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: 10509159
• 负责人: MARSHALL J GLESBY
• 金额: $ 213.34万
• 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 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10509159
• 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 Pulmonary Disease; Clinical; Conduct Clinical Trials; Data; Data Coordinating Center; Development; 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; Persons; Pharmacy facility; Phase; Phase II Clinical Trials; Pilot Projects; Placebo Control; 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; radiological imaging; 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.

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 口服 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。我们成功地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. 强力霉素可改善患有肺气肿的感染者的呼吸生活质量和功能状态。