Sleep Apnea Treatment with Positive Airway Pressure for Prevention of Diabetes Mellitus

摘要 该应用程序是对美国国家糖尿病、消化和肾脏疾病研究所(NIDDK)的响应 计划公告PAR-18-423用于实施多中心随机临床试验以测试 PAP治疗阻塞性睡眠呼吸暂停(OSA)的假说 糖尿病前期患者将减少进展为2型糖尿病(T2 DM)。对于U34规划 阶段，我们已经建立了一个由十个临床站点组成的网络，由经验丰富的调查团队指导， 在进行多中心随机试验方面有广泛的背景。为了为审判提供领导，我们有 建立了一个由特殊研究人员组成的财团，并包括以下内容：(A)位于 约翰霍普金斯大学彭博公共卫生学院建立中央数据协调中心； (B)宾夕法尼亚大学睡眠临床研究中心组织睡眠阅读中心 用于家庭睡眠测试；(C)PAP依从性核心；(D)布朗大学的减肥核心；和(E)生物测试 明尼苏达大学的核心实验室。在本应用程序中，我们描述了我们的指挥和 管理多中心研究计划；整合和管理复杂研究网络的策略； 以及在肺部和睡眠医学、内分泌学、临床方面具有专业知识的优秀协查团队 试验方法、减肥干预、流行病学和生物统计学。U34的具体目标 规划期为：(1)细化审判的组织结构和领导方案；(2)敲定 研究方案和相关的原始文件，提供临床现场培训，并制定手册 睡眠阅读中心、PAP遵守核心和临床站点的运营；(3)构建数据 管理系统，建立数据质量保证方法，并为 DCC；(4)数据分析和处理与研究有关的出版物和演示文稿的大纲计划；和(5) 从中央IRB获得人类受试者和监管部门的批准。U34财团将开发一款U01 关于PAP疗法预防2型糖尿病的多中心临床试验的批准申请 阻塞性睡眠呼吸暂停综合征和糖尿病前期。U01试验的具体目标如下。目标1：确定人类是否 对于糖尿病前期和中到重度OSA，在生活方式干预的基础上增加PAP治疗是 与从糖尿病前期到T2 DM的进展率较低有关。目标2：评估在患有糖尿病的患者中 糖尿病前期和中到重度OSA，在生活方式干预计划中增加PAP治疗是 与单独的生活方式干预相比，在以下方面有更大的改善：(A)评估的胰岛素敏感性 通过稳态模型评估指数(HOMA-IR)：(B)将血红蛋白A1c模拟为连续变量； (C)交感神经系统活动；(D)炎症标志物，包括C-反应蛋白(CRP)和 白介素6(IL-6)；(E)静息血压；(F)体重和中心性肥胖指标(即腰围) (G)与阻塞性睡眠呼吸暂停综合症相关的症状和生活质量。

ABSTRACT This application is in response to the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK) program announcement PAR-18-423 for implementing a multi-center randomized clinical trial to test the hypothesis that treatment of obstructive sleep apnea (OSA) with positive airway pressure (PAP) therapy in people with prediabetes will reduce the progression to type 2 diabetes mellitus (T2DM). For the U34 planning phase, we have established a network of ten clinical sites guided by an experienced team of investigators with an extensive background in conducting multicenter randomized trials. To provide leadership for the trial, we have built a consortium of exceptional investigators and include the following: (a) The Center for Clinical Trials at the Johns Hopkins University Bloomberg School of Public Health to establish a central Data Coordinating Center; (b) The Clinical Research Center for Sleep at the University of Pennsylvania to organize a Sleep Reading Center for home sleep testing; (c) a PAP adherence core; (d) a weight loss core at Brown University; and (e) a bioassay core laboratory at the University of Minnesota. In this application, we describe our record of conducting and managing multi-center research programs; strategies for assembling and managing a complex research network; and the talented team of coinvestigators with expertise in pulmonary and sleep medicine, endocrinology, clinical trials methodology, weight loss interventions, epidemiology, and biostatistics. The Specific Aims for the U34 planning period are to: (1) refine the organizational structure and the leadership plan for the trial; (2) finalize the study protocol and associated source documents, provide clinical site training, and develop a manual of operations for the Sleep Reading Center, the PAP Adherence Core, and the Clinical Sites; (3) construct a data management system, establish methods of data quality assurance, and develop a manual of operations for the DCC; (4) outline plans for data analysis and handling of study-related publications and presentations; and (5) obtain human subjects and regulatory approvals from a central IRB. The U34 consortium will develop a U01 grant application for a multi-center clinical trial on the utility of PAP therapy in preventing T2DM in people with OSA and prediabetes. The Specific Aims of the U01 trial are as follows. Aim 1: To determine whether, in people with prediabetes and moderate-to-severe OSA, the addition of PAP therapy to a lifestyle intervention is associated with lower rate of progression from prediabetes to T2DM. Aim 2: To assess whether, in people with prediabetes and moderate-to-severe OSA, the addition of PAP therapy to a lifestyle intervention program is associated with greater improvements than with lifestyle intervention alone in: (a) insulin sensitivity, as assessed by the homeostasis model assessment index (HOMA-IR); (b) hemoglobin A1c modeled as a continuous variable; (c) sympathetic nervous system activity; (d) inflammatory markers including C-reactive protein (CRP) and interleukin-6 (IL-6); (e) resting blood pressure; (f) body weight and measures of central obesity (i.e., waist circumference); and (g) OSA-related symptoms and quality of life.