Identifying Optimal Treatment Strategies for Tuberculosis Treatment

确定结核病治疗的最佳治疗策略

• 批准号: 10544160
• 负责人: David Alland
• 金额: $ 72.48万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-16 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10544160
• 关键词: AIDS clinical trial group; Adherence; Algorithms; Automobile Driving; Bacteria; Biological; Body mass index; Budgets; Caring; Categories; Characteristics; Chest; Clinical; Clinical Trials; Cohort Studies; Complement; Concentration measurement; Data; Data Analyses; Data Collection; Data Set; Databases; Development; Disease; Disease Marker; Disease stratification; Dose; Drug Kinetics; Drug Tolerance; Drug resistance in tuberculosis; Drug toxicity; Drug usage; Early treatment; Engineering; Ensure; Ethambutol; Event; Financial Support; Friends; Funding; Future; Genome; Genus Mycobacterium; Goals; Grant; Growth; HIV; Health system; Individual; Intervention; Investigation; Leadership; Learning; Link; M. tuberculosis genome; Measurement; Measures; Microbiology; Modeling; Modernization; Moxifloxacin; Multidrug-Resistant Tuberculosis; Mutation; Mycobacterium tuberculosis; Outcome; Patient Schedules; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Phenotype; Population; Prediction of Response to Therapy; Predisposition; Public Health; Pyrazinamide; Recommendation; Recording of previous events; Regimen; Relapse; Research Design; Rifampin; Risk; Safety; Sampling; Severities; Severity of illness; Sputum; Techniques; Testing; Therapeutic; Time; Toxic effect; Treatment Failure; Treatment Protocols; Treatment outcome; Tuberculosis; United States National Institutes of Health; Variant; Work; absorption; acquired drug resistance; advanced analytics; biomarker identification; clinical care; combinatorial; comparative efficacy; compliance behavior; computerized tools; cost; data access; digital health; drug-sensitive; efficacy evaluation; high risk; improved; individualized medicine; industry partner; innovation; isoniazid; minimal inhibitory concentration; novel; novel marker; optimal treatments; participant enrollment; patient oriented; patient population; patient subsets; patient variability; persistent bacteria; pharmacokinetic model; pharmacologic; phase III trial; public health priorities; pyrazinoic acid; radiological imaging; rate of change; relapse risk; response; rifapentine; risk stratification; standard of care; success; time use; tool; treatment duration; treatment optimization; treatment response; treatment strategy; tuberculosis drugs; tuberculosis treatment

Project Summary/Abstract The current standard of care for drug-sensitive TB is a “one-size-fits-all” approach, putting hard-to-treat patients at higher risk of relapse and mycobacteria at higher risk of acquiring drug resistance. The Phase 3 treatment-shortening study TBTC/ACTG (Study 31/A5349) is evaluating the efficacy and safety of two new short-course regimens containing high-dose rifapentine. The primary aim of our proposal is to embed full pharmacology and microbiology analyses (PK/PD) in this clinical trial to provide detailed drug pharmacokinetic, MIC response and safety data - including novel data (markers of persisters) for more than 2,000 patients. Our goal is to understand and quantify the interactions among individual drug PK/PD, MICs, new markers of genome load, new markers for persisters, active disease severity and early treatment response in a diverse patient population and recognize how they relate to clinical outcome and safety events. By doing so, we will be able to understand and quantify the contributions of pharmacological (multidrug pharmacokinetic) and non- pharmacological (host, disease severity) components of treatment response and to understand the phenotypes of patients who are hard to treat, allowing us to derive optimal treatment strategies for all patients with drug- sensitive TB, including choice of regimen, treatment duration, and dose. We propose the innovative hypothesis that both the infecting bacteria and the host can be seen as “low” and “high” risk and that it is the combination of these two risks that together determine treatment outcome and the required duration of treatment, regardless of the drugs used. Our approach will stratify bacterial risk by burden, MIC - even among drug-susceptible Mtb - and the presence of drug-tolerant subpopulations. The host risk will be stratified by disease severity, HIV status and ability to absorb and metabolize drugs (PK). We will then use advanced analytic and modeling strategies to develop tools and algorithms to identify low-risk patients infected with low-risk bacteria who can be treated with ultra-short treatment (<=four months) and high-risk patients infected with high-risk bacteria who will need treatment for longer than six months. Through our analyses, we will be able to select for each patient the regimen that results in the highest likelihood of cure. Our findings will completely change the future of TB clinical trials and care worldwide. This study will address fundamental questions, such as what the exposure-response/safety relationships and favorable AUC/MIC targets are for all first-line TB drugs using a major clinical outcome (relapse) and how early response to treatment relates to clinical outcome in a large and diverse patient population. The project has unprecedented support from the TBTC/ACTG leadership and our industry partner (Sanofi Aventis). The funds in this R01 requests the budget needed to complete drug measures and MIC not included in Study 31 (i.e., all drugs other than rifapentine and moxifloxacin) and the full suite of PK/PD modeling and learnings that go beyond the trial's primary goal of testing the non-inferiority of the experimental four-month regimens.

项目摘要/摘要 当前对药物敏感的结核病的护理标准是一种“千篇一律的”方法 患有较高救济和分枝杆菌风险较高的患者获得耐药性的风险较高。阶段3 治疗缩短研究TBTC/ACTG（研究31/A5349）正在评估两个新的效率和安全性 含有大剂量利福丁的短道方案。我们建议的主要目的是嵌入完整 在这项临床试验中，药理学和微生物学分析（PK/PD）提供详细的药代动力学， MIC响应和安全数据 - 包括2,000多名患者的新数据（持久标记）。我们的 目标是了解和量化单个药物PK/PD，MIC，新标记的相互作用 潜水 患者群体并认识到他们与临床结果和安全事件的关系。这样，我们将 可以理解和量化药理学（多药药代动力学）和非 - 治疗反应的药理（宿主，疾病严重程度）成分并了解表型 难以治疗的患者，使我们能够为所有药物患者提供最佳治疗策略 敏感的结核病，包括选择方案，治疗持续时间和剂量。 我们提出了一种创新的假设，即感染细菌和宿主都可以看作是“低” 和“高”风险，正是这两个风险的结合在一起决定治疗 不管使用的药物如何，结果和所需的治疗持续时间。我们的方法将分层 伯恩（Burnen）的细菌风险，麦克风（MIC） - 甚至在吸毒的MTB中，也存在耐药的存在 亚群。宿主风险将根据疾病的严重程度，艾滋病毒状况和吸收能力来分层 代谢药物（PK）。然后，我们将使用先进的分析和建模策略来开发工具和 鉴定可通过超短毛治疗治疗的低风险细菌感染的低风险患者的算法 （<=四个月）和感染高风险细菌的高危患者，他们需要治疗比 六个月。通过我们的分析，我们将能够为每个患者选择最高的方案 治愈的可能性。我们的发现将彻底改变全球结核病临床试验和护理的未来。 这项研究将解决基本问题，例如暴露响应/安全关系 有利的AUC/MIC目标是使用主要的临床结果（复发）以及如何用于所有一线结核病药物 在大量多样化的患者人群中，早期对治疗关系对临床结果的反应。该项目有 TBTC/ACTG领导力和我们的行业合作伙伴（Sanofi Aventis）的前所未有的支持。资金进来 该R01要求完成药物测量所需的预算和研究31中未包括的麦克风（即 除利福丁和莫西法沙星以外的其他药物）以及PK/PD建模和学习的完整套件超出 该试验测试实验四个月方案的不效率的主要目标。

项目成果

Longitudinal Model-Based Biomarker Analysis of Exposure-Response Relationships in Adults with Pulmonary Tuberculosis.

• DOI: 10.1128/aac.01794-20
• 发表时间: 2021-09-17
• 期刊: Antimicrobial agents and chemotherapy
• 影响因子: 4.9
• 作者: Gewitz AD;Solans BP;Mac Kenzie WR;Heilig C;Whitworth WC;Johnson JL;Nsubuga P;Dorman S;Weiner M;Savic RM;Tuberculosis Trials Consortium of the Centers for Disease Control and Prevention
• 通讯作者: Tuberculosis Trials Consortium of the Centers for Disease Control and Prevention

Pragmatic global dosing recommendations for the 3-month, once-weekly rifapentine and isoniazid preventive TB regimen in children.

• DOI: 10.1183/13993003.01756-2020
• 发表时间: 2021-01
• 期刊: The European respiratory journal
• 作者: Radtke KK;Hibma JE;Hesseling AC;Savic RM
• 通讯作者: Savic RM

Development of New Tuberculosis Drugs: Translation to Regimen Composition for Drug-Sensitive and Multidrug-Resistant Tuberculosis.

• DOI: 10.1146/annurev-pharmtox-030920-011143
• 发表时间: 2021-01-06
• 期刊: Annual review of pharmacology and toxicology
• 影响因子: 12.5
• 作者: Ernest JP;Strydom N;Wang Q;Zhang N;Nuermberger E;Dartois V;Savic RM
• 通讯作者: Savic RM

Combination of Mycobacterium tuberculosis RS Ratio and CFU Improves the Ability of Murine Efficacy Experiments to Distinguish between Drug Treatments.

• DOI: 10.1128/aac.02310-21
• 发表时间: 2022-04-19
• 期刊: ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
• 影响因子: 4.9
• 作者: Dide-Agossou, Christian;Bauman, Allison A.;Ramey, Michelle E.;Rossmassler, Karen;Al Mubarak, Reem;Pauly, Samantha;Voskuil, Martin, I;Garcia-Cremades, Maria;Savic, Rada M.;Nahid, Payam;Moore, Camille M.;Tasneen, Rokeya;Nuermberger, Eric L.;Robertson, Gregory T.;Walter, Nicholas D.
• 通讯作者: Walter, Nicholas D.