DRAMATIC Phase 2 Duration Randomized MDR-TB Treatment Trial

戏剧性的项目摘要/摘要 据估计，2017年耐多药结核病(MDR-TB)患者为60万人。新产品的推出 基因Xpert™检测大大增加了对耐多药结核病治疗的需求。然而， 目前的耐多药结核病治疗方案需要9个月或更长时间才能完成，而且具有很大的毒性。 因此，需要一种更短、毒性更低的治疗方案。我们设计了一种养生法，不会 含有PZA或注射剂，并将利奈唑胺的给药限制在治疗的最初8周， 在利奈唑胺的神经性副作用发生之前。动物研究支持这种疗法可能的疗效。 研究固定疗程方案以实现治疗缩短与高风险相关，因为 没有经过验证的方法来预测治疗的最佳持续时间。我们开发了一种创新的 第二阶段研究设计(“持续时间-随机”)，以确定最短的有效治疗持续时间。在这 设计，参与者被随机分成四个疗程，从最短的到最长的 有效持续时间。然后对结果进行综合分析，以确定最佳治疗时间。 在拟议的多中心、随机、部分失明、四臂、第二阶段戏剧性试验中(持续时间 随机抗耐多药结核病和量身定制干预临床试验)我们将检查 贝达奎林、地拉曼、左氧氟沙星、利奈唑胺和氯法齐明的全口服方案，分别为16、24、32或40岁 几周。通过将四个持续时间的结果一起建模，设计实现了大量的统计 效率。在这项试验中确定的最佳治疗持续时间随后可以在更大的前瞻性中得到验证 3期临床试验。此外，最近的研究表明，基线患者的特征可以 预测结核病的治疗结果；因此，我们将参与者分为“广泛的”参与者和 为“非广泛性”疾病的临床治疗提供指导。 目的1：确定符合以下条件的实验性耐多药结核病治疗方案的最佳疗程 成功的治疗结果。 目的2：描述基线预后风险分层与成功治疗结果的关系。 目的：建立以结核分枝杆菌前体rRNA为基础的新的生物标志物--rRNA合成率。 在试验中研究的持续时间范围内，与个人层面的复发有关。 开发一种更短、耐受性更好的治疗方案将大大提高结核病控制的能力 治疗越来越多的患者的计划。这场戏剧性的审判将采用创新和高效的 新的设计，以建立一个强大的，无毒的耐多药结核病治疗方案，并确定最低持续时间 需要对其进行管理。这些结果将加快向确认性转变的进程 3期临床试验，并增加此类试验成功的可能性。

DRAMATIC PROJECT SUMMARY / ABSTRACT Multidrug-resistant tuberculosis (MDR-TB) was estimated to occur in 600,000 people in 2017. The roll-out of the GeneXpert™ test has generated a substantial increase in the demand for MDR-TB treatment. However, current MDR-TB treatment regimens take 9 months or longer to complete and have substantial toxicity. Therefore, a shorter, less toxic treatment regimen is needed. We have designed a regimen that does not contain PZA or an injectable agent and limits the administration of linezolid to the initial 8 weeks of treatment, before the neuropathic side effects of linezolid occur. Animal studies support the likely efficacy of this regimen. Studies of fixed duration regimens to achieve treatment shortening are associated with high risk, since there are no validated ways to predict what duration of treatment will be optimal. We have developed an innovative Phase 2 study design (“duration-randomization”) to identify the shortest effective treatment duration. In this design, participants are randomized to four durations of treatment from the shortest to the longest likely effective duration. The results are then analyzed together to determine the optimal treatment duration. In the proposed multicenter, randomized, partially blinded, four-arm, phase 2 DRAMATIC Trial (Duration Randomized Anti-MDR-TB And Tailored Intervention Clinical Trial) we will examine the efficacy and safety of an all-oral regimen of bedaquiline, delamanid, levofloxacin, linezolid, and clofazimine given for 16, 24, 32 or 40 weeks. By modeling the results of the four durations together, the design achieves substantial statistical efficiency. The optimal treatment duration identified in this trial can then be validated in a larger prospective Phase 3 clinical trial. In addition, recent studies have demonstrated that baseline patient characteristics can predict TB treatment outcomes; we will therefore stratify participants into those with “extensive” and those with “non-extensive” disease to provide guidance for clinical treatment. Aim 1: To identify the optimal duration of an experimental MDR-TB treatment regimen consistent with a successful treatment outcome. Aim 2: To describe the relationship between baseline prognostic risk strata and successful treatment outcome. Aim 3: To establish that the rRNA synthesis ratio, a novel biologic marker based on M. tb precursor rRNA, is associated with relapse at the individual-level across the range of durations studied in the trial. Development of a shorter, better-tolerated treatment regimen will greatly enhance the ability of TB control programs to treat the growing number of patients. The DRAMATIC Trial will employ an innovative and efficient new design to establish a robust, nontoxic MDR-TB treatment regimen and identify the minimal duration for which it needs to be administered. These results will speed the process of moving forward to a confirmatory phase 3 clinical trial and increase the likelihood that such a trial is successful.