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.

DEPTH试验代表了一种创新的方法，可以减缓生活在肺气肿患者的肺气肿进展。 艾滋病毒感染者（PLWH），一个加速疾病进展的人群， 疗法我们提出了一项II期、多中心、随机、双盲、安慰剂对照试验， 多西环素100 mg po BID，以减缓肺气肿的进展，通过弥散指数的变化进行评估 吸烟者的吸烟能力（DLCO）。符合条件的肺气肿受试者 控制良好的HIV将按1：1随机分配至多西环素组或安慰剂组，按吸烟状态分层（目前 与前吸烟者相比）和临床中心，利用动态随机化。研究的主要终点是 72周治疗期间预测DLCO百分比的下降率（斜率）。我们组建了一个 由经验丰富的临床研究中心组成的团队，拥有患者人群和专业知识，可有效招募和开展 这次审判 在我们以前的研究中，我们观察到早期肺气肿的HIV阳性个体， 支气管肺泡上皮细胞中的金属蛋白酶（MMP-2、MMP-7、MMP-9、MMP-12;每种都与肺气肿发病机制有关） 灌洗液（BAL）样品。MMPs因此是旨在修饰的干预的潜在靶点。 肺气肿的进展，特别是在艾滋病毒感染者。我们成功地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， 多西环素（FDA批准的MMP抑制剂，用于预防组织破坏）的安全性和耐受性 牙龈疾病）24周（NCT 01744093）。我们研究了27名艾滋病毒感染者和COPD/肺气肿患者 以2：1的比例随机分配至多西环素100 mg po BID或安慰剂组。除了可接受的安全性和耐受性外， 有弥散量（DLCO）稳定和BAL液MMP-9降低的趋势 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，在这项拟议的研究完成后，我们的数据将支持重新利用廉价的 抗生素强力霉素，以减缓肺气肿进展PLWH。具体来说，我们希望展示： 1.多西环素可减缓PLWH患者肺气肿的进展，主要通过DLCO和 其次是HRCT。 2.多西环素口服治疗肺气肿患者72周是安全和耐受的。 3.强力霉素改善肺气肿PLWH患者的呼吸系统生活质量和功能状态。