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

大剂量左氧氟沙星治疗耐多药结核病的2期药效学研究

• 批准号: 8544616
• 负责人: Charles Robert Horsburgh
• 金额: $ 153.62万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-09 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8544616
• 关键词: Address; Adult; Affect; Age; Algorithms; Animals; Antibiotics; Antimycobacterial Agents; Antitubercular Agents; Area; Arrhythmia; Award; Cessation of life; Chronic; Clinical; Clinical Trials; Country; Creatinine clearance measurement; Dose; Drug Exposure; Effectiveness; Enrollment; Epidemiologic Factors; Fluoroquinolones; Frequencies; Funding; Gatifloxacin; Gram-Negative Bacteria; HIV; Health; Human; International; Levaquin; Lung; Marketing; Methods; Modeling; Moxifloxacin; Multidrug-Resistant Tuberculosis; New Agents; Outcome; Patients; Persons; Peru; Pharmaceutical Preparations; Pharmacodynamics; Phase; Race; Randomized; Reaction; Regimen; Reporting; Research; Research Design; Research Priority; Resistance; Resources; Risk; Safety; Serum; Site; Solid; South Africa; Sputum; Staging; Time; Toxic effect; Treatment Protocols; Treatment outcome; Tuberculosis; Uncertainty; animal data; effective therapy; human data; improved; mycobacterial; novel; phase 2 study; prevent; public health relevance; response; success; tuberculosis drugs; tuberculosis treatment

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.

描述（由申请人提供）：耐多药结核病对国际健康构成日益严重的威胁。世界卫生组织最近的一份报告估计，2008年127个国家新增耐多药结核病病例超过44万例，造成15万人死亡；这意味着自 2000 年以来病例数增加了 55%。目前的治疗方案的成功率仅为 58-67%，治疗无效的患者中有多达 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其他人。 氟喹诺酮类药物 (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，持续观察到明显更好的结果，而新型 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，莫西沙星会导致明显的 QT 延长，增加致命性心律失常的风险。相比之下，左氧氟沙星的 QT 研究发现，剂量高达 (20mg/kg) 时 QT 延长极小。目前左氧氟沙星用于治疗结核病的剂量为 11-14 mg/kg/天，剂量高达 20 mg/kg 时耐受性良好。尽管在结核病动物研究和革兰氏阴性菌人体研究中，左氧氟沙星的疗效随着暴露量的增加而增加，但尚未研究其在较高剂量下对人类结核病的疗效。因此，确定左氧氟沙星最有效和耐受性良好的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耐多药结核病成人，确定左氧氟沙星的剂量和暴露量，以在可接受的耐受性下最大程度地减少分枝杆菌负荷。左氧氟沙星将采用优化的背景方案 (OBR) 进行给药，以实现以下具体目标： 具体目标 1：确定左氧氟沙星 AUC/MIC，以提供固体培养基中痰培养转化的最短时间。 具体目标 2：确定左氧氟沙星最高 AUC，既安全又与不到 25% 的患者停止或减少左氧氟沙星剂量相关。 具体目标 3：开发一种剂量算法，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。 这项临床试验将通过优化剂量和提高现有抗分枝杆菌药物的有效性，采用新颖且多功能的研究设计，更快速、更有效地确定这一关键领域的进展，从而提高我们治愈耐多药结核病的能力，并防止对新结核病药物类别出现耐药性。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大的地区。