Obstructive Sleep Apnea, OSA
Conditions
Keywords
sleep, drug
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).
Interventions
DRUGAcetazolamide
Acetazolamide tablet (encapsulated)
DRUGEszopiclone
Eszopiclone tablet (encapsulated)
DRUGPlacebo
Sugar capsule manufactured to match encapsulated Acetazolamide/Eszopiclone
DRUGVenlafaxine
Venlafaxine capsule
Sponsors
American Thoracic Society
University of California, San Diego
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Randomized, double-blind, placebo-controlled, cross-over trial.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Apnea Hypopnea Index (AHI) | 3 nights | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pathophysiological Traits: Vpassive, Vactive, Arousal Threshold | 3 nights | Pathophysiological traits were quantified as %Veupnea from polysomnography data using a validated algorithm. |
| Pathophysiological Trait: Loop Gain | 3 nights | 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) |
| Percent Responders | 3 nights | Full responders were defined as a drop in AHI\>50% to \<10/h. |
| Blood Pressure | 3 nights | Systolic/Diastolic Blood Pressure (measured at rest in the morning following the overnight sleep study). |
| SpO2 Nadir | 3 nights | The lowest measured blood oxygen saturation during the overnight sleep study measured in percent. |
| Sleep Quality: PROMIS (Patient-Reported Outcomes Measurement Information System) Sleep Disturbance | 3 nights | 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. |
| Psychomotor Vigilance: Response Speed | 3 nights | 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). |
| Psychomotor Vigilance: Lapses | 3 nights | 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). |
| Subjective Sleepiness: Stanford Sleepiness Scale (SSS) | 3 nights | 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. |
Countries
United States
Participant flow
Pre-assignment details
Of 88 subjects who were assessed for eligibility, 20 were randomized. The other 68 were excluded due to not meeting eligibility criteria or not being interested.
Participants by arm
| Arm | Count |
|---|---|
| All Participants Who Were Enrolled Into the Trial All 20 participants who were randomized, completed the dual-therapy and placebo phases (blinded/random order) 18 of these 20 participants went on to also complete the the open label triple therapy phase | 20 |
| Total | 20 |
Baseline characteristics
| Characteristic | All Participants Who Were Enrolled Into the Trial |
|---|---|
| Age, Continuous | 49 years |
| Apnea Hypopnea Index (AHI) AHI4 (overall) | 21.8 events/hour of sleep |
| Apnea Hypopnea Index (AHI) AHI (overall) | 39.2 events/hour of sleep |
| Apnea Hypopnea Index (AHI) AHI (supine, NREM) | 32.8 events/hour of sleep |
| Body Mass Index | 29.1 kg/m^2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Pathophysiological Trait: Loop Gain | 0.56 dimensionless |
| Pathophysiological Traits: Vpassive, Vactive, Arousal Threshold Arousal Threshold, transformed | 142 % Veupnea |
| Pathophysiological Traits: Vpassive, Vactive, Arousal Threshold Vactive | 92.1 % Veupnea |
| Pathophysiological Traits: Vpassive, Vactive, Arousal Threshold Vpasssive, transformed | 69.9 % Veupnea |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 8 Participants |
| Region of Enrollment United States | 20 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 20 | 0 / 18 |
| other Total, other adverse events | 11 / 20 | 10 / 20 | 16 / 18 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 | 0 / 18 |
Outcome results
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.
Time frame: 3 nights
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dual-Therapy | Apnea Hypopnea Index (AHI) | AHI (overall) | 23.6 events/hour of sleep |
| Dual-Therapy | Apnea Hypopnea Index (AHI) | AHI (supine, NREM) | 17.1 events/hour of sleep |
| Dual-Therapy | Apnea Hypopnea Index (AHI) | AHI4 (overall) | 14.1 events/hour of sleep |
| Placebo | Apnea Hypopnea Index (AHI) | AHI (overall) | 37.4 events/hour of sleep |
| Placebo | Apnea Hypopnea Index (AHI) | AHI (supine, NREM) | 32.7 events/hour of sleep |
| Placebo | Apnea Hypopnea Index (AHI) | AHI4 (overall) | 20.3 events/hour of sleep |
| Triple-Therapy | Apnea Hypopnea Index (AHI) | AHI (supine, NREM) | 26 events/hour of sleep |
| Triple-Therapy | Apnea Hypopnea Index (AHI) | AHI4 (overall) | 9 events/hour of sleep |
| Triple-Therapy | Apnea Hypopnea Index (AHI) | AHI (overall) | 25.8 events/hour of sleep |
Secondary
Blood Pressure
Systolic/Diastolic Blood Pressure (measured at rest in the morning following the overnight sleep study).
Time frame: 3 nights
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dual-Therapy | Blood Pressure | Systolic Blood Pressure | 112.5 mmHg |
| Dual-Therapy | Blood Pressure | Diastolic Blood Pressure | 72 mmHg |
| Placebo | Blood Pressure | Systolic Blood Pressure | 116.5 mmHg |
| Placebo | Blood Pressure | Diastolic Blood Pressure | 74 mmHg |
| Triple-Therapy | Blood Pressure | Systolic Blood Pressure | 116 mmHg |
| Triple-Therapy | Blood Pressure | Diastolic Blood Pressure | 70.5 mmHg |
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)
Time frame: 3 nights
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dual-Therapy | Pathophysiological Trait: Loop Gain | 0.54 dimensionless |
| Placebo | Pathophysiological Trait: Loop Gain | 0.57 dimensionless |
| Triple-Therapy | Pathophysiological Trait: Loop Gain | 0.49 dimensionless |
Secondary
Pathophysiological Traits: Vpassive, Vactive, Arousal Threshold
Pathophysiological traits were quantified as %Veupnea from polysomnography data using a validated algorithm.
Time frame: 3 nights
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dual-Therapy | Pathophysiological Traits: Vpassive, Vactive, Arousal Threshold | Vactive | 96.2 % Veupnea |
| Dual-Therapy | Pathophysiological Traits: Vpassive, Vactive, Arousal Threshold | Vpasssive, transformed | 69.5 % Veupnea |
| Dual-Therapy | Pathophysiological Traits: Vpassive, Vactive, Arousal Threshold | Arousal Threshold, transformed | 140.1 % Veupnea |
| Placebo | Pathophysiological Traits: Vpassive, Vactive, Arousal Threshold | Vactive | 92.1 % Veupnea |
| Placebo | Pathophysiological Traits: Vpassive, Vactive, Arousal Threshold | Vpasssive, transformed | 67.4 % Veupnea |
| Placebo | Pathophysiological Traits: Vpassive, Vactive, Arousal Threshold | Arousal Threshold, transformed | 149.8 % Veupnea |
| Triple-Therapy | Pathophysiological Traits: Vpassive, Vactive, Arousal Threshold | Vpasssive, transformed | 70.4 % Veupnea |
| Triple-Therapy | Pathophysiological Traits: Vpassive, Vactive, Arousal Threshold | Arousal Threshold, transformed | 137.2 % Veupnea |
| Triple-Therapy | Pathophysiological Traits: Vpassive, Vactive, Arousal Threshold | Vactive | 94.4 % Veupnea |
Secondary
Percent Responders
Full responders were defined as a drop in AHI\>50% to \<10/h.
Time frame: 3 nights
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dual-Therapy | Percent Responders | Based on AHI in supine NREM sleep | 5 Participants |
| Dual-Therapy | Percent Responders | Based on AHI overall | 1 Participants |
| Placebo | Percent Responders | Based on AHI in supine NREM sleep | 0 Participants |
| Placebo | Percent Responders | Based on AHI overall | 1 Participants |
| Triple-Therapy | Percent Responders | Based on AHI in supine NREM sleep | 4 Participants |
| Triple-Therapy | Percent Responders | Based on AHI overall | 4 Participants |
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).
Time frame: 3 nights
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dual-Therapy | Psychomotor Vigilance: Lapses | 3 Number of lapses |
| Placebo | Psychomotor Vigilance: Lapses | 3 Number of lapses |
| Triple-Therapy | Psychomotor Vigilance: Lapses | 5 Number of lapses |
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).
Time frame: 3 nights
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dual-Therapy | Psychomotor Vigilance: Response Speed | 3 1/seconds |
| Placebo | Psychomotor Vigilance: Response Speed | 3.1 1/seconds |
| Triple-Therapy | Psychomotor Vigilance: Response Speed | 2.9 1/seconds |
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.
Time frame: 3 nights
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dual-Therapy | Sleep Quality: PROMIS (Patient-Reported Outcomes Measurement Information System) Sleep Disturbance | 53 t-score |
| Placebo | Sleep Quality: PROMIS (Patient-Reported Outcomes Measurement Information System) Sleep Disturbance | 53.9 t-score |
| Triple-Therapy | Sleep Quality: PROMIS (Patient-Reported Outcomes Measurement Information System) Sleep Disturbance | 53 t-score |
Secondary
SpO2 Nadir
The lowest measured blood oxygen saturation during the overnight sleep study measured in percent.
Time frame: 3 nights
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dual-Therapy | SpO2 Nadir | 83.5 Percent Oxygen Saturation |
| Placebo | SpO2 Nadir | 84 Percent Oxygen Saturation |
| Triple-Therapy | SpO2 Nadir | 86 Percent Oxygen Saturation |
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.
Time frame: 3 nights
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dual-Therapy | Subjective Sleepiness: Stanford Sleepiness Scale (SSS) | 2 units on a scale |
| Placebo | Subjective Sleepiness: Stanford Sleepiness Scale (SSS) | 2 units on a scale |
| Triple-Therapy | Subjective Sleepiness: Stanford Sleepiness Scale (SSS) | 2 units on a scale |