1/2 Doxycycline for Emphysema in People Living with HIV: The DEPTH Trial

1/2 强力霉素治疗艾滋病毒感染者肺气肿：DEPTH 试验

基本信息

批准号：
10259295
负责人：
MARSHALL J GLESBY
金额：
$ 143.29万
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：
2021
资助国家：
美国
起止时间：
2021-09-20 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10259295
关键词：
Address Adult Age of Onset Air Alveolar Macrophages Antibiotics Biological Blood Bronchoalveolar Lavage Bronchoalveolar Lavage Fluid Carboxyhemoglobin Cause of Death Chronic Obstructive Airway Disease Clinical Conduct Clinical Trials Data Data Coordinating Center Development Diagnostic radiologic examination Diffuse Disease Disease Progression Double-Blind Method Doxycycline Enrollment FDA approved Funding Gelatinase A Gelatinase B Gene Expression General Population Generic Drugs HIV HIV Infections HIV Seronegativity Health Status Hemoglobin High Prevalence Incidence Individual Interdisciplinary Study Intervention Investigation Lung Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Measures Metalloproteinase Gene National Heart, Lung, and Blood Institute Natural History Oral Organism Oxygen Participant Pathogenesis Performance Pharmacy facility Phase Phase II Clinical Trials Pilot Projects Placebos Population Prevalence Proteins Pulmonary Emphysema Quality of life Randomized Reading Records Reporting Resistance Safety Sampling Side Site Smoke Smoking Status Surveys Testing Time Tissues Training Walking X-Ray Computed Tomography antiretroviral therapy arm barometric pressure base clinical care clinical research site comorbidity density double-blind placebo controlled trial eligible participant epidemiologic data experience former smoker functional status improved innovation interest lung imaging patient oriented patient population prevent primary endpoint pulmonary function randomized placebo controlled trial respiratory safety testing success targeted treatment transcriptome sequencing treatment duration trend

项目摘要

The DEPTH trial represents an innovative approach to slowing the progression of emphysema in people living with HIV (PLWH), a population that has accelerated disease progression for which there is no targeted therapy. We propose a phase II, multi-center, randomized, double-blind, placebo-controlled trial of doxycycline 100 mg po BID to slow the progression of emphysema as assessed by change in diffusing capacity (DLCO) among PLWH who are current or former smokers. Eligible participants with emphysema and well-controlled HIV will be randomized 1:1 to doxycycline or placebo, stratified by smoking status (current vs former smoker) and clinical site, utilizing dynamic randomization. The primary endpoint of the study is the rate of decline (slope) of percent predicted DLCO over the 72-week treatment period. We have assembled a team of experienced clinical sites that has the patient population and expertise to efficiently enroll and conduct this trial. In our previous studies, we observed that HIV+ individuals with early emphysema have increased matrix metalloproteinases (MMP-2, -7, -9, -12; each implicated in emphysema pathogenesis) in bronchoalveolar lavage (BAL) fluid samples. MMPs are therefore potential targets for intervention aimed at modifying progression of emphysema specifically in people with HIV. We successfully demonstrated the feasibility of this approach in our NHLBI-funded single-center randomized, double-blind, placebo-controlled pilot study to test the safety and tolerability of doxycycline (FDA-approved as an MMP inhibitor to prevent tissue breakdown in gum disease) over 24 weeks (NCT 01744093). We studied 27 individuals with HIV and COPD/emphysema randomized 2:1 to doxycycline 100 mg po BID or placebo. In addition to acceptable safety and tolerability, there were trends toward stabilization of the diffusing capacity (DLCO) and a reduction of BAL fluid MMP-9 activity in participants assigned to the doxycycline arm. The DEPTH trial will extend these promising pilot data to a formal Phase II clinical trial. We anticipate that upon completion of this proposed study, our data will support repurposing the inexpensive antibiotic doxycycline, to slow emphysema progression in PLWH. Specifically we expect to show: 1. Doxycycline slows the progression of emphysema in PLWH, as assessed primarily by DLCO and secondarily by HRCT. 2. Doxycycline is safe and tolerable when taken orally for 72 weeks in PLWH who have emphysema. 3. Doxycycline improves respiratory quality of life and functional status in PLWH who have emphysema.

DEPTH 试验代表了一种减缓肺气肿进展的创新方法艾滋病毒携带者（PLWH）是一个加速疾病进展的人群，目前尚无针对性的治疗方案治疗。我们提出一项 II 期、多中心、随机、双盲、安慰剂对照试验多西环素 100 mg po BID 可减缓肺气肿的进展（通过扩散变化进行评估）目前或曾经吸烟的 PLWH 的能力（DLCO）。患有肺气肿的合格参与者控制良好的 HIV 将按 1:1 随机分配至多西环素或安慰剂，并按吸烟状况分层（当前与前吸烟者）和临床地点，利用动态随机化。该研究的主要终点是 72 周治疗期间预测 DLCO 的下降率（斜率）百分比。我们组装了一个由经验丰富的临床中心组成的团队，拥有患者群体和专业知识，可以有效地招募和进行这次审判。在我们之前的研究中，我们观察到患有早期肺气肿的 HIV+ 个体的基质增加支气管肺泡中的金属蛋白酶（MMP-2、-7、-9、-12；每种都与肺气肿发病机制有关）灌洗 (BAL) 液体样本。因此，MMP 是干预的潜在目标，旨在改变肺气肿的进展，特别是在艾滋病毒感染者中。我们成功论证了这个方案的可行性我们在 NHLBI 资助的单中心随机、双盲、安慰剂对照试点研究中测试了该方法强力霉素的安全性和耐受性（FDA 批准作为 MMP 抑制剂，用于防止组织破裂）牙龈疾病）超过 24 周（NCT 01744093）。我们研究了 27 名患有 HIV 和 COPD/肺气肿的个体按 2:1 随机分配至多西环素 100 mg po BID 或安慰剂。除了可接受的安全性和耐受性之外，存在扩散能力 (DLCO) 稳定和 BAL 液 MMP-9 减少的趋势分配到多西环素组的参与者的活动。 DEPTH 试验将扩展这些有希望的试点数据进入正式的II期临床试验。我们预计，在完成这项拟议的研究后，我们的数据将支持重新利用廉价的抗生素强力霉素，以减缓 PLWH 肺气肿的进展。具体来说，我们希望展示： 1. 多西环素可减缓 PLWH 肺气肿的进展，主要由 DLCO 和其次是HRCT。 2. 对于患有肺气肿的感染者，口服强力霉素 72 周是安全且可耐受的。 3.强力霉素可改善肺气肿感染者的呼吸生活质量和功能状态。