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

Primary Purpose

OSA, Obstructive Sleep Apnea

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Acetazolamide
Eszopiclone
Placebo
Venlafaxine
Sponsored by
University of California, San Diego
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for OSA focused on measuring sleep, drug

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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).

Sites / Locations

  • Altman Clinical and Translational Research Institute BuildingRecruiting
  • UCSD Health - Pulmonary and Sleep ClinicRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

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

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

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Apnea Hypopnea Index (AHI) during supine Non-Rapid Eye Movement (NREM) sleep
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

SpO2 Nadir
The lowest measured blood oxygen saturation during the overnight sleep study measured in percent.
Pathophysiological Traits
Changes in pathophysiological traits (Vpassive, Vactive, Arousal Threshold, Loop Gain) will be quantified as %Veupnea from polysomnography data using a validated algorithm.
Percent Responders
Responders will be defined as a drop in AHI>50% to <10/h.
Subjective Sleepiness: Stanford Sleepiness Scale (SSS)
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.
Vigilance
Vigilance will be assessed using the 5-minute psychomotor vigilance test (PVT) in the morning following the overnight sleep study.
Sleep Quality: PROMIS (Patient-Reported Outcomes Measurement Information System) Sleep Disturbance
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.
Blood Pressure
Systolic/Diastolic Blood Pressure (measured at rest in the morning following the overnight sleep study).

Full Information

First Posted
November 12, 2020
Last Updated
September 22, 2021
Sponsor
University of California, San Diego
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1. Study Identification

Unique Protocol Identification Number
NCT04639193
Brief Title
Combination Drug-Therapy for Patients With Untreated Obstructive Sleep Apnea
Acronym
RESCUE-Combo
Official Title
Rescuing OSA Patients Unable to Tolerate CPAP Using Endotype-Targeted Combination Drug Therapy: a Randomized, Double-Blind, Placebo-Controlled Trial
Study Type
Interventional

2. Study Status

Record Verification Date
September 2021
Overall Recruitment Status
Recruiting
Study Start Date
January 1, 2020 (Actual)
Primary Completion Date
December 1, 2022 (Anticipated)
Study Completion Date
December 1, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of California, San Diego

4. Oversight

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
Data Monitoring Committee
No

5. 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.
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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
OSA, Obstructive Sleep Apnea
Keywords
sleep, drug

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Model Description
Randomized, double-blind, placebo-controlled, cross-over trial.
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
20 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Placebo, then Dual-Therapy, then Single/Triple-Therapy
Arm Type
Experimental
Arm Description
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.
Arm Title
Dual-Therapy, then Placebo, then Single/Triple-Therapy
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Acetazolamide
Other Intervention Name(s)
Diamox
Intervention Description
Acetazolamide tablet (encapsulated)
Intervention Type
Drug
Intervention Name(s)
Eszopiclone
Other Intervention Name(s)
Lunesta
Intervention Description
Eszopiclone tablet (encapsulated)
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Sugar capsule manufactured to match encapsulated Acetazolamide/Eszopiclone
Intervention Type
Drug
Intervention Name(s)
Venlafaxine
Other Intervention Name(s)
Effexor
Intervention Description
Venlafaxine capsule
Primary Outcome Measure Information:
Title
Apnea Hypopnea Index (AHI) during supine Non-Rapid Eye Movement (NREM) sleep
Description
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.
Time Frame
3 nights
Secondary Outcome Measure Information:
Title
SpO2 Nadir
Description
The lowest measured blood oxygen saturation during the overnight sleep study measured in percent.
Time Frame
3 nights
Title
Pathophysiological Traits
Description
Changes in pathophysiological traits (Vpassive, Vactive, Arousal Threshold, Loop Gain) will be quantified as %Veupnea from polysomnography data using a validated algorithm.
Time Frame
3 nights
Title
Percent Responders
Description
Responders will be defined as a drop in AHI>50% to <10/h.
Time Frame
3 nights
Title
Subjective Sleepiness: Stanford Sleepiness Scale (SSS)
Description
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.
Time Frame
3 nights
Title
Vigilance
Description
Vigilance will be assessed using the 5-minute psychomotor vigilance test (PVT) in the morning following the overnight sleep study.
Time Frame
3 nights
Title
Sleep Quality: PROMIS (Patient-Reported Outcomes Measurement Information System) Sleep Disturbance
Description
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.
Time Frame
3 nights
Title
Blood Pressure
Description
Systolic/Diastolic Blood Pressure (measured at rest in the morning following the overnight sleep study).
Time Frame
3 nights

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
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).
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Pamela DeYoung, RPSGT
Phone
8582462183
Email
pdeyoung@health.ucsd.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Christopher Schmickl, MD, PhD
Organizational Affiliation
Associate Physician and Postdoctoral Fellow
Official's Role
Principal Investigator
Facility Information:
Facility Name
Altman Clinical and Translational Research Institute Building
City
La Jolla
State/Province
California
ZIP/Postal Code
92037
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Pamela DeYoung, RPSGT
Phone
858-246-2183
Email
pdeyoung@health.ucsd.edu
First Name & Middle Initial & Last Name & Degree
Dillon Gilbertson, MS
Phone
8582462155
Email
dcgilbertson@health.ucsd.edu
Facility Name
UCSD Health - Pulmonary and Sleep Clinic
City
La Jolla
State/Province
California
ZIP/Postal Code
92121
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Pamela DeYoung, RPSGT
Phone
858-246-2183
Email
pdeyoung@health.ucsd.edu

12. IPD Sharing Statement

Plan to Share IPD
No

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Combination Drug-Therapy for Patients With Untreated Obstructive Sleep Apnea

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