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

May 1, 2024 updated by: Christopher Schmickl, University of California, San Diego

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

Completed

Conditions

Intervention / Treatment

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 (Actual)

20

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • La Jolla, California, United States, 92037
        • Altman Clinical and Translational Research Institute Building
      • La Jolla, California, United States, 92121
        • UCSD Health - Pulmonary and Sleep Clinic

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

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)
Time Frame: 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.
3 nights

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
SpO2 Nadir
Time Frame: 3 nights
The lowest measured blood oxygen saturation during the overnight sleep study measured in percent.
3 nights
Blood Pressure
Time Frame: 3 nights
Systolic/Diastolic Blood Pressure (measured at rest in the morning following the overnight sleep study).
3 nights
Pathophysiological Traits: Vpassive, Vactive, Arousal Threshold
Time Frame: 3 nights
Pathophysiological traits were quantified as %Veupnea from polysomnography data using a validated algorithm.
3 nights
Percent Responders
Time Frame: 3 nights
Full responders were defined as a drop in AHI>50% to <10/h.
3 nights
Subjective Sleepiness: Stanford Sleepiness Scale (SSS)
Time Frame: 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.
3 nights
Sleep Quality: PROMIS (Patient-Reported Outcomes Measurement Information System) Sleep Disturbance
Time Frame: 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.
3 nights
Pathophysiological Trait: Loop Gain
Time Frame: 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)
3 nights
Psychomotor Vigilance: Response Speed
Time Frame: 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).
3 nights
Psychomotor Vigilance: Lapses
Time Frame: 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).
3 nights

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of California, San Diego

Collaborators

American Thoracic Society

Investigators

  • Principal Investigator: Christopher Schmickl, MD, PhD, Associate Physician and Postdoctoral Fellow

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 1, 2020

Primary Completion (Actual)

January 27, 2022

Study Completion (Actual)

January 27, 2022

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)

May 29, 2024

Last Update Submitted That Met QC Criteria

May 1, 2024

Last Verified

May 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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