Identifying Sleep Apnea Patients That Best Respond to Atomoxetine Plus Oxybutynin Therapy

Study Overview
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Brief Summary
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Atomoxetine-plus-oxybutynin therapy (AtoOxy) has been shown to substantially reduce obstructive sleep apnea severity (OSA) in about half of patients. Here, the investigators will study which patients respond meaningfully to therapy using pathophysiological traits measured at baseline sleep studies.

Detailed Description
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The primary goal of the current study is to test the central hypothesis that therapeutic efficacy of AtoOxy depends on underlying patient pathophysiology. Aim 1 - Advanced analysis of clinical polysomnography will be used to estimate the OSA traits and classify patients as 'predicted responders' or 'predicted nonresponders'. Investigators will prospectively test whether AtoOxy efficacy is greater in predicted responders. Aim 2 - Pooling preliminary and prospective data, investigators will test the hypotheses that the following pathophysiological traits are associated with, and therefore predict, greater efficacy: less-severe upper airway collapsibility (less improvement needed to re-establish airflow), lower loop gain (less severe ventilatory control instability), higher arousal threshold (greater scope for muscle activation without arousal), and greater upper airway muscle compensation (functional muscle reflex apparatus). Aim 3 - Investigators will test the hypothesis that treatment efficacy will be greater in patients with tongue-related upper airway obstruction per previous drug-induced sleep endoscopy results (anterior-posterior collapse patterns).

Official Title
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Identifying Sleep Apnea Patients That Best Respond to Atomoxetine Plus Oxybutynin Therapy

Conditions
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Obstructive Sleep Apnea

Intervention / Treatment
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* Drug: Atomoxetine
* Drug: Oxybutynin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Suspected or diagnosed OSA Recent drug induced sleep endoscopy results available (performed as part of routine clinical care). Exclusion Criteria: Any uncontrolled medical condition Current use of the medications under investigation Use of medications expected to stimulate or depress respiration (including opioids, barbiturates, doxapram, almitrine, theophylline, 4-hydroxybutanoic acid). Current use of hypnotic medications (trazodone, eszopiclone, benzodiazepines). Current use of SNRIs/SSRIs or anticholinergic medications. Conditions likely to affect obstructive sleep apnea physiology: neuromuscular disease or other major neurological disorder, heart failure (also below), or any other unstable major medical condition. Respiratory disorders other than sleep disordered breathing: chronic hypoventilation/hypoxemia (awake SaO2 < 92% by oximetry) due to chronic obstructive pulmonary disease or other respiratory conditions. Other sleep disorders: periodic limb movements, narcolepsy, or parasomnias. Contraindications for atomoxetine and oxybutynin, including: hypersensitivity to atomoxetine or oxybutynin (angioedema or urticaria) pheochromocytoma use of monoamine oxidase inhibitors benign prostatic hypertrophy, urinary retention untreated narrow angle glaucoma bipolar disorder, mania, psychosis history of major depressive disorder (age<24). history of attempted suicide or suicidal ideation within one year prior to screening clinically significant constipation, gastric retention pre-existing seizure disorders clinically-significant kidney disorders (eGFR<60 ml/min/1.73m2) clinically-significant liver disorders clinically-significant cardiovascular conditions moderate-to-severe hypertension (SBP>180 mmHg or DBP>110 mmHg measured at baseline; average of evening and morning measures*) cardiomyopathy (LVEF<50%) or heart failure advanced atherosclerosis 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 Claustrophobia Pregnancy or nursing n.b. Development of new hypertension that is recognized on the final day of study medications during outcomes collection will not be used as stopping criteria for discontinuing outcomes collection. Participants that are sexually active and able to become pregnant must agree to use birth control for the entire study.

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AtoOxy Predicted Responders<br>Participants will take Atomoxetine (80mg) and Oxybutynin (5mg) before bedtime for 3 nights. Half doses will be given on the first night. | Drug: Atomoxetine<br>* Treatment given for 3 nights<br>Drug: Oxybutynin<br>* Treatment given for 3 nights<br>|
| Experimental: AtoOxy Predicted Nonresponders<br>Participants will take Atomoxetine (80mg) and Oxybutynin (5mg) before bedtime for 3 nights. Half doses will be given on the first night. | Drug: Atomoxetine<br>* Treatment given for 3 nights<br>Drug: Oxybutynin<br>* Treatment given for 3 nights<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Apnea-hypopnea index (AHI) | Apneas and hypopneas per hour (3% desat and/or arousal), % change from baseline | 3 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hypoxic Burden | Desaturation area under curve × event frequency | 3 days | 
| Arousal Index | Number of arousals per hour (>=3-sec), % change from baseline | 3 days |