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

项目总结/摘要 在2011年近900万新的结核病病例中，估计有50万是 多药耐药（MDR），但不到20%的人开始接受MDR-TB治疗。无法使 在门诊环境中诊断出耐多药结核病，专科治疗中心的床位有限， 资源密集型、毒性药物治疗方案疗程延长， 启动耐多药结核病治疗，这导致死亡率上升并助长社区传播。幸运的是， 像Xpert MTB/RIF这样的诊断现在可以在一次诊所就诊的时间内检测出MDR-TB， 正在向门诊筛查中心推广（包括我们在孟加拉国和坦桑尼亚的研究中心）。 然而，新的，大部分是流动的患者的膨胀将进一步造成治疗瓶颈，除非 政府结核病规划得到大规模扩展，或者治疗方案的持续时间可以缩短 并在医院外给药后者是最容易实现的。为此，我们提出一个 创新的方法，以尽量减少延长住院的必要性，并缩短总 治疗持续时间。我们将通过（1）采用优化的药代动力学方案 根据当地的定量易感性测试，（2）将暴露限制在资源最密集的地区， 多药方案的毒性组分，可注射的氨基糖苷类，和（3）将该方案应用于 低细菌负荷的流动人群。因此，拟定的IIb期非劣效性试验， （E）Xpert MDR-TB（RISE试验）的短期注射剂，将随机分配新诊断的门诊患者 Xpert MTB/RIF检测新方案（1个月注射氨基糖苷类，12 总治疗持续时间为6个月）或当前标准治疗（6个月以上可注射氨基糖苷类，20个月以上 月总治疗持续时间），以比较治疗成功率和药物相关不良反应。 事件该提案利用了与弗吉尼亚大学和临床试验的密切合作， 坦桑尼亚的基利曼哈罗临床研究所和孟加拉国的ICDDR，B的基础设施。的 R34将允许对试验设计进行关键评估，为制定完整的研究方案提供支持， 业务手册和数据管理系统，并获得初步批准。

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.