Trial of Metformin for TB/HIV Host-directed Therapy

二甲双胍用于结核病/艾滋病毒宿主定向治疗的试验

基本信息

批准号：
9926218
负责人：
Hardy Kornfeld
金额：
$ 78.79万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9926218
关键词：
Address Adoption Adverse event Aerosols Antibiotic Therapy Antibiotics Antidiabetic Drugs Antitubercular Agents Autophagocytosis Biological Biological Assay CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cause of Death Cavia Cell Count Cells Cessation of life Clinical Clinical Data Clinical Trials Complement Data Diabetes Mellitus Diagnostic radiologic examination Drug Kinetics Drug resistance Future Gene Expression Goals Growth HIV HIV Infections HIV/TB Host Defense Human Immune Immune response Immunity Immunologics Impairment Individual Infection Inflammation Inflammatory Institutes Lead Lung Measures Mediating Metabolic Metformin Mus Mycobacterium tuberculosis Mycobacterium tuberculosis antigens Non-Insulin-Dependent Diabetes Mellitus Participant Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Phase Placebos Pulmonary Function Test/Forced Expiratory Volume 1 Pulmonary Tuberculosis Quality of life Questionnaires Randomized Regimen Respiratory physiology Risk Safety Sampling Severities Signal Pathway Signal Transduction South Africa Speed Sputum Sterilization Symptoms Syndrome T cell response T memory cell Testing Therapy trial Time Toxic effect Treatment Efficacy Tuberculosis Viral Load result Vulnerable Populations Whole Blood adenylate kinase antimicrobial antiretroviral therapy base biosignature clinical research site co-infection cohort cost diabetic double-blind placebo controlled trial drug discovery gastrointestinal gastrointestinal symptom immune reconstitution immunoregulation improved insight lung injury lung preservation macrophage non-diabetic novel strategies pathogen phase III trial pre-clinical preclinical study prevent primary endpoint respiratory respiratory health response secondary endpoint standard care transcriptomics trial design tuberculosis immunity tuberculosis treatment

项目摘要

PROJECT SUMMARY 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 people living with HIV. Treatment shortening trials for TB have been disappointing. One to get past this obstacle could be stimulating endogenous host defense pathways to accelerate the response to antibiotics. The anti-diabetic drug metformin is a candidate host-directed therapy (HDT) agent for TB based on its activation of AMP kinase, induction of autophagy in macrophages, and expansion of Mycobacterium tuberculosis antigen-specific CD8+ central memory T(CM) cells. Preclinical data in mice and guinea pigs, and retrospective clinical data from seven studies of diabetic TB patients support the HDT potential of metformin. We plan to test this in TB/HIV coinfected patients because they are at increased risk for delayed sputum clearance, death during treatment and pulmonary impairment after TB. By expanding CD8+ T cells, metformin could be particularly effective in HIV coinfected individuals and there is a basis to predict that metformin will have direct HDT activity against HIV. We plan a randomized, placebo-controlled trail of metformin added to standard treatment of pulmonary TB and HIV. The primary goal of this phase 2A trial to test whether metformin, which causes gastrointestinal (GI) symptoms, is tolerable and safe in this vulnerable population. The primary endpoint is grade 3 or higher GI adverse events in the 3-month period of metformin treatment plus 4 weeks after stopping metformin. We expect that mild GI symptoms will be common but that severe symptoms requiring discontinuation will be rare. The trial will also test the HDT efficacy of metformin with secondary endpoints of sputum conversion and respiratory health. The anti-HIV efficacy of metformin will be tested with exploratory endpoints of viral load, CD4+ T cell count and the occurrence of immune reconstitution inflammatory syndrome. Biological samples from this trial will be used to address fundamental questions about the mechanisms of HDT efficacy including the modulation of harmful inflammation and the expansion of CD8+ TCM cells. If the METHOD trial demonstrates that metformin is safe in patients treated concurrently for TB and HIV, and if HDT efficacy is supported, this would provide a basis in evidence for a multi-center phase 3 trial and ultimately inform a paradigm shift in the treatment of TB.

项目概要由于遵守多项规定的挑战，结核病 (TB) 仍然是感染死亡的主要原因。持续 6 个月或更长时间的药物治疗方案以及弱势群体，包括艾滋病毒感染者。结核病缩短治疗试验结果令人失望。克服这一障碍可能会令人兴奋内源性宿主防御途径加速对抗生素的反应。抗糖尿病药物二甲双胍是一种针对结核病的候选宿主定向治疗 (HDT) 药物，基于其 AMP 激酶的激活，诱导巨噬细胞中的自噬以及结核分枝杆菌抗原特异性 CD8+ 中枢的扩增记忆 T(CM) 细胞。小鼠和豚鼠的临床前数据，以及七种动物的回顾性临床数据对糖尿病结核病患者的研究支持二甲双胍的 HDT 潜力。我们计划在结核病/艾滋病毒中进行测试合并感染的患者，因为他们在治疗期间痰液清除延迟和死亡的风险增加以及结核病后的肺损伤。通过扩大 CD8+ T 细胞，二甲双胍可能特别有效 HIV 合并感染者，并且有基础预测二甲双胍将具有直接的 HDT 活性艾滋病病毒。我们计划进行一项随机、安慰剂对照试验，将二甲双胍添加到肺结核的标准治疗中结核病和艾滋病毒。这项 2A 期试验的主要目标是测试二甲双胍是否会导致胃肠道疾病（胃肠道）症状对于这一弱势群体来说是可以忍受且安全的。主要终点是 3 级或更高 GI 二甲双胍治疗 3 个月期间以及停止二甲双胍后 4 周内的不良事件。我们预计轻微的胃肠道症状将很常见，但需要停药的严重症状将很少见。该试验还将测试二甲双胍的 HDT 功效，次要终点为痰液转化和呼吸系统健康。二甲双胍的抗艾滋病毒功效将通过病毒载量的探索性终点进行测试， CD4+ T细胞计数与免疫重建炎症综合征的发生。生物样本该试验的结果将用于解决有关 HDT 功效机制的基本问题，包括有害炎症的调节和 CD8+ TCM 细胞的扩增。如果方法试验表明二甲双胍对于同时治疗结核病和艾滋病毒的患者是安全的，并且如果 HDT 疗效是如果得到支持，这将为多中心 3 期试验提供证据基础，并最终为结核病治疗范式的转变。