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

项目摘要/摘要 结核病是传染病死亡的主要原因，特别是在艾滋病毒流行地区，而 高耐药性结核病的出现进一步威胁到全球结核病控制。需要高度有效的结核病 可以在不到六个月的时间内治愈疾病的治疗方法。 PA-824是一种研究中的硝基咪唑，具有杀菌和杀菌活性，对结核分枝杆菌具有 当作为多药结核病治疗的一部分使用时，作为一种治疗缩短药物的巨大潜力。这个 硝基咪唑类化合物之所以特别令人感兴趣，是因为它们具有抗“持久菌”的活性。 当结核病没有得到足够长的时间治疗时，很难杀死并导致复发。在一只实验小鼠身上 结核模型PA-824在结核病治疗的早期阶段具有杀菌活性， 单药给药时结核病治疗持续阶段的灭菌活性。在随后的 小鼠研究，PA-824与含有利福平和吡嗪酰胺的多药方案联合使用 将治愈所需的治疗时间从6个月减少到4个月。第一阶段和早期第二阶段研究 提示PA-824耐受性良好，具有可测量的、剂量依赖的早期杀菌活性， 在每日一次给药的两周内显著减少结核分枝杆菌的痰菌落计数。主 拟议的II期临床试验的目标是评估PA-824在添加到 在结核病治疗的前12周内接受标准剂量的结核病治疗。痰涂片阳性的患者 南非开普敦的肺结核患者将全部接受标准剂量的异烟肼、利福平和 将随机接受PA-824 200 mg每日一次，为期8周(组1)，PA-824 200 每日1次，共12周(第2组)，或乙胺丁醇标准剂量共8周(对照组)。初级阶段 疗效终点将是液体介质中稳定痰培养转换的时间，定义为从 开始治疗，直到至少两次痰培养阴性的第一次，超过12周。首要安全 终点为3级或更高级别的不良事件。8周后的药代动力学、固体培养结果 治疗、液体培养痰培养阳性的时间变化和程度的量化变化 计算机断层扫描上的疾病也将被评估。结果将决定其抗菌活性。 每日PA-824，并通知PA-824的进一步开发，PA-824是一种非常有前途的缩短结核病治疗的药物。

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.