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Abstract：
BACKGROUNDFXLEARN, the first-ever large multisite trial of effects of disease-targeted pharmacotherapy on learning, was designed to explore a paradigm for measuring effects of mechanism-targeted treatment in fragile X syndrome (FXS). In FXLEARN, the effects of metabotropic glutamate receptor type 5 (mGluR5) negative allosteric modulator (NAM) AFQ056 on language learning were evaluated in 3- to 6-year-old children with FXS, expected to have more learning plasticity than adults, for whom prior trials of mGluR5 NAMs have failed.METHODSAfter a 4-month single-blind placebo lead-in, participants were randomized 1:1 to AFQ056 or placebo, with 2 months of dose optimization to the maximum tolerated dose, then 6 months of treatment during which a language-learning intervention was implemented for both groups. The primary outcome was a centrally scored videotaped communication measure, the Weighted Communication Scale (WCS). Secondary outcomes were objective performance-based and parent-reported cognitive and language measures.RESULTSFXLEARN enrolled 110 participants, randomized 99, and had 91 who completed the placebo-controlled period. Although both groups made language progress and there were no safety issues, the change in WCS score during the placebo-controlled period was not significantly different between the AFQ056 and placebo-treated groups, nor were there any significant between-group differences in change in any secondary measures.CONCLUSIONDespite the large body of evidence supporting use of mGluR5 NAMs in animal models of FXS, this study suggests that this mechanism of action does not translate into benefit for the human FXS population and that better strategies are needed to determine which mechanisms will translate from preclinical models to humans in genetic neurodevelopmental disorders.TRIAL REGISTRATIONClincalTrials.gov NCT02920892.FUNDING SOURCESNeuroNEXT network NIH grants U01NS096767, U24NS107200, U24NS107209, U01NS077323, U24NS107183, U24NS107168, U24NS107128, U24NS107199, U24NS107198, U24NS107166, U10NS077368, U01NS077366, U24NS107205, U01NS077179, and U01NS077352; NIH grant P50HD103526; and Novartis IIT grant AFQ056X2201T for provision of AFQ056.
摘要：
背景：FXLEARN，首次针对疾病靶向药物治疗对学习的影响的大型多站点试验，旨在探索一种新的范式，用于测量脆性X综合征（FXS）的机制靶向治疗的效果。在FXLEARN,mGluR5负变构调节剂（NAM）AFQ056对3-6岁FXS儿童语言学习的影响进行了评估，预期比成年人有更多的学习可塑性，先前的mGluR5NAMs试验失败。
方法：经过4个月的单盲安慰剂导入，参与者以1:1的比例随机分配到AFQ056或安慰剂，2个月的剂量优化至最大耐受剂量，然后进行6个月的治疗,期间对两组患者实施语言学习干预.主要结果是集中评分的视频沟通措施，加权通信标度(WCS)。次要结果是基于客观表现和父母报告的认知和语言测量。
结果：FXLEARN注册了110名参与者，随机分组99，91完成安慰剂对照期。尽管两组语言都取得了进步，并且没有安全问题，安慰剂对照期间WCS评分的变化在AFQ056和安慰剂治疗组之间没有显着差异，在任何次要指标的变化方面,组间也没有显著差异.
结论：尽管大量证据支持在FXS动物模型中使用mGluR5NAMs，这项研究表明,这种作用机制并未转化为人类FXS人群的益处,因此需要更好的策略来确定在遗传性神经发育障碍中,哪些机制将从临床前模型转化为人类.
背景：ClincalTrials.govNCT02920892资助。这项研究得到了NeuroNEXT网络NIH授予U01NS096767、U24NS107200、U24NS107209、U01NS077323、U24NS107183、U24NS107168、U24NS107128、U24NS107198、U24NS107166、U24NS107NovQ2017166、UQ201UNS107grant、U
方法：经过4个月的单盲安慰剂导入，参与者以1:1的比例随机分配到AFQ056或安慰剂，2个月的剂量优化至最大耐受剂量，然后进行6个月的治疗,期间对两组患者实施语言学习干预.主要结果是集中评分的视频沟通措施，加权通信标度(WCS)。次要结果是基于客观表现和父母报告的认知和语言测量。
结果：FXLEARN注册了110名参与者，随机分组99，91完成安慰剂对照期。尽管两组语言都取得了进步，并且没有安全问题，安慰剂对照期间WCS评分的变化在AFQ056和安慰剂治疗组之间没有显着差异，在任何次要指标的变化方面,组间也没有显著差异.
结论：尽管大量证据支持在FXS动物模型中使用mGluR5NAMs，这项研究表明,这种作用机制并未转化为人类FXS人群的益处,因此需要更好的策略来确定在遗传性神经发育障碍中,哪些机制将从临床前模型转化为人类.
背景：ClincalTrials.govNCT02920892资助。这项研究得到了NeuroNEXT网络NIH授予U01NS096767、U24NS107200、U24NS107209、U01NS077323、U24NS107183、U24NS107168、U24NS107128、U24NS107198、U24NS107166、U24NS107NovQ2017166、UQ201UNS107grant、U
