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: 10661811
• 负责人: SERENA Patricia KOENIG
• 金额: $ 118.07万
• 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/10661811
• 关键词: Address; Adult; Adverse event; Aftercare; Artificial Intelligence; Biological; Characteristics; Clinical; Clinical Data; Clinical Trials; Combined Modality Therapy; Confidence Intervals; Country; Data; Data Collection; Dose; Drug Combinations; Drug Exposure; Drug Interactions; Drug Kinetics; Drug resistance; 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; 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; clinical practice; clinical research site; design; drug repurposing; 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.

项目概要/摘要 药物敏感结核病 (DS-TB) 的标准一线治疗非常有效，但由于长期治疗而变得复杂 治疗持续时间和利福霉素药物间相互作用，特别是在高 HIV 患者中使用抗逆转录病毒治疗 (ART) 结核病负担国家。一种耐受性良好且有效的无利福霉素疗法，可缩短结核病治疗时间 实现世界卫生组织 (WHO) 终结结核病的目标迫切需要持续时间。我们组 率先使用人工智能支持的抛物线响应面（PRS）平台，允许快速 通过仅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。这种方法确定了药物组合，包括贝达喹啉（BDQ）、 最佳剂量比的氯法齐明 (CFZ) 和吡嗪酰胺 (PZA) 比标准 DS-TB 更有效 治疗，小鼠模型在 3-4 周内实现无复发治愈。添加德拉马尼 (DLM) 作为第四种药物 疗效相当，仅 3 周即可实现 100% 无复发治愈。这大大短于 支持其他结核病治疗缩短试验的小鼠研究中的无复发治愈时间。杀菌和 其他实验证实的灭菌能力以及良好的病灶内药代动力学 (PK)，提供了 评估 BDQ-CFZ-PZA-DLM (BCZD) 组合缩短治疗时间的额外理由。 这种为期 8 周的不含利福霉素的超短疗程满足 WHO 针对 DS- 的目标方案概况的关键要求 结核病：药物间相互作用的可能性较低，已确定的耐受性和安全性，成分已注册 以及基于临床数据的可获取且优化的剂量。我们假设 BCZD 将证明 对于患有以下疾病的患者，在治疗的前 8 周内，相对于标准治疗，微生物学疗效更佳 DS-TB。为了测试这一点，我们将进行 IIc 期、开放标签、随机对照试验来调查 BCZD 8 周治疗方案的有效性和安全性，为最终的缩短治疗试验铺平了道路 潜在地改变临床实践。我们的试验名为 PRESCIENT，将随机抽取 156 名涂片呈阳性的成年人 DS-TB，无论是否患有 HIV，接受 BCZD 8 周与标准治疗 26 周（1:1 比例）。这 主要目标是比较 8 周内液体培养物转化时间的优效性；这 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（最多 56 周（目标 1a - 功效）。次要目标包括严格评估安全性和耐受性（目标 1b - 安全性），以及药物敏感性测试和全基因组测序以确定治疗频率 - 对 BCZD 的新兴耐药性（目标 1c - 耐药性）。我们还将探讨实验药物的效果 根据群体 PK 模型得出的暴露时间，培养物呈阳性的时间作为分枝杆菌负荷的衡量标准 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。

项目成果

Efficacy and Safety of Intensified vs Standard Prophylactic Anticoagulation Therapy in Patients Hospitalized With Coronavirus Disease 2019: Updated Systematic Review and Meta-analysis.

• DOI: 10.1093/ofid/ofad506
• 发表时间: 2023-11
• 期刊: OPEN FORUM INFECTIOUS DISEASES
• 影响因子: 4.2
• 作者: Scheier, Thomas C.;Carlin, Stephanie;Wills, Nicola K.;Wasserman, Sean;Mertz, Dominik;Eikelboom, John W.
• 通讯作者: Eikelboom, John W.