Phase 2 Study of PA-824 for Treatment of Pulmonary Tuberculosis

PA-824治疗肺结核的2期研究

• 批准号: 8913045
• 负责人: Kelly E. Dooley
• 金额: $ 40万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8913045
• 关键词: Phase; Study; PA; 824; Treatment

DESCRIPTION (provided by applicant): Tuberculosis (TB) is a leading cause of infectious disease death, especially in HIV-prevalent regions, and the emergence of highly resistant TB further threatens global TB control. There is a need for highly potent TB treatments that can cure disease in substantially fewer than the six months currently required. PA-824, an investigational nitroimidazole with bactericidal and sterilizing activity against Mycobacterium tuberculosis (M. tuberculosis), has potential as a treatment-shortening drug when used as part of multidrug TB therapy. In an experimental murine model of TB, PA-824 was shown to have bactericidal activity during the early phase of TB treatment and sterilizing activity during the continuation phase of TB therapy when given as monotherapy. In subsequent murine studies, using PA-824 in combination with a multidrug regimen containing rifampin and pyrazinamide reduced the treatment time required for cure from six months to four months. The applicant reported that Phase 1 and early Phase 2 studies suggest that PA-824 is well tolerated and has measurable, dose-dependent early bactericidal activity, reducing sputum colony counts of M. tuberculosis over two weeks of once-daily dosing. The main objective of the proposed Phase 2 clinical trial is to evaluate the antimicrobial activity of PA-824 when added to standard-dose TB treatment over the first 12 weeks of TB treatment. Patients with sputum smear-positive pulmonary TB in Cape Town, South Africa, will receive standard doses of isoniazid, rifampin, and pyrazinamide and will be randomized to receive PA-824 200 mg once daily for 8 weeks (Arm 1), PA-824 200 mg once daily for 12 weeks (Arm 2), or ethambutol at standard doses for 8 weeks (control arm). The primary efficacy endpoint will be time to stable sputum culture conversion in liquid media, defined as the time from the start of treatment until the first of at least two negative sputum cultures, over 12 weeks. The primary safety endpoint is grade 3 or higher adverse events. Pharmacokinetics, solid culture results after 8 weeks of treatment, change in time to sputum culture positivity in liquid culture, and quantitative change in extent of disease on computed tomography will also be assessed. Results will determine the antimicrobial activity of daily PA-824 and inform further development of PA-824.

描述（由申请人提供）： 结核病（TB）是传染病死亡的主要原因，特别是在艾滋病毒流行地区，高耐药性结核病的出现进一步威胁到全球结核病控制。需要一种高效的结核病治疗方法，可以在比目前所需的六个月短得多的时间内治愈疾病。PA-824是一种对结核分枝杆菌（M.结核病），作为多药结核病治疗的一部分时，有可能作为治疗缩短药物。在TB的实验鼠模型中，PA-824在TB治疗的早期阶段显示出杀菌活性，在TB治疗的持续阶段显示出灭菌活性。在随后的小鼠研究中，使用PA-824联合含有利福平和吡嗪酰胺的多药方案将治愈所需的治疗时间从6个月缩短至4个月。申请方报告称，I期和早期II期研究表明，PA-824耐受性良好，具有可测量的剂量依赖性早期杀菌活性，可减少痰液中的支原体菌落计数。每日一次给药两周后， 拟议的2期临床试验的主要目的是评价抗菌活性 在TB治疗的前12周内，PA-824添加到标准剂量TB治疗中。南非开普敦的痰涂片阳性肺结核患者将接受标准剂量的异烟肼、利福平和吡嗪酰胺治疗，并随机接受PA-824 200 mg每日一次治疗8周（第1组）、PA-824 200 mg每日一次治疗12周（第2组）或乙胺丁醇标准剂量治疗8周（对照组）。主要疗效终点将是至液体培养基中痰培养物稳定转化的时间，定义为12周内从治疗开始至至少两次阴性痰培养物中的第一次的时间。主要安全性终点为3级或以上不良事件。还将评估药代动力学、治疗8周后的固体培养结果、液体培养中痰培养阳性时间的变化以及计算机断层扫描显示的疾病程度的定量变化。结果将确定每日PA-824的抗菌活性，并为PA-824的进一步开发提供信息。