Importance There are no approved medications for the core symptoms of autism spectrum disorder (ASD), socialization and communication difficulties. Objective To evaluate the efficacy and safety of balovaptan, an oral selective vasopressin 1a receptor antagonist, compared with placebo in children and adolescents with ASD. Design, Setting, and Participants The aV1ation study was a randomized, double-blind, 24-week, parallel-group, placebo-controlled phase 2 trial. Between November 22, 2016, and September 3, 2019, individuals were screened and randomly assigned to treatment groups. The primary efficacy analysis population comprised participants taking age-adjusted balovaptan equivalent to a 10-mg adult dose and participants from the concurrently randomized placebo group. This multicenter trial took place across 41 sites in the US. Participants were aged 5 to 17 years with diagnosed ASD and an IQ of 70 or greater. Data were analyzed from April 8 to November 16, 2020. Interventions Participants were randomly assigned to daily 4-mg or 10-mg adult-equivalent balovaptan or placebo, until the 4-mg group was discontinued. Main Outcomes and Measures The primary end point was change from baseline on the Vineland-II two-domain composite (2DC; socialization and communication domains) score at week 24. Results Between November 2016 and September 2019, a total of 599 individuals were screened and 339 participants were randomly assigned to receive 4-mg balovaptan adult-equivalent dose (91 [26.8%]), 10-mg balovaptan adult-equivalent dose (126 [37.2%]), or placebo (122 [36.0%]). Primary analysis included 86 participants assigned to receive 10-mg balovaptan adult-equivalent dose and 81 assigned to receive placebo (mean [SD] age, 12.1 [3.4] years; 139 male participants [83.2%]). No statistically significant differences were observed between the balovaptan and placebo groups in change from baseline on the Vineland-II 2DC score at week 24 (difference in adjusted least-squares mean, -0.16; 90% CI, -2.56 to 2.23; P = .91). No improvements for balovaptan vs placebo were observed at week 24 for any secondary end points. Balovaptan was well tolerated with no emerging safety concerns. Similar proportions of participants reported adverse events (balovaptan, 66 of 86 [76.7%] vs placebo, 61 of 81 [75.3%]) and serious adverse events (balovaptan, 1 of 86 [1.2%] vs placebo, 4 of 81 [4.9%]). Conclusions and Relevance In this randomized clinical trial, balovaptan did not demonstrate efficacy in improvement of socialization and communication in this population with pediatric ASD. Balovaptan was well tolerated in children 5 years or older. Further development of robust, sensitive, and objective outcome measures may help to improve future studies in the assessment of therapies targeting communication and socialization in pediatric ASD. Trial Registration ClinicalTrials.gov Identifier: NCT02901431.

中文翻译：

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Balovaptan 与安慰剂在儿童自闭症谱系障碍中的社交沟通：一项随机临床试验。

重要性 对于自闭症谱系障碍 (ASD)、社交和沟通困难的核心症状，目前尚无批准的药物。目的 评估与安慰剂相比，口服选择性加压素 1a 受体拮抗剂 balovaptan 在患有 ASD 的儿童和青少年中的疗效和安全性。设计、设置和参与者 aV1ation 研究是一项随机、双盲、为期 24 周、平行组、安慰剂对照的 2 期试验。2016 年 11 月 22 日至 2019 年 9 月 3 日期间，对个体进行筛选并随机分配到治疗组。主要疗效分析人群包括服用相当于 10 毫克成人剂量的经年龄调整的 balovaptan 的参与者和来自同时随机安慰剂组的参与者。这项多中心试验在美国的 41 个地点进行。参与者年龄在 5 至 17 岁之间，诊断为 ASD，智商为 70 或更高。分析了 2020 年 4 月 8 日至 11 月 16 日的数据。干预参与者被随机分配到每日 4 毫克或 10 毫克成人等效巴洛伐普坦或安慰剂组，直到 4 毫克组停药。主要成果和措施 主要终点是第 24 周时 Vineland-II 双领域综合（2DC；社会化和沟通领域）评分相对于基线的变化。结果 2016 年 11 月至 2019 年 9 月期间，共有 599 人接受了筛查和评估339 名参与者被随机分配接受 4 mg balovaptan 成人等效剂量 (91 [26.8%])、10 mg balovaptan 成人等效剂量 (126 [37.2%]) 或安慰剂 (122 [36.0%])。主要分析包括 86 名分配接受 10 mg balovaptan 成人等效剂量的参与者和 81 名分配接受安慰剂的参与者（平均 [SD] 年龄，12.1 [3.4] 岁；139 名男性参与者 [83.2%]）。在第 24 周时，balovaptan 组和安慰剂组之间的 Vineland-II 2DC 评分相对于基线的变化没有统计学显着差异（调整后的最小二乘平均值的差异，-0.16；90% CI，-2.56 至 2.23；P = . 91). 在第 24 周时，没有观察到 balovaptan 与安慰剂相比有任何次要终点的改善。Balovaptan 耐受性良好，没有新出现的安全问题。相似比例的参与者报告了不良事件（balovaptan，86 人中的 66 人 [76.7%] 对比安慰剂，81 人中的 61 人 [75.3%]）和严重不良事件（balovaptan，86 人中的 1 人 [1.2%] 对比安慰剂，81 人中的 4 人 [4.9] %]). 结论和相关性 在这项随机临床试验中，balovaptan 并未证明在改善儿童 ASD 人群的社交和沟通方面的功效。Balovaptan 在 5 岁或以上的儿童中耐受性良好。进一步开发稳健、敏感和客观的结果测量可能有助于改进未来针对儿科 ASD 沟通和社会化治疗的研究。试验注册 ClinicalTrials.gov 标识符：NCT02901431。客观的结果测量可能有助于改进未来针对儿科 ASD 沟通和社会化治疗的评估研究。试验注册 ClinicalTrials.gov 标识符：NCT02901431。客观的结果测量可能有助于改进未来针对儿科 ASD 沟通和社会化治疗的评估研究。试验注册 ClinicalTrials.gov 标识符：NCT02901431。