DRAMATIC Phase 2 Duration Randomized MDR-TB Treatment Trial

戏剧性的 2 期持续时间随机耐多药结核病治疗试验

• 批准号: 10405011
• 负责人: Charles Robert Horsburgh
• 金额: $ 134.25万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-21 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10405011
• 关键词: Address; Animals; Biological Markers; Blinded; Characteristics; Clinical; Clinical Treatment; Clinical Trials; Detection; Development; Enrollment; Extreme drug resistant tuberculosis; Failure; Future; Goals; Hepatitis; Human; Individual; Injectable; Intervention; Levaquin; Linezolid; Microbiology; Modeling; Multidrug-Resistant Tuberculosis; Mycobacterium tuberculosis; National Institute of Allergy and Infectious Disease; Neuropathy; Oral; Outcome; Outcome Measure; Participant; Patients; Persons; Pharmaceutical Preparations; Phase; Phase III Clinical Trials; Process; Pyrazinamide; Randomized; Regimen; Relapse; Reporting; Research; Research Design; Research Priority; Resistance; Ribosomal RNA; Rifampin; Risk; Safety; Speed; Sputum; Strategic Planning; Testing; Time; Toxic effect; Treatment Protocols; Treatment outcome; Tuberculosis; Widespread Disease; arm; bactericide; base; burden of illness; cost; deafness; design; early detection biomarkers; effective therapy; efficacy evaluation; four-arm study; high risk; improved; individual patient; individualized medicine; innovation; isoniazid; molecular marker; novel; optimal treatments; phase 2 study; phase II trial; phase III trial; prognostic; programs; prospective; rRNA Precursor; risk stratification; side effect; success; treatment duration; treatment trial; trial design; tuberculosis treatment

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.

戏剧性的项目总结/摘要 据估计，2017年有60万人患有耐多药结核病（MDR-TB）。推出 GeneXpert™测试已经产生了对MDR-TB治疗的需求的显著增加。然而，在这方面， 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，并且具有相当大的毒性。 因此，需要更短、毒性更小的治疗方案。我们设计了一个方案， 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该方案的可能疗效。 为缩短治疗时间而进行的固定持续时间方案研究与高风险相关，因为 没有有效的方法来预测治疗的持续时间将是最佳的。我们开发了一种创新的 2期研究设计（“持续时间-随机化”），以确定最短的有效治疗持续时间。在这 设计，参与者被随机分配到四个持续时间的治疗，从最短到最长的可能 有效期限。然后对结果进行分析，以确定最佳治疗持续时间。 在拟定的多中心、随机化、部分设盲、四组、II期DRAMATIC试验（持续时间 随机抗耐多药结核病和定制干预临床试验），我们将检查 贝达喹啉、地拉曼尼、左氧氟沙星、利奈唑胺和氯法齐明的全口服方案，给药16、24、32或40 周通过对四个持续时间的结果进行建模，该设计实现了实质性的统计分析。 效率本试验中确定的最佳治疗持续时间可以在更大的前瞻性研究中进行验证。 3期临床试验。此外，最近的研究表明，基线患者特征可以 预测结核病治疗结果;因此，我们将参与者分为“广泛”和“广泛”两类。 为临床治疗“非广泛性”疾病提供指导。 目的1：确定与耐多药结核病治疗方案一致的实验性耐多药结核病治疗方案的最佳持续时间。 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局之间的关系。 目的3：建立一种基于M. tb前体rRNA， 在试验研究的持续时间范围内，与个体水平的复发相关。 开发更短、耐受性更好的治疗方案将大大提高结核病控制的能力 治疗越来越多的病人。DRAMATIC试验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 这是需要管理的。这些结果将加速向验证性的方向迈进的过程。 3期临床试验，并增加这种试验成功的可能性。