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

• 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
• 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

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）：慢性阻塞性肺部疾病（COPD）已成为艾滋病毒感染患者发病率的重要原因，这可能是由于多种因素，包括增加吸烟，慢性炎症和免疫激活，氧化剂应激，氧化剂应激和呼吸道感染。我们的初步数据表明，在HIV感染的吸烟者中，几种肺基质金属蛋白酶（MMP）上调，这可能会因其降解细胞外基质和地下膜成分的能力而导致加速肺气肿。基于这些观察结果，我们假设由Doxycycline（唯一由FDA批准的MMPS抑制剂）对MMP的药理抑制作用将有利地改变了感染HIV感染的患者COPD的自然史。为了检验这一假设，我们建议在HIV感染的患者中对COPD进行II期随机，安慰剂对照试验。由肺科医生 /翻译研究人员领导的，在与HIV相关的COPD和传染病专家 /临床试验专家领导的领导下，我们的研究团队擅长向NIH资助的AIDS临床试验小组（ACTG）提出此类试验。为了实现这一目标，我们首先建议进行一项试点研究，以使我们能够解决以下特定目的：目标1。确定每天两次多西环素在6个月内使用COPD的安全性，耐受性和生物学作用；和目标2。准备并提交申请艾滋病毒感染受试者的COPD的II期临床试验申请。为了解决第一个目标，我们将在30名患有COPD的30名HIV感染受试者中，每天两次对强力霉素100毫克进行随机，双盲，安慰剂对照的试点研究（2：1 Doxy：安慰剂）。主要终点将是安全性/耐受性，次要终点将包括FEV1的变化，上皮衬里流体中MMP活性的降低以及通过支气管镜检查获得的细胞以及血液，ELF和BAL细胞颗粒中的多西环素水平。除了对肺中强力霉素的生物学作用提供新的见解外，该试点研究还将为II期试验的终点选择提供信息，最终将解决对HIV感染的患者的COPD/Emphysema新干预措施的未满足医学需求。