Combination Drug-Therapy for Patients With Untreated Obstructive Sleep Apnea

Phase 2

Completed

Conditions: OSA
Obstructive Sleep Apnea

Interventions: Drug: Acetazolamide
Drug: Eszopiclone
Drug: Placebo
Drug: Venlafaxine

Registration Number: NCT04639193

Lead Sponsor: University of California, San Diego

Brief Summary: 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.

Detailed Description: 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).

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 20

Inclusion Criteria

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

Exclusion Criteria

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).

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Placebo, then Dual-Therapy, then Single/Triple-Therapy	Placebo	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.
Dual-Therapy, then Placebo, then Single/Triple-Therapy	Placebo	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.
Placebo, then Dual-Therapy, then Single/Triple-Therapy	Eszopiclone	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.
Placebo, then Dual-Therapy, then Single/Triple-Therapy	Acetazolamide	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.
Placebo, then Dual-Therapy, then Single/Triple-Therapy	Venlafaxine	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.
Dual-Therapy, then Placebo, then Single/Triple-Therapy	Eszopiclone	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.
Dual-Therapy, then Placebo, then Single/Triple-Therapy	Acetazolamide	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.
Dual-Therapy, then Placebo, then Single/Triple-Therapy	Venlafaxine	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.

Primary Outcome Measures

Name	Time	Method
Apnea Hypopnea Index (AHI)	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.

Secondary Outcome Measures

Name	Time	Method
Pathophysiological Traits: Vpassive, Vactive, Arousal Threshold	3 nights	Pathophysiological traits were quantified as %Veupnea from polysomnography data using a validated algorithm.
Psychomotor Vigilance: Response Speed	3 nights	Vigilance was assessed using the 10-minute psychomotor vigilance test (PVT) in the morning following the overnight sleep study. Primary focus was on "response speed" 1/reaction time (1/RT) and lapses (reaction time \>500ms).
SpO2 Nadir	3 nights	The lowest measured blood oxygen saturation during the overnight sleep study measured in percent.
Pathophysiological Trait: Loop Gain	3 nights	Loop Gain 1 was quantified from polysomnography data using a validated algorithm. This metric measures the increase in respiratory drive relative to a preceding drop in ventilation and thus is dimensionless (typical range is approximately 0.2 to 1.5, with values \>0.7 being considered high loop gain, indicating ventilatory instability)
Percent Responders	3 nights	Full responders were defined as a drop in AHI\>50% to \<10/h.
Blood Pressure	3 nights	Systolic/Diastolic Blood Pressure (measured at rest in the morning following the overnight sleep study).
Subjective Sleepiness: Stanford Sleepiness Scale (SSS)	3 nights	Subjective sleepiness was assessed using the Stanford Sleepiness Scale (SSS) in the morning following the overnight sleep study. The score ranges from 1 to 7, with greater values indicating more sleepiness.
Psychomotor Vigilance: Lapses	3 nights	Vigilance was assessed using the 10-minute psychomotor vigilance test (PVT) in the morning following the overnight sleep study. Primary focus was on "response speed" 1/reaction time (1/RT) and lapses (reaction time \>500ms).
Sleep Quality: PROMIS (Patient-Reported Outcomes Measurement Information System) Sleep Disturbance	3 nights	Sleep quality was assessed based on a modified 8-question PROMIS Sleep Disturbance (SDA 8b) questionnaire in the morning following the overnight sleep study. The raw score ranges from 8 to 40 and is translated into a T-score, a standardized score with a mean of 50 and a standard deviation of 10. Greater T-scores indicate greater sleep disturbance.

Trial Locations

Locations (2): Altman Clinical and Translational Research Institute Building
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La Jolla, California, United States
UCSD Health - Pulmonary and Sleep Clinic
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La Jolla, California, United States