CLINICAL TRIAL: EVAL OF A MOXIFLOXACIN-BASED REGIMEN FOR TB TREATMENT, STUDY 28

临床试验：评估基于莫西沙星的结核病治疗方案，研究 28

• 批准号: 7718710
• 负责人: MARC H WEINER
• 金额: $ 0.3万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7718710
• 关键词: Adverse event; Adverse reactions; Animal Model; Antibiotics; Antitubercular Agents; Calendar; Clinical Trials; 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; 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; Adverse event; Adverse reactions; Animal Model; Antibiotics; Antitubercular Agents; Calendar; Clinical Trials; 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; 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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 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两个月的痰液涂片阳性肺结核的治疗。 抗菌活性的评估将是痰培养转换。 次要目标是：比较莫西法沙星方案的安全性和耐受性与异烟肼方案的安全性；使用来自2-，4-，6-和8周培养物的数据，确定莫西法沙星疗法和异烟肼方案的培养时间；比较任何3或4级不良反应的患者的比例；比较感染HIV的患者与HIV未感染的患者的不良事件和2个月的培养率；比较莫西法沙星方案的治疗失败率与异烟肼方案；并确定是否存在延迟毒性归因于莫西法沙星（毒性在2个月的莫西沙星治疗后变得明显）。 研究计划和方法：这种多中心，安慰剂控制的双盲，第二阶段研究将评估使用Moxifloxin（M）代替Isoniazid（H），结合利福平（R）（R），吡嗪酰胺（Z）（Z）和Ethambutol（e）（E）对2个小时的培养培养率在putecip corsectissscristis conspersists corsectiss smececums smececums smececulmares中，并将其结合使用。 该方案将招募HIV感染和未感染的患者。 在两个研究臂中，在首席研究人员的前2周中，每周可以给予治疗5-7天（仅在完成治疗的四个药物阶段才能计算5剂剂量）。 所有剂量的研究药物都将在完成四毒阶段的治疗阶段的完成时，将直接观察到治疗。 Moxifloxatin剂量将是当前许可的400mg剂量。 每种剂量的治疗将给予维生素B6（50 mg）。 如实验室研究所证明的那样，如果患者的结核分离菌分离株易受异念珠菌，利福平，吡嗪酰胺和氟喹诺酮的敏感，则可能会停产乙巴丁。 密集阶段治疗的持续时间将取决于摄入的剂量的数量，而不是按日历时间确定。 当患者每天有40（每周5天）直接观察剂量时，他们将完成密集型阶段。 该疗法必须在不少于54天内完成，不超过70天。 在完成强化期治疗后，所有研究臂中的患者将通过ATS/IDSA/CDC凸起的延续阶段治疗。 治疗的总持续时间为26周（6个月），除了患有空化的患者以及在治疗的强化阶段结束时呈阳性痰培养，他们将接受总计38周（9个月）的治疗。 符合纳入标准的受试者将以1：1的比例与两个治疗组之一的比例随机分配。 由于基线时的空气（诊断时间）与2个月培养转化率的大幅降低有关，因此随机化将通过空化的存在分层。 此外，随机分组将由地理大陆进行分层。 研究终点： 1。痰培养转化 - 在治疗的强化阶段结束时获得的痰培养没有结核分枝杆菌的生长。 密集型治疗阶段的末端将通过完成40个所需数量的直接剂量的剂量来定义。 2。安全性和耐受性终点 - 分析安全性和耐受性的主要终点是由于任何原因而停止指定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速度和类型。 3.治疗失败 - 完成4个月结核病治疗后的痰液培养阳性。 使用DNA指纹识别，将将所有治疗衰竭分离株与初始分离株进行比较。 临床相关性：目前对涂抹阳性肺结核阳性的治疗至少需要6个月，这是对患者和结核病控制程序具有挑战性的治疗持续时间。 因此，结核病研究的高度优先级是鉴定可以缩短治疗的药物。 在临床前测试中，几种氟喹诺酮抗生素具有对结核分枝杆菌的有效活性。 在当前可用的氟喹诺酮类药物中，莫西法沙星在体外具有出色的活性，在结核病的动物模型中，有利的药代动力学特征（血清半衰期为10-12个小时），缺乏有问题的药物相互作用，不需要进行肾和肝剂量调整的需求，以及甲基肝素的剂量不足以及良好的安全性。 此外，在结核病的鼠模型中，与标准组合利福平，异辛二氮嗪和吡嗪酰胺相比，莫西法沙星代替异尼二氮二氮化物的替代导致培养时间转化的时间显着减少和消毒时间。 然而，在人类中尚未对结核病治疗进行全面评估莫西沙星。 不仅需要评估含莫西沙星的抗结核活性，而且还需要评估莫西沙星疗法更长的治疗的安全性。