PRESCIENT: A phase IIc, open-label, randomized controlled trial of ultra-short course bedaquiline, clofazimine, pyrazinamide and delamanid versus standard therapy for drug-susceptible tuberculosis

项目摘要/摘要 标准一线治疗药物敏感结核病(ds-TB)是非常有效的，但复杂的长期 治疗持续时间和利福霉素药物-药物相互作用，特别是与抗逆转录病毒疗法(ART)在高HIV- 结核病负担国家。一种耐受性良好且有效的可缩短结核病治疗时间的无利福霉素方案 要实现世界卫生组织(世卫组织)消灭结核病的目标，迫切需要持续的时间。我们的团队 率先使用启用人工智能的抛物线响应面(PRS)平台，实现快速 通过只测试总药物剂量的一小部分来确定最有效的药物剂量组合 功效响应面。这种方法确定了包括贝达奎兰(BDQ)、 氯法齐明(CFZ)和吡嗪酰胺(PZA)在最佳剂量比例下比标准DS-TB更有效 治疗，在3-4周内实现了小鼠模型的无复发治愈。加入地拉帕尼特(DLm)作为第四种药物 药效相当，只需3周即可100%无复发治愈。这大大短于 在支持其他结核病治疗缩短试验的小鼠研究中，是时候无复发治愈了。杀菌和杀菌 在其他实验中证实的灭菌能力，以及良好的皮内药物动力学(PK)，提供了 评估BDQ-CFZ-PZA-DLM(BCZD)组合缩短治疗的其他理由。 这一为期8周的不含利福霉素的超短程方案满足了WHO针对DS的目标方案简介的关键要求。 结核病：药物-药物相互作用的可能性较低，已确定的耐受性和安全性，已登记的成分 和可获得性，并基于临床数据优化剂量。我们假设BCZD将证明 在前8周的治疗中，与标准治疗相比，微生物学疗效更好 DS-TB。为了验证这一点，我们将进行一项IIc阶段的开放标签随机对照试验，以研究 为期8周的BCZD方案的有效性和安全性，为最终的治疗铺平了道路-缩短试验和 潜在地改变了临床实践。我们的试验名为先见之明，将随机抽查156名涂阳患者 患有和不患有HIV的DS-TB接受BCZD治疗8周，而标准治疗26周(1：1比率)。这个 主要目标是通过8周的液体培养转换时间的优势疗效比较； IIc期设计还可以通过延长治疗后随访时间来评估临床终点，最高可达56 3周(目标1a--疗效)。次要目标包括严格评估安全性和耐受性(目标1b -安全性)，药物敏感性测试和全基因组测序，以确定治疗频率- 对BCZD的紧急抗性(目标1c-抗性)。我们还将探索实验药物的效果 暴露，源自群体PK模型，按时培养阳性作为衡量分枝杆菌负荷的指标 和治疗反应，以及校正的QT间期(目标2-PK/Pd)。先见之明将在 在海地和南非建立了临床研究基地，可以接触到大量患者 与结核病有关，并拥有成功实施该项目所需的专业知识和基础设施。

PROJECT SUMMARY/ABSTRACT Standard first-line therapy for drug-susceptible tuberculosis (DS-TB) is highly effective but complicated by long treatment duration and rifamycin drug-drug interactions, particularly with antiretroviral therapy (ART) in high HIV- TB burden countries. A well-tolerated and efficacious rifamycin-free regimen that can shorten TB treatment duration is critically needed to achieve World Health Organization (WHO) targets towards ending TB. Our group pioneered the use of an artificial-intelligence-enabled parabolic response surface (PRS) platform allowing rapid identification of the most effective drug-dose combinations by testing only a small fraction of the total drug-dose efficacy response surface. This approach determined that drug combinations including bedaquiline (BDQ), clofazimine (CFZ), and pyrazinamide (PZA) at optimal dose ratios were more effective than standard DS-TB treatment, achieving relapse-free cure in mouse models within 3-4 weeks. Adding delamanid (DLM) as a 4th drug was equivalent in potency, achieving 100% relapse-free cure in only 3 weeks. This is substantially shorter than time to relapse-free cure in mouse studies supporting other TB treatment shortening trials. Bactericidal and sterilizing ability confirmed in other experiments, and favorable intra-lesional pharmacokinetics (PK), provides additional justification for evaluation of the BDQ-CFZ-PZA-DLM (BCZD) combination for treatment shortening. This 8-week rifamycin-free ultrashort regimen fulfills key requirements of the WHO target regimen profile for DS- TB: lower potential for drug-drug interactions, established tolerability and safety, constituent agents registered and accessible, and optimized dosing based on clinical data. We hypothesize that BCZD will demonstrate superior microbiologic efficacy relative to standard therapy during the first 8 weeks of treatment for patients with DS-TB. To test this, we shall conduct a Phase IIc, open-label, randomized controlled trial to investigate the efficacy and safety of an 8-week regimen of BCZD, paving the way for a definitive treatment-shortening trial and potentially shifting clinical practice. Our trial, called PRESCIENT, will randomize 156 adults with smear-positive DS-TB, with and without HIV, to receive BCZD for 8 weeks versus standard therapy for 26 weeks (1:1 ratio). The primary objective is a superiority efficacy comparison of time to liquid culture conversion through 8 weeks; the Phase IIc design also enables evaluation of clinical endpoints through extended post-treatment follow up to 56 weeks (Aim 1a - efficacy). Secondary objectives include rigorous assessment of safety and tolerability (Aim 1b - safety), and drug susceptibility testing and whole genome sequencing to determine frequency of treatment- emergent resistance to BCZD (Aim 1c - resistance). We shall also explore the effect of experimental drug exposure, derived from population PK models, on time to culture positivity as a measure of mycobacterial burden and treatment response, and on corrected QT interval (Aim 2 - PK/PD). PRESCIENT will be conducted at established clinical research sites in Haiti and South Africa which have access to large populations of patients with DS-TB and have the necessary expertise and infrastructure to successfully implement this project.