PHASE II TRIAL OF SLEEP APNEA TREATMENT TO REDUCE CARDIOVASCULAR MORBIDITY

描述(由申请人提供)： 项目概述/摘要这项申请解决了巨大的机遇：HLB病新疗法的第二阶段临床试验计划。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)风险增加2-4倍有关。尽管有了有效缓解呼吸道阻塞的正压(PAP)治疗，但大多数OSA患者仍然没有得到治疗，因此增加了心血管疾病的风险。OSA患者的次优病例识别和治疗部分是由于诊断算法的复杂性和使用夜间用具的负担，在某些人中，这会导致不适和睡眠中断。因此，有必要开发和测试OSA治疗的替代方法，以应对心血管疾病风险。新出现的数据表明，间歇性低氧血症作为OSA的促炎、促氧化和代谢失调反应的关键介质发挥了核心作用。因此，严格评估一种相对简单的疗法--夜间补充氧气(NSO)--对心血管疾病风险的中间标记物的疗效是有强有力的科学依据的。在这项第二阶段的随机对照试验中，我们将利用现有的合作研究团队(睡眠心脏健康研究调查人员)，该团队在进行OSA的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换和临床试验研究人员，以评估NSO在治疗心血管疾病高危OSA患者中的新使用。将进行一项以通路为导向的结果评估，以确定推测的促炎、促氧化和血管反应对OSA的可逆性。结果将包括低氧血症影响的关键调节因素，以及患者报告的结果的变化，如生活质量。对PAP和NSO进行逐头比较，我们将从4个心脏科实习地点招募1400名有心血管事件高危且无明显嗜睡的患者进行家庭睡眠监测。我们将这些患有中度到重度阻塞性睡眠呼吸暂停综合征的患者中的354名随机分为三个治疗组之一：a)为预防CVD事件而优化的药物治疗；b)优化的药物治疗加PAP；或c)优化的药物治疗加NSO。参与者将接受每月电话评估和为期3个月的随访，评估遵守情况、阻塞性睡眠呼吸暂停严重程度的变化、生活质量/嗜睡，以及根据其对心血管疾病的预测价值和/或对低氧血症的敏感性而选择的一组有针对性的中间心血管风险因素。这些指标包括：24小时血压；心血管疾病风险的生化指标；交感神经活动；以及夜间心脏电生理活动指数。领先机构的这些协调努力将通过组建一个多学科、多机构的团队；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；以及建立新型干预措施(NSO)在阻塞性睡眠呼吸暂停患者中的安全性和有效性，来加快进行大规模3期临床试验的能力。 (摘要结束)

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)