EVAL OF A MOXIFLOXACIN-BASED REGIMEN FOR TB TREATMENT, STUDY 28 (HIV)

基于莫西沙星的结核病治疗方案的评估，研究 28（HIV）

• 批准号: 7627504
• 负责人: MARC H WEINER
• 金额: $ 5.87万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7627504
• 关键词: Adverse event; Adverse reactions; Animal Model; Antibiotics; Antitubercular Agents; Calendar; Computer Retrieval of Information on Scientific Projects Database; Count; DNA Fingerprinting; Daily; Data; Diagnosis; Directly Observed Therapy; Dose; Double-Blind Method; Drug Interactions; Drug Kinetics; End Point; Enrollment; Ethambutol; Fluoroquinolones; Funding; Grant; Growth; HIV; Half-Life; Hepatic Insufficiency; Hour; Human; In Vitro; Institution; Kidney; Laboratory Study; Licensing; Modeling; Moxifloxacin; Mus; Mycobacterium tuberculosis; Numbers; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Placebo Control; Preclinical Testing; Principal Investigator; Protocols documentation; Pulmonary Tuberculosis; Pyrazinamide; Randomized; Rate; Research; Research Personnel; Resources; Rifampin; Safety; Serum; Source; Sputum; Standards of Weights and Measures; Sterilization for infection control; Thinking; Time; Toxic effect; Treatment Failure; Treatment Protocols; Tuberculosis; United States National Institutes of Health; Upper arm; Vitamin B6; Week; antimicrobial; base; clinically relevant; day; dosage; inclusion criteria; isoniazid; mortality; programs; therapy duration; treatment duration; tuberculosis treatment

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. OBJECTIVE: The primary objective of this study is to compare the safety and antimicrobial activity of a moxifloxacin-containing regimen (moxifloxacin, rifampin, pyrazinamide, ethambutol) in which moxifloxacin has been substituted for isoniazid, to the standard control regimen (isoniazid, rifampin, pyrazinamide, ethambutol) in the first two months of treatment of sputum smear-positive pulmonary tuberculosis. The assessment of antimicrobial activity will be sputum culture-conversion. Secondary objectives are: to compare the safety and tolerability of the moxifloxacin regimen to that of the isoniazid regimen; to determine the time to culture-conversion of the moxifloxacin regimen and the isoniazid regimen, using data from 2-, 4-, 6-, and 8-week cultures; to compare the proportion of patients with any Grade 3 or 4 adverse reactions; to compare adverse events and 2-month culture conversion rate among HIV-infected patients vs. HIV-uninfected patients; to compare the rates of treatment failure of the moxifloxacin regimen to the isoniazid regimen; and to determine whether there is delayed toxicity attributable to moxifloxacin (toxicity that becomes evident after the 2 months of moxifloxacin therapy). RESEARCH PLAN AND METHODS: This multicenter, placebo-controlled, double-blind, Phase 2 study will evaluate the effect of using moxifloxacin (M) in place of isoniazid (H), in combination with rifampin (R), pyrazinamide (Z) and ethambutol (E) on 2-month culture conversion rates among patients with sputum smear-positive pulmonary tuberculosis. The protocol will enroll HIV-infected and uninfected patients. In both study arms, treatment can be given 5-7 days per week during the first 2 weeks at the discretion of the principal investigator (only 5 doses will be counted toward completion of the four-drug phase of therapy). All doses of study medication counted toward completion of the four-drug phase of therapy will be given as directly observed therapy. The moxifloxacin dose will be the currently licensed dose of 400mg. Vitamin B6 (50 mg) will be given with each dose of therapy. Ethambutol may be discontinued if the patient's M. tuberculosis isolate is susceptible to isoniazid, rifampin, pyrazinamide, and fluoroquinolones, as demonstrated by laboratory studies. The duration of the intensive phase of therapy will be determined by the number of doses ingested, not by calendar time. Patients will complete the intensive phase when they have had 40 daily (5 days per week) directly-observed doses. This therapy must have been completed within no less than 54 days and no more than 70 days. After completion of intensive phase therapy, patients in all study arms will then be treated with an ATS/IDSA/CDC-recommended continuation phase regimen. The total duration of therapy will be 26 weeks (6 months) except for patients who have cavitation plus a positive sputum culture at the end of the intensive phase of therapy who will receive a total of 38 weeks (9 months) of therapy. Subjects who meet the inclusion criteria will be randomized in a 1:1 ratio to one of two treatment arms. Because cavitation at baseline (time of diagnosis) is associated with a substantially decreased rate of 2-month culture conversion, randomization will be stratified by presence of cavitation. In addition, randomization will be stratified by geographic continent. Study Endpoints: 1. Sputum culture conversion - sputum culture obtained at the end of the intensive phase of therapy has no growth of M. tuberculosis. The end of the intensive phase of therapy will be defined by completion of the 40 required number of directly-observed doses. 2. Safety and tolerability endpoints - the primary endpoint for the analysis of safety and tolerability will be the proportion of patients who discontinue the assigned study regimen for any reason. Secondary endpoints include mortality, the occurrence of Grade 3 and 4 toxicities, and the rate and types of toxicity thought related to study drug. 3. Treatment failure - a positive sputum culture after completion of 4 months of TB treatment. All treatment failure isolates will be compared to the initial isolate using DNA fingerprinting. CLINICAL RELEVANCE: Current treatment of smear positive pulmonary tuberculosis requires a minimum of 6 months, a treatment duration that is challenging for patients and tuberculosis control programs. Therefore, a high priority in tuberculosis research is the identification of agents that can shorten treatment. Several fluoroquinolone antibiotics have potent activity against Mycobacterium tuberculosis in preclinical testing. Of the currently available fluoroquinolones, moxifloxacin has excellent activity in vitro and in animal models of tuberculosis, a favorable pharmacokinetic profile (serum half-life of 10-12 hours), lack of problematic drug-drug interactions, no need for dosage adjustment for renal and hepatic insufficiency, and an excellent safety profile. In addition, in the murine model of tuberculosis, the substitution of moxifloxacin for isoniazid resulted in significant reductions in the time to culture conversion and the time to sterilization when compared to the standard combination rifampin, isoniazid, and pyrazinamide. However, moxifloxacin has not been fully evaluated in humans for tuberculosis treatment. There is a need to assess not only the anti-tuberculosis activity of moxifloxacin-containing regimens, but also the safety of more prolonged therapy with moxifloxacin.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 目的：本研究的主要目的是在痰涂片阳性肺结核患者治疗的前两个月内，比较含阿替沙星的方案（阿替沙星、利福平、吡嗪酰胺、乙胺丁醇）与标准对照方案（异烟肼、利福平、吡嗪酰胺、乙胺丁醇）的安全性和抗菌活性。 抗菌活性的评估将是痰培养转化。 次要目的是：比较利福沙星方案与异烟肼方案的安全性和耐受性;使用2周、4周、6周和8周培养的数据确定利福沙星方案和异烟肼方案的培养转化时间;比较发生任何3级或4级不良反应的患者比例;比较HIV感染患者与HIV未感染患者的不良事件和2个月培养转化率;比较利多卡因方案与异烟肼方案的治疗失败率;并确定是否存在可归因于阿托沙星的延迟毒性（在阿托沙星治疗2个月后变得明显的毒性）。 研究方法：这项多中心、安慰剂对照、双盲、II期研究将评估使用利福沙星（M）代替异烟肼（H），联合利福平（R）、吡嗪酰胺（Z）和乙胺丁醇（E）对痰涂片阳性肺结核患者2个月培养转换率的影响。 该方案将招募艾滋病毒感染者和未感染者。 在两个研究组中，根据主要研究者的决定，在前2周内每周可给予5-7天治疗（仅5次给药将计入完成四种药物治疗期）。 完成四种药物治疗阶段的所有研究药物剂量将作为直接观察治疗给予。 利多卡因剂量将是目前许可的400 mg剂量。 维生素B6（50 mg）将与每剂治疗一起给予。 如果患者的M.实验室研究表明，结核病分离株对异烟肼、利福平、吡嗪酰胺和氟喹诺酮类药物敏感。 强化治疗期的持续时间将由摄入的剂量数而不是日历时间决定。 当患者接受40次每日（每周5天）直接观察剂量时，将完成强化期。 该治疗必须在不少于54天且不超过70天内完成。 在完成强化阶段治疗后，所有研究组的患者将接受ATS/IDSA/CDC推荐的继续阶段方案治疗。 治疗的总持续时间为26周（6个月），但在强化治疗期结束时出现空洞且痰培养阳性的患者除外，这些患者将接受总计38周（9个月）的治疗。 符合入选标准的受试者将以1：1的比例随机分配至两个治疗组之一。 由于基线（诊断时间）时的空化与2个月培养转化率大幅降低相关，因此将根据是否存在空化对随机化进行分层。 此外，随机化将按地理大洲分层。 研究终点： 1. 痰培养转化-强化治疗期结束时获得的痰培养物无M生长。结核 强化治疗期结束将定义为完成40次所需的直接观察剂量。 2. 安全性和耐受性终点-安全性和耐受性分析的主要终点将是因任何原因中止分配的研究方案的患者比例。 次要终点包括死亡率、3级和4级毒性的发生率以及认为与研究药物相关的毒性的发生率和类型。 3. 治疗失败-完成4个月结核病治疗后痰培养阳性。 将使用DNA指纹图谱将所有治疗失败分离株与初始分离株进行比较。 临床相关性：目前，涂阳肺结核的治疗需要至少6个月，这对患者和结核病控制计划来说是一个挑战。 因此，结核病研究的一个高度优先事项是确定可以缩短治疗时间的药物。 几种氟喹诺酮类抗生素在临床前试验中对结核分枝杆菌具有有效的活性。 在目前可用的氟喹诺酮类药物中，利福沙星在结核病的体外和动物模型中具有优异的活性，有利的药代动力学特征（血清半衰期为10-12小时），没有问题的药物-药物相互作用，不需要针对肾和肝功能不全调整剂量，以及优异的安全性特征。 此外，在结核病小鼠模型中，与标准组合利福平、异烟肼和吡嗪酰胺相比，用替诺氟沙星替代异烟肼导致培养物转化时间和灭菌时间显著缩短。 然而，阿托沙星尚未在人类结核病治疗中得到充分评价。 不仅需要评估含阿托沙星方案的抗结核活性，还需要评估阿托沙星更长时间治疗的安全性。