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

描述（由申请人提供）：耐多药结核病是对国际卫生日益严重的威胁。世卫组织最近的一份报告估计，2008年127个国家发生了44万多例耐多药结核病新病例，造成15万人死亡；这表明自2000年以来病例数增加了55%。目前的治疗方案只有58-67%的成功率，治疗无效的患者中多达20%死于结核病；那些没有死亡的人成为慢性携带者，并将耐多药结核病传播给他人。氟喹诺酮类药物是耐多药结核病治疗方案的重要组成部分；在耐多药结核病患者中，使用FQ治疗的结果一直明显较好，而较新的FQ（左氧氟沙星、加替沙星和莫西沙星）是可用于耐多药结核病治疗的最有效的抗结核药物。然而，由于血糖异常反应，加替沙星已退出市场，莫西沙星可显著延长QT期，增加致死性心律失常的风险。相比之下，左氧氟沙星的QT间期研究发现，当剂量高达（20mg/kg）时，延长时间最小。目前，左氧氟沙星用于治疗结核病的剂量为11-14毫克/公斤/天，并且高达20毫克/公斤的剂量耐受性良好。尽管在结核病动物研究和革兰氏阴性细菌人体研究中，左氧氟沙星的功效随着接触量的增加而增加，但尚未对其在较高剂量下对人类结核病的功效进行研究。因此，确定最有效和耐受性良好的左氧氟沙星剂量是一个重要的研究重点。在这项2期研究中，我们将通过研究秘鲁和南非的100名涂片和培养阳性肺部耐多药结核病成人患者，确定左氧氟沙星剂量和暴露量，以最大限度地减少分枝杆菌负担，并具有可接受的耐受性。左氧氟沙星将以优化的背景方案（OBR）给药，以满足以下具体目的：具体目的1：确定在固体培养基中提供最短痰培养转化时间的左氧氟沙星AUC/MIC。具体目标2：确定左氧氟沙星的最高AUC，该AUC既安全，又与小于25%的患者停止或减少左氧氟沙星剂量相关。具体目标3：开发一种给药算法，以实现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和防止出现对新型结核病药物耐药的能力，方法是优化现有抗结核药物的剂量和提高其有效性，采用一种新颖和通用的研究设计，更迅速和有效地确定这一关键领域的进展。构建预测最佳左氧氟沙星剂量的算法将使左氧氟沙星的使用更加有效，特别是在资源有限、耐多药结核病负担最重的地区。

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.