Effect of a novel nasal oxytocin spray with enhanced bioavailability on autism: a randomized trial
Effect of a novel nasal oxytocin spray with enhanced bioavailability on autism: a randomized trial
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DOI：
10.1093/brain/awab291
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发表时间：
2022-04-18
期刊：
影响因子：
14.5
通讯作者：
Okada, Takashi
中科院分区：
文献类型：
--
作者：
Yamasue, Hidenori;Kojima, Masaki;Okada, Takashi
虽然鼻内催产素有望成为一种治疗自闭症谱系障碍核心症状的新疗法，但目前尚无批准的药物，但多次给药的效果并不一致，这表明单次给药的最佳剂量并不是多次给药的最佳剂量。目前的双盲、安慰剂对照、多中心、交叉试验（ClinicalTrials.gov）NCT03466671)旨在测试TTA-121的效果，TTA-121是一种新的鼻内催产素喷雾剂，具有增强的生物利用度（比Syntocinon (R)喷雾剂高3.6倍，通过兔脑浓度-时间曲线下的面积来评估），使我们能够测试大范围的多剂量，对自闭症频谱障碍的核心症状，并确定剂量-反应关系。以交叉方式给药四周的TTA-121，低剂量每天1次（3u /天），低剂量每天2次（6u /天），高剂量每天1次（10u /天），或高剂量每天2次（20u /天），以及4周安慰剂。主要结果为每个给药期基线和终点在自闭症诊断观察表上互惠得分的平均差异（范围：0-14，数值越高代表结果越差）。这项试验分为两个给药期和八个组，在日本的七所大学医院进行，招募了患有高功能自闭症谱系障碍的成年男性。招生于2018年6月开始，2019年12月结束。随访于2020年3月结束。109名患有高功能自闭症谱系障碍的男性被随机抽取，其中103人完成了试验。作为剂量-反应关系的判断，最小的P值与TTA-121 6U/天的峰值相反，在全分析集（P = 0.182）和每个方案集（P = 0.073）均呈倒u形。与安慰剂组相比，在TTA-121 6 U/天给药期间，自闭症诊断观察计划互惠评分（主要结局）降低（完整分析集：P = 0.118，平均差异= -0.5;95% CI: -1.1至0.1；每个方案集：P = 0.012，平均差异= -0.8;95% CI: -1.3至-0.2）。每个方案集是分析目标人群，包括所有完整的分析集参与者，除了那些偏离方案的参与者。从完整分析集到每个方案集的大多数退出是由于对试验药物的依从性差（第一期12人中有9人，第二期15人中有8人）。在完整的分析集中，与安慰剂相比，ta -121的次要临床和行为结果没有显着改善。一种新型的增强生物利用度的鼻内催产素喷雾剂使我们能够测试大范围的多种剂量，显示出倒u型剂量-反应曲线，剂量峰值低于先前研究的预期。目前探索性研究中显示的TTA-121的疗效需要在未来的大规模平行组试验中得到验证。
Although intranasal oxytocin is expected to be a novel therapy for the core symptoms of autism spectrum disorder, which has currently no approved medication, the efficacy of repeated administrations was inconsistent, suggesting that the optimal dose for a single administration of oxytocin is not optimal for repeated administration.The current double-blind, placebo-controlled, multicentre, crossover trial (ClinicalTrials.gov Identifier: NCT03466671) was aimed to test the effect of TTA-121, a new formulation of intranasal oxytocin spray with an enhanced bioavailability (3.6 times higher than Syntocinon (R) spray, as assessed by area under the concentration-time curve in rabbit brains), which enabled us to test a wide range of multiple doses, on autism spectrum disorder core symptoms and to determine the dose-response relationship. Four-week administrations of TTA-121, at low dose once per day (3 U/day), low dose twice per day (6 U/day), high dose once per day (10 U/day), or high dose twice per day (20 U/day), and 4-week placebo were administered in a crossover manner. The primary outcome was the mean difference in the reciprocity score (range: 0-14, higher values represent worse outcomes) on the Autism Diagnostic Observation Schedule between the baseline and end point of each administration period. This trial with two administration periods and eight groups was conducted at seven university hospitals in Japan, enrolling adult males with high-functioning autism spectrum disorder. Enrolment began from June 2018 and ended December 2019. Follow-up ended March 2020.Of 109 males with high-functioning autism spectrum disorder who were randomized, 103 completed the trial. The smallest P-value, judged as the dose-response relationship, was the contrast with the peak at TTA-121 6U/day, with inverted U-shape for both the full analysis set (P = 0.182) and per protocol set (P = 0.073). The Autism Diagnostic Observation Schedule reciprocity score, the primary outcome, was reduced in the TTA-121 6 U/day administration period compared with the placebo (full analysis set: P = 0.118, mean difference = -0.5; 95% CI: -1.1 to 0.1; per protocol set: P = 0.012, mean difference = -0.8; 95% CI: -1.3 to -0.2). The per protocol set was the analysis target population, consisting of all full analysis set participants except those who deviated from the protocol. Most dropouts from the full analysis set to the per protocol set occurred because of poor adherence to the test drug (9 of 12 in the first period and 8 of 15 in the second period). None of the secondary clinical and behavioural outcomes were significantly improved with the TTA-121 compared with the placebo in the full analysis set.A novel intranasal spray of oxytocin with enhanced bioavailability enabled us to test a wide range of multiple doses, revealing an inverted U-shape dose-response curve, with the peak at a dose that was lower than expected from previous studies. The efficacy of TTA-121 shown in the current exploratory study should be verified in a future large-scale, parallel-group trial.