A Novel Pharmacological Therapy for Obstructive Sleep Apnea

Study Overview
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Brief Summary
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A pharmacological, non-mechanical therapy for OSA that is efficacious and tolerable remains elusive. Here the investigators study the effect on sleep apnea severity of a combination of pharmacological agents (atomoxetine and oxybutynin, AtoOxy) over a 1 month period of time. The current study will answer the following questions: Does ongoing, repeated-dose administration of atomoxetine-plus-oxybutynin (referred to as AtoOxy) improve OSA severity, and do patients exhibit signs of symptomatic relief? Most importantly, which phenotypic subgroup of patients preferentially benefit from this intervention?

Detailed Description
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Aim 1 - Effect of AtoOxy on sleep apnea severity. In a randomized controlled double-blind crossover study, 48 patients with moderate-to-severe OSA will take atomoxetine-plus-oxybutynin (AtoOxy) versus placebo nightly for 1 month, with a 2-week washout in between. The investigators will test the hypothesis that AtoOxy reduces the Apnea-hypopnea index (primary outcome measure), and improves the following secondary outcomes: Nocturnal oxygenation, per hypoxic burden of sleep apnea Frequency of arousals from sleep (Arousal index) Self-reported sleepiness (Epworth Sleepiness Scale) Disease-specific quality of life (Functional Outcomes of Sleep Questionnaire, Short Form). Disease-specific quality of life (Sleep Apnea Quality of Life Index, Short Form) Additional pre-specified exploratory outcome measures will be assessed, including Visual Analog Scales (Sleep Quality, Treatment Satisfaction) and additional polysomnographic measures of sleep (Stage 1 sleep, %total sleep time). Adherence and adverse events will also be carefully monitored to assess repeated-dose tolerance of the intervention. Aim 2 - Determine which patient phenotypes respond best to AtoOxy. Patients will also take part in an additional night before initiating study medication to measure the key mechanisms causing OSA. The investigators will prospectively test the hypothesis that greater pharyngeal collapsibility determines a reduced response to therapy. They will also separately test the hypotheses that a reduced muscle responsiveness, reduced baseline muscle activation, a higher arousal threshold, and a lower loop gain will facilitate a greater response to therapy.

Official Title
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A Novel Pharmacological Therapy for Obstructive Sleep Apnea

Conditions
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Sleep Apnea

Intervention / Treatment
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* Drug: Atomoxetine
* Drug: Oxybutynin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Ages 21-70 years Diagnosed OSA or clinically-suspected OSA Not using CPAP (>1 month). 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 (periodic limb movement arousal index > 10/hr), narcolepsy, or parasomnias. Contraindications for atomoxetine and oxybutynin, including: hypersensitivity to study drugs (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 severe hypertension (SBP>180 mmHg or DBP>110 mmHg measured at baseline) 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 pregnancy/breast-feeding Allergy to lidocaine (Aim 2 only) Claustrophobia Pregnancy or nursing

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: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Atomoxetine and Oxybutynin<br>Participants will take Atomoxetine and Oxybutynin nightly for one month. Half doses will be given on the first three nights. | Drug: Atomoxetine<br>* Atomoxetine 80 mg, per mouth, before bed<br>* Other names: Strattera;Drug: Oxybutynin<br>* Oxybutynin 5 mg, per mouth, before bed<br>* Other names: Ditropan;|
| Placebo Comparator: Placebo<br>Participants will take Placebos nightly for one month. Half doses will be given on the first three nights. | Drug: Placebo<br>* Placebo, per mouth, before bed<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 | one month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hypoxic Burden | Desaturation area under curve × event frequency | one month | 
| Arousal index | Scored EEG arousals per hour (>3 s), % change from baseline | one month | 
| Epworth Sleepiness Scale | Self-reported sleepiness on scale of 0-24, higher being more sleepy | one month | 
| Functional Outcomes of Sleep Questionnaire, Short Form | Disease-specific quality of life | one month | 
| Sleep Apnea Quality of Life Index, Short Form | Disease-specific quality of life | one month |