Rescuing OSA Patients Unable to Tolerate CPAP Using Endotype-Targeted Combination Drug Therapy: a Randomized, Double-Blind, Placebo-Controlled Trial
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 20
- 试验地点
- 2
- 主要终点
- Apnea Hypopnea Index (AHI)
研究概览
简要总结
Obstructive sleep apnea (OSA) is common and associated with many adverse health consequences, but many patients are unable to tolerate standard therapies such as continuous positive airway pressure (CPAP) and thus remain untreated. Single-drug therapies have shown promising results in treating sleep apnea, but on average patients have only experienced partial relief. Multi-drug therapy may offer a more effective treatment approach. The goal of this study is to test the effect of combination therapy with three FDA-approved drugs (Diamox [acetazolamide], Lunesta [eszopiclone] +/- Effexor [venlafaxine]) on OSA severity and physiology.
详细描述
Study participants will undergo three 3-day drug regimens. On days 1 and 2 of each drug regimen, subjects will take the study drugs at home; on day 3 of each drug regimen subjects will take the study drugs as part of an overnight inlab sleep study (including assessments of sleepiness/alertness, sleep quality and blood pressure). Initially subjects will take dual-therapy (acetazolamide+eszopiclone) vs placebo in random order; if sleep apnea resolved with dual-therapy, then subjects will undergo an open-label single-drug regimen (acetazolamide), else an open-label triple-drug regimen (acetazolamide + eszopiclone + venlafaxine).
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)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •BMI 18-40 kg/m2
- •Untreated Moderate or Severe OSA (AHI during supine NREM sleep >15/h) with a fraction of hypopneas >25% of all events
排除标准
- •Pregnancy
- •Breastfeeding
- •Prisoners
- •Adherent with effective therapy for OSA
- •Other known untreated sleep fragmenting disorder, such as periodic limb movement disorder, or narcolepsy
- •Inability to sleep supine for overnight sleep studies
- •Circadian rhythm disorder
- •Unrevascularized coronary artery disease, angina, prior heart attack or stroke, congestive heart failure
- •Uncontrolled hypertension (systolic blood pressure >160mmHg, diastolic blood pressure >95mmHg)
- •Presence of tracheostomy
- •Hospitalization within the past 90 days
- •Prior peptic ulcer disease, esophageal varices, or gastrointestinal bleeding (< 5 years)
- •Prior gastric bypass surgery
- •Chronic liver disease or end-stage kidney disease
- •Active illicit substance use or >2 oz daily alcohol use (i.e. >2 12 oz bottles of beers, >2 5 oz glasses of wine, >2 1.5 oz glasses of hard liquor such as spirits, gin, whiskey, etc.)
- •Psychiatric disease, other than well controlled depression/anxiety
- •Cognitive impairment, inability to provide consent, or inability to complete research procedures (e.g. questionnaires that are only available/validated in English)
- •Chronically using study drugs or drugs with similar pharmacodynamic effects (acetazolamide - carbonic anhydrase inhibitors, eszopiclone - benzodiazepine receptor agonists, venlafaxine - serotonin/norepinephrine reuptake inhibitors and other antidepressants)
- •Regular use of medications known to affect control of breathing (opioids, benzodiazepines, theophylline)
- •Contraindications to taking study drugs, including allergies to any of the drugs or sulfa allergy; concomitant use of antidepressants, opioids, sedatives/hypnotics, thiazide diuretics or angiotensin-receptor blockers; or severe nocturnal hypoxia (SpO2 nadir <70% on diagnostic sleep study).
研究组 & 干预措施
Placebo, then Dual-Therapy, then Single/Triple-Therapy
Subjects will start with a 3-day PLACEBO regimen:
- Day 1: Placebo (matching Acetazolamide 250mg) at bedtime at home.
- Day 2: Placebo (matching Acetazolamide 500mg) at bedtime at home.
- Day 3: Placebo (matching Acetazolamide 500mg + Eszopiclone 2mg) at bedtime in the sleep laboratory.
After a wash-out period of 4+ days, subjects will then cross-over to a 3-day EXPERIMENTAL DUAL-regimen:
- Day 1: Acetazolamide 250mg at bedtime at home.
- Day 2: Acetazolamide 500mg at bedtime at home.
- Day 3: Acetazolamide 500mg + Eszopiclone 2mg at bedtime in the sleep laboratory.
After a wash-out period of 4+ days, subjects will then undergo an OPEN-LABEL SINGLE/TRIPLE-regimen:
- Day 1: Acetazolamide 250mg at bedtime at home.
- Day 2: Acetazolamide 500mg at bedtime at home.
- Day 3: Acetazolamide 500mg alone or Acetazolamide 500mg + Eszopiclone 2mg + Venlafaxine 50mg at bedtime in the sleep laboratory, if sleep apnea resolved or did not resolve with the dual regimen, respectively.
干预措施: Acetazolamide (Drug)
Placebo, then Dual-Therapy, then Single/Triple-Therapy
Subjects will start with a 3-day PLACEBO regimen:
- Day 1: Placebo (matching Acetazolamide 250mg) at bedtime at home.
- Day 2: Placebo (matching Acetazolamide 500mg) at bedtime at home.
- Day 3: Placebo (matching Acetazolamide 500mg + Eszopiclone 2mg) at bedtime in the sleep laboratory.
After a wash-out period of 4+ days, subjects will then cross-over to a 3-day EXPERIMENTAL DUAL-regimen:
- Day 1: Acetazolamide 250mg at bedtime at home.
- Day 2: Acetazolamide 500mg at bedtime at home.
- Day 3: Acetazolamide 500mg + Eszopiclone 2mg at bedtime in the sleep laboratory.
After a wash-out period of 4+ days, subjects will then undergo an OPEN-LABEL SINGLE/TRIPLE-regimen:
- Day 1: Acetazolamide 250mg at bedtime at home.
- Day 2: Acetazolamide 500mg at bedtime at home.
- Day 3: Acetazolamide 500mg alone or Acetazolamide 500mg + Eszopiclone 2mg + Venlafaxine 50mg at bedtime in the sleep laboratory, if sleep apnea resolved or did not resolve with the dual regimen, respectively.
干预措施: Eszopiclone (Drug)
Placebo, then Dual-Therapy, then Single/Triple-Therapy
Subjects will start with a 3-day PLACEBO regimen:
- Day 1: Placebo (matching Acetazolamide 250mg) at bedtime at home.
- Day 2: Placebo (matching Acetazolamide 500mg) at bedtime at home.
- Day 3: Placebo (matching Acetazolamide 500mg + Eszopiclone 2mg) at bedtime in the sleep laboratory.
After a wash-out period of 4+ days, subjects will then cross-over to a 3-day EXPERIMENTAL DUAL-regimen:
- Day 1: Acetazolamide 250mg at bedtime at home.
- Day 2: Acetazolamide 500mg at bedtime at home.
- Day 3: Acetazolamide 500mg + Eszopiclone 2mg at bedtime in the sleep laboratory.
After a wash-out period of 4+ days, subjects will then undergo an OPEN-LABEL SINGLE/TRIPLE-regimen:
- Day 1: Acetazolamide 250mg at bedtime at home.
- Day 2: Acetazolamide 500mg at bedtime at home.
- Day 3: Acetazolamide 500mg alone or Acetazolamide 500mg + Eszopiclone 2mg + Venlafaxine 50mg at bedtime in the sleep laboratory, if sleep apnea resolved or did not resolve with the dual regimen, respectively.
干预措施: Placebo (Drug)
Placebo, then Dual-Therapy, then Single/Triple-Therapy
Subjects will start with a 3-day PLACEBO regimen:
- Day 1: Placebo (matching Acetazolamide 250mg) at bedtime at home.
- Day 2: Placebo (matching Acetazolamide 500mg) at bedtime at home.
- Day 3: Placebo (matching Acetazolamide 500mg + Eszopiclone 2mg) at bedtime in the sleep laboratory.
After a wash-out period of 4+ days, subjects will then cross-over to a 3-day EXPERIMENTAL DUAL-regimen:
- Day 1: Acetazolamide 250mg at bedtime at home.
- Day 2: Acetazolamide 500mg at bedtime at home.
- Day 3: Acetazolamide 500mg + Eszopiclone 2mg at bedtime in the sleep laboratory.
After a wash-out period of 4+ days, subjects will then undergo an OPEN-LABEL SINGLE/TRIPLE-regimen:
- Day 1: Acetazolamide 250mg at bedtime at home.
- Day 2: Acetazolamide 500mg at bedtime at home.
- Day 3: Acetazolamide 500mg alone or Acetazolamide 500mg + Eszopiclone 2mg + Venlafaxine 50mg at bedtime in the sleep laboratory, if sleep apnea resolved or did not resolve with the dual regimen, respectively.
干预措施: Venlafaxine (Drug)
Dual-Therapy, then Placebo, then Single/Triple-Therapy
Subjects will start with a 3-day EXPERIMENTAL DUAL-regimen:
- Day 1: Acetazolamide 250mg at bedtime at home.
- Day 2: Acetazolamide 500mg at bedtime at home.
- Day 3: Acetazolamide 500mg + Eszopiclone 2mg at bedtime in the sleep laboratory.
After a wash-out period of 4+ days, subjects will then cross-over to a 3-day PLACEBO regimen:
- Day 1: Placebo (matching Acetazolamide 250mg) at bedtime at home.
- Day 2: Placebo (matching Acetazolamide 500mg) at bedtime at home.
- Day 3: Placebo (matching Acetazolamide 500mg + Eszopiclone 2mg) at bedtime in the sleep laboratory.
After a wash-out period of 4+ days, subjects will then undergo an OPEN-LABEL SINGLE/TRIPLE-regimen:
- Day 1: Acetazolamide 250mg at bedtime at home.
- Day 2: Acetazolamide 500mg at bedtime at home.
- Day 3: Acetazolamide 500mg alone or Acetazolamide 500mg + Eszopiclone 2mg + Venlafaxine 50mg at bedtime in the sleep laboratory, if sleep apnea resolved or did not resolve with the dual regimen, respectively.
干预措施: Acetazolamide (Drug)
Dual-Therapy, then Placebo, then Single/Triple-Therapy
Subjects will start with a 3-day EXPERIMENTAL DUAL-regimen:
- Day 1: Acetazolamide 250mg at bedtime at home.
- Day 2: Acetazolamide 500mg at bedtime at home.
- Day 3: Acetazolamide 500mg + Eszopiclone 2mg at bedtime in the sleep laboratory.
After a wash-out period of 4+ days, subjects will then cross-over to a 3-day PLACEBO regimen:
- Day 1: Placebo (matching Acetazolamide 250mg) at bedtime at home.
- Day 2: Placebo (matching Acetazolamide 500mg) at bedtime at home.
- Day 3: Placebo (matching Acetazolamide 500mg + Eszopiclone 2mg) at bedtime in the sleep laboratory.
After a wash-out period of 4+ days, subjects will then undergo an OPEN-LABEL SINGLE/TRIPLE-regimen:
- Day 1: Acetazolamide 250mg at bedtime at home.
- Day 2: Acetazolamide 500mg at bedtime at home.
- Day 3: Acetazolamide 500mg alone or Acetazolamide 500mg + Eszopiclone 2mg + Venlafaxine 50mg at bedtime in the sleep laboratory, if sleep apnea resolved or did not resolve with the dual regimen, respectively.
干预措施: Eszopiclone (Drug)
Dual-Therapy, then Placebo, then Single/Triple-Therapy
Subjects will start with a 3-day EXPERIMENTAL DUAL-regimen:
- Day 1: Acetazolamide 250mg at bedtime at home.
- Day 2: Acetazolamide 500mg at bedtime at home.
- Day 3: Acetazolamide 500mg + Eszopiclone 2mg at bedtime in the sleep laboratory.
After a wash-out period of 4+ days, subjects will then cross-over to a 3-day PLACEBO regimen:
- Day 1: Placebo (matching Acetazolamide 250mg) at bedtime at home.
- Day 2: Placebo (matching Acetazolamide 500mg) at bedtime at home.
- Day 3: Placebo (matching Acetazolamide 500mg + Eszopiclone 2mg) at bedtime in the sleep laboratory.
After a wash-out period of 4+ days, subjects will then undergo an OPEN-LABEL SINGLE/TRIPLE-regimen:
- Day 1: Acetazolamide 250mg at bedtime at home.
- Day 2: Acetazolamide 500mg at bedtime at home.
- Day 3: Acetazolamide 500mg alone or Acetazolamide 500mg + Eszopiclone 2mg + Venlafaxine 50mg at bedtime in the sleep laboratory, if sleep apnea resolved or did not resolve with the dual regimen, respectively.
干预措施: Placebo (Drug)
Dual-Therapy, then Placebo, then Single/Triple-Therapy
Subjects will start with a 3-day EXPERIMENTAL DUAL-regimen:
- Day 1: Acetazolamide 250mg at bedtime at home.
- Day 2: Acetazolamide 500mg at bedtime at home.
- Day 3: Acetazolamide 500mg + Eszopiclone 2mg at bedtime in the sleep laboratory.
After a wash-out period of 4+ days, subjects will then cross-over to a 3-day PLACEBO regimen:
- Day 1: Placebo (matching Acetazolamide 250mg) at bedtime at home.
- Day 2: Placebo (matching Acetazolamide 500mg) at bedtime at home.
- Day 3: Placebo (matching Acetazolamide 500mg + Eszopiclone 2mg) at bedtime in the sleep laboratory.
After a wash-out period of 4+ days, subjects will then undergo an OPEN-LABEL SINGLE/TRIPLE-regimen:
- Day 1: Acetazolamide 250mg at bedtime at home.
- Day 2: Acetazolamide 500mg at bedtime at home.
- Day 3: Acetazolamide 500mg alone or Acetazolamide 500mg + Eszopiclone 2mg + Venlafaxine 50mg at bedtime in the sleep laboratory, if sleep apnea resolved or did not resolve with the dual regimen, respectively.
干预措施: Venlafaxine (Drug)
结局指标
主要结局
Apnea Hypopnea Index (AHI)
时间窗: 3 nights
The AHI is a measure of sleep apnea severity and based on the American Academy of Sleep Medicine (AASM)-recommended criteria is defined as the number of apneas (no breathing for 10+ seconds) and hypopneas (reduced breathing for 10+ seconds associated with a \>=3% desaturation or cortical arousal) per hour of sleep. To avoid confounding by sleep stages and positions across study nights the primary focus was on the AHI during supine non rapid eye movement (NREM) sleep. For comparability with other studies, we also explored the AASM-acceptable "AHI4", which defines hypopneas as reduced breathing for 10+ seconds associated with a \>=4% desaturation.
次要结局
- Pathophysiological Traits: Vpassive, Vactive, Arousal Threshold(3 nights)
- Psychomotor Vigilance: Response Speed(3 nights)
- SpO2 Nadir(3 nights)
- Pathophysiological Trait: Loop Gain(3 nights)
- Percent Responders(3 nights)
- Blood Pressure(3 nights)
- Subjective Sleepiness: Stanford Sleepiness Scale (SSS)(3 nights)
- Psychomotor Vigilance: Lapses(3 nights)
- Sleep Quality: PROMIS (Patient-Reported Outcomes Measurement Information System) Sleep Disturbance(3 nights)
研究者
Christopher Schmickl
Assistant Professor
University of California, San Diego