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：全球，八分之一的成年人患有阻塞性睡眠呼吸暂停（OSA），这使令人惊讶 睡眠，白天嗜睡，并增加了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OSA患者无法使用持续的正气道压力 治疗，并且由于替代选择有限，大多数仍未治疗。但是OSA是一种异源条件， 现在可以量化单个患者（“内型”）OSA的机制（“内型”），从而允许针对性 操纵并提供了开发OSA药物疗法作为此类患者的替代方案的清晰途径。 通气不稳定性（“高环增益”）在三分之一的患者中有助于OSA发病机理。 PI的数据 表明乙酰唑胺 - 一种安全的低成本（每天0.66美元），每天降低环路增益，可以 在某些患者中明显改善了OSA及其后遗症，可能对患有A的患者特别有益 高循环增益内型。但是，先前的研究通常没有测量循环增益和临床上的数据 重要的结果很少。为了定义更好的乙唑胺对患者护理的价值，PI将进行 随机，安慰剂对照，分频试验，是否在OSA患者中进行4周的乙唑胺测试 提高OSA的严重性（AIM 1）和临床上重要的结果（AIM 2），并评估预测因子/机制 （包括循环增益）这些结果的变化（AIM 3），以帮助更精确地识别可能的响应者。 职业发展计划：PI，Chris Schmickl医学博士/博士学位，在流行病学方面具有强大的背景 生物统计学和临床​​睡眠医学。这项K23奖将为他提供受保护的时间和培训 实现自己成为独立身体科学家的长期目标，转化了身体见解 进入无法使用当前疗法的OSA患者的精确药物疗法。 为了实现这一长期目标，schmickl博士将在三个关键领域中发展高级技能 与圣地亚哥分校的潜水员和杰出的心理/顾问团队的专业知识保持一致：1）OSA Patho- 生理学（Malhotra/Owens/Nemati博士）； 2）设计/执行临床试验（Jain博士）； 3）评估 临床上重要的结果（Drs Banks/Taub）。基于差距分析，全面的培训计划是 设计的，仔细平衡动手研究经验与完善课程，以及 强调负责任的研究的重要性。清晰的物体和里程碑已经 定义以跟踪奖励期间的进度。获得的数据和技能将使PI可以扩展 与R01一起研究乙唑胺（和/或其他干预措施）在病情中的长期影响 可能反应者的物理定义的亚组。更广泛地，这个奖项将使他能够发展 针对许多目前未经治疗的OSA患者的新型，高影响，精确干预措施，从而加入 NHLBI的使命是提高所有个人的健康，以便他们的生活更长，更充实的生活。