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: 7977337
• 负责人: Charles Robert Horsburgh
• 金额: $ 28.1万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-03 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7977337
• 关键词: Affect; Anti-Retroviral Agents; Antibiotics; Antimycobacterial Agents; Antitubercular Agents; Area; Bacterial Infections; Budgets; Caring; Case Report Form; Centers for Disease Control and Prevention (U.S.); Chemosensitization; Chronic; Clinical; Clinical Treatment; Clinical Trials; Clinical Trials Data Monitoring Committees; Collaborations; Commit; Companions; Contracts; Controlled Clinical Trials; Country; Data; Death Rate; Detection; Development; Disease; Dose; Drug Exposure; Drug Kinetics; Drug Resistant Tuberculosis; Drug resistance; Effectiveness; Enrollment; Ensure; Ethics; Evaluation; Extreme drug resistant tuberculosis; Failure; Fluoroquinolones; Frequencies; Future; Gatifloxacin; Good Clinical Practice; Government; Grant; HIV; HIV drug resistance; Hand; Health Priorities; Heterogeneity; Human; Informed Consent; Laboratories; Laboratory Procedures; Lead; Levaquin; Licensure; Light; Linezolid; Liquid substance; Manuals; Manufacturer Name; Maximum Tolerated Dose; Measures; Mediation; Methodology; Methods; Methyl Green; Moxifloxacin; Multi-Drug Resistance; Multidrug-Resistant Tuberculosis; Mycobacterium tuberculosis; National Institute of Allergy and Infectious Disease; New Agents; Observational Study; Outcome; Patients; Pattern; Persons; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase II Clinical Trials; Phase III Clinical Trials; Philippines; Predictive Value; Predisposition; Preparation; Probability; Procedures; Protocols documentation; Provider; Randomized; Regimen; Relapse; Reporting; Research; Research Design; Research Infrastructure; Research Personnel; Resistance; Resources; Risk; Risk Factors; Sample Size; Sampling; Secure; Shipping; Ships; Site; Solid; Sputum; Surrogate Endpoint; Surrogate Markers; Surveys; T-20; Testing; Therapeutic; Time; Training; Treatment Protocols; Treatment outcome; Tuberculosis; Validation; Work; World Health; World Health Organization; arm; bactericide; base; clinical practice; clinical research site; clinically relevant; clinically significant; drug intolerance; experience; fluoroquinolone resistance; global health; good laboratory practice; improved; interest; man; minimal risk; mortality; mouse model; mycobacterial; novel; prevent; programs; prospective; public health relevance; quinolone resistance; randomized trial; response; standard care; success; tipranavir; treatment effect; treatment program; treatment response; treatment strategy; treatment trial; tuberculosis treatment

DESCRIPTION (provided by applicant): Multiple Drug-Resistant Tuberculosis (MDR-TB) and Extensively Drug-Resistant Tuberculosis (XDR- TB) are rapidly growing threats to the world's health. Nearly 500,000 new cases of MDR-TB occurred in 2006, and reports of highly lethal XDR-TB have been documented from 45 countries. Current treatment regimens are inadequate, with failure in a quarter of cases of MDR-TB and three-quarters of cases of XDR-TB, resulting in spread of the disease to many others. NIAID, the World Health Organization, and the STOP-TB Partnership have identified research on and treatment of MDR-TB and XDR-TB as urgent global health priorities. The fluoroquinolones (FQ) are the most active class of antimycobacterial agents currently available for use in patients with MDR-TB. However, no prospective clinical trials have been performed to define the optimal way to use FQ for MDR-TB treatment. Several lines of evidence suggest that current doses are suboptimal, and may even promote acquisition of resistance. Maximizing AUC/MIC ratio is likely to lead to optimal antimycobacterial effect, as it does in serious bacterial infections. The investigators, Drs. Horsburgh, Tupasi, Burman, Drusano, Mitnick and Metchock, have been working together for three years, and the clinical site in Manila has experience with clinical trials of both drug- susceptible and MDR-TB. This planning grant will support preparation for initiation of the proposed clinical trial, surrogate marker and pharmacodynamic studies by developing materials, identifying and resolving logistical problems, and securing regulatory approval for these studies. All activities will be carried out in collaboration with NIAID, CDC and regulatory agencies. The U01 proposal that will result will have three Specific Aims: 1) To define in man the optimal pharmacodynamic parameters of FQ for achieving sputum culture conversion of MDR-TB. 2) To validate a surrogate marker of TB treatment response, rate of rise in time to positivity in liquid medium, that will allow reduced sample sizes in future MDR-TB trials. 3) To define the completion, failure, loss-to-follow-up and relapse rates achieved with the initially implemented MDR-TB treatment regimen when given for 18 months following sputum culture conversion. This clinical trial will increase our ability to cure MDR-TB by optimizing dosing and thereby improving the effectiveness of an existing antimycobacterial agent, using a novel and versatile study design which more rapidly and efficiently provides advances in this critical area. Validation of surrogate markers for clinical response to antituberculosis treatment will streamline subsequent trials of combination treatment regimens for MDR-TB. Determining the rates of and risk factors for long term outcomes of optimized therapy for MDR-TB will facilitate planning future studies to improve outcomes of patients with MDR-TB and prevent emergence of XDR-TB. PUBLIC HEALTH RELEVANCE (provided by applicant): Multi-drug-resistant tuberculosis affects nearly 500,000 persons each year around the world. This type of tuberculosis is very difficult to treat, and many patients die from it. New drugs are urgently needed to treat this disease. This application proposes a study to determine the best way of using levofloxacin, an effective antibiotic, to treat multi-drug-resistant tuberculosis. The patients will receive their usual treatment, plus the normal dose of levofloxacin or a higher dose. The study will be performed in the Philippines, where multi-drug-resistant TB is common.

描述（由申请人提供）：耐多药结核病（MDR-TB）和广泛耐药结核病（XDR-TB）是对世界健康的快速增长的威胁。2006年发生了近50万例新的耐多药结核病例，45个国家记录了高度致命的广泛耐药结核报告。目前的治疗方案是不够的，四分之一的耐多药结核病例和四分之三的广泛耐药结核病例失败，导致疾病传播到许多其他人。NIAID、世界卫生组织和STOP-TB伙伴关系已将耐多药结核病和广泛耐药结核病的研究和治疗确定为紧迫的全球卫生优先事项。 氟喹诺酮类药物（FQ）是目前可用于耐多药结核病患者的活性最高的一类抗分枝杆菌药物。然而，尚未进行前瞻性临床试验来确定使用FQ治疗耐多药结核病的最佳方法。几条证据表明，目前的剂量是次优的，甚至可能促进获得耐药性。最大化AUC/MIC比值可能导致最佳的抗分枝杆菌作用，就像在严重细菌感染中一样。 研究人员Horsburgh、Tupasi、Burman、Drusano、Mitnick和Metchock博士已经合作了三年，马尼拉的临床中心拥有药物敏感性和耐多药结核病临床试验的经验。该规划补助金将通过开发材料，确定和解决后勤问题以及确保这些研究的监管批准，支持拟议的临床试验，替代标志物和药效学研究的准备工作。所有活动都将与NIAID、CDC和监管机构合作开展。将产生的U 01提案将具有三个具体目的：1）在人体中定义FQ的最佳药效学参数，以实现MDR-TB的痰培养转化。2)为了验证结核病治疗反应的替代标志物，液体培养基中阳性时间的上升率，这将允许在未来的耐多药结核病试验中减少样本量。3)定义痰培养转化后最初实施的MDR-TB治疗方案持续18个月时达到的完成率、失败率、失访率和复发率。 这项临床试验将通过优化剂量来提高我们治愈耐多药结核病的能力，从而提高现有抗分枝杆菌药物的有效性，使用一种新的多功能研究设计，更快速有效地在这一关键领域取得进展。验证抗结核治疗临床应答的替代标志物将简化随后的耐多药结核联合治疗方案试验。确定耐多药结核病优化治疗的长期结局的发生率和风险因素将有助于规划未来的研究，以改善耐多药结核病患者的结局并预防广泛耐药结核病的出现。 公共卫生相关性（由申请人提供）：耐多药结核病每年影响全世界近50万人。这种结核病很难治疗，很多病人因此而死亡，迫切需要新药来治疗这种疾病。本申请提出了一项研究，以确定使用左氧氟沙星，一种有效的抗生素，治疗耐多药结核病的最佳方法。患者将接受常规治疗，加上正常剂量或更高剂量的左氧氟沙星。这项研究将在菲律宾进行，那里的耐多药结核病很常见。