A Planning Study: Sleep Apnea Intervention for Cardiovascular Disease Reduction

描述（由申请人提供）： 阻塞性睡眠呼吸暂停（OSA）困扰着> 5%的成年人，并与心血管疾病（CVD）的风险增加2至4倍有关。小型短期研究提供了初步证据，表明气道正压通气（PAP）治疗OSA可改善CVD风险因素。鉴于OSA的高患病率及其严重的生理紊乱，有效的治疗有望显著降低这些患者的CVD负担。然而，PAP对CVD的一级或二级预防的作用尚不清楚，这是由于对长期PAP依从性的担忧以及相对缺乏严格设计的大规模前瞻性临床试验来评估OSA治疗对临床终点的影响。我们已经组建了一个多学科的研究者团队，以解决与启动后期大规模III期随机对照试验（RCT）相关的关键研究设计问题。在这项计划研究中，我们建议进行一项II期RCT，其中包括评价替代研究设计特征，例如对照组的选择、优化PAP依从性的方法和研究终点的选择。我们的目标是从一个大型的区域性睡眠障碍中心网络中招募患有中度至重度OSA和CVD危险因素或确诊CVD的患者。在2周的导入期后，180名受试者将被随机分配到3个干预组之一：主动PAP治疗组或两个对照组之一（假CPAP vs.保守药物治疗，CMT）。使用两个对照组将允许评估使用替代控制干预措施的权衡，这些干预措施造成不同程度的负担并允许不同程度的设盲。增强PAP依从性的替代方法（其中之一包括增强的基于行为的干预）也将通过第二阶段随机化程序进行评估。所有参与者将在基线和12个月时接受CVD风险因素的标准化评估，包括测量24小时血压、动脉张力测定、心脏超声心动图、CVD发病机制途径中标志物的生物测定和患者报告的结局。将每两个月进行一次安全性和依从性的中期监测。分析将：1）量化每个研究组内的保留率和依从率、招募率和安全性参数; 2）比较各组间主要临床结局、平均收缩压的变化; 3）估计其他中间标志物和患者报告结局变化的效应量; 4）探索应答的亚组差异。拟议的数据收集，包括对安全性指标、替代设计特征和中间标记物的严格评估，将为以后的大规模研究奠定基础，该研究将首次设计为提供I级证据，以说明OSA治疗降低CVD发病率和死亡率的有效性。 (End摘要）

DESCRIPTION (provided by applicant): Obstructive sleep apnea (OSA) afflicts > 5% of adults and is associated with a 2 to 4-fold increased risk of cardiovascular disease (CVD). Small, short term studies have provided preliminary evidence that treatment of OSA with positive airway pressure (PAP) improves CVD risk factors. Given the high prevalence of OSA and its profound physiological disturbances, effective treatment could be expected to significantly reduce CVD burden in these patients. However, the role of PAP for primary or secondary prevention of CVD is unclear due to both concerns about long-term PAP adherence and the relative absence of rigorously designed large-scale prospective clinical trials evaluating the impact of OSA treatment on clinical endpoints. We have assembled a multi-disciplinary investigator team to address the critical study design issues relevant for launching a later large-scale Phase 3 randomized controlled trial (RCT). In this planning study, we propose to conduct a Phase 2 RCT which includes evaluation of alternative study design features such as the choice of control arms, approaches for optimizing PAP adherence, and choice of study endpoints. We aim to recruit patients with moderate to severe OSA and with CVD risk factors or established CVD from a network of large, regional sleep disorders centers. After a 2-week run-in period, 180 participants will be randomized to one of 3 intervention arms: an active PAP treatment arm or one of two control arms (sham-CPAP vs. conservative medical therapy, CMT). The use of two control arms will allow assessment of the trade-offs of using alternative control interventions that pose different levels of burden and allow different degrees of blinding. Alternative approaches for enhancing adherence to PAP, one of which includes an augmented behavioral-based intervention, also will be evaluated through a second-stage randomization procedure. All participants will undergo a standardized assessment of CVD risk factors at baseline and at 12 months, including measurement of 24 hour blood pressure, arterial tonometry, cardiac echocardiography, bioassays for markers in CVD pathogenesis pathways, and patient-reported outcomes. Interim monitoring for safety and adherence will be performed every two months. Analyses will: 1) quantify the retention and adherence rates, recruitment yields, and safety parameters within each study arm; 2) compare changes in the primary clinical outcome, average systolic blood pressure, across arms; 3) estimate effect sizes for changes in other intermediate markers and patient-reported outcomes; and 4) explore subgroup differences in responses. The proposed data collection, including a rigorous evaluation of safety indicators, alternative design features, and intermediate markers, will lay the foundation for a later large-scale study that will be designed, for the first time, to provide Level I evidence that addresses the effectiveness of OSA treatment for reducing CVD morbidity and mortality. (End of Abstract)