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

Sponsor
University of California, San Diego (Other)
Overall Status
Recruiting
CT.gov ID
NCT04639193
Collaborator
(none)
20
Enrollment
2
Locations
2
Arms
47
Anticipated Duration (Months)
10
Patients Per Site
0.2
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 2

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 Design

Study Type:
Interventional
Anticipated Enrollment :
20 participants
Allocation:
Randomized
Intervention Model:
Crossover Assignment
Intervention Model Description:
Randomized, double-blind, placebo-controlled, cross-over trial.Randomized, double-blind, placebo-controlled, cross-over trial.
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
Rescuing OSA Patients Unable to Tolerate CPAP Using Endotype-Targeted Combination Drug Therapy: a Randomized, Double-Blind, Placebo-Controlled Trial
Actual Study Start Date :
Jan 1, 2020
Anticipated Primary Completion Date :
Dec 1, 2022
Anticipated Study Completion Date :
Dec 1, 2023

Arms and Interventions

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

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Apnea Hypopnea Index (AHI) during supine Non-Rapid Eye Movement (NREM) sleep [3 nights]

      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.

    Secondary Outcome Measures

    1. SpO2 Nadir [3 nights]

      The lowest measured blood oxygen saturation during the overnight sleep study measured in percent.

    2. Pathophysiological Traits [3 nights]

      Changes in pathophysiological traits (Vpassive, Vactive, Arousal Threshold, Loop Gain) will be quantified as %Veupnea from polysomnography data using a validated algorithm.

    3. Percent Responders [3 nights]

      Responders will be defined as a drop in AHI>50% to <10/h.

    4. Subjective Sleepiness: Stanford Sleepiness Scale (SSS) [3 nights]

      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.

    5. Vigilance [3 nights]

      Vigilance will be assessed using the 5-minute psychomotor vigilance test (PVT) in the morning following the overnight sleep study.

    6. Sleep Quality: PROMIS (Patient-Reported Outcomes Measurement Information System) Sleep Disturbance [3 nights]

      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.

    7. Blood Pressure [3 nights]

      Systolic/Diastolic Blood Pressure (measured at rest in the morning following the overnight sleep study).

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 65 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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).

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Altman Clinical and Translational Research Institute Building La Jolla California United States 92037
    2 UCSD Health - Pulmonary and Sleep Clinic La Jolla California United States 92121

    Sponsors and Collaborators

    • University of California, San Diego

    Investigators

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

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Christopher Schmickl, Associate Physician & T32 Postdoctoral Fellow, University of California, San Diego
    ClinicalTrials.gov Identifier:
    NCT04639193
    Other Study ID Numbers:
    • 191990
    First Posted:
    Nov 20, 2020
    Last Update Posted:
    Sep 24, 2021
    Last Verified:
    Sep 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    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
    Keywords provided by Christopher Schmickl, Associate Physician & T32 Postdoctoral Fellow, University of California, San Diego
    sleep
    drug
    Additional relevant MeSH terms:
    Sleep Apnea Syndromes
    Sleep Apnea, Obstructive
    Acetazolamide
    Eszopiclone
    Venlafaxine Hydrochloride

    Study Results

    No Results Posted as of Sep 24, 2021