Ph2a Study: Rifampin, Merrem, Augmentin for Tuberculosis IND 129159; 12/31/2015

项目总结/摘要 结核病（TB）是全球最大的传染病杀手。耐多药结核病， 支原体引起对异烟肼和利福平耐药的结核病威胁着全球结核病控制。冗长的， 能够治愈耐多药结核病的昂贵治疗往往无法为需要它们的患者所用， 50%成功，并造成不可接受的高毒性。利福平，由于其杀菌活性， M.结核病，发挥着不可或缺的作用，在现代六个月的“短程”治疗药物敏感的 TB.在耐多药结核病中，感染细菌对利福平的耐药性是导致耐多药结核病的主要原因。 当不能使用利福平时，需要延长18-24个月的治疗时间。截至目前为止， 目前还没有任何抗结核病药物具有与利福平相当的杀菌效力。 恢复利福平活性的策略，即使是部分恢复，也可能对缩短治疗时间有重要作用。 耐多药结核病。加强利福平活性的策略--即增加给定利福平的抗结核作用， 利福平的剂量--也可能与药物敏感结核病的治疗有关。Lamichhane及其同事 最近约翰霍普金斯大学的研究表明，利福平加碳青霉烯/β- 内酰胺酶抑制剂具有协同作用，降低了利福平的有效MIC，甚至恢复了 利福平体外抗利福平耐药M.结核此外，美罗培南加 阿莫西林/克拉维酸在人结核病中具有有效的抗结核活性，并且安全且耐受性良好。 我们提出了一个集中的，概念验证的临床试验，以确定是否，在肺结核患者， 碳青霉烯/ β-内酰胺酶抑制剂组合可作为利福平“增敏剂”， 利福平的抗结核活性。在这项2a期随机开放标签试验中，我们将招募患者 对利福平敏感的肺结核患者以及对利福平耐药的肺结核患者。 受试者将随机接受5种治疗之一，持续7天： 基线DST方案和方案组分 利福平 耐 随机 （1：1）至：A利福平美罗培南Amx/Clv B -美罗培南Amx/Clv 利福平 易感 随机 （1：1：1）至：C利福平美罗培南Amx/Clv D -美罗培南Amx/Clv 利福平 缩略语：DST，药敏试验; Amx/Clv，阿莫西林/克拉维酸 主要终点是M的log 10菌落形成单位的平均每日下降。每毫升痰中结核菌数 7天的治疗。将评估方案的安全性。我们将强化 药代动力学（PK）和分枝杆菌学评估，在一系列M. 结核病最低抑制剂浓度（MIC）和预期个体间利福平PK变异性， 将允许确定利福平之间的药效学关系， 浓度-时间曲线（AUC）和利福平联合给药时的抗结核活性 美罗培南和阿莫西林/克拉维酸 通过与抗结核药物联合使用， 碳青霉烯和β-内酰胺酶抑制剂将改变耐多药结核病的治疗， 患者和公众健康。利福平活性的增强也可能与以下因素有关： 治疗药物敏感性结核病，不仅在某些患者亚组中，而且作为 缩短治疗时间的策略适用于全球大多数结核病患者。

Project Summary/Abstract Tuberculosis (TB) is the single greatest infectious disease killer globally. Multidrug-resistant (MDR) TB, caused by M. tuberculosis resistant to isoniazid and rifampin, threatens global TB control. The lengthy, expensive treatments that can cure MDR-TB are often not accessible by patients who need them, are only 50% successful, and cause unacceptably high toxicity. Rifampin, by virtue of its sterilizing activity against M. tuberculosis, plays an indispensable role in modern six-month `short-course' therapy for drug-susceptible TB. In MDR-TB, it is the infecting bacteria's resistance to rifampin that is primarily responsible for the prolonged treatment duration of 18-24 months that is required when rifampin cannot be used. Up to now, there are simply no anti-TB drugs with demonstrated sterilizing potency equivalent to that of rifampin. Strategies that restore rifampin activity, even partially, may have important treatment shortening effects for MDR-TB. Strategies to potentiate rifampin activity -- that is, to increase the antituberculosis effect of a given dose of rifampin -- may also be relevant for treatment of drug-susceptible TB. Lamichhane and colleagues at Johns Hopkins University recently showed that the combination of rifampin plus a carbapenem/β- lactamase inhibitor is synergistic and lowers the effective rifampin MIC, even restoring the activity of rifampin in vitro against rifampin-resistant M. tuberculosis. Further, the combination of meropenem plus amoxicillin/clavulanate has potent antituberculosis activity in human TB and is safe and well-tolerated. We propose a focused, proof-of-concept clinical trial to determine whether, in pulmonary TB patients, a carbapenem/ β-lactamase inhibitor combination can serve as a rifampin `sensitizer' and thereby potentiate the antituberculosis activity of rifampin. In this phase 2a randomized, open-label trial we will enroll patients with rifampin-susceptible pulmonary TB as well as patients with rifampin-resistant pulmonary TB. Participants will be randomized to receive one of 5 treatments for 7 days: Baseline DST Regimen Regimen Components Rifampin resistant Randomized (1:1) to: A Rifampin Meropenem Amx/Clv B - Meropenem Amx/Clv Rifampin susceptible Randomized (1:1:1) to: C Rifampin Meropenem Amx/Clv D - Meropenem Amx/Clv E Rifampin - - Abbreviations: DST, drug-susceptibility testing; Amx/Clv, amoxicillin/clavulanate The primary endpoint is mean daily fall in log10 colony forming units of M. tuberculosis per mL of sputum over 7 days of treatment. Safety of the regimens will be assessed. We will incorporate intensive pharmacokinetic (PK) and mycobacteriology assessments which, in the context of a range of M. tuberculosis minimum inhibitor concentrations (MICs) and expected inter-individual rifampin PK variability, will allow determination of the pharmacodynamic relationships between rifampin, rifampin area under the concentration-time curve (AUC), and antituberculosis activity when rifampin is administered in combination with meropenem and amoxicillin/clavulanate. The ability to recoup rifampin's antituberculosis activity, even partially, through combination with a carbapenem and β-lactamase inhibitor would transform the treatment of MDR-TB and have implications for individual patients and public health. Potentiation of rifampin activity is also likely to be relevant for treatment of drug-susceptible TB, not only in certain patient sub-groups but also as a component of a treatment-shortening strategy applicable to the majority of TB patients worldwide.