Two-month Regimens Using Novel Combinations to Augment Treatment Effectiveness for drug-sensitive Tuberculosis: the "TRUNCATE-TB" trial

使用新组合的两个月治疗方案来增强药物敏感结核病的治疗效果：“TRUNCATE-TB”试验

• 批准号: MR/L004356/1
• 负责人: Patrick Phillips
• 金额: $ 638.75万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL004356%2F1
• 关键词: Two; month; Regimens; Using; Novel

TB incidence rates are falling only very slowly in many high burden countries that have healthcare systems for TB that are overstretched and experiencing large funding gaps. Current tools and systems are clearly not able to solve the problem in the near future and alternatives must be explored - as a matter of urgency - that allow healthcare systems to use resources more effectively and economically to treat and cure more patients with drug-sensitive disease. Multi-drug-resistant (MDR)-TB is also an increasing problem, and a further advantage of improving treatment for drug-sensitive TB may be that it reduces the drive towards generating new cases of MDR-TB. We propose a new strategic approach: instead of the current standard of care of 6 months treatment for drug-sensitive TB, we propose an approach that focuses resources on optimizing individual treatment for just 2 months, then stopping and following patients in order to re-treat the small proportion of those who relapse subsequently (which is expected to be with drug-sensitive organisms). In addition to saving programme resources, stopping after 2 months may reduce the drug pressure for generating MDR-TB as patients not taking medication cannot breed drug resistance. If relapse rates are relatively low, it is possible that such a strategy could be highly cost effective. With recent advances in TB drug development, it is now likely that we can find one or more 2-month combination regimens with low rate of relapse that can be used in such a strategy. Previous trials show that, even with standard drugs, rates of relapse with shorter course TB treatment are low (usually below 10%). With the new drugs that have new mechanisms of action, it is likely that 2-month treatment combinations can be constructed that will have very low rates of relapse - this has already been shown in a mouse model of TB. The only way to test which of the many promising regimens may achieve good cure rate of TB with just 2 months of treatment is to do human trials in which treatment is stopped at this time point and patients are followed for relapse. The Two-month Regimens Using Novel Combinations to Augment Treatment Effectiveness for drug-sensitive TB (TRUNCATE TB) trial is a randomized open label, multi-arm multi-stage, parallel group trial in which we will compare four novel strategies - each using a different initial 2 month treatment combination including one or more novel drugs, and a subsequent 6-month retreatment course with standard drugs for those who relapse - against a 6 month treatment course with standard drugs from the outset. TRUNCATE TB will recruit 1300 patients with confirmed drug-sensitive pulmonary TB and allocate them at random to receive one of the novel 2 month treatment combinations or 6 months standard-of-care treatment. All patients will be followed for 2 years to detect exacerbation of symptoms and be evaluated for relapse. Information on clinical outcomes, microbiological clearance of TB, adverse events, quality of life and healthcare utilisation and costs will be collected. Treatments will be compared for their overall outcome (what proportion of people still have TB in their sputum at 2 years after study entry). If the strategies are equivalent on this outcome then the various advantages and disadvantages of the strategies can be compared including safety, patient acceptability and quality of life, resource use and costs, and drug resistance. We will also look for markers of response that could permit refinements of the strategy (e.g. by identifing groups of patients, if any, in whom 2 months' treatment can be reliably predicted to be inadequate). The trial will be conducted at approximately 12 large TB treatment centres within an Asian TB trials network. This trial addresses a question of high relevance to real-world TB programme settings. It has the potential to transform the way TB programmes operate and to have a major impact on global health.

在许多负担沉重的国家，结核病发病率的下降速度非常缓慢，这些国家的结核病医疗系统负担过重，并经历着巨大的资金缺口。目前的工具和系统显然不能在不久的将来解决这个问题，必须作为紧急事项探索替代方案，使医疗保健系统能够更有效、更经济地使用资源来治疗和治愈更多患有药物敏感疾病的患者。耐多药结核病也是一个日益严重的问题，改进对药物敏感结核病的治疗的另一个好处可能是它减少了产生新的耐多药结核病病例的动力。我们提出了一种新的战略方法：取代目前对药物敏感结核病6个月治疗的护理标准，我们提出了一种方法，将资源集中在优化个人治疗2个月，然后停止并跟踪患者，以便重新治疗随后复发的一小部分人(预计是使用药物敏感微生物)。除了节省方案资源外，由于不服药的患者不会产生耐药性，因此在2个月后停止治疗可能会减少产生耐多药结核病的药物压力。如果复发率相对较低，这样的策略可能具有很高的成本效益。随着结核病药物开发的最新进展，我们现在很可能找到一个或多个复发率较低的2个月联合方案，可以用于这样的策略。以前的试验表明，即使使用标准药物，较短疗程的结核病治疗的复发率也很低(通常低于10%)。有了具有新作用机制的新药，很可能构建出复发率非常低的2个月治疗组合--这已经在结核病的小鼠模型中得到了证明。要测试在许多有希望的方案中，哪一种可能在短短两个月的治疗时间内达到良好的结核病治愈率，唯一的方法是进行人体试验，在这个时间点停止治疗，并跟踪患者的复发。为期两个月的药物敏感型结核病(截短型结核病)试验是一项随机开放标签、多臂多阶段、平行分组试验，使用新的组合来提高药物敏感型结核病(Truncate TB)的治疗效果。在试验中，我们将比较四种新策略--每种使用不同的初始2个月治疗组合，包括一种或多种新药，以及随后6个月的复发者使用标准药物的再治疗疗程--与从一开始就使用标准药物的6个月疗程进行比较。截断结核病将招募1300名确诊为药物敏感型肺结核的患者，并随机分配他们接受新的2个月治疗组合或6个月标准治疗之一。所有患者将被跟踪2年，以发现症状的恶化并评估其复发情况。将收集有关临床结果、结核病微生物清除、不良事件、生活质量、医疗保健利用和成本的信息。治疗将根据他们的总体结果进行比较(进入研究两年后，有多大比例的人在痰中仍有结核病)。如果在这一结果上这些策略是等价的，那么可以比较这些策略的各种优缺点，包括安全性、患者可接受性和生活质量、资源使用和成本以及耐药性。我们还将寻找能够改进策略的反应标志(例如，通过确定可以可靠地预测2个月治疗不足的患者组)。该试验将在亚洲结核病试验网络内的大约12个大型结核病治疗中心进行。这项试验解决了一个与现实世界结核病规划环境高度相关的问题。它有可能改变结核病规划的运作方式，并对全球健康产生重大影响。