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

深度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)，这一人群加速了疾病的发展，但没有 靶向治疗。与我们的CCC合作者一起，我们提出了第二阶段，多中心，随机，双盲， 多西环素100 mg口服减缓肺气肿进展的安慰剂对照试验 现吸烟者或曾经吸烟者对一氧化碳(DLCO)的扩散能力参与者 将根据吸烟状况(现任吸烟者与以前吸烟者)和临床地点进行分层，采用动态随机分组。 研究的主要终点是经校正的预测DLCO的下降率(斜率 72周治疗期间的血红蛋白、碳氧血红蛋白和大气压。我们的临床 合作者已经在NHLBI资助的先导研究中成功地证明了这项研究的可行性 在24周内对27人进行多西环素的安全性和耐受性测试(NCT 01744093)，并有 集结了一批经验丰富的临床站点。深度试验将把他们有希望的飞行员数据扩展到 正式的II期临床试验。 经验丰富的数据协调中心(DCC)具有强大的统计领导力和专业知识，是 设计和分析，特别是在临床试验期间出现意想不到的问题时。这个 密歇根大学(UM)生物医学和教育研究(SABER)单位的统计分析 顶尖的生物统计学系将担任DCC，汇集了一批经验丰富的教职员工和 生物统计、项目管理、研究监测、数据库设计和数据管理、软件方面的工作人员 开发和研究管理。Saber在与Weill的合作方面有着良好的记录 康奈尔大学医学肺科团队为临床协调中心(CCC)。UM的首要目标是 DCC将与研究调查人员、CCC和NHLBI合作，使成功实现 在时间和预算内进行研究。我们将通过三个具体目标实现这些目标：(一)增强 通过提供统计和临床试验方法专业知识来设计、分析和 传播研究结果；(2)确保收集及时、准确和可重复使用的数据；以及 最大限度地遵守研究议定书；以及(3)为研究提供既定的基础设施和服务 管理和操作以及研究利益相关者之间的沟通。我们的领导力、经验、 和专门知识将促进合作，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的益处的研究结果。我们预计在完工后 在这项拟议的研究中，我们的数据将支持改变廉价抗生素多西环素的用途，以减缓 PLWH中的肺气肿进展，并证明它是安全和耐受性良好的。

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.