Baseline pRescription According to Direct from Sputum Sequencing and TArgeted drug Concentration Strategy (BRASS TACS)

根据直接痰测序和靶向药物浓度策略 (BRASS TACS) 进行基线处方

• 批准号: 10419566
• 负责人: Jeffrey Tornheim
• 金额: $ 70.6万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-07 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10419566
• 关键词: Adherence; Adult; Bacterial Infections; Biological Assay; Bone Marrow Suppression; COVID-19; Caring; Cellular Phone; Clinical; Collaborations; Communicable Diseases; Complex; Cycloserine; Data; Development; Diagnostic tests; Disease; Dose; Drug Kinetics; Drug Monitoring; Drug Targeting; Drug resistance; Drug resistance in tuberculosis; Electrocardiogram; Enrollment; Ensure; Evaluation; Frequencies; Future; Genotype; Goals; Guidelines; Hospitals; Hour; India; Individual; Infrastructure; Laboratories; Lead; Linezolid; Longitudinal cohort; Longitudinal cohort study; Lung; Measures; Methods; Minimum Inhibitory Concentration measurement; Modeling; Molecular; Monitor; Moxifloxacin; Multidrug-Resistant Tuberculosis; Mutation; National Institute of Allergy and Infectious Disease; Neuropathy; Oral; Outcome; Participant; Patient-Focused Outcomes; Patients; Persons; Pharmaceutical Preparations; Phenotype; Plasma; Predisposition; Preparation; Prospective, cohort study; Provider; Pulmonary Tuberculosis; Recommendation; Regimen; Reporting; Resistance; Rifampicin resistance; Rifampin; Safety; Sampling; Selection for Treatments; Severities; Site; Sputum; Strategic Planning; Test Result; Testing; Therapeutic; Time; Toxic effect; Treatment outcome; Tuberculosis; United States National Institutes of Health; Validation; Vision; Work; biomedical referral center; brass; clinical research site; cohort; diagnostic algorithm; diagnostic tool; drug testing; efficacy evaluation; efficacy outcomes; follow-up; implementation tool; improved; improved outcome; individualized medicine; ineffective therapies; innovation; liver injury; meetings; mortality; next generation sequencing; novel; novel diagnostics; novel therapeutics; observational cohort study; personalized strategies; pharmacokinetic model; prevent; prognostic assays; side effect; tool; transmission process; treatment response; treatment strategy; trial comparing; tuberculosis drugs; tuberculosis treatment

Project Summary Tuberculosis is the bacterial infection that kills the most people worldwide, especially in India, which has the highest burden in of multidrug-resistant tuberculosis (MDR-TB) in the world. Delays in adequate treatment due to slow diagnostic tests and the usual one-size-fits-all MDR-TB treatment strategy lead to additional drug resistance, terrible treatment-associated side effects, and high mortality. Rapid next generation sequencing (NGS) from uncultured samples is a novel diagnostic tool that can predict resistance and minimum inhibitory concentration (MIC) ranges for MDR-TB within 2 days of presentation–weeks before culture-based susceptibility tests provide results. NGS-predictions allow providers to tailor MDR-TB treatment and choose doses to target specific drug levels at the start of treatment. Most MDR-TB drugs reach steady state within 2 weeks, so early therapeutic drug monitoring (TDM) supported by direct observation of therapy could verify that predicted efficacy targets are achieved as soon as possible, ensuring that patients get the right drugs at the right dose as early as possible and before suffering side effects from poorly tailored treatment. This would be a dramatic improvement over current culture-based methods of regimen selection, where results return 2 months later, if at all. Our clinical site has previously enrolled ~800 participants with MDR-TB into cohort studies for longitudinal follow-up, monitored participants for side effects and treatment outcomes, and developed on-site workflows for phenotypic drug resistance, MIC testing, NGS from uncultured sputum, and plasma drug level testing of MDR-TB drugs. Each of these tools is available at our site, but they are only employed sporadically, are rarely used in the same patients, and have not been systematically analyzed for their relative contributions to patient outcomes. We will conduct a single-site observational cohort study of 210 adult participants with pulmonary smear-positive, rifampin-resistant TB to systematically evaluate the impact of a combination Baseline pRescription According to Direct from Sputum Sequencing and TArgeted drug Concentration Strategy (BRASS TACS) for personalized MDR-TB therapy as access to these tools expands. The specific aims of this proposal are to: 1) determine the proportion of patients with MDR-TB in Mumbai, India with resistance-associated mutations that would prevent treatment with moxifloxacin, linezolid, bedaquiline, clofazimine, or cycloserine using culture-free NGS; 2) identify the proportion of cohort participants with MDR-TB that achieve model-derived steady-state plasma levels meeting efficacy and toxicity targets; and 3) assess the time to final regimen, frequency of treatment-associated side effects, time to culture conversion, and final outcome of cohort participants who complete culture-free NGS and TDM. The results of this observational cohort will determine the combined benefit of these tools as they are deployed at a referral center with clinical and laboratory expertise in complex drug resistance. These data will describe the real-world outcomes of MDR-TB care using NGS and TDM for MDR-TB in a unique setting and will inform the future application of these tools to improved strategies for personalized MDR-TB treatment worldwide.

项目摘要 结核病是一种细菌感染，在全世界造成最多人死亡，特别是在印度， 耐多药结核病（MDR-TB）是世界上负担最高的结核病。适当治疗的延误， 减缓诊断测试和通常的一刀切的耐多药结核病治疗策略导致额外的药物 耐药性、可怕的治疗相关副作用和高死亡率。下一代快速测序 (NGS)是一种新的诊断工具，可以预测耐药性和最低抑制率， 在基于培养的敏感性研究之前2天内的耐多药结核菌浓度（MIC）范围 测试提供结果。NGS预测允许提供者定制耐多药结核病治疗并选择目标剂量 治疗开始时的特定药物水平。大多数耐多药结核病药物在2周内达到稳态， 治疗药物监测（TDM）支持的直接观察治疗可以验证预测的疗效， 尽快实现目标，确保患者尽早获得正确剂量的正确药物， 可能的，并在遭受不良定制治疗的副作用之前。这将是一个巨大的进步 而不是目前基于培养的方案选择方法，如果有的话，结果将在2个月后返回。我们的临床 研究中心之前已招募了约800名MDR-TB受试者进入队列研究进行纵向随访， 监测参与者的副作用和治疗结果，并制定了表型分析的现场工作流程。 耐多药结核病药物的耐药性、MIC检测、来自未培养痰的NGS和血浆药物水平检测。 这些工具中的每一个都可以在我们的网站上使用，但它们只是偶尔使用，很少用于相同的应用程序。 患者，尚未系统分析其对患者结局的相对贡献。我们将 对210名肺涂片阳性的成年受试者进行单中心观察性队列研究， 利福平耐药结核病，以系统地评价联合治疗的影响 直接从痰液测序和靶向药物浓度策略（BRASS TACS）进行个性化 随着获得这些工具的机会的扩大，耐多药结核病治疗。本提案的具体目标是：1）确定 印度孟买耐多药结核病患者中耐药相关突变的比例， 使用无培养的NGS，用利奈唑胺、贝达喹啉、氯法齐明或环丝氨酸治疗; 2）鉴定 达到模型推导的稳态血浆水平的MDR-TB队列参与者比例 达到疗效和毒性目标; 3）评估至最终方案的时间、治疗相关不良反应的频率 完成无培养NGS的队列参与者的副作用、培养转换时间和最终结局 的TDM。该观察性队列的结果将确定这些工具的综合获益 部署在转诊中心，具有复杂耐药性的临床和实验室专业知识。这些数据将 描述在独特的环境中使用NGS和TDM治疗耐多药结核病的耐多药结核病护理的实际结果， 为这些工具的未来应用提供信息，以改进全球个性化耐多药结核病治疗战略。