mediated excitotoxicity. Electrophysiologic studies of these mice show enhanced excitability in the hippocampus and rhythmic discharges in cortex on EEG. As dextromethorphan (DM) competitively blocks NMDA receptor channels, the applicant proposes that it will improve the clinical manifestations of RTT (abnormal behaviors, cognitive deficits, neurophysiological abnormalities, and seizures) by reducing excitatory synaptic activity thereby rescuing brain tissue from excitotoxicity. Presently, RTT has no cure. The objective is to test the efficacy and safety of DM in RTT to improve communication and alleviate behavioral and physical symptoms. Towards this goal, the outcome measures are: Primary outcome: Improvement in the receptive language age equivalent scores on the Mullen scale; Secondary outcomes: a) Improvement in other subscales of the Mullen; b) Improvement in the Socialization and Communication scales of Vineland Adaptive Behavior; c) Improvement in the Ghuman- Folstein Screen for Social Interaction. Exploratory variables are a) Change in the Aberrant Behavior Checklist scores; b) Rett Syndrome Behavior Questionnaire; c) EEG and MisMatch Negativity; d) Quality of Life Questionnaire. A total of 60 subjects who are fast metabolizers of DM, with clinical features of RTT and a known mutation in the MECP2 gene, will be equally randomized in a double-masked trial to placebo or treatment with 5mg dextromethorphan /kg/day for twelve weeks using a blocked and stratified (for age and the presence of seizures) randomization. Analyses will be done on an intention-to-treat basis.