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

在许多结核病高负担国家，结核病发病率下降非常缓慢，这些国家的结核病医疗保健系统负担过重，资金缺口很大。目前的工具和系统显然无法在不久的将来解决这个问题，必须探索替代方案-作为紧急事项-使医疗保健系统能够更有效和经济地使用资源来治疗和治愈更多患有药物敏感性疾病的患者。耐多药结核病也是一个日益严重的问题，改善对药物敏感的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进行6个月治疗的标准治疗，我们提出了一种方法，将资源集中在优化仅2个月的个体治疗上，然后停止并随访患者，以便重新治疗随后复发的一小部分患者（预计将与药物敏感生物体一起）。除了节省规划资源外，在两个月后停止用药还可以减少产生耐多药结核病的药物压力，因为不服药的患者不会产生耐药性。如果复发率相对较低，这种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种或多种复发率低的2个月联合治疗方案，可用于这种策略。以前的试验表明，即使使用标准药物，疗程较短的结核病治疗复发率也很低（通常低于10%）。使用具有新作用机制的新药，很可能可以构建具有非常低复发率的2个月治疗组合-这已经在结核病小鼠模型中显示。测试许多有希望的治疗方案中哪一种可以在短短2个月的治疗中实现良好的结核病治愈率的唯一方法是进行人体试验，其中在这个时间点停止治疗，并跟踪患者的复发。使用新组合的两个月方案提高药物敏感结核病的治疗效果（TRUNCATE TB）试验是一项随机开放标签、多组多阶段、平行组试验，其中我们将比较四种新策略-每种策略使用不同的初始2个月治疗组合，包括一种或多种新药，对于复发的患者，随后进行为期6个月的标准药物复治-而不是从一开始就接受为期6个月的标准药物治疗。TRUNCATE TB将招募1300名确诊为药物敏感性肺结核的患者，并将他们随机分配接受一种新的2个月治疗组合或6个月标准治疗。将对所有患者进行2年随访，以检测症状加重并评估复发情况。将收集有关临床结局、结核菌清除率、不良事件、生活质量和医疗保健利用率及成本的信息。将比较治疗的总体结局（进入研究后2年痰液中仍有结核病的患者比例）。如果这些策略在这一结果上是等效的，那么可以比较这些策略的各种优点和缺点，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。我们还将寻找可能允许改进策略的反应标志物（例如，通过确定患者组，如果有的话，可以可靠地预测2个月的治疗是不充分的）。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。该试验解决了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，并对全球卫生产生重大影响。

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.