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Obstructive sleep apnea (OSA) is common and has major health implications but treatment options are limited. OSA patients show a marked reduction in upper airway (UA) dilator muscle activity at sleep onset and this phenomenon leads to increased collapsibility of UA compared to normal subjects. Until recently, the search for medicines to activate pharyngeal muscles in sleeping humans has been discouraging. However, exciting new animal research has shown that drugs with noradrenergic and antimuscarinic effects can restore pharyngeal muscle activity to waking levels. In this protocol the investigators will test the effect of atomoxetine (a norepinephrine reuptake inhibitor) and oxybutynin (an antimuscarinic drug) administered together on OSA phenotype traits and OSA severity during sleep.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Placebo | Placebo Comparator | Placebo 2 hours before bedtime |
|
| Combination product of Atomoxetine and Oxybutynin | Active Comparator | Combination product of Atomoxetine 80 mg and Oxybutynin 5 mg 2 hours before sleep |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Combination product of Atomoxetine and Oxybutynin | Drug | Combination product of Atomoxetine 80 mg and Oxybutynin 5 mg 2 hours before sleep |
|
| Measure | Description | Time Frame |
|---|---|---|
| Apnea Hypopnea Index (AHI, Events/Hour of Sleep) | Based on previous studies the investigators anticipate that Atomoxetine and Oxybutynin will reduce AHI more effectively in subjects with moderate sleep apnea, mildly obese (BMI<32), Vpassive > 50% of Veupnea (ventilation during eupneic ventilatory drive), low muscle compensation (Vactive - Vpassive <1 L/min) | 1 night |
| Measure | Description | Time Frame |
|---|---|---|
| Genioglossus Muscle Responsiveness to Increased Ventilatory Drive (Esophageal Pressure Swings) | For genioglossus muscle responsiveness, data will be expressed as change in electromyography of genioglossus (GG EMG) for cmH2O change in esophageal pressure. | 1 night |
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Inclusion Criterion:
- AHI > 20
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Sleep Disorders Research Program Brigham and Women's Hospital | Boston | Massachusetts | 02115 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 30395486 | Derived | Taranto-Montemurro L, Messineo L, Sands SA, Azarbarzin A, Marques M, Edwards BA, Eckert DJ, White DP, Wellman A. The Combination of Atomoxetine and Oxybutynin Greatly Reduces Obstructive Sleep Apnea Severity. A Randomized, Placebo-controlled, Double-Blind Crossover Trial. Am J Respir Crit Care Med. 2019 May 15;199(10):1267-1276. doi: 10.1164/rccm.201808-1493OC. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Placebo First, Ato-Oxy Second | Placebo-matching ato-oxy administered 30 mins before normal sleep time on first study night, then a 1-week non-treatment period, then ato-oxy administered 30 mins before normal sleep time on second study night. |
| FG001 | Ato-Oxy First, Placebo Second | Ato-Oxy administered 30 mins before normal sleep time on first study night, then a 1-week non-treatment period, then placebo administered 30 mins before normal sleep time on second study night. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
All participants who were randomized, completed both study nights, and were included in the analysis.
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| ID | Title | Description |
|---|---|---|
| BG000 | All Analyzed Participants | All participants who were randomized, completed both study nights, and were included in the analysis. |
| 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, Events/Hour of Sleep) | Based on previous studies the investigators anticipate that Atomoxetine and Oxybutynin will reduce AHI more effectively in subjects with moderate sleep apnea, mildly obese (BMI<32), Vpassive > 50% of Veupnea (ventilation during eupneic ventilatory drive), low muscle compensation (Vactive - Vpassive <1 L/min) | 2 participants were not analyzed because they dropped out between the 2 intervention arms | Posted | Median | Inter-Quartile Range | events/hours of sleep | 1 night |
|
1 night
All randomized participants who received at least one dose of desipramine or placebo.
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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 | Placebo | Placebo 2 capsules 30 mins before bedtime | 0 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| delayed micturition | Renal and urinary disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Luigi Taranto Montemurro, MD | Brigham and women's Hospital | 6177326541 | ltarantomontemurro@bwh.harvard.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 26, 2017 | Dec 18, 2018 | Prot_SAP_000.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 |
|---|---|
| C005419 | oxybutynin |
| D000069445 | Atomoxetine Hydrochloride |
| ID | Term |
|---|---|
| D011437 | Propylamines |
| D000588 | Amines |
| D009930 | Organic Chemicals |
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|
| Placebo, 2 tablets | Drug | Placebo 2 tablets 2 hours before sleep |
|
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
Combination product of Atomoxetine 80 mg and Oxybutynin 5 mg 30 minutes before sleep
|
|
|
| Secondary | Genioglossus Muscle Responsiveness to Increased Ventilatory Drive (Esophageal Pressure Swings) | For genioglossus muscle responsiveness, data will be expressed as change in electromyography of genioglossus (GG EMG) for cmH2O change in esophageal pressure. | 4 patients did not accept to perform intramuscular EMG measurement (genioglossus electromyography) 2 patients were not analyzed because they dropped out after the first arm of the study | Posted | Median | Inter-Quartile Range | %GG/cmH2O | 1 night |
|
|
|
| 20 |
| 0 |
| 20 |
| 3 |
| 20 |
| EG001 | Combination Product of Atomoxetine and Oxybutynin | Combination product of Atomoxetine 80 mg and Oxybutynin 5 mg 30 mins before sleep | 0 | 20 | 0 | 20 | 5 | 20 |
| Dry mouth | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
|
| insomnia | Nervous system disorders | Non-systematic Assessment |
|
| headache | Nervous system disorders | Non-systematic Assessment |
|
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| D020919 |
| Sleep Disorders, Intrinsic |
| D020920 | Dyssomnias |
| D012893 | Sleep Wake Disorders |
| D009422 | Nervous System Diseases |