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.

项目摘要/摘要 药物敏感结核病（DS-TB）的标准一线疗法非常有效，但长期很复杂 治疗持续时间和利福胺药物 - 药物相互作用，特别是在高HIV中的抗逆转录病毒疗法（ART） 结核病负担国家。可以缩短结核病治疗的一种耐受性和有效的不含利由霉素的方案 需要持续时间来实现世界卫生组织（WHO）的目标，以结束结核病。我们的小组 开创了使用人工智能的抛物线响应表面（PRS）平台的使用，允许快速 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 功效响应表面。这种方法确定了包括Bedaquiline（BDQ）在内的药物组合， 最佳剂量比的氯富齐胺（CFZ）和吡嗪酰胺（PZA）比标准DS-TB更有效 治疗，在3-4周内实现小鼠模型中无复发的治疗。将Delamanid（DLM）添加为第四药 在效力方面是等效的，仅在3周内实现了100％无复发的治疗方法。这比 在支持其他结核病治疗缩短试验的小鼠研究中无复发治疗的时间。杀菌和 在其他实验中确认的灭菌能力和有利的内部药代动力学（PK）提供 用于评估BDQ-CFZ-PZA-DLM（BCZD）组合以进行治疗缩短的其他理由。 这项为期8周的利福霉素无效疗法满足了WHO目标方案的关键要求DS- 结核病：较低的药物相互作用的潜力，已建立的耐受性和安全性，已注册的组成剂 可访问并根据临床数据进行优化的给药。我们假设BCZD将证明 在治疗的前8周内，相对于标准治疗的高级微生物学疗效针对患者 DS-TB。为了测试这一点，我们将进行IIC期，开放标签，随机对照试验，以研究 BCZD为期8周的疗效和安全性，为确定治疗方法铺平了道路 有可能改变临床实践。我们的试验称为Prescient，将随机将156名成年人随机涂片阳性 DS-TB，有或没有HIV，将BCZD与标准治疗相比26周（1：1）接受BCZD。这 主要目标是在8周之前对液体培养时间转化时间的优势疗效进行比较。这 IIC阶段设计还可以通过扩展后处理进行评估临床终点 周（AIM 1A-功效）。次要目标包括对安全性和耐受性的严格评估（AIM 1B - 安全）和药物敏感性测试和整个基因组测序以确定治疗的频率 - 对BCZD的紧急抗性（AIM 1C-电阻）。我们还将探索实验药物的效果 从人口PK模型中得出的暴露，随着培养阳性的时间，作为分生不清负担的量度 和治疗反应，并在校正的QT间隔（AIM 2 -PK/PD）上进行。先见者将在 在海地和南非建立的临床研究地点，可以使用大量患者人群 使用DS-TB，并具有成功实施该项目的必要专业知识和基础架构。