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

项目总结/摘要 结核病（TB）是传染病死亡的主要原因，特别是在HIV流行地区， 高度耐药结核病的出现进一步威胁全球结核病控制。需要一种高效的结核病药物 可以在比目前所需的六个月短得多的时间内治愈疾病的治疗方法。 PA-824是一种对M.肺结核， 作为多药结核病治疗的一部分，作为缩短治疗时间的药物具有显著的潜力。的 硝基咪唑特别令人感兴趣，因为它们对“持留菌”（persisters）具有活性， 结核病很难消灭，如果结核病没有得到足够长时间的治疗，就会导致复发。在一个实验鼠 在结核病模型中，PA-824显示在结核病治疗的早期阶段具有杀菌活性， 在结核病治疗的持续阶段，当作为单一疗法给予时，具有杀菌活性。在随后 小鼠研究，使用PA-824联合含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。I期和早期II期研究 表明PA-824耐受性良好，且具有可测量的剂量依赖性早期杀菌活性， 显著降低痰中M.每日一次给药两周后，主要 拟定的II期临床试验的目的是评价PA-824添加到 在结核病治疗的前12周进行标准剂量的结核病治疗。痰涂片阳性患者 南非开普敦的肺结核患者都将接受标准剂量的异烟肼、利福平和 吡嗪酰胺，并将随机接受PA-824 200 mg每日一次，持续8周（组1），PA-824 200 mg每日一次，持续8周（组2）， mg每日一次，持续12周（组2），或乙胺丁醇标准剂量，持续8周（对照组）。主 疗效终点将是液体培养基中痰培养物稳定转化的时间，定义为从 开始治疗，直至至少两次痰培养阴性中的第一次，持续12周。主要安全性 终点为3级或以上不良事件。药代动力学，8周后的固体培养结果 治疗，液体培养中痰培养阳性时间的变化，以及 还将评估计算机断层扫描的疾病。结果将确定 每日PA-824，并告知PA-824的进一步开发，这是一种非常有前途的结核病治疗缩短药物。

Project Summary/Abstract 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 M. tuberculosis, has significant potential as a treatment-shortening drug when used as part of multidrug TB therapy. The nitroimidazoles are of particular interest because of their activity against "persisters," those bacteria that are hard to kill and lead to relapse when TB is not treated for a long enough duration. 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 6 months to 4 months. Phase I and early Phase II studies suggest that PA-824 is well tolerated and has measurable, dose-dependent early bactericidal activity, significantly reducing sputum colony counts of M. tuberculosis over two weeks of once-daily dosing. The main objective of the proposed Phase II 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 all 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, a highly promising drug for TB treatment shortening.