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

DEPTH试验代表了一种减缓肺气肿进展的创新方法， 艾滋病毒感染者（PLWH），这是一个加速疾病进展的人群， 靶向治疗与我们的CCC合作者，我们提出了一个II期，多中心，随机，双盲， 一项多西环素100 mg po BID减缓肺气肿进展的安慰剂对照试验， 一氧化碳弥散量（DLCO）在PLWH谁是当前或以前的吸烟者。参与者 将采用动态随机化，根据吸烟状态（当前吸烟者vs既往吸烟者）和临床研究中心进行分层。 研究的主要终点是校正的预测DLco百分比的下降率（斜率）。 血红蛋白、碳氧血红蛋白和大气压。我们的临床 合作者已经成功地证明了这项研究的可行性，在他们的NHLBI资助的试点研究， 在27名受试者中测试多西环素的安全性和耐受性，持续24周（NCT 01744093）， 聚集了一批经验丰富的临床站点。DEPTH试验将把他们有希望的试验数据扩展到 正式的II期临床试验。 一个具有强大统计领导力和专业知识的经验丰富的数据协调中心（DCC）是 设计和分析，特别是在临床试验过程中出现意外问题时。的 密歇根大学（UM）生物医学和教育研究统计分析（SABER）单位 一流的生物统计学系将担任DCC，汇集了一批经验丰富的教师和 生物统计学、项目管理、研究监查、数据库设计和数据管理、软件 发展和研究管理。SABER与Weill有着良好的合作记录 康奈尔医学肺团队作为临床协调中心（CCC）。UM的总体目标 DCC将与研究者、CCC和NHLBI合作， 在预算内按时完成研究。我们将通过三个具体目标来实现这些目标：（1）加强 通过提供统计和临床试验方法学专业知识来设计，分析和 传播研究成果;（2）确保收集及时、准确和可复制的数据， 最大限度地遵守研究方案;以及（3）为研究提供既定的基础设施和服务 管理和运营以及研究利益相关者之间的沟通。我们的领导能力、经验， 和专业知识将促进合作，鼓励科学生产力，并促进及时传播 多西环素对患有肺气肿的PLWH患者的益处的研究结果。我们预计， 在这项拟议的研究中，我们的数据将支持重新利用廉价的抗生素强力霉素， 肺气肿的进展，并证明它是安全的，耐受性良好。

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. With our CCC collaborators, 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 quantified by diffusing capacity for carbon monoxide (DLCO) among PLWH who are current or former smokers. Participants will be 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 corrected for hemoglobin, carboxyhemoglobin and barometric pressure over the 72-week treatment period. Our clinical collaborators have successfully demonstrated the feasibility of this study in their NHLBI-funded pilot study to test the safety and tolerability of doxycycline in 27 individuals over 24 weeks (NCT 01744093), and have assembled a group of experienced clinical sites. The DEPTH trial will extend their promising pilot data to a formal phase II clinical trial. An experienced data coordinating center (DCC) with strong statistical leadership and expertise is key in both design and analysis, particularly when unanticipated issues arise during the conduct of a clinical trial. The University of Michigan (UM) Statistical Analysis of Biomedical and Educational Research (SABER) unit in a top-ranked department of biostatistics will serve as DCC, bringing together an experienced group of faculty and staff in biostatistics, project management, study monitoring, database design and data management, software development, and research administration. SABER has a strong track record of collaborations with Weill Cornell Medicine pulmonary team as the clinical coordinating center (CCC). The overarching goal of the UM DCC is to collaborate with study investigators, the CCC, and NHLBI to enable successful achievement of the study on time and within budget. We will accomplish these goals through the three specific aims: (1) Enhance scientific rigor by providing statistical and clinical trials methodological expertise to design, analyze, and disseminate research findings; (2) Ensure the collection of timely, accurate and reproducible data, and maximize adherence to the study protocol; and (3) Provide established infrastructure and services for study administration and operations and for communication among study stakeholders. Our leadership, experience, and expertise will promote collaborations, encourage scientific productivity, and facilitate timely dissemination of findings on the benefits of doxycycline in PLWH who have emphysema. We anticipate that upon completion of this proposed study, our data will support repurposing the inexpensive antibiotic doxycycline, to slow emphysema progression in PLWH, and demonstrate that it is safe and well tolerated.