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| Name | Class |
|---|---|
| American Thoracic Society | OTHER |
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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.
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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Placebo, then Dual-Therapy, then Single/Triple-Therapy | Experimental | Subjects will start with a 3-day PLACEBO regimen:
After a wash-out period of 4+ days, subjects will then cross-over to a 3-day EXPERIMENTAL DUAL-regimen:
After a wash-out period of 4+ days, subjects will then undergo an OPEN-LABEL SINGLE/TRIPLE-regimen:
|
|
| Dual-Therapy, then Placebo, then Single/Triple-Therapy | Experimental | Subjects will start with a 3-day EXPERIMENTAL DUAL-regimen:
After a wash-out period of 4+ days, subjects will then cross-over to a 3-day PLACEBO regimen:
After a wash-out period of 4+ days, subjects will then undergo an OPEN-LABEL SINGLE/TRIPLE-regimen:
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Acetazolamide | Drug | Acetazolamide tablet (encapsulated) |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| SpO2 Nadir | The lowest measured blood oxygen saturation during the overnight sleep study measured in percent. | 3 nights |
| Pathophysiological Traits: Vpassive, Vactive, Arousal Threshold | Pathophysiological traits were quantified as %Veupnea from polysomnography data using a validated algorithm. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Christopher Schmickl, MD, PhD | Associate Physician and Postdoctoral Fellow | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Altman Clinical and Translational Research Institute Building | La Jolla | California | 92037 | United States | ||
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 39514000 | Derived | Schmickl CN, Orr JE, Alex RM, Gruenberg E, Parra G, White S, Spenceley A, DeSarkar T, Kong M, DeYoung PN, Sands SA, Owens RL, Malhotra A. Combination Drug Therapy with Acetazolamide, Eszopiclone +/- Venlafaxine for Obstructive Sleep Apnea (RESCUE-Combo): A Randomized, Double-Blind, Placebo-controlled Clinical Trial. Ann Am Thorac Soc. 2025 Feb;22(2):263-273. doi: 10.1513/AnnalsATS.202407-736OC. |
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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.
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| ID | Title | Description |
|---|---|---|
| FG000 | Placebo, Then Dual-Therapy, Then Triple-Therapy | Subjects started with a 3-day PLACEBO regimen:
After a wash-out period of 4+ days, subjects then crossed over to a 3-day EXPERIMENTAL DUAL-regimen:
After a wash-out period of 4+ days, subjects then underwent an OPEN-LABEL TRIPLE-regimen: Day 1: Acetazolamide 250mg at bedtime at home. Day 2: Acetazolamide 500mg at bedtime at home. Day 3: Acetazolamide 500mg + Eszopiclone 2mg + Venlafaxine 50mg at bedtime in the sleep laboratory Acetazolamide: Acetazolamide tablet (encapsulated) Eszopiclone: Eszopiclone tablet (encapsulated) Placebo: Sugar capsule manufactured to match encapsulated Acetazolamide/Eszopiclone Venlafaxine: Venlafaxine capsule |
| FG001 | Dual-Therapy, Then Placebo, Then Triple-Therapy | Subjects started with a 3-day EXPERIMENTAL DUAL-regimen:
After a wash-out period of 4+ days, subjects then crossed over to a 3-day PLACEBO regimen:
After a wash-out period of 4+ days, subjects then underwent an OPEN-LABEL TRIPLE-regimen: Day 1: Acetazolamide 250mg at bedtime at home. Day 2: Acetazolamide 500mg at bedtime at home. Day 3: Acetazolamide 500mg + Eszopiclone 2mg + Venlafaxine 50mg at bedtime in the sleep laboratory Acetazolamide: Acetazolamide tablet (encapsulated) Eszopiclone: Eszopiclone tablet (encapsulated) Placebo: Sugar capsule manufactured to match encapsulated Acetazolamide/Eszopiclone Venlafaxine: Venlafaxine capsule |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Intervention |
| |||||||||||||
| Second Intervention |
| |||||||||||||
| Third Intervention |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Posted | Median | Inter-Quartile Range | events/hour of sleep | 3 nights |
|
During the trial subjects were asked at each visit whether any adverse events had occurred during that 3-day study phase.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Dual-Therapy |
|
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Bad Dreams | General disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr Chris Schmickl | University of California San Diego | 8582462154 | cschmickl@health.ucsd.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jun 17, 2021 | Apr 26, 2023 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Aug 17, 2021 | Apr 26, 2023 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D020181 | Sleep Apnea, Obstructive |
| ID | Term |
|---|---|
| D012891 | Sleep Apnea Syndromes |
| D001049 | Apnea |
| D012120 | Respiration Disorders |
| D012140 | Respiratory Tract Diseases |
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| ID | Term |
|---|---|
| D000086 | Acetazolamide |
| D000069582 | Eszopiclone |
| D000069470 | Venlafaxine Hydrochloride |
| ID | Term |
|---|---|
| D013830 | Thiadiazoles |
| D013844 | Thiazoles |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
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Randomized, double-blind, placebo-controlled, cross-over trial.
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|
| Eszopiclone | Drug | Eszopiclone tablet (encapsulated) |
|
|
| Placebo | Drug | Sugar capsule manufactured to match encapsulated Acetazolamide/Eszopiclone |
|
| Venlafaxine | Drug | Venlafaxine capsule |
|
|
| 3 nights |
| 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 |
| Percent Responders | Full responders were defined as a drop in AHI>50% to <10/h. | 3 nights |
| Blood Pressure | Systolic/Diastolic Blood Pressure (measured at rest in the morning following the overnight sleep study). | 3 nights |
| 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 |
| 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 |
| 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 |
| 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 |
| UCSD Health - Pulmonary and Sleep Clinic |
| La Jolla |
| California |
| 92121 |
| United States |
| NOT COMPLETED |
|
| NOT COMPLETED |
|
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Body Mass Index | Median | Inter-Quartile Range | kg/m^2 |
|
| Apnea Hypopnea Index (AHI) | 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 the primary focus was on the AHI during supine non rapid eye movement (NREM) sleep. The "AHI4" defines hypopneas as reduced breathing for 10+ seconds associated with a >=4% desaturation. | Median | Inter-Quartile Range | events/hour of sleep |
|
| Pathophysiological Traits: Vpassive, Vactive, Arousal Threshold | Pathophysiological traits were quantified as %Veupnea from polysomnography data using a validated algorithm. | Median | Inter-Quartile Range | % Veupnea |
|
| 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). | Median | Inter-Quartile Range | dimensionless |
|
| OG001 | Placebo |
|
| OG002 | Triple-Therapy |
|
|
|
| Secondary | SpO2 Nadir | The lowest measured blood oxygen saturation during the overnight sleep study measured in percent. | Posted | Median | Inter-Quartile Range | Percent Oxygen Saturation | 3 nights |
|
|
|
| Secondary | Pathophysiological Traits: Vpassive, Vactive, Arousal Threshold | Pathophysiological traits were quantified as %Veupnea from polysomnography data using a validated algorithm. | Posted | Median | Inter-Quartile Range | % Veupnea | 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) | Posted | Median | Inter-Quartile Range | dimensionless | 3 nights |
|
|
|
| Secondary | Percent Responders | Full responders were defined as a drop in AHI>50% to <10/h. | Posted | Count of Participants | Participants | 3 nights |
|
|
|
| Secondary | Blood Pressure | Systolic/Diastolic Blood Pressure (measured at rest in the morning following the overnight sleep study). | Posted | Median | Inter-Quartile Range | mmHg | 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. | Posted | Median | Inter-Quartile Range | units on a scale | 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. | Posted | Median | Inter-Quartile Range | t-score | 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). | Posted | Median | Inter-Quartile Range | 1/seconds | 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). | Posted | Median | Inter-Quartile Range | Number of lapses | 3 nights |
|
|
|
| 0 |
| 20 |
| 0 |
| 20 |
| 11 |
| 20 |
| EG001 | Placebo |
| 0 | 20 | 0 | 20 | 10 | 20 |
| EG002 | Triple-Therapy |
| 0 | 18 | 0 | 18 | 16 | 18 |
| Cloudy Urine | Renal and urinary disorders | Systematic Assessment |
|
| Dizziness | Nervous system disorders | Systematic Assessment |
|
| Abnormal Taste when Drinking Carbonated Beverages | General disorders | Systematic Assessment |
|
| Fatigue | General disorders | Systematic Assessment |
|
| Gastrointestinal Upset | Gastrointestinal disorders | Systematic Assessment |
|
| Hand Pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Headache | General disorders | Systematic Assessment |
|
| Heartburn | Gastrointestinal disorders | Systematic Assessment |
|
| Hot Flashes | General disorders | Systematic Assessment |
|
| Itchiness | General disorders | Systematic Assessment |
|
| Metallic Taste | General disorders | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | Systematic Assessment |
|
| Paresthesia | Nervous system disorders | Systematic Assessment |
|
| Polyuria | Renal and urinary disorders | Systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Shoulder Cramp | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Sleepiness | General disorders | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | Systematic Assessment |
|
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| D020919 |
| Sleep Disorders, Intrinsic |
| D020920 | Dyssomnias |
| D012893 | Sleep Wake Disorders |
| D009422 | Nervous System Diseases |
| D001393 |
| Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D010879 | Piperazines |
| D011719 | Pyrazines |
| D011725 | Pyridines |
| D003511 | Cyclohexanols |
| D000441 | Hexanols |
| D005233 | Fatty Alcohols |
| D000438 | Alcohols |
| D010627 | Phenethylamines |
| D005021 | Ethylamines |
| D000588 | Amines |
| D003510 | Cyclohexanes |
| D003516 | Cycloparaffins |
| D006840 | Hydrocarbons, Alicyclic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D008055 | Lipids |
|
| Arousal Threshold, transformed |
|
|
|