Ligsay Andrew, Van Dijck Anke, Nguyen Danh V, Lozano Reymundo, Chen Yanjun, Bickel Erika S, Hessl David, Schneider Andrea, Angkustsiri Kathleen, Tassone Flora, Ceulemans Berten, Kooy R Frank, Hagerman Randi J
Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California, Davis Medical Center, 2825 50th Street, Sacramento, CA, 95817, USA.
University of California, Davis School of Medicine, Sacramento, CA, USA.
J Neurodev Disord. 2017 Aug 2;9(1):26. doi: 10.1186/s11689-017-9207-8.
Gamma-aminobutyric acid (GABA) system deficits are integral to the pathophysiologic development of fragile X syndrome (FXS). Ganaxolone, a GABA receptor positive allosteric modulator, is hypothesized to improve symptoms such as anxiety, hyperactivity, and attention deficits in children with FXS.
This study was a randomized, double-blind, placebo-controlled, crossover trial of ganaxolone in children with FXS, aged 6-17 years.
Sixty-one participants were assessed for eligibility, and 59 were randomized to the study. Fifty-five participants completed at least the first arm and were included in the intention-to-treat analysis; 51 participants completed both treatment arms. There were no statistically significant improvements observed on the primary outcome measure (Clinical Global Impression-Improvement), the key secondary outcome measure (Pediatric Anxiety Rating Scale-R), or any other secondary outcome measures in the overall study population. However, post-hoc analyses revealed positive trends in areas of anxiety, attention, and hyperactivity in participants with higher baseline anxiety and low full-scale IQ scores. No serious adverse events (AEs) occurred, although there was a significant increase in the frequency and severity of AEs related to ganaxolone compared to placebo.
While ganaxolone was found to be safe, there were no significant improvements in the outcome measures in the overall study population. However, ganaxolone in subgroups of children with FXS, including those with higher anxiety or lower cognitive abilities, might have beneficial effects.
ClinicalTrials.gov, NCT01725152.
γ-氨基丁酸（GABA）系统缺陷是脆性X综合征（FXS）病理生理发展的一个组成部分。甘氨酰环己酮，一种GABA受体正向变构调节剂，被认为可以改善FXS患儿的焦虑、多动和注意力缺陷等症状。
本研究是一项针对6至17岁FXS患儿的甘氨酰环己酮随机、双盲、安慰剂对照、交叉试验。
61名参与者接受了资格评估，59名被随机分配到该研究中。55名参与者至少完成了第一个治疗组，并被纳入意向性分析；51名参与者完成了两个治疗组。在总体研究人群中，主要结局指标（临床总体印象-改善）、关键次要结局指标（儿童焦虑评定量表-R）或任何其他次要结局指标均未观察到统计学上的显著改善。然而，事后分析显示，基线焦虑水平较高且全量表智商得分较低的参与者在焦虑、注意力和多动方面呈现出积极趋势。尽管与安慰剂相比，与甘氨酰环己酮相关的不良事件的频率和严重程度显著增加，但未发生严重不良事件。
虽然发现甘氨酰环己酮是安全的，但总体研究人群的结局指标没有显著改善。然而，甘氨酰环己酮在FXS患儿亚组中，包括那些焦虑程度较高或认知能力较低的患儿，可能具有有益效果。
ClinicalTrials.gov，NCT01725152。
