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: 10703241
• 负责人: MARSHALL J GLESBY
• 金额: $ 209.2万
• 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/10703241
• 关键词: Acceleration; 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; Clinical stratification; Conduct Clinical Trials; Data; Data Coordinating Center; Development; Diffusion; 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; 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; Tissues; Training; Walking; X-Ray Computed Tomography; antiretroviral therapy; arm; barometric pressure; clinical care; clinical research site; comorbidity; comparison control; 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人类肺气肿进展的创新方法