Rescue Pharmacotherapy for OSA

Study Overview
=================
Brief Summary
-----------------
Persistent obstructive sleep apnea (OSA) is common in people treated with mandibular advancement device (MAD) or hypoglossal nerve stimulation (HGNS). For most patients, these treatments are the last line of defense. If MAD or HGNS do not work, then patients are left to suffer the consequences of undertreated OSA. In this study, the investigators want to test the addition of a drug treatment to their regimen. Endotypes will be targeted pharmacologically with one of the following drugs: acetazolamide for a high loop gain, atomoxetine-plus-eszopiclone for poor pharyngeal muscle compensation, or trazodone for a low arousal threshold. This aim is expected to provide treatment strategies for rescuing non-responders to MAD or HGNS therapy.

Official Title
-----------------
Treating Residual OSA With Endotype-directed Pharmacotherapy (Aim 3)

Conditions
-----------------
Obstructive Sleep Apnea

Intervention / Treatment
-----------------
* Drug: Placebo
* Drug: Acetazolamide
* Drug: Trazodone
* Drug: Atomoxetine and eszopiclone


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Individuals who have failed MAD or HGNS therapy, defined as a residual AHI ≥ 15 events/hr on MAD or HGNS therapy. Exclusion Criteria: Sleep disordered breathing or respiratory disorders other than obstructive sleep apnea: central sleep apnea (>50% of respiratory events scored as central), chronic hypoventilation/hypoxemia (awake SaO2 < 92% by oximetry) due to chronic obstructive pulmonary disease or other respiratory conditions. Other sleep disorders: periodic limb movements (periodic limb movement index > 20/hr), narcolepsy, or parasomnias. Any unstable major medical condition. Medications expected to stimulate or depress respiration (including opioids, barbiturates, benzodiazepines, doxapram, almitrine, theophylline, 4-hydroxybutanoic acid). Use of SSRIs/SNRIs. Contraindications for atomoxetine, including: pheochromocytoma use of monoamine oxidase inhibitors benign prostatic hypertrophy, urinary retention untreated narrow angle glaucoma bipolar disorder, mania, psychosis clinically significant constipation, gastric retention pre-existing seizure disorders clinically-significant kidney disorders clinically-significant liver disorders clinically-significant cardiovascular conditions severe hypertension (SBP>180 mmHg or DBP>110 mmHg measured at baseline) cardiomyopathy (LVEF<50%) or heart failure advanced atherosclerosi history of cerebrovascular events history of cardiac arrhythmias e.g., atrial fibrillation, QT prolongation other serious cardiac conditions that would raise the consequences of an increase in blood pressure or heart rate myasthenia gravis pregnancy/breast-feeding Contraindications for eszopiclone, including: Hypersensitivity to eszopiclone Chronic Obstructive Pulmonary Disease (COPD) Pregnancy Breast feeding Liver disease Contraindications for acetazolamide, including: Hyperchloremic acidosis Hypokalemia Hyponatremia Adrenal insufficiency Impaired kidney function Hypersensitivity to acetazolamide or other sulfonamides. Marked liver disease or impairment of liver function, including cirrhosis. Contraindications for trazodone, including: suicidal ideation bipolar disorder, mania use of monoamine oxidase inhibitors coronary artery disease cardiac arrhythmias QT prolongation hepatic disease renal failure or impairment closed angle glaucoma priapism pregnancy/breast-feeding

Ages Eligible for Study
-----------------
Minimum Age: 21 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>This is a two arm study. Patients will receive only one of the following drugs based on their altered sleep apnea trait. Patients with decreased arousal threshold will undergo treatment with placebo or Trazodone 100 mg in random order (one pill before 30 minutes before bedtime), patients with decreased pharyngeal muscle responsiveness will undergo treatment with placebo or Atomoxetine 80 mg + Eszopiclone 3 mg in random order (one pill before 30 minutes before bedtime), patients with increased loop gain will undergo treatment with placebo or Acetazolamide 500 mg in random order (one pill before 30 minutes before bedtime). | Drug: Placebo<br>* Placebo capsule 30 min before bedtime<br>|
| Active Comparator: Interventional arm<br>This is a two arm study. Patients will receive only one of the following drugs based on their altered sleep apnea trait. Patients with decreased arousal threshold will undergo treatment with placebo or Trazodone 100 mg in random order (one pill before 30 minutes before bedtime), patients with decreased pharyngeal muscle responsiveness will undergo treatment with placebo or Atomoxetine 80 mg + Eszopiclone 3 mg in random order (one pill before 30 minutes before bedtime), patients with increased loop gain will undergo treatment with placebo or Acetazolamide 500 mg in random order (one pill before 30 minutes before bedtime). | Drug: Acetazolamide<br>* The intervention drug will be determined based on altered endotype and administered 30 min before bedtime. Patients will only take one drug of this intervention, which will be subsequently compared to placebo. Patients with increased loop gain will be given Acetazolamide 500 mg.<br>Drug: Trazodone<br>* The intervention drug will be determined based on altered endotype and administered 30 min before bedtime. Patients will only take one drug of this intervention, which will be subsequently compared to placebo. Patients with decreased arousal threshold will be given Trazodone 100 mg.<br>Drug: Atomoxetine and eszopiclone<br>* The intervention drug will be determined based on altered endotype and administered 30 min before bedtime. Patients will only take one drug of this intervention, which will be subsequently compared to placebo. Patients with decreased muscle responsiveness will be given Atomoxetine and Eszopiclone 80 + 3 mg.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Apnea Hypopnea Index (AHI, Events/Hour of Sleep) | Based on previous studies the investigators anticipate that the interventional arm will reduce AHI through a positive effect on the abnormal endotype. | 1 night | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Nadir oxygen saturation during sleep (LSpO2, %) | Based on previous studies the investigators anticipate that the interventional arm will reduce LSpO2 through a positive effect on the abnormal endotype. | 1 night | 
| Arousal Index (AI, Events/Hours of Sleep) | Based on previous studies the investigators anticipate that the interventional arm will reduce AI through inducing less fragmented sleep, which will be driven by a positive effect on the abnormal endotype. | 1 night |