PHASE II TRIAL OF SLEEP APNEA TREATMENT TO REDUCE CARDIOVASCULAR MORBIDITY

描述（由申请人提供）： 项目摘要/摘要本申请解决大机会：HLB疾病新疗法的2期临床试验计划。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。尽管气道正压通气（PAP）治疗可以有效缓解气道阻塞，但大多数OSA患者仍未经治疗，因此CVD风险增加。OSA患者的次优病例识别和治疗部分来自诊断算法的复杂性和使用夜间器具的感知负担，这在一些个体中导致不适和睡眠中断。因此，需要开发和测试解决CVD风险的OSA治疗的替代方法。新出现的数据表明，间歇性低氧血症的核心作用，作为一个关键的调解人的促炎，促氧化和代谢失调的反应，OSA。因此，有一个强大的科学基础，严格评估一个相对简单的治疗，夜间补充氧气（NSO）的疗效，对中间标志物的心血管疾病的风险。在这项II期随机对照试验中，我们将利用现有的合作研究团队（睡眠心脏健康研究研究者），他们在进行OSA多中心研究方面经验丰富，将团队扩大到包括经验丰富的心血管转化和临床试验研究者，以评估NSO在治疗CVD事件高风险OSA患者中的新用途。将进行路径导向的结局评估，以确定假定的促炎、促氧化和血管对OSA反应的可逆性。结局将包括低氧血症效应的关键介质，以及患者报告结局的变化，如生活质量。进行PAP和NSO的头对头比较，我们将从4个心脏病学实践中心招募1400名CVD事件高风险且无显著嗜睡的患者，进行家庭睡眠监测。我们将354例中重度OSA患者随机分配至三个治疗组之一：a）预防CVD事件的优化药物治疗; B）优化药物治疗加PAP;或c）优化药物治疗加NSO。将通过每月一次的电话评估和3个月的随访访视对参与者进行评估，评估依从性、OSA严重程度的变化、生活质量/嗜睡以及根据其对CVD的预测价值和/或对低氧血症的敏感性选择的中间CVD风险因素的目标组。其中包括：24小时血压;心血管疾病风险的生化指标;交感神经活动;和心脏电生理活动的过夜指标。这些领先机构的协调努力将通过组建多学科，多机构团队来加速进行大规模3期临床试验的能力;建立关键的研究核心和基础设施;完善招募，保留和测量程序;确定关键的中间研究终点;并确定新型干预措施（NSO）在OSA患者中的安全性和有效性。 (End摘要）

DESCRIPTION (provided by applicant): Project Summary/Abstract This application addresses Grand Opportunity: Phase 2 Clinical Trials Program of Novel Therapies for HLB Diseases. Obstructive sleep apnea (OSA) afflicts > 5% of adults and is associated with a 2 to 4-fold increased risk of cardiovascular disease (CVD). Despite the availability of positive airway pressure (PAP) therapy, which effectively relieves airway obstruction, most OSA patients remain untreated, and thus at increased CVD risk. Suboptimal case-identification and treatment of patients with OSA is, in part, from the complexity of diagnostic algorithms and the perceived burden of using a nightly appliance, which in some individuals results in discomfort and sleep disruption. Thus, there is a need to develop and test alternative approaches to OSA treatment that address CVD risk. Emerging data indicate the central role of intermittent hypoxemia as a key mediator of pro-inflammatory, pro-oxidative and metabolic dysregulatory responses to OSA. There is thus a strong scientific basis for rigorously evaluating the efficacy of a relatively simple therapy, nocturnal supplemental oxygen (NSO), on intermediate markers of CVD risk. In this Phase 2 randomized controlled trial, we will capitalize on an existing collaborative research team (Sleep Heart Health Study investigators) experienced with the conduct of multicenter studies of OSA, expanding the team to include experienced cardiovascular translational and clinical trials investigators, to evaluate the novel use of NSO in the treatment of patients with OSA at high risk for CVD events. A pathways-directed outcomes assessment will be conducted to identify the reversibility of putative pro-inflammatory, pro-oxidative, and vascular responses to OSA. Outcomes will include critical mediators of hypoxemia effects, as well as changes in patient-reported outcomes, such as quality of life. Performing a head-to-head comparison of PAP and NSO, we will recruit 1400 patients at high risk for CVD events without significant sleepiness from 4 cardiology practice sites to undergo home sleep monitoring. We will randomize 354 of these patients with moderate to severe OSA to one of three treatment arms: a) optimized medical therapy for prevention of CVD events; b) optimized medical therapy plus PAP; or c) optimized medical therapy plus NSO. Participants will be evaluated with monthly telephone assessments and a 3-month follow-up visit, evaluating adherence, changes in OSA severity, quality of life/sleepiness, and a targeted group of intermediate CVD risk factors chosen for their predictive value for CVD and/or their sensitivity to hypoxemia. These include: 24 hour blood pressure; biochemical indices of CVD risk; sympathetic activity; and overnight indices of cardiac electrophysiologic activity. These coordinated efforts of leading institutions will accelerate the ability to conduct a large-scale Phase 3 clinical trial by assembling a multidisciplinary, multi-institutional team; establishing key study cores and infrastructure; refining recruitment, retention and measurement procedures; identifying key intermediate study endpoints; and establishing the safety and efficacy of the novel intervention (NSO) in OSA patients. (End of Abstract)