Combination Drug-Therapy for Patients With Untreated Obstructive Sleep Apnea (RESCUE-Combo)

Rescuing OSA Patients Unable to Tolerate CPAP Using Endotype-Targeted Combination Drug Therapy: a Randomized, Double-Blind, Placebo-Controlled Trial

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.

Study Overview

• Status: Recruiting
• Conditions: Obstructive Sleep Apnea; OSA
• Intervention / Treatment: Drug: Acetazolamide; Drug: Eszopiclone; Drug: Placebo; Drug: Venlafaxine

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).

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • La Jolla, California, United States, 92037
      • Recruiting
      • Altman Clinical and Translational Research Institute Building
      • Contact: Dillon Gilbertson, MS; Phone Number: 8582462155; Email: dcgilbertson@health.ucsd.edu
    • La Jolla, California, United States, 92121
      • Recruiting
      • UCSD Health - Pulmonary and Sleep Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Acetazolamide; Acetazolamide tablet (encapsulated); Other Names: Diamox; Drug: Eszopiclone; Eszopiclone tablet (encapsulated); Other Names: Lunesta; Drug: Placebo; Sugar capsule manufactured to match encapsulated Acetazolamide/Eszopiclone; Drug: Venlafaxine; Venlafaxine capsule; Other Names: Effexor
Experimental: 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.	Drug: Acetazolamide; Acetazolamide tablet (encapsulated); Other Names: Diamox; Drug: Eszopiclone; Eszopiclone tablet (encapsulated); Other Names: Lunesta; Drug: Placebo; Sugar capsule manufactured to match encapsulated Acetazolamide/Eszopiclone; Drug: Venlafaxine; Venlafaxine capsule; Other Names: Effexor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Apnea Hypopnea Index (AHI) during supine Non-Rapid Eye Movement (NREM) sleep	The AHI is a measure of sleep apnea severity and 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 we will focus on the AHI during supine NREM sleep.	3 nights

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
SpO2 Nadir	The lowest measured blood oxygen saturation during the overnight sleep study measured in percent.	3 nights
Pathophysiological Traits	Changes in pathophysiological traits (Vpassive, Vactive, Arousal Threshold, Loop Gain) will be quantified as %Veupnea from polysomnography data using a validated algorithm.	3 nights
Percent Responders	Responders will be defined as a drop in AHI>50% to <10/h.	3 nights
Subjective Sleepiness: Stanford Sleepiness Scale (SSS)	Subjective sleepiness will be 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.	3 nights
Vigilance	Vigilance will be assessed using the 5-minute psychomotor vigilance test (PVT) in the morning following the overnight sleep study.	3 nights
Sleep Quality: PROMIS (Patient-Reported Outcomes Measurement Information System) Sleep Disturbance	Sleep quality will be assessed based on a modified 8-question PROMIS Sleep Disturbance 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.	3 nights
Blood Pressure	Systolic/Diastolic Blood Pressure (measured at rest in the morning following the overnight sleep study).	3 nights

Collaborators and Investigators

• Sponsor: University of California, San Diego
• Investigators: Principal Investigator: Christopher Schmickl, MD, PhD, Associate Physician and Postdoctoral Fellow

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2020
• Primary Completion (Anticipated): December 1, 2022
• Study Completion (Anticipated): December 1, 2023

Study Registration Dates

• First Submitted: November 12, 2020
• First Submitted That Met QC Criteria: November 18, 2020
• First Posted (Actual): November 20, 2020

Study Record Updates

• Last Update Posted (Actual): September 24, 2021
• Last Update Submitted That Met QC Criteria: September 22, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: sleep; drug
• Additional Relevant MeSH Terms: Nervous System Diseases; Respiratory Tract Diseases; Apnea; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Carbonic Anhydrase Inhibitors; Natriuretic Agents; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Antidepressive Agents; Hypnotics and Sedatives; Diuretics; Anticonvulsants; Antidepressive Agents, Second-Generation; Serotonin and Noradrenaline Reuptake Inhibitors; Acetazolamide; Venlafaxine Hydrochloride; Eszopiclone
• Other Study ID Numbers: 191990

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No