Reduced Injectable, Short-course for (E)Xpert MDR-TB [RISE trial]

项目摘要/摘要 在2011年新增的近900万结核病病例中，估计有50万人是 多药耐药(MDR)，但只有不到20%的人开始接受MDR-TB治疗。没有能力使 在门诊环境中诊断耐多药结核病，专门治疗中心床位容量有限，以及 资源密集，有毒药物方案的疗程延长，导致未能 启动耐多药结核病治疗，这会增加死亡率并助长社区传播。幸运的是速度很快 像Xpert MTB/RIF这样的诊断方法现在可以在一次诊所就诊的时间内大规模检测到耐多药结核病 目前正在向门诊筛查地点推广(包括我们在孟加拉国和坦桑尼亚的研究地点)。 然而，新的、主要是非门诊患者的激增将进一步造成治疗瓶颈，除非 政府的结核病计划被大规模扩大，或者治疗方案的持续时间可以缩短 并在医院外实施。后者是最直接可实现的。为此，我们提出了一项 创新的方法，既最大限度地减少长期住院的必要性，又缩短总住院时间 治疗持续时间。我们将通过(1)使用优化的药代动力学方案来测试这种方法 根据当地的定量易感测试，(2)限制接触最资源密集型和 多药方案的有毒成分，可注射的氨基糖苷，以及(3)将该方案应用于 细菌负荷低的流动种群。因此，拟议的第二阶段b非劣质审判减少。 (E)Xpert MDR-TB(RISE试验)的可注射、短期疗程，将随机选择新诊断的门诊患者 通过Xpert MTB/RIF试验将MDR-TB患者添加到新方案(1个月可注射氨基糖苷，12 总疗程)或目前的护理标准(6个月以上可注射氨基糖苷类，20+ 月总疗程)比较治疗成功率和与药物有关的不良反应 事件。这项建议充分利用了与弗吉尼亚大学和临床试验的密切合作 坦桑尼亚乞力马扎罗临床研究所和孟加拉国的ICDDR，B的基础设施。这个 R34将允许对试验设计进行批判性评估，为制定完整的研究方案提供支持， 操作手册和数据管理系统，并确保初步批准。

PROJECT SUMMARY/ABSTRACT Of the nearly 9 million new case of tuberculosis (TB) in 2011, it is estimated that 500,000 were multidrug-resistant (MDR), but less than 20% were started on MDR-TB treatment. The inability to make the diagnosis of MDR-TB in the ambulatory setting, limited bed capacity at specialized treatment centers, and resource-intensive, prolonged treatment courses of toxic medication regimens, contribute to the failure to initiate MDR-TB treatment which drives mortality and fuels community transmission. Fortunately rapid diagnostics like the Xpert MTB/RIF can now detect MDR-TB in the time of a single clinic visit, and large scale roll-out to ambulatory screening sites are underway (including at our study sites in Bangladesh and Tanzania). Yet the swell of new, largely ambulatory, patients will further create a treatment bottleneck unless governmental TB programs are massively expanded, or the duration of treatment regimens can be shortened and administered outside of the hospital. The latter is most immediately achievable. To do so, we propose an innovative approach to both minimize the necessity for prolonged hospitalization and to shorten the total treatment duration. We will test this approach by (1) employing a regimen of optimized pharmacokinetics based on local quantitative susceptible testing, (2) limiting the exposure to the most resource-intensive and toxic component of the multidrug regimen, the injectable aminoglycoside, and (3) applying the regimen to an ambulatory population with low bacterial burden. Thus, the proposed phase IIb non-inferiority trial, Reduced Injectable, Short-course for (E)Xpert MDR-TB (RISE trial), will randomize ambulatory patients newly diagnosed with MDR-TB by the Xpert MTB/RIF assay to the novel regimen (1 month injectable aminoglycoside, 12 months total treatment duration) or the current standard of care (6+ months injectable aminoglycoside, 20+ months total treatment duration) to compare rates of treatment success, and medication related adverse events. This proposal leverages strong collaboration with the University of Virginia and the clinical trials infrastructure of the Kilimanjaro Clinical Research Institute in Tanzania and the ICDDR,B in Bangladesh. The R34 will allow critical assessment of trial design, provide support for development of a complete study protocol, operations manual, and data management system, and securing of preliminary approvals.