EVALUATION OF A MOXIFLOXACIN-BASED REGIMEN FOR TB TREATMENT, STUDY 28

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。目的：比较含莫西沙星方案(莫西沙星、利福平、吡津胺、乙胺丁醇)与标准对照方案(异烟肼、利福平、吡津胺、乙胺丁醇)治疗涂阳肺结核前2个月的安全性和抗菌活性。抗菌活性的评估将是痰培养转化。第二个目标是：比较莫西沙星方案和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，确定莫西沙星方案和异烟肼方案的培养转换时间；比较出现3级或4级不良反应的患者的比例；比较艾滋病毒感染患者和未感染艾滋病毒的患者的不良事件和2个月培养转换率；比较莫西沙星方案和异烟肼方案的治疗失败率；并确定是否存在可归因于莫西沙星的迟发性毒性(在莫西沙星治疗2个月后毒性明显)。研究计划和方法：这项多中心、安慰剂对照、双盲的第二阶段研究将评估莫西沙星(M)替代异烟肼(H)与利福平(R)、吡津酰胺(Z)和乙胺丁醇(E)联合使用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和未感染的患者。在这两个研究分支中，在头两周内，首席研究人员可以酌情决定每周进行5-7天的治疗(只有5剂将计入完成四种药物的治疗阶段)。完成四种药物治疗阶段的所有剂量的研究药物将作为直接观察治疗给予。莫西沙星的剂量将是目前许可的400毫克。每次治疗都要服用维生素B6(50毫克)。实验室研究表明，如果患者的结核分枝杆菌分离株对异烟肼、利福平、吡津酰胺和氟喹诺酮类药物敏感，则可以停用乙胺丁醇。强化治疗阶段的持续时间将由摄入剂量的数量决定，而不是由日历时间决定。当患者每天(每周5天)有40次直接观察到的剂量时，他们将完成强化阶段。此疗法必须在不少于54天且不超过70天内完成。在强化阶段治疗完成后，所有研究分支中的患者将接受ATS/IDSA/CDC推荐的持续阶段方案治疗。总疗程为26周(6个月)，但在强化治疗阶段结束时有空洞和痰培养阳性的患者将接受总计38周(9个月)的治疗。符合纳入标准的受试者将按1：1的比例随机分配到两个治疗组中的一个。由于基线(诊断时)的空化与2个月培养转换率的显著降低有关，随机分组将根据空化的存在进行分层。此外，随机化将按地理大陆分层。研究终点：1.痰培养转换--在强化治疗结束时获得的痰培养未见结核分枝杆菌生长。密集治疗阶段的结束将通过完成所需的40个直接观察剂量来确定。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终止所分配研究方案的患者的比例。次要终点包括死亡率，3级和4级毒性的发生，以及与研究药物有关的毒性的比率和类型。3.治疗失败--完成4个月的结核病治疗后痰培养阳性。所有治疗失败的分离株将使用DNA指纹技术与初始分离株进行比较。临床相关性：目前对涂阳肺结核的治疗至少需要6个月，这一治疗持续时间对患者和结核病控制计划都是具有挑战性的。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制剂。几种氟喹诺酮类抗生素在临床前试验中具有较强的抗结核分枝杆菌活性。在目前可用的氟喹诺酮类药物中，莫西沙星在体外和结核病动物模型中具有良好的活性，具有良好的药代动力学特征(血清半衰期为10-12小时)，不存在有问题的药物-药物相互作用，不需要调整肾和肝功能不全的剂量，并且具有极好的安全性。此外，在小鼠结核病模型中，与利福平、异烟肼和吡嗪酰胺的标准组合相比，莫西沙星替代异烟肼导致培养转化时间和灭菌时间显著减少。然而，莫西沙星还没有在人类身上进行全面的结核病治疗评估。不仅需要评估含有莫西沙星的方案的抗结核活性，还需要评估使用莫西沙星进行更长时间治疗的安全性。

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 ration 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.