Combination Drug-Therapy for Patients With Untreated Obstructive Sleep Apnea

NCT ID: NCT04639193

Last Updated: 2024-05-29

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 20 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-12-01
• Study Completion Date: 2022-01-27

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).

Conditions

OSA; Obstructive Sleep Apnea

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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.

Group Type: EXPERIMENTAL

Acetazolamide

Intervention Type: DRUG

Acetazolamide tablet (encapsulated)

Eszopiclone

Intervention Type: DRUG

Eszopiclone tablet (encapsulated)

Placebo

Intervention Type: DRUG

Sugar capsule manufactured to match encapsulated Acetazolamide/Eszopiclone

Venlafaxine

Intervention Type: DRUG

Venlafaxine capsule

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.

Group Type: EXPERIMENTAL

Acetazolamide

Intervention Type: DRUG

Acetazolamide tablet (encapsulated)

Eszopiclone

Intervention Type: DRUG

Eszopiclone tablet (encapsulated)

Placebo

Intervention Type: DRUG

Sugar capsule manufactured to match encapsulated Acetazolamide/Eszopiclone

Venlafaxine

Intervention Type: DRUG

Venlafaxine capsule

Interventions

Acetazolamide

Acetazolamide tablet (encapsulated)

Intervention Type: DRUG

Eszopiclone

Eszopiclone tablet (encapsulated)

Intervention Type: DRUG

Placebo

Sugar capsule manufactured to match encapsulated Acetazolamide/Eszopiclone

Intervention Type: DRUG

Venlafaxine

Venlafaxine capsule

Intervention Type: DRUG

Other Intervention Names

Diamox; Lunesta; Effexor

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).

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

American Thoracic Society

OTHER

Sponsor Role: collaborator

University of California, San Diego

OTHER

Sponsor Role: lead

Responsible Party

Christopher Schmickl

Assistant Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Christopher Schmickl, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Associate Physician and Postdoctoral Fellow

Locations

Altman Clinical and Translational Research Institute Building

La Jolla, California, United States

UCSD Health - Pulmonary and Sleep Clinic

La Jolla, California, United States

Countries

United States

References

Schmickl CN, Orr JE, Alex RM, Gruenberg E, Parra G, White S, Spenceley A, DeSarkar T, Kong M, DeYoung PN, Sands SA, Owens RL, Malhotra A. Combination Drug Therapy with Acetazolamide, Eszopiclone +/- Venlafaxine for Obstructive Sleep Apnea (RESCUE-Combo): A Randomized, Double-Blind, Placebo-controlled Clinical Trial. Ann Am Thorac Soc. 2025 Feb;22(2):263-273. doi: 10.1513/AnnalsATS.202407-736OC.

Reference Type: DERIVED

PMID: 39514000 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

191990

Identifier Type: -

Identifier Source: org_study_id