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

PRESCIENT：一项针对药物敏感结核病的超短疗程贝达喹啉、氯法齐明、吡嗪酰胺和德拉马尼与标准疗法的 IIc 期、开放标签、随机对照试验

• 批准号: 10488329
• 负责人: SERENA Patricia KOENIG
• 金额: $ 122.1万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-07 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10488329
• 关键词: Address; Adult; Adverse event; Aftercare; Artificial Intelligence; Characteristics; Clinical; Clinical Data; Clinical Trials; Confidence Intervals; Country; Data Collection; Dose; Drug Combinations; Drug Exposure; Drug Interactions; Drug Kinetics; Drug resistance; Ensure; Evaluation; Frequencies; Future; Goals; Guidelines; HIV; HIV Seropositivity; HIV/TB; Haiti; Hepatitis; Inbred BALB C Mice; Individual; Infrastructure; Laboratory Procedures; Liquid substance; Lung; Measures; Methods; Microbiology; Minimum Inhibitory Concentration measurement; Monitor; Mus; Outcome; Participant; Patients; Pharmaceutical Preparations; Phase; Phenotype; Population; Predisposition; Probability; Process; Pyrazinamide; Randomized; Randomized Controlled Trials; Regimen; Relapse; Resistance; Rifampin; Rifamycins; Safety; Sample Size; Skin; South Africa; Surface; Testing; Time; Translating; Translations; Treatment Failure; Treatment Protocols; Tuberculosis; Width; World Health Organization; adverse event monitoring; antiretroviral therapy; bactericide; base; clinical practice; clinical research site; design; drug standard; drug-sensitive; efficacy trial; experimental study; follow-up; genome sequencing; hazard; high throughput screening; mouse model; mycobacterial; novel; open label; patient population; pharmacokinetic model; pre-clinical; preclinical evaluation; research clinical testing; resistance frequency; resistance mutation; response; risk sharing; safety assessment; standard care; treatment adherence; treatment arm; treatment duration; treatment response; tuberculosis drugs; tuberculosis treatment; whole genome

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.

项目总结/摘要 药物敏感性结核病（DS-TB）的标准一线治疗非常有效，但由于长期使用， 治疗持续时间和利福霉素药物相互作用，特别是在艾滋病毒感染率高的患者中与抗逆转录病毒治疗（ART）的相互作用， 结核病负担国家。一种耐受性良好且有效的无利福霉素方案，可缩短结核病治疗时间 为实现世界卫生组织（世卫组织）消灭结核病的目标，我们集团 率先使用人工智能抛物线响应面（PRS）平台， 通过仅测试总药物剂量的一小部分来鉴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喹啉（BDQ）在内的药物组合， 氯法齐明（CFZ）和吡嗪酰胺（PZA）在最佳剂量比下比标准DS-TB更有效 治疗，在3-4周内在小鼠模型中实现无复发治愈。添加delamanid（DLM）作为第4种药物 在效力上相当，仅在3周内实现100%无复发治愈。这大大短于 小鼠研究中的无复发治愈时间，支持其他结核病治疗缩短试验。杀菌和 在其他实验中证实的杀菌能力和有利的病灶内药代动力学（PK）， 评价BDQ-CFZ-PZA-DLM（BCZD）复方制剂缩短治疗时间的其他依据。 这一8周无利福霉素超短方案符合DS的WHO目标方案特征的关键要求- TB：药物间相互作用的可能性较低，已确定耐受性和安全性，已注册的成分药物 并且基于临床数据优化给药。我们假设BCZD将证明 在治疗的前8周内， DS-TB为了验证这一点，我们将进行一项IIc期、开放标签、随机对照试验， 为期8周的BCZD治疗方案的有效性和安全性，为确定性治疗缩短试验铺平了道路， 可能会改变临床实践。我们的试验名为PRESCIENT，将随机抽取156名涂片阳性的成年人， DS-TB，有和没有HIV，接受BCZD 8周与标准治疗26周（1：1比例）。的 主要目的是比较8周内液体培养转化时间的优效性; IIc期设计还可以通过延长治疗后随访至56例来评价临床终点 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），以及药敏测试和全基因组测序以确定治疗频率- 对BCZD的紧急抗性（Aim 1c -抗性）。我们还将探讨实验药物的作用 暴露量，来源于群体PK模型，至培养阳性时间作为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）。PRESCIENT将在 在海地和南非建立了临床研究中心，可以接触到大量患者 与DS-TB合作，并拥有成功实施该项目所需的专业知识和基础设施。