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