Sputum Transcriptomic Expression Profiling in Study 31: Express 31

研究 31 中的痰转录组表达谱：Express 31

• 批准号: 9349412
• 负责人: John Lucian Davis
• 金额: $ 114.39万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-03 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9349412
• 关键词: AIDS clinical trial group; Affect; Bacillus (bacterium); Biological; Centers for Disease Control and Prevention (U.S.); Characteristics; Chest; Clinical; Clinical Trials; Code; Computing Methodologies; DNA Gyrase; DNA Repair; DNA-Directed RNA Polymerase; Data; Diagnostic radiologic examination; Dose; Drug Exposure; Drug Kinetics; Drug Targeting; Drug Tolerance; Enrollment; Evaluation; Fluoroquinolones; Future; Gene Expression Profile; Genes; Genetic Transcription; Genotype; Germ; Goals; HIV; Kenya; Measurable; Measures; Messenger RNA; Microbiology; Modeling; Molecular; Molecular Profiling; Monitor; Moxifloxacin; Mycobacterium tuberculosis; National Institute of Allergy and Infectious Disease; Outcome; Pathway interactions; Patients; Peru; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacotherapy; Phase; Phase III Clinical Trials; Phenotype; Physiological; Physiological Adaptation; Physiology; Plant Roots; Population; Proteins; Protocols documentation; Pulmonary Tuberculosis; RNA; Randomized Clinical Trials; Regimen; Relapse; Research; Resources; Rifamycins; Safety; Site; Sputum; Surrogate Endpoint; Surrogate Markers; System; Testing; Transcript; Treatment outcome; Tuberculosis; Uganda; Vietnam; arm; bactericide; base; case control; cohort; design; drug development; drug mechanism; follow-up; functional adaptation; genome-wide; high risk; in vivo; insight; molecular marker; next generation; novel; novel marker; open label; pathogen; pharmacodynamic biomarker; pharmacokinetic model; programs; public health priorities; relapse prediction; relapse risk; response; rifapentine; transcriptome; transcriptomics; tuberculosis drugs; tuberculosis treatment

PROJECT SUMMARY/ ABSTRACT Developing shorter, safer, more effective drug regimens for active tuberculosis (TB) is a critical public health priority. However, a lack of reliable intermediate clinical trial endpoints constrains accurate regimen selection for Phase 3 trials. Moreover, current surrogate markers cannot explain the root causes of poor outcomes, namely the functional adaptations that enable survival of genetically-susceptible, drug-tolerant M. tuberculosis (Mtb) subpopulations. Our objective is to evaluate sputum Mtb transcriptional profiling as a novel biomarker for predicting relapse and as a surrogate endpoint for clinical trials. Our central hypothesis is that TB treatment outcomes are driven by Mtb physiologic changes measurable via pathogen-targeted transcriptional profiling. Our long-term objective is to develop novel surrogate markers and provide new biologic insights into drug tolerance through direct, in vivo molecular monitoring of Mtb populations during treatment. Our scientific approach will be to perform sputum Mtb transcriptional profiling in culture-confirmed, drug-susceptible pulmonary TB patients co-enrolled in a large, Phase 3, open-label, randomized clinical trial led by the CDC TB Trials Consortium (TBTC) and the NIAID/DAIDS AIDS Clinical Trials Group (ACTG). Study 31/ACTG 5349 will compare two 4-month, high-dose rifapentine-based regimens (one including a fluoroquinolone) with standard 6-month TB treatment. At sites in Kenya, Peru, Uganda, and Vietnam, we will collect RNA-preserved sputum at baseline and throughout treatment from patients at high risk of relapse, including HIV-infected patients, and HIV-uninfected patients with cavitation on baseline chest radiograph. In Aim 1, we will perform genome-wide Mtb transcriptional profiling in protocol-correct patients in each treatment arm to provide a comprehensive roadmap of physiologic and pharmacodynamic effects of TB treatment on the Mtb transcriptome, with biological interpretations of key drug-tolerance pathways. Specifically, we will test hypotheses that transcriptional changes specific to drug mechanism of action can serve as pharmacodynamic markers, as well as distinct hypotheses related to rifamycin and moxifloxacin exposure levels. In Aim 2, we will perform Mtb transcriptional profiling in all culture-/genotype-confirmed relapses and matched controls with relapse-free cure. We will build advanced pharmacokinetic models to select Mtb transcripts that can accurately predict relapse and serve as surrogate endpoints for clinical trials. Aim 2 will also produce an integrative systems pharmacology model to explain between-patient differences in treatment outcomes. Our research program has the potential to inaugurate a new era in which drug-development is based not on culture-based surrogates but on precise, in vivo molecular markers of pathogen physiologic state during TB treatment.

项目摘要/摘要 开发较短，更安全，更有效的活性结核病（TB）是关键的公共卫生 优先事项。但是，缺乏可靠的中间临床试验终点会限制准确的方案选择 对于第三阶段试验。此外，当前的替代标记无法解释结果不良的根本原因， 即功能适应能够使遗传敏感的，耐药的结核分枝杆菌的生存 （MTB）亚群。我们的目标是评估痰液MTB转录分析作为一种新型生物标志物 预测复发和作为临床试验的替代端点。我们的中心假设是结核病治疗 结果是由MTB生理变化驱动的，可以通过靶向病原体的转录分析来测量。 我们的长期目标是开发新颖的替代标记，并为药物提供新的生物学见解 通过直接的，在治疗过程中对MTB种群进行直接的体内分子监测的耐受性。我们的科学 方法将是在培养，预先确认的药物敏感的情况下进行痰MTB转录分析 肺结核病患者在CDC TB领导的大型3期开放标签，随机临床试验中共同入围 试验财团（TBTC）和NIAID/daids AIDS临床试验组（ACTG）。研究31/ACTG 5349将 比较两个与标准 6个月结核病治疗。在肯尼亚，秘鲁，乌干达和越南的地点，我们将在 基线和整个患者的治疗，患者有高复发风险，包括感染HIV的患者， 艾滋病毒未感染的患者在基线胸部X光片上。在AIM 1中，我们将执行全基因组的执行 MTB在每个治疗组中的方案校正患者中的MTB转录分析，以提供全面的 结核病治疗对MTB转录组的生理和药效学效应的路线图， 关键药物耐受途径的生物学解释。具体来说，我们将测试假设 针对药物机制的转录变化也可以用作药效标记 作为与利福非霉素和莫西法沙星暴露水平有关的不同假设。在AIM 2中，我们将执行MTB 所有培养/基因型确认复发和匹配的对照中的转录分析，无复发 治愈。我们将构建高级药代动力学模型，以选择可以准确预测的MTB成绩单 复发并充当临床试验的替代端点。 AIM 2还将产生一个集成系统 解释治疗结果的药理学模型。我们的研究计划有 开设一个新时代的潜力，在该时代中，药物开发不是基于基于文化的替代物，而是基于 确切地说，在结核病治疗期间，病原体生理状态的体内分子标记物。