Obstructive Sleep Apnea (OSA)
Conditions
Brief summary
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.
Interventions
DRUGCombination product of Atomoxetine and Oxybutynin
Combination product of Atomoxetine 80 mg and Oxybutynin 5 mg 2 hours before sleep
DRUGPlacebo, 2 tablets
Placebo 2 tablets 2 hours before sleep
Sponsors
Brigham and Women's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
Inclusion Criterion: \- AHI \> 20
Exclusion criteria
* Any medical condition other than well controlled hypertension. * Any medication known to influence breathing, sleep/arousal or muscle physiology. * Claustrophobia. * Inability to sleep supine. * Allergy to lidocaine, Oxymetazoline HCl, atomoxetine/oxybutynin. * Individuals with underlying cardiac disease, such as arrhythmias. * Individuals taking psychiatric medications, such as atomoxetine, or any of the studied medications for medical care. * History of seizures * For women: Pregnancy. * History of panic disorder / hyperventilation syndrome / Attention deficit-hyperactivity disorder (ADHD) / autism
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Apnea Hypopnea Index (AHI, Events/Hour of Sleep) | 1 night | 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Genioglossus Muscle Responsiveness to Increased Ventilatory Drive (Esophageal Pressure Swings) | 1 night | For genioglossus muscle responsiveness, data will be expressed as change in electromyography of genioglossus (GG EMG) for cmH2O change in esophageal pressure. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Analyzed Participants All participants who were randomized, completed both study nights, and were included in the analysis. | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 2 |
Baseline characteristics
| Characteristic | All Analyzed Participants |
|---|---|
| Age, Continuous | 53 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 10 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 |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 20 |
| other Total, other adverse events | 3 / 20 | 5 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 |
Outcome results
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)
Time frame: 1 night
Population: 2 participants were not analyzed because they dropped out between the 2 intervention arms
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Apnea Hypopnea Index (AHI, Events/Hour of Sleep) | 28.5 events/hours of sleep |
| Combination Product of Atomoxetine and Oxybutynin | Apnea Hypopnea Index (AHI, Events/Hour of Sleep) | 7.5 events/hours of sleep |
p-value: <0.001Wilcoxon (Mann-Whitney)
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.
Time frame: 1 night
Population: 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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Genioglossus Muscle Responsiveness to Increased Ventilatory Drive (Esophageal Pressure Swings) | 2.2 %GG/cmH2O |
| Combination Product of Atomoxetine and Oxybutynin | Genioglossus Muscle Responsiveness to Increased Ventilatory Drive (Esophageal Pressure Swings) | 6.3 %GG/cmH2O |