Acetazolamide to Improve Clinically Important Outcomes in Obstructive Sleep Apnea Patients with a High Loop Gain Endotype

乙酰唑胺可改善具有高环增益内型的阻塞性睡眠呼吸暂停患者的临床重要结果

• 批准号: 10524708
• 负责人: Christopher Nikolaus Schmickl
• 金额: $ 17.26万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10524708
• 关键词: Acetazolamide; Address; Adult; Affect; Apnea; Arousal; Award; Biometry; Blood Pressure; Body mass index; Carbonic Anhydrase Inhibitors; Clinic; Clinical; Clinical Trials; Cognition; Continuous Positive Airway Pressure; Cross-Over Trials; Data; Development; Development Plans; Diuretics; Doctor of Philosophy; Dose; Drowsiness; Enrollment; Epidemiology; Equilibrium; Functional disorder; Goals; Health; Hypertension; Hypoxemia; Hypoxia; Impaired cognition; Impairment; Individual; Intervention; Long-Term Effects; Longitudinal Studies; Measures; Medicine; Mentored Patient-Oriented Research Career Development Award; Mentors; Mission; Myocardial Infarction; National Heart, Lung, and Blood Institute; Neurocognitive; Obstructive Sleep Apnea; Outcome; Oxygen; Pathogenesis; Patient Care; Patient Outcomes Assessments; Patients; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phase; Physicians; Physiological; Physiology; Placebo Control; Placebos; Positioning Attribute; Publishing; Quality of life; Questionnaires; Randomized; Research; Research Infrastructure; Research Personnel; Risk; Scientist; Severities; Sleep; Sleep Apnea Syndromes; Sleep Fragmentations; Sleep disturbances; Stimulant; Stroke; Subgroup; Testing; Time; Training; Translating; United States National Institutes of Health; Vision; Work; alternative treatment; awake; base; blood pressure reduction; career development; cost; design; drug development; experience; functional outcomes; hands on research; hangover; improved; indexing; individual patient; insight; instrument; novel; personalized care; personalized intervention; response; responsible research conduct; sedative; skills; sleep quality; standard of care; vehicular accident; vigilance

PROJECT SUMMARY/ABSTRACT Research Plan: Worldwide, one in 8 adults has obstructive sleep apnea (OSA) which results in disturbed sleep, daytime sleepiness, and increases the risk for many health issues including cognitive impairment, heart attacks and strokes. Unfortunately, half of OSA patients are unable to use continuous positive airway pressure therapy, and due to limited alternative options, most remain untreated. But OSA is a heterogenous condition, and mechanisms underlying OSA in individual patients (“endotypes”) can now be quantified, allowing targeted manipulation and providing a clear avenue to develop OSA drug therapy as an alternative for such patients. Ventilatory instability (“high loop gain”) contributes to OSA pathogenesis in one third of patients. The PI’s data suggests that acetazolamide—a safe, low-cost ($0.66/day), once daily drug which lowers loop gain—can markedly improve OSA and its sequelae in some patients, and may be particularly beneficial for patients with a high loop gain endotype. However, prior studies generally did not measure loop gain and data on clinically important outcomes are scarce. To define better acetazolamide’s value for patient-care, the PI will conduct a randomized, placebo-controlled, crossover trial, testing if 4 weeks of acetazolamide in general OSA patients improves OSA severity (aim 1) and clinically important outcomes (aim 2), and assess predictors/mechanisms (including loop gain) of changes in these outcomes (aim 3) to help identify likely responders more precisely. Career Development Plan: The PI, Dr Chris Schmickl MD/PhD, has a strong background in epidemiology, biostatistics and clinical sleep medicine. This K23 award will provide him with the protected time and training to achieve his long-term goal of becoming an independent physician-scientist, translating physiological insights into precision pharmacotherapy for patients with OSA who are unable to use current therapies. To achieve this long-term goal Dr Schmickl will develop advanced skills in three key domains which perfectly align with the expertise of his diverse and outstanding mentor/advisor team from UC San Diego: 1) OSA patho- physiology (Drs Malhotra/Owens/Nemati); 2) Designing/executing clinical trials (Dr Jain); and 3) Assessing clinically important outcomes (Drs Banks/Taub). Based on a gap analysis, a comprehensive training plan was designed which carefully balances hands-on research experiences with complementary coursework, and emphasizes the importance of a responsible conduct of research. Clear objectives and milestones have been defined to track progress during the award. The acquired data and skills will allow the PI to expand on this work with an R01 studying the long-term effects of acetazolamide (and/or other interventions) in patho- physiologically defined subgroups of likely responders. More broadly, this award will enable him to develop novel, high-impact, precision interventions for the many currently untreated OSA patients, thereby joining the NHLBI mission to enhance the health of all individuals so that they can live longer and more fulfilling lives.

项目摘要/摘要 研究计划：在世界范围内，每8名成年人中就有一人患有阻塞性睡眠呼吸暂停(OSA)，这会导致睡眠障碍 睡眠、白天困倦，并增加许多健康问题的风险，包括认知障碍、心脏 攻击和中风。不幸的是，一半的阻塞性睡眠呼吸暂停患者不能使用持续的正压气道。 由于替代选择有限，大多数人仍然得不到治疗。但阻塞性睡眠呼吸暂停综合征是一种异质性疾病， 个体患者的阻塞性睡眠呼吸暂停的潜在机制(“内型”)现在可以被量化，允许有针对性的 操作，并为开发OSA药物疗法作为此类患者的替代方案提供了一条明确的途径。 在三分之一的患者中，呼吸不稳定(“高环增益”)导致了OSA的发病。PI的数据 提示乙酰唑胺-一种安全、低成本(0.66美元/天)的每日一次药物，可以降低环路增益-可以 显著改善一些患者的阻塞性睡眠呼吸暂停及其后遗症，可能对患有 高环路增益内型。然而，以前的研究一般没有在临床上测量环路增益和数据 重要成果寥寥无几。为了更好地确定乙酰唑胺在病人护理中的价值，PI将进行一项 随机、安慰剂对照、交叉试验，测试普通阻塞性睡眠呼吸暂停患者是否服用4周的乙酰唑胺 改善OSA严重程度(目标1)和临床重要结局(目标2)，并评估预测因素/机制 (包括环路增益)这些结果的变化(目标3)，以帮助更准确地识别可能的应答者。 职业发展计划：PI，Chris Schmickl医学博士/博士，在流行病学方面有很强的背景， 生物统计学和临床睡眠医学。这项K23奖项将为他提供受保护的时间和培训，以 实现他的长期目标，成为一名独立的内科科学家，翻译生理见解 为无法使用现有疗法的阻塞性睡眠呼吸暂停患者提供精确的药物治疗。 为了实现这一长期目标，施密克博士将在三个关键领域发展高级技能，这三个领域 与他来自加州大学圣地亚哥分校的多样化和杰出的导师/顾问团队的专业知识保持一致：1)OSA PATHO- 生理学(DRS Malhotra/Owens/Nemati)；2)设计/执行临床试验(Jain博士)；以及3)评估 临床重要结局(DRS Banks/TOUB)。根据差距分析，制定了一项全面的培训计划 精心设计，在实践研究经验和互补课程之间取得平衡，以及 强调负责任的研究行为的重要性。明确的目标和里程碑是 定义为跟踪颁奖过程中的进度。所获得的数据和技能将使PI能够在此基础上进行扩展 与R01合作研究乙酰唑胺(和/或其他干预措施)在病理中的长期影响 生理上定义的可能应答者的亚群。更广泛地说，这个奖项将使他能够发展 为许多目前未接受治疗的阻塞性睡眠呼吸暂停患者提供新颖、高影响、精确的干预措施，从而加入 NHLBI的使命是增进所有人的健康，使他们能够活得更长、更有成就感。