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).

项目摘要 ORC-13661是一种开发的新化学实体，以防止暴露于 氨基糖苷抗生素（AGS）。 AG是一类重要的广谱抗生素类 有效防止革兰氏阴性细菌和分枝杆菌。不幸的是，多达20％的患者 管理肠胃外AGS超过5天，遭受永久性，可衡量的听力损失，以上 长期治疗的患者中有60％。主要是由于耳毒性副作用，AG当前是 仅针对威胁生命的情况或它们是唯一有效的治疗方法的管理。此时 没有FDA批准的药物可以防止任何形式的感觉性听力损失。 防止AG引起的听力损失将是目前正在接受AG治疗的巨大受益患者。它 还可以更常规地使用这种廉价且有效的抗生素类别。 口服ORC-13661WA从一个小分子屏幕开发，旨在寻找一种减轻Ag诱导头发的方法 细胞毒性。它在防止长时间高剂量AG治疗的大鼠的听力损失方面非常有效。 ORC-13661在正常健康志愿者中完成了非临床评估和第1阶段测试。 肺和传播的非结核分枝杆菌（NTM）感染是慢性传染病 随着时间的流逝，这种发展逐渐发展，需要长时间的肠胃外AG治疗才能实现控制或治愈。 当前的指南建议肠胃外氨基糖苷（AG）治疗，通常是90天的amikacin课程， 对于患有严重表现的疾病，特别是支气管扩张的患者。 我们提出了一个随机的，双盲的，安慰剂对照的，多中心的，2阶段的ORC-13661研究 与严重NTM患者的静脉内给予amikacin一起口服 感染。这样做的目的是评估ORC-13661对缓解或预防耳毒性的疗效。 如果听力阈值和 在接受药物治疗之前和治疗后在接受治疗的患者中停止噪音的听力 单独使用amikacin或与Amikacin Plus Orc-13661。其他评估将改变患者的感知 听力和平衡健康以及ORC-13661在NTM患者中的安全性和耐受性。 AES，临床实验室发现，生命体征和心电图（ECG）。