Phase 2 Pharmacodynamic Study of High-dose Levofloxacin in MDR-TB Treatment

描述(申请人提供)：耐多药结核病对国际健康构成日益严重的威胁。世卫组织最近的一份报告估计，2008年在127个国家发生了超过44万例耐多药结核病新病例，造成15万人死亡；这意味着自2000年以来病例数量增加了55%。目前的治疗方案只有58%-67%的成功率，治疗无效的人中多达20%死于结核病；那些没有死亡的人会成为慢性携带者，并将耐多药结核病传播给其他人。氟喹诺酮类(FQ)是耐多药结核病治疗方案的重要组成部分；在接受FQ治疗的耐多药结核病患者中，一直可以看到显著更好的结果，而较新的FQ(左氧氟沙星、加替沙星和莫西沙星)是可用于治疗耐多药结核病的最有效的抗结核药物。然而，加替沙星因血糖异常反应而被下架，莫西沙星导致QT显著延长，增加了致命心律失常的风险。相比之下，左氧氟沙星的QT研究发现，剂量达到20 mg/kg时，延长时间最小。左氧氟沙星目前用于治疗结核病，剂量为每天11-14毫克/公斤，最高剂量为20毫克/公斤，耐受性良好。尽管在结核病的动物研究和革兰氏阴性细菌的人体研究中，左氧氟沙星的疗效随着暴露的增加而增加，但它在更高剂量下对人类结核病的疗效尚未被研究。因此，确定左氧氟沙星最有效和耐受性最好的剂量是一个重要的研究重点。在这项第二阶段的研究中，我们将通过对秘鲁和南非100名涂阳和培养阳性肺多药耐药结核病患者的研究，确定在可接受的耐受性下实现最大限度减少分枝杆菌负担的左氧氟沙星剂量和暴露。左氧氟沙星将与优化的本底方案(OBR)一起使用，以解决以下特定目标：特定目标1：确定在固体培养中提供最短时间痰培养转换的左氧氟沙星AUC/MIC。具体目的2：确定最高的左氧氟沙星AUC是安全的，并且与停用或减少左氧氟沙星剂量的患者少于25%相关。具体目标3：开发一种剂量算法，以获得与最大疗效和可接受的安全性/耐受性相关的左氧氟沙星AUC。这项临床试验将提高我们治愈耐多药结核病的能力，并通过优化剂量和提高现有抗分枝杆菌药物的有效性，防止出现对新的结核病药物类别的耐药性，使用一种新颖和多功能的研究设计，更快、更有效地确定这一关键领域的进展。构建预测左氧氟沙星最佳剂量的算法将允许更有效地使用左氧氟沙星，特别是在耐多药结核病负担最大的资源有限的地区。

DESCRIPTION (provided by applicant): MDR-TB is a growing threat to international health. A recent report from WHO estimated that over 440,000 new cases of MDR-TB occurred in 127 countries in 2008, causing 150,000 deaths; this represents a 55% increase in the number of cases since 2000. Current treatment regimens have only a 58-67% success rate, and as many as 20% of those who fail to respond to treatment die of tuberculosis; those who do not die become chronic carriers and spread MDR-TB to others. Fluoroquinolones (FQ) are an essential part of regimens for the treatment of MDR-TB; substantially better outcomes have consistently been seen in patients with MDR-TB who are treated with FQ, and newer FQ (levofloxacin, gatifloxacin and moxifloxacin) are the most potent antituberculosis agents available for MDR-TB treatment. However, gatifloxacin has been taken off the market because of dysglycemic reactions and moxifloxacin produces marked QT prolongation, increasing risk of fatal arrhythmia. In contrast, QT studies of levofloxacin have found minimal prolongation at doses up to (20mg/kg). Levofloxacin is currently given for TB at doses of 11-14 mg/kg/day and has been well tolerated at doses up to 20 mg/kg. Although the efficacy of levofloxacin increases as exposure increases both in animal studies of TB and in human studies of gram-negative bacteria, its efficacy at higher doses against TB in humans has not been studied. Thus, determination of the most efficacious and well-tolerated dose of levofloxacin is an important research priority. In this Phase 2 study, we will determine the levofloxacin dose and exposure that achieve the greatest reduction in mycobacterial burden with acceptable tolerability by studying 100 adults with smear- and culture-positive pulmonary MDR-TB at sites in Peru and South Africa. Levofloxacin will be administered with an optimized background regimen (OBR) to address the following Specific Aims: Specific Aim 1: To determine the levofloxacin AUC/MIC that provides the shortest time to sputum culture conversion in solid medium. Specific Aim 2: To determine the highest levofloxacin AUC that is both safe and associated with fewer than 25% of patients discontinuing or reducing their dose of levofloxacin. Specific Aim 3: To develop a dosing algorithm to achieve the levofloxacin AUC associated with maximal efficacy and acceptable safety/tolerability. This clinical trial will increase our ability to cure MDR-TB and prevent the emergence of resistance to new TB drug classes by optimizing dosing and improving the effectiveness of an existing antimycobacterial agent, using a novel and versatile study design which more rapidly and efficiently identifies advances in this critical area. Construction of an algorithm to predict the optimal levofloxacin dose will allow more effective use of levofloxacin, particularly in areas with limited resources, where the burden of MDR-TB is the greatest.