Planning for the Metformin for TB/HIV Host-directed Therapy (METHOD) Trial

规划二甲双胍用于结核病/艾滋病毒宿主定向治疗 (METHOD) 试验

• 批准号: 9138531
• 负责人: Hardy Kornfeld
• 金额: $ 25.39万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9138531
• 关键词: 5' -AMP-activated protein kinase; Accounting; Acquired Immunodeficiency Syndrome; Address; Aerosols; Anti-Retroviral Agents; Antibiotic Therapy; Antibiotics; Antidiabetic Drugs; Antigens; Autophagocytosis; Biological Assay; Biological Markers; CD8B1 gene; Cause of Death; Cessation of life; Clinical; Clinical Trials; Data; Development; Diabetes Mellitus; Documentation; Drug Kinetics; Drug resistance; Drug usage; Enrollment; Failure; Funding; Future; Gene Expression; Genes; Goals; HIV; HIV/TB; Health; Immune; Immune response; Immunity; Infection; Inflammation; Inflammatory; Institutes; Institution; Lesion; Mediating; Metabolic; Metformin; Modeling; Morbidity - disease rate; Mus; Mycobacterium tuberculosis; Outcome; Oxygen; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Placebos; Population; Positioning Attribute; Pulmonary Tuberculosis; Randomized; Randomized Clinical Trials; Recurrence; Regimen; Research Personnel; Resolution; Respiratory physiology; Safety; Sampling; Severities; Signal Pathway; South Africa; Sputum; Sterilization; Syndrome; T cell response; T-Lymphocyte; Testing; Therapy trial; Treatment Efficacy; Treatment Protocols; Treatment outcome; Tuberculosis; Viral Load result; Virus Diseases; Vulnerable Populations; Walking; adenylate kinase; antimicrobial drug; base; biomarker discovery; clinical practice; clinical research site; cohort; cost; cost effective; design; diabetic; drug discovery; health related quality of life; improved; insight; macrophage; mortality; novel strategies; pathogen; pre-clinical; preclinical study; reconstitution; respiratory health; response; restoration; transcriptomics; treatment response; tuberculosis treatment

 DESCRIPTION (provided by applicant): Tuberculosis (TB) remains a leading cause of death from infection due to challenges of compliance with multi- drug regimens lasting 6 months or longer and vulnerable populations including patients coinfected with HIV. Treatment shortening trials for TB have been disappointing. One way past this obstacle could be stimulating endogenous defense pathways to accelerate and enhance the response to antibiotics. The anti-diabetic drug metformin (MET) is a candidate host-directed therapy (HDT) agent for TB based on its activation of AMP kinase and induction of autophagy in macrophages. Our preclinical data in the mouse TB model and analysis of existing data on diabetic TB patients establish the HDT potential of MET. Notably, we found that MET expands M. tuberculosis antigen-specific CD8+ T cells that may have particular benefit for TB in AIDS. We plan a clinical trial in TB/HIV coinfecte patients to test the hypothesis that adding MET to standard directly observed treatment, short course (DOTS) antibiotic therapy increase the proportion of patients with a negative sputum culture at 2 months. To test this hypothesis, TB/HIV patients will be randomized to MET or placebo added to DOTS for the duration of TB treatment. Finding a significant effect of MET on month-2 sputum conversion would demonstrate its potential to enhance the efficacy of shortened TB treatment regimens. The Metformin for TB/HIV Host-directed Therapy (METHOD) trial will also test the effects of adjunctive MET on TB outcomes (cure, failure, death, default), radiographic severity, lung function as well as HIV viral load and the rate of immune reconstitution inflammatory syndrome. Conducting this HDT trial in HIV-coinfected patients focuses on the population in greatest need of a better approach to TB treatment and provides a rigorous test that would predict benefit for all patients with TB. Patient samples from this trial ill also be used to address fundamental questions about the mechanisms of HDT efficacy that may include control of harmful inflammation and expansion of CD8+ effector T cells in addition to the enhancement of lesion sterilization. A long range goal of this study component is to identify cost-effective biomarkers of treatment response that could be used in future HDT trials and potentially in clinical practice as guideposts for optimal TB treatment. In the current application we seek R34 funding to support all of the tasks needed to prepare a compelling UO1 application for the METHOD trial. This clinical trial development phase will involve the collaborative effort o future METHOD trial investigators from all three participating institutions and will position us fo the

 描述（由申请方提供）：由于持续6个月或更长时间的多种药物治疗方案的依从性以及包括合并感染HIV的患者在内的脆弱人群的挑战，结核病（TB）仍然是感染导致死亡的主要原因。结核病治疗缩短试验令人失望。克服这一障碍的一种方法可能是刺激内源性防御途径，以加速和增强对抗生素的反应。抗糖尿病药物二甲双胍（MET）是基于其激活AMP激酶和诱导巨噬细胞自噬的TB的候选宿主定向治疗（HDT）药物。我们在小鼠TB模型中的临床前数据和对糖尿病TB患者的现有数据的分析确立了MET的HDT潜力。值得注意的是，我们发现MET扩展了M。结核抗原特异性CD 8 + T细胞可能对艾滋病中的结核病特别有益。我们计划在TB/HIV合并感染患者中进行一项临床试验，以检验以下假设：在标准直接观察治疗、短程（DOTS）抗生素治疗中添加MET可增加2个月痰培养阴性患者的比例。为了检验这一假设，TB/HIV患者将在TB治疗期间随机接受MET或安慰剂加DOTS治疗。发现MET对第2个月痰菌阴转的显著影响将证明其有可能增强缩短的TB治疗方案的疗效。结核病/艾滋病病毒宿主导向治疗（METHOD）试验还将测试预防性MET对结核病结局（治愈，失败，死亡，默认），放射学严重程度，肺功能以及艾滋病病毒载量和免疫重建炎症综合征的影响。在HIV合并感染患者中进行这项HDT试验的重点是最需要更好的结核病治疗方法的人群，并提供了一项严格的测试，可以预测所有结核病患者的获益。来自该试验的患者样本也将用于解决关于HDT功效机制的基本问题，除了增强病变灭菌之外，HDT功效机制可能包括有害炎症的控制和CD 8+效应T细胞的扩增。本研究的一个长期目标是确定具有成本效益的治疗反应生物标志物，这些生物标志物可用于未来的HDT试验，并可能用于临床实践，作为最佳TB治疗的路标。当前应用程序中 我们寻求R34资金，以支持为METHOD试验准备令人信服的UO 1申请所需的所有任务。该临床试验开发阶段将涉及来自所有三个参与机构的未来METHOD试验研究者的合作努力，并将使我们处于