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

ORC-13661预防静脉阿米卡星治疗非结核分枝杆菌感染患者耳毒性的有效性和安全性的2期研究

• 批准号: 10706468
• 负责人: Edwin W Rubel
• 金额: $ 104.46万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10706468
• 关键词: Adult; Adverse event; Aftercare; Air; Amikacin; Aminoglycoside Antibiotics; Aminoglycosides; Animal Model; Antibiotic Therapy; Antibiotics; Auditory Threshold; Azithromycin; Biological Availability; Bronchiectasis; Canis familiaris; Chronic; Chronic Disease; Clarithromycin; Clinical; Cochlea; Communicable Diseases; Control Animal; Data Reporting; Deterioration; Diagnosis; Disease; Disease Progression; Dose; Double-Blind Method; Drug Exposure; Drug Kinetics; Elderly; Electrocardiogram; Equilibrium; Equipment and supply inventories; Evaluation; Exposure to; FDA approved; Frequencies; Genus Mycobacterium; Goals; Gram-Negative Bacteria; Guidelines; Hair Cells; Half-Life; Health; Hearing; Hearing Protection; Human Volunteers; In Vitro; Intravenous; Laboratories; Laboratory Finding; Legal patent; Life; Lung; Measurable; Measures; Metabolic; Multi-Institutional Clinical Trial; Mus; Mycobacterium Infections; Neonatal; Oral; Oral Administration; Organ of Corti; Patients; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phase; Placebo Control; Plasma; Prevention; Publishing; Quality of life; Randomized; Rattus; Recommendation; Research; Rifampin; Safety; Sensorineural Hearing Loss; Sensory Hair; Serious Adverse Event; Swimming; Symptoms; Testing; Therapeutic Index; Time; Tinnitus; Toxic effect; Toxicology; Treatment Protocols; United States; Universities; Vertigo; Washington; Woman; Work; Zebrafish; aminoglycoside-induced ototoxicity; awake; bactericide; bone; chronic infection; clinically relevant; design; effective therapy; effectiveness evaluation; efficacy evaluation; efficacy study; experimental study; healthy volunteer; hearing impairment; in vivo; indexing; intravenous administration; men; neonatal mice; new chemical entity; non-tuberculosis mycobacteria; non-tuberculous mycobacterial infection; novel; novel therapeutics; ototoxicity; overtreatment; parenteral administration; phase 1 testing; phase 2 study; pre-clinical; prevent; prevent hearing loss; primary endpoint; programs; response; safety study; secondary endpoint; side effect; small molecule; speech in noise; tool; treatment duration

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).

项目概要 ORC-13661是一种新的化学实体，正在开发中，用于预防暴露于以下环境的患者的听力损失： 氨基糖苷类抗生素（AG）。 AG 是一类重要的广谱抗生素，尤其是 对革兰氏阴性菌和分枝杆菌有效。不幸的是，多达 20% 的患者 注射 AG 超过 5 天会出现永久性、可测量的听力损失，超过 5 天也会出现这种情况。 60%的患者接受长期治疗。主要是由于耳毒性副作用，目前 AG 仅在危及生命的情况下或当它们是唯一有效的治疗时才进行。此时 目前还没有 FDA 批准的药物被证明可以预防任何形式的感音神经性听力损失。 预防 AG 引起的听力损失将对目前接受 AG 治疗的患者带来巨大益处。它 也将使这种廉价且有效但未得到充分利用的抗生素类别得到更常规的使用。 口服 ORC-13661 是通过小分子筛选开发的，旨在寻找减轻 AG 引起的毛发的方法 细胞毒性。对于长期接受高剂量 AG 治疗的大鼠来说，它可以非常有效地预防听力损失。 ORC-13661已在正常健康志愿者中完成非临床评估和一期测试。 肺部和播散性非结核分枝杆菌 (NTM) 感染是慢性传染病 随着时间的推移逐渐发展，需要长期肠外 AG 治疗才能实现控制或治愈。 目前的指南推荐肠外氨基糖苷类 (AG) 治疗，通常是 90 天的阿米卡星疗程， 对于有严重疾病表现的患者，特别是支气管扩张的患者。 我们提出了一项针对 ORC-13661 的随机、双盲、安慰剂对照、多中心、2 期研究 严重 NTM 患者口服阿米卡星联合静脉注射阿米卡星 感染。目的是评估 ORC-13661 缓解或预防耳毒性的功效。 主要和次要终点是基线测量之间的变化，如果听力阈值和 在接受治疗的患者组中，在药物治疗前和停止治疗后采集噪音中的听力 单独使用阿米卡星或阿米卡星加 ORC-13661。额外的评估将改变患者的感知 NTM 患者的听力和平衡健康状况以及 ORC-13661 的安全性和耐受性经评估 AE、临床实验室检查结果、生命体征和心电图 (ECG)。