Atomoxetine and Oxybutynin in Obstructive Sleep Apnea (ATOSA)

Effect of Atomoxetine and Oxybutynin on Phenotype Traits and OSA Severity

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.

Study Overview

• Status: Completed
• Conditions: Obstructive Sleep Apnea (OSA)
• Intervention / Treatment: Drug: Placebo, 2 tablets; Drug: Combination product of Atomoxetine and Oxybutynin

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Sleep Disorders Research Program Brigham and Women's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo 2 hours before bedtime	Drug: Placebo, 2 tablets; Placebo 2 tablets 2 hours before sleep
Active Comparator: Combination product of Atomoxetine and Oxybutynin; Combination product of Atomoxetine 80 mg and Oxybutynin 5 mg 2 hours before sleep	Drug: Combination product of Atomoxetine and Oxybutynin; Combination product of Atomoxetine 80 mg and Oxybutynin 5 mg 2 hours before sleep; Other Names: Strattera + Ditropan

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 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

Secondary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: September 1, 2016
• Primary Completion (Actual): December 1, 2017
• Study Completion (Actual): January 1, 2018

Study Registration Dates

• First Submitted: September 14, 2016
• First Submitted That Met QC Criteria: September 16, 2016
• First Posted (Estimate): September 21, 2016

Study Record Updates

• Last Update Posted (Actual): January 29, 2019
• Last Update Submitted That Met QC Criteria: January 10, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Respiratory Tract Diseases; Apnea; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Muscarinic Antagonists; Cholinergic Antagonists; Cholinergic Agents; Urological Agents; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Adrenergic Uptake Inhibitors; Oxybutynin; Atomoxetine Hydrochloride
• Other Study ID Numbers: BWH-2014P001033

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes