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

• 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
• 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

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.

深度试验代表了一种创新的方法，用于减慢生活中肺气肿的发展 与艾滋病毒（PLWH）一起，该人口加速了疾病进展，没有目标 治疗。我们提出了II期，多中心，随机，双盲，安慰剂对照试验 强力霉素100毫克Po bid降低肺气肿的进展 当前或以前吸烟者的PLWH中的容量（DLCO）。有资格的肺气肿参与者 良好控制的艾滋病毒将被随机分配给多西环素或安慰剂，通过吸烟状态分层（当前 与以前的吸烟者和临床部位，利用动态随机化。该研究的主要终点是 在72周的治疗期间，下降率（坡度）为预测DLCO。我们已经组装了 经验丰富的临床站点团队具有患者人数和专业知识，可以有效地注册和进行 这个试验。 在我们先前的研究中，我们观察到患有早期肺气肿的艾滋病毒+个体已经增加了基质 金属蛋白酶（MMP -2，-7，-9，-12；每个与肺气肿发病机理有关） 灌洗液（BAL）流体样品。因此，MMP是旨在修改干预措施的潜在目标 在艾滋病毒患者中特别是肺气肿的进展。我们成功证明了这一点的可行性 在我们的NHLBI资助的单中心随机，双盲，安慰剂对照的试点研究中 强力霉素的安全性和耐受性（FDA批准为MMP抑制剂，以防止组织分解 牙龈疾病）在24周内（NCT 01744093）。我们研究了27名HIV和COPD/Emphysema的人 随机2：1到多西环素100毫克PO BID或安慰剂。除了可接受的安全性和耐受性外， 存在稳定能力（DLCO）的趋势和BAL流体MMP-9的降低 分配给强力霉素组的参与者的活动。深度试验将扩展这些有希望的飞行员数据 进行正式的II期临床试验。 我们预计这项拟议的研究完成后，我们的数据将支持重新利用廉价 抗生素强力霉素，以减慢PLWH的肺气肿进展。具体来说，我们希望显示： 1。强力霉素减慢了PLWH中肺气肿的进展，主要由DLCO和DLCO评估 其次由HRCT。 2.强力霉素在口服72周的PLWH中是安全可容忍的，患有肺气肿。 3。强力霉素改善具有肺气肿的PLWH的呼吸质量和功能状态。