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

描述(由申请人提供)： 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，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治疗方法，能够在比目前要求的6个月短得多的时间内治愈疾病。PA-824是一种研究中的硝基咪唑类药物，对结核分枝杆菌具有杀菌和杀菌活性，作为多药结核病治疗的一部分，具有缩短治疗时间的潜力。在实验性的小鼠结核病模型中，PA-824被证明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具有杀菌活性。在随后的小鼠研究中，将PA-824与含有利福平和吡嗪酰胺的多种药物方案结合使用，将治愈所需的治疗时间从6个月缩短到4个月。申请人报告说，第一阶段和第二阶段早期研究表明，PA-824耐受性良好，具有可测量的、剂量依赖的早期杀菌活性，在每日一次剂量的两周内减少结核分枝杆菌的痰菌落计数。 拟议的第二阶段临床试验的主要目标是评估抗菌活性 在结核病治疗的头12周内，将PA-824添加到标准剂量的结核病治疗中。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、利福平和吡津酰胺的治疗，并将被随机分成三组，分别接受PA-824 200毫克、每天一次、持续8周(第一组)、PA-824 200毫克、每天一次、持续12周(第二组)，或标准剂量的乙胺丁醇，为期八周(对照组)。主要的疗效终点将是在液体介质中稳定痰培养转化的时间，定义为从开始治疗到至少两种阴性痰培养中的第一种为止的时间，超过12周。主要安全终点为3级或更高级别的不良事件。还将评估药物动力学、治疗8周后的固体培养结果、液体培养中痰培养阳性的时间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。

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.