Clinical trial NCT04639193: Combination Drug-Therapy for Patients With Untreated Obstructive Sleep Apnea
Official title: Rescuing OSA Patients Unable to Tolerate CPAP Using Endotype-Targeted Combination Drug Therapy: a Randomized, Double-Blind, Placebo-Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: OSA
Obstructive Sleep Apnea
Keywords: sleep
drug
Lead sponsor: University of California, San Diego
Sponsor class: OTHER
Collaborators: name: American Thoracic Society
First posted: 2020-11-20
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Randomized, double-blind, placebo-controlled, cross-over trial.
Primary purpose: TREATMENT

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).

Eligibility criteria: 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).

Primary outcomes:
measure: Apnea Hypopnea Index (AHI)
timeFrame: 3 nights
Secondary outcomes:
measure: SpO2 Nadir
timeFrame: 3 nights
measure: Pathophysiological Traits: Vpassive, Vactive, Arousal Threshold
timeFrame: 3 nights
measure: Pathophysiological Trait: Loop Gain
timeFrame: 3 nights
measure: Percent Responders
timeFrame: 3 nights
measure: Blood Pressure
timeFrame: 3 nights
measure: Subjective Sleepiness: Stanford Sleepiness Scale (SSS)
timeFrame: 3 nights
measure: Sleep Quality: PROMIS (Patient-Reported Outcomes Measurement Information System) Sleep Disturbance
timeFrame: 3 nights
measure: Psychomotor Vigilance: Response Speed
timeFrame: 3 nights
measure: Psychomotor Vigilance: Lapses
timeFrame: 3 nights
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: Altman Clinical and Translational Research Institute Building
state: California
city: La Jolla
country: United States
facility: UCSD Health - Pulmonary and Sleep Clinic
state: California
Study officials:
affiliation: Associate Physician and Postdoctoral Fellow
name: Christopher Schmickl, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: