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: 9751204
• 负责人: John Lucian Davis
• 金额: $ 146.82万
• 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/9751204
• 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; Development; Diagnostic radiologic examination; Dose; Drug Exposure; Drug Kinetics; Drug Targeting; Drug Tolerance; Enrollment; Evaluation; Expression Profiling; Fluoroquinolones; Future; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic Transcription; Genotype; Germ; Goals; HIV; Kenya; Longterm Follow-up; Measurable; Measures; Messenger RNA; Microbiology; Modeling; Molecular; 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; bactericide; base; case control; cohort; design; drug development; drug mechanism; functional adaptation; genome-wide; high risk; in vivo; insight; molecular marker; next generation; novel; novel marker; open label; pathogen; pharmacodynamic biomarker; pharmacokinetic model; preservation; programs; public health priorities; relapse prediction; relapse risk; response; rifapentine; transcriptome; transcriptomics; treatment arm; 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.

项目总结/摘要 为活动性结核病（TB）开发更短、更安全、更有效的药物方案是一项关键的公共卫生 要务然而，缺乏可靠的中间临床试验终点限制了准确的方案选择 用于第三阶段试验。此外，目前的替代标志物不能解释不良结局的根本原因， 即使遗传易感的耐药M存活的功能适应。结核 (Mtb)亚群我们的目的是评估痰结核分枝杆菌转录谱作为一种新的生物标志物， 预测复发并作为临床试验的替代终点。我们的中心假设是结核病治疗 结果由通过病原体靶向转录谱可测量的Mtb生理变化驱动。 我们的长期目标是开发新的替代标记物，并为药物治疗提供新的生物学见解。 通过治疗期间对Mtb群体进行直接体内分子监测来实现耐受性。我们的科学 一种方法将是在培养确认的药物敏感的痰中进行Mtb转录谱分析。 肺结核患者共同参加了一项由CDC TB领导的大型3期开放标签随机临床试验 试验联盟（TBTC）和NIAID/DAIDS艾滋病临床试验组（ACTG）。研究31/ACTG 5349将 比较两个4个月，高剂量利福喷丁为基础的方案（一个包括氟喹诺酮）与标准 6-结核病治疗一个月在肯尼亚、秘鲁、乌干达和越南的研究中心，我们将收集RNA保存的痰液， 基线和整个治疗期间复发风险高的患者，包括HIV感染患者，以及 基线胸片上有空洞的未感染HIV的患者。在目标1中，我们将进行全基因组 每个治疗组中方案正确的患者中的MTB转录谱分析，以提供全面的 结核病治疗对结核分枝杆菌转录组的生理和药效学作用路线图， 关键耐药途径的生物学解释。具体来说，我们将测试假设， 药物作用机制特异性的转录变化也可以作为药效学标志物， 作为与利福霉素和利福沙星暴露水平相关的不同假设。在目标2中，我们将执行Mtb 所有培养物/基因型证实的复发和无复发的匹配对照中的转录谱分析 疗方我们将建立先进的药代动力学模型，以选择可以准确预测结核分枝杆菌转录本， 复发并作为临床试验的替代终点。目标2还将产生一个综合系统 药理学模型来解释治疗结果的患者间差异。我们的研究计划 有可能开创一个新时代，在这个时代，药物开发不是基于文化的替代品， 结核病治疗过程中病原体生理状态的精确体内分子标记。