Combination Drug-Therapy for Patients With Untreated Obstructive Sleep Apnea

Obstructive Sleep Apnea Clinical Trial

— RESCUE-Combo  

Official title:

Rescuing OSA Patients Unable to Tolerate CPAP Using Endotype-Targeted Combination Drug Therapy: a Randomized, Double-Blind, Placebo-Controlled Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04639193
• Other study ID #: 191990
• Status: Completed
• Phase: Phase 2
• Start date: December 1, 2020
• Est. completion date: January 27, 2022

Study information

• Verified date: May 2024
• Source: University of California, San Diego
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: January 27, 2022
• Est. primary completion date: January 27, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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).

Related Conditions & MeSH terms

• Obstructive Sleep Apnea
• OSA
• Sleep Apnea Syndromes
• Sleep Apnea, Obstructive

Intervention

Drug:
• Acetazolamide
Acetazolamide tablet (encapsulated)
• Eszopiclone
Eszopiclone tablet (encapsulated)
• Placebo
Sugar capsule manufactured to match encapsulated Acetazolamide/Eszopiclone
• Venlafaxine
Venlafaxine capsule

Locations

Country	Name	City	State
United States	Altman Clinical and Translational Research Institute Building	La Jolla	California
United States	UCSD Health - Pulmonary and Sleep Clinic	La Jolla	California

Sponsors (2)

Lead Sponsor	Collaborator
University of California, San Diego	American Thoracic Society

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	SpO2 Nadir	The lowest measured blood oxygen saturation during the overnight sleep study measured in percent.	3 nights
Secondary	Pathophysiological Traits: Vpassive, Vactive, Arousal Threshold	Pathophysiological traits were quantified as %Veupnea from polysomnography data using a validated algorithm.	3 nights
Secondary	Pathophysiological Trait: Loop Gain	Loop Gain 1 was quantified from polysomnography data using a validated algorithm. This metric measures the increase in respiratory drive relative to a preceding drop in ventilation and thus is dimensionless (typical range is approximately 0.2 to 1.5, with values >0.7 being considered high loop gain, indicating ventilatory instability)	3 nights
Secondary	Percent Responders	Full responders were defined as a drop in AHI>50% to <10/h.	3 nights
Secondary	Blood Pressure	Systolic/Diastolic Blood Pressure (measured at rest in the morning following the overnight sleep study).	3 nights
Secondary	Subjective Sleepiness: Stanford Sleepiness Scale (SSS)	Subjective sleepiness was 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.	3 nights
Secondary	Sleep Quality: PROMIS (Patient-Reported Outcomes Measurement Information System) Sleep Disturbance	Sleep quality was assessed based on a modified 8-question PROMIS Sleep Disturbance (SDA 8b) 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.	3 nights
Secondary	Psychomotor Vigilance: Response Speed	Vigilance was assessed using the 10-minute psychomotor vigilance test (PVT) in the morning following the overnight sleep study. Primary focus was on "response speed" 1/reaction time (1/RT) and lapses (reaction time >500ms).	3 nights
Secondary	Psychomotor Vigilance: Lapses	Vigilance was assessed using the 10-minute psychomotor vigilance test (PVT) in the morning following the overnight sleep study. Primary focus was on "response speed" 1/reaction time (1/RT) and lapses (reaction time >500ms).	3 nights