Combination Drug-Therapy for Patients With Untreated Obstructive Sleep Apnea

NCT04639193 | Completed Phase 2 Results FDA Drug

• 1 other identifier: 191990
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 2

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.

Conditions

OSA; Obstructive Sleep Apnea

Keywords

sleep; drug

Outcome Measures

Primary Outcomes (1)

• Apnea Hypopnea Index (AHI)

  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 Outcomes (9)

• SpO2 Nadir

  3 nights

• Pathophysiological Traits: Vpassive, Vactive, Arousal Threshold

  3 nights

• Pathophysiological Trait: Loop Gain

  3 nights

• Percent Responders

  3 nights

• Blood Pressure

  3 nights

Study Arms (2)

Placebo, then Dual-Therapy, then Single/Triple-Therapy

EXPERIMENTAL

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; Drug: Eszopiclone; Drug: Placebo; Drug: Venlafaxine

Dual-Therapy, then Placebo, then Single/Triple-Therapy

EXPERIMENTAL

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; Drug: Eszopiclone; Drug: Placebo; Drug: Venlafaxine

Interventions

Acetazolamide DRUG

Acetazolamide tablet (encapsulated)

Also known as: Diamox

Dual-Therapy, then Placebo, then Single/Triple-Therapy; Placebo, then Dual-Therapy, then Single/Triple-Therapy

Eszopiclone DRUG

Eszopiclone tablet (encapsulated)

Also known as: Lunesta

Dual-Therapy, then Placebo, then Single/Triple-Therapy; Placebo, then Dual-Therapy, then Single/Triple-Therapy

Placebo DRUG

Sugar capsule manufactured to match encapsulated Acetazolamide/Eszopiclone

Dual-Therapy, then Placebo, then Single/Triple-Therapy; Placebo, then Dual-Therapy, then Single/Triple-Therapy

Venlafaxine DRUG

Venlafaxine capsule

Also known as: Effexor

Dual-Therapy, then Placebo, then Single/Triple-Therapy; Placebo, then Dual-Therapy, then Single/Triple-Therapy

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.)

Sponsors & Collaborators

• University of California, San Diego: lead
• American Thoracic Society: collaborator

Study Sites (2)

Altman Clinical and Translational Research Institute Building

La Jolla, California, 92037, United States

Location

UCSD Health - Pulmonary and Sleep Clinic

La Jolla, California, 92121, United States

Location

Related Publications (1)

• 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.

  PMID: 39514000 DERIVED

MeSH Terms

Conditions

Sleep Apnea, Obstructive

Interventions

Acetazolamide; Eszopiclone; Venlafaxine Hydrochloride

Condition Hierarchy (Ancestors)

Sleep Apnea Syndromes; Apnea; Respiration Disorders; Respiratory Tract Diseases; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Thiadiazoles; Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Piperazines; Pyrazines; Pyridines; Cyclohexanols; Hexanols; Fatty Alcohols; Alcohols; Phenethylamines; Ethylamines; Amines; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Lipids

Results Point of Contact

• Title: Dr Chris Schmickl
• Organization: University of California San Diego

cschmickl@health.ucsd.edu

8582462154

Study Officials

• Christopher Schmickl, MD, PhD

  Associate Physician and Postdoctoral Fellow

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Model Details: Randomized, double-blind, placebo-controlled, cross-over trial.

Study Record Dates

• First Submitted: November 12, 2020
• First Posted: November 20, 2020
• Study Start: December 1, 2020
• Primary Completion: January 27, 2022
• Study Completion: January 27, 2022
• Last Updated: May 29, 2024
• Results First Posted: May 2, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)