Acetazolamide as a Means to Mitigate Falling Ventilatory Drive and Drive-dependent OSA
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 36
- 试验地点
- 1
- 主要终点
- Percentage reduction of apnea-hypopnea Index (AHI) with active versus placebo therapy in drive-dependent vs classic OSA groups
研究概览
简要总结
Obstructive sleep apnea (OSA) is a highly prevalent disorder that has major consequences for cardiovascular health, neurocognitive function, risk of traffic accidents, daytime sleepiness, and quality of life. For years, a "classic" model of OSA has been used to describe the disorder, which fails to capture it's complexity. Recently, a model for OSA called drive-dependent OSA was discovered be more prevalent in the OSA population. This drive-dependent OSA is due to ventilation instability that occurs during respiratory events however these individuals have spontaneous increases in drive during respiratory events that stabilize their airway (i.e., via improving upper airway muscle activity) and reduce the risk of respiratory events in people with OSA. Therefore, by stabilizing the ventilatory drive, OSA should be treatable. Acetazolamide is a pharmacological ventilatory stimulant and has been previously shown to reduce OSA severity. As such in this study, the goal is to demonstrate acetazolamide improves OSA severity in 'drive-dependent' OSA people by improving drive-related pharyngeal obstructions compared to the 'classic' OSA people.
详细描述
The goal of this detailed randomized controlled mechanistic clinical study, with gold-standard measurements of ventilatory drive and dilator muscle activity, is to test the hypotheses that acetazolamide improves OSA in patients with (N=18) but not without (N=18) drive-dependent OSA (i.e. drive-dependent status explains treatment efficacy). We will also show that acetazolamide efficacy is explained by mitigating drive-related reduction in pharyngeal obstruction. A 4-wk open-label extension will explore repeated-dose efficacy without invasive measurements in both subgroups.
Subjects will attend a virtual Screening and Consent visit to assess eligibility for enrollment. Participants will take part in a video call with the consenting doctor to obtain consent (Zoom).
After consent, subjects will first attend a baseline routine sleep study to confirm eligibility (apnea-hypopnea index >15 events/hr) and establish the baseline characteristics. Patients will subsequently attend a specialized physiology night with additional gold-standard measurement of ventilation, ventilatory drive, genioglossus muscle activity, which will serve to establish drive-dependent status.
Those eligible for the study will receive in randomized order the following:
A) Acetazolamide (2x250mg) B) Placebo
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
4-week open-label acetazolamide extension and optional
入排标准
- 年龄范围
- 21 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Ages 21-80 years
- •Suspected OSA (snoring, sleepiness, witnessed apneas, other clinical symptoms) or diagnosed OSA (severity not required)
- •Untreated; No use of OSA treatments within 2 weeks of the baseline study. No plans to start OSA treatments for the duration of the study protocol
排除标准
- •Any unstable medical condition
- •Current use of the study medication.
- •Use of ventilatory stimulant or depressant medications that may complicated interpretation of results (including opioids, barbiturates, doxapram, almitrine, theophylline, 4-hydroxybutanoic acid).
- •Contraindications for acetazolamide, including:
- •Allergies to sulfonamides - e.g. acetazolamide, hydrochlorothiazide, furosemide, sulfasalazine, celecoxib, sumatriptan, and zonisamide.
- •closed-angle glaucoma
- •adrenal insufficiency
- •known electrolyte or acid/base imbalance (hyponatremia, hypokalemia, hyperchloremia, metabolic acidosis, acidemia)
- •clinically-significant kidney disorders (eGFR<60 ml/min/1.73m2)
- •clinically-significant liver disorders
- •Use of more than 500 mg/day of Aspirin, due to the potential for an interaction of acetazolamide and very high doses of Aspirin (acetylsalicylic acid, a salicylate drug)
- •Adrenocortical insufficiency
- •Low sodium or potassium
- •hyperchloremic acidosis
- •Conditions likely to affect obstructive sleep apnea physiology: neuromuscular disease or other major neurological disorder, heart failure, or any other unstable major medical condition.
- •Respiratory disorders other than obstructive sleep apnea:
- •central sleep apnea (>75% of respiratory events scored as central)
- •chronic hypoventilation/hypoxemia (awake SaO2 < 92% by oximetry) due to chronic obstructive pulmonary disease or other respiratory conditions
- •Conditions likely to increase arousability from sleep: insomnia
- •Other sleep disorders that may complicate establishment of sleep: periodic limb movements (periodic limb movement arousal index > 10/hr), narcolepsy, or parasomnias
- •For intramuscular electrodes and catheter: allergy to lidocaine
- •Highly-sensitive gag reflex. Patients with a self-reported 'highly-sensitive gag reflex', including an affirmative response to 'Do you sometimes gag when brushing your teeth?', will not take part in the physiology studies given the placement of an esophageal catheter
- •For intramuscular electrodes: use of aspirin or other oral anti-platelets / anti-coagulants
- •For oronasal mask: severe claustrophobia
- •Pregnancy or nursing
研究组 & 干预措施
Acetazolamide
Acetazolamide administered for 3 nights, half-dose (1 pill) on the first night followed by full dose (2x250mg pills) for 2 nights
干预措施: Acetazolamide (Drug)
Placebo
Placebo sugar pills administered for 3 nights, half-dose (1 pill) on the first night followed by full dose (2 pills) for 2 nights
干预措施: Placebo (Drug)
结局指标
主要结局
Percentage reduction of apnea-hypopnea Index (AHI) with active versus placebo therapy in drive-dependent vs classic OSA groups
时间窗: 1 night
The primary efficacy outcome measure is the apnea hypopnea index (3% desaturation or arousal), presented as a percent reduction from baseline. Differences in this measure with active versus placebo therapy will be assessed. The primary comparison will be the difference in this measure in drive-dependent versus classic OSA subgroups.
次要结局
- Hypoxic burden, %.min/hr(1 night)
- N1 sleep, %total sleep time(1 night)
- Arousal index, events/hr(1 night)
研究者
Scott Aaron Sands
Assistant Professor
Brigham and Women's Hospital