Phase 2 Study of the Efficacy and Safety of ORC-13661 for the Prevention of Ototoxicity in Patients Receiving Intravenous Amikacin for Treatment of Non-Tuberculous Mycobacterium Infection

项目总结 ORC-13661是一种正在开发的新化学物质，用于预防暴露于辐射的患者的听力损失 氨基糖苷类抗生素(AGs)。Ags是一类重要的广谱抗生素。 对革兰氏阴性细菌和分枝杆菌有效。不幸的是，多达20%的患者 静脉注射超过5天的AGG会导致永久性的、可测量的听力损失， 60%的患者接受长期治疗。很大程度上是因为耳毒性副作用，AGG目前 仅在危及生命或是唯一有效治疗方法的情况下使用。在这个时候 目前还没有FDA批准的药物被证明可以预防任何形式的感觉神经性听力损失。 预防AG引起的听力损失将对目前正在接受AG治疗的患者有极大的好处。它 这也将使这种廉价有效但未得到充分利用的抗生素能够更常规地使用。 口服ORC-13661是从一种小分子筛选器开发出来的，目的是找到一种减轻AG诱导的头发的方法 细胞毒性。对长期服用大剂量银杏叶提取物所致大鼠听力损失有明显的预防作用。 ORC-13661已经在正常健康志愿者身上完成了非临床评估和第一阶段测试。 肺部和播散性非结核分支杆菌(NTM)感染是慢性传染病。 随着时间的推移逐渐发展，需要长期的AG非肠道治疗才能达到控制或治愈的目的。 目前的指南推荐氨基糖苷(AG)肠外治疗，通常为90天的阿米卡星疗程， 适用于有严重症状的患者，尤其是支气管扩张症患者。 我们提出了一项随机、双盲、安慰剂对照、多中心、ORC-13661的2期研究 口服联合静脉注射阿米卡星治疗重症NTM 感染。其目的是评估ORC-13661在减轻或预防耳毒性方面的疗效。 主要和次要终点是基线测量之间的变化，如果听力阈值和 在药物治疗前和治疗后，接受治疗的患者组停止在噪音中听力 阿米卡星单独或与阿米卡星和ORC-13661合用。额外的评估将改变患者感知的 听力和平衡健康以及ORC-13661在非脑膜瘤患者中的安全性和耐受性 临床实验室检查、生命体征和心电图检查。

PROJECT SUMMARY ORC-13661 is a new chemical entity being developed to prevent hearing loss in patients exposed to aminoglycoside antibiotics (AGs). AGs are an important class of broad spectrum antibiotics especially effective against gram-negative bacteria and Mycobacteria. Unfortunately, as many as 20% of patients administered parenteral AGs for over 5 days suffer permanent, measurable hearing loss, as do upwards of 60% of patients on long term therapy. Largely because of the ototoxic side effects, AGs are currently administered only for life threatening situations or where they are the only effective treatment. At this time there are no FDA approved drugs that have been shown to prevent any form of sensorineural hearing loss. Preventing AG-induced hearing loss would be of enormous benefit patients currently being treated with AGs. It would also allow this inexpensive and effective but underused class of antibiotics to be used more routinely. Oral ORC-13661was developed from a small molecule screen aimed finding a way to mitigate AG-induced hair cell toxicity. It is robustly effective at preventing hearing loss in rats treated with prolonged high dose AGs. ORC-13661 has completed nonclinical evaluation and Phase 1 testing in normal healthy volunteers. Pulmonary and disseminated non-tuberculous Mycobacteria (NTM) infections are chronic infectious diseases that develop progressively over time, and require prolonged parenteral AG therapy to achieve control or a cure. Current guidelines recommend parenteral aminoglycoside (AG) therapy, usually a 90 day course of amikacin, for patients with severe manifestations of the disease, particularly bronchiectasis. We propose a randomized, double-blind, placebo-controlled, multicenter, phase 2 study of ORC-13661 administered orally in conjunction with intravenously administered amikacin to patients with severe NTM infections. The goal of this to evaluate the efficacy of ORC-13661 for mitigation or prevention of ototoxicity. Primary and secondary endpoints are changes in between baseline measures if hearing thresholds and hearing in noise taken prior to drug treatment and after treatment is discontinued in groups of patients treated with amikacin alone or with amikacin plus ORC-13661. Additional evaluations will changes in patient perceived hearing and balance health and the safety and tolerability of ORC-13661 in patients with NTM as assessed by AEs, clinical laboratory findings, vital signs, and electrocardiogram (ECG).