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

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ClinicalTrials.gov Identifier: NCT04639193
Recruitment Status : Recruiting
First Posted : November 20, 2020
Last Update Posted : August 23, 2021
Sponsor:
Information provided by (Responsible Party):
Christopher Schmickl, University of California, San Diego

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
OSA Obstructive Sleep Apnea Drug: Acetazolamide Drug: Eszopiclone Drug: Placebo Drug: Venlafaxine 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).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: 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 : January 1, 2020
Estimated Primary Completion Date : December 1, 2022
Estimated Study Completion Date : December 1, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Sleep Apnea

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 Name: Diamox

Drug: Eszopiclone
Eszopiclone tablet (encapsulated)
Other Name: Lunesta

Drug: Placebo
Sugar capsule manufactured to match encapsulated Acetazolamide/Eszopiclone

Drug: Venlafaxine
Venlafaxine capsule
Other Name: 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 Name: Diamox

Drug: Eszopiclone
Eszopiclone tablet (encapsulated)
Other Name: Lunesta

Drug: Placebo
Sugar capsule manufactured to match encapsulated Acetazolamide/Eszopiclone

Drug: Venlafaxine
Venlafaxine capsule
Other Name: Effexor




Primary Outcome Measures :
  1. Apnea Hypopnea Index (AHI) during supine Non-Rapid Eye Movement (NREM) sleep [ Time Frame: 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 [ Time Frame: 3 nights ]
    The lowest measured blood oxygen saturation during the overnight sleep study measured in percent.

  2. Pathophysiological Traits [ Time Frame: 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 [ Time Frame: 3 nights ]
    Responders will be defined as a drop in AHI>50% to <10/h.

  4. Subjective Sleepiness: Stanford Sleepiness Scale (SSS) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 3 nights ]
    Systolic/Diastolic Blood Pressure (measured at rest in the morning following the overnight sleep study).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • BMI 18-35 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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04639193


Contacts
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Contact: Pamela DeYoung, RPSGT 8582462183 pdeyoung@health.ucsd.edu

Locations
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United States, California
Altman Clinical and Translational Research Institute Building Recruiting
La Jolla, California, United States, 92037
Contact: Pamela DeYoung, RPSGT    858-246-2183    pdeyoung@health.ucsd.edu   
Contact: Dillon Gilbertson, MS    8582462155    dcgilbertson@health.ucsd.edu   
UCSD Health - Pulmonary and Sleep Clinic Recruiting
La Jolla, California, United States, 92121
Contact: Pamela DeYoung, RPSGT    858-246-2183    pdeyoung@health.ucsd.edu   
Sponsors and Collaborators
University of California, San Diego
Investigators
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Principal Investigator: Christopher Schmickl, MD, PhD Associate Physician and Postdoctoral Fellow
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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: November 20, 2020    Key Record Dates
Last Update Posted: August 23, 2021
Last Verified: August 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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, University of California, San Diego:
sleep
drug
Additional relevant MeSH terms:
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Sleep Apnea Syndromes
Sleep Apnea, Obstructive
Apnea
Respiration Disorders
Respiratory Tract Diseases
Sleep Disorders, Intrinsic
Dyssomnias
Sleep Wake Disorders
Nervous System Diseases
Acetazolamide
Eszopiclone
Venlafaxine Hydrochloride
Serotonin and Noradrenaline Reuptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Physiological Effects of Drugs
Antidepressive Agents, Second-Generation
Antidepressive Agents
Psychotropic Drugs
Anticonvulsants
Carbonic Anhydrase Inhibitors
Enzyme Inhibitors
Diuretics
Natriuretic Agents
Hypnotics and Sedatives
Central Nervous System Depressants