Doxycycline for COPD in HIV-Infected Patients

多西环素治疗 HIV 感染者的慢性阻塞性肺病

基本信息

批准号：
8554373
负责人：
MARSHALL J GLESBY
金额：
$ 52.07万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-27 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8554373
关键词：
AIDS clinical trial group Address Alveolar Macrophages Award Basement membrane Biological Assay Biology Blood Bronchoalveolar Lavage Fluid Bronchoscopy Cells Chronic Chronic Obstructive Airway Disease Clinical Trials Communicable Diseases Data Disease Double-Blind Method Doxycycline Epithelial Extracellular Matrix FDA approved Funding Gelatinases General Population Goals HIV HIV Infections Individual Inflammation Inhibition of Matrix Metalloproteinases Pathway Intervention Knowledge Liquid substance Lung Lymphocyte Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Medical Morbidity - disease rate Natural History Patients Persons Phase Phase II Clinical Trials Pilot Projects Placebo Control Placebos Population Positioning Attribute Public Health Pulmonary Emphysema Pulmonary Function Test/Forced Expiratory Volume 1 Randomized Research Research Personnel Respiratory Tract Infections Risk Role Safety Serum Smoker Specialist Spirometry Testing United States National Institutes of Health Work antiretroviral therapy base design immune activation improved insight mortality neutrophil novel oxidant stress pulmonary function randomized placebo controlled trial smoking prevalence

项目摘要

DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) is emerging as an important cause of morbidity in HIV-infected patients, likely due to multiple factors, including an increased prevalence of smoking, chronic inflammation and immune activation, oxidant stress and respiratory infections. Our preliminary data suggest that several lung matrix metalloproteinases (MMPs) are upregulated in HIV-infected smokers, which could contribute to accelerated emphysema by virtue of their ability to degrade extracellular matrix and basement membrane components. Based on these observations, we hypothesize that pharmacologic inhibition of MMPs by doxycycline, the only FDA-approved inhibitor of MMPs, will favorably modify the natural history of COPD in HIV-infected patients. To test this hypothesis, we propose conducting a phase II randomized, placebo-controlled trial of doxycycline for COPD in HIV-infected patients. Our research team, led by a pulmonologist / translational researcher with expertise in HIV-associated COPD and an infectious diseases specialist/clinical trials expert, is well positioned to propose such a trial to the NIH-funded AIDS Clinical Trials Group (ACTG). To achieve this end, we first propose to conduct a pilot study to enable us to address the following Specific aims: Aim 1. To determine the safety, tolerability, and biologic effects of twice daily doxycycline for 6 months in HIV-infected subjects with COPD; and Aim 2. To prepare and submit an application for a phase II clinical trial of doxycycline for COPD in HIV-infected subjects. To address the first aim, we will conduct a randomized, double-blind, placebo-controlled pilot study of doxycycline 100 mg twice daily in 30 HIV-infected subjects with COPD (2:1 doxy:placebo). The primary endpoint will be safety/tolerability and secondary endpoints will include change in FEV1, reduction of MMP activity in epithelial lining fluid and cells obtained by bronchoscopy and doxycycline levels in blood, ELF and BAL cell pellets. In addition to providing novel insights into the biologic effects of doxycycline in the lung, the pilot study will inform selection of endpoints for a phase II trial, which ultimately will address an unmet medical need for novel interventions for COPD/emphysema in HIV-infected patients.

描述（由申请人提供）：慢性阻塞性肺病（COPD）正在成为艾滋病毒感染者发病的一个重要原因，可能是由于多种因素造成的，包括吸烟率增加、慢性炎症和免疫激活、氧化应激和呼吸道感染。我们的初步数据表明，几种肺基质金属蛋白酶（MMP）在感染艾滋病毒的吸烟者中表达上调，这可能因其降解细胞外基质和基底膜成分的能力而加速肺气肿。基于这些观察结果，我们假设多西环素（FDA 批准的唯一 MMP 抑制剂）对 MMP 的药理抑制将有利地改变 HIV 感染患者 COPD 的自然史。为了检验这一假设，我们建议对 HIV 感染者进行多西环素治疗 COPD 的 II 期随机、安慰剂对照试验。我们的研究团队由一位在 HIV 相关慢性阻塞性肺病方面具有专业知识的肺科医生/转化研究员和一位传染病专家/临床试验专家领导，完全有能力向 NIH 资助的艾滋病临床试验组 (ACTG) 提出这样的试验。为了实现这一目标，我们首先建议进行一项试点研究，使我们能够实现以下具体目标：目标 1. 确定每日两次多西环素对于患有慢性阻塞性肺病 (COPD) 的 HIV 感染受试者为期 6 个月的安全性、耐受性和生物效应;目标 2. 准备并提交多西环素治疗 HIV 感染者 COPD 的 II 期临床试验申请。为了实现第一个目标，我们将在 30 名患有慢性阻塞性肺病 (COPD) 的 HIV 感染受试者中进行一项随机、双盲、安慰剂对照的初步研究，使用强力霉素 100 毫克，每天两次（2:1 强力霉素：安慰剂）。主要终点是安全性/耐受性，次要终点包括 FEV1 的变化、上皮衬里液和支气管镜检查获得的细胞中 MMP 活性的降低以及血液、ELF 和 BAL 细胞沉淀中的多西环素水平。除了提供关于多西环素在肺部的生物学效应的新见解外，该试点研究还将为 II 期试验终点的选择提供信息，最终将解决艾滋病毒感染患者慢性阻塞性肺病/肺气肿新干预措施未得到满足的医疗需求。