A Novel Pharmacological Therapy for Obstructive Sleep Apnea

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?

Study Overview

• Status: Recruiting
• Conditions: Sleep Apnea
• Intervention / Treatment: Drug: Atomoxetine; Drug: Oxybutynin; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 75
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Scott A Sands, PhD; Phone Number: 6172780911; Email: sasands@bwh.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Brigham and Women's Hospital
      • Contact: Lauren Hess; Phone Number: 617-732-8976; Email: lhess1@bwh.harvard.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

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
Experimental: Atomoxetine and Oxybutynin; Participants will take Atomoxetine and Oxybutynin nightly for one month. Half doses will be given on the first three nights.	Drug: Atomoxetine; Atomoxetine 80 mg, per mouth, before bed; Other Names: Strattera; Drug: Oxybutynin; Oxybutynin 5 mg, per mouth, before bed; Other Names: Ditropan
Placebo Comparator: Placebo; Participants will take Placebos nightly for one month. Half doses will be given on the first three nights.	Drug: Placebo; Placebo, per mouth, before bed

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Investigators: Principal Investigator: Scott A Sands, PhD, Brigham and Women's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): September 3, 2019
• Primary Completion (Estimated): October 20, 2023
• Study Completion (Estimated): October 20, 2023

Study Registration Dates

• First Submitted: April 16, 2019
• First Submitted That Met QC Criteria: April 16, 2019
• First Posted (Actual): April 18, 2019

Study Record Updates

• Last Update Posted (Actual): October 17, 2023
• Last Update Submitted That Met QC Criteria: October 16, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Respiratory Tract Diseases; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Signs and Symptoms, Respiratory; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Apnea; 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: 2019P000666

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All IPD collected during the study, after deidentification, will be available immediately after publication to researchers who provide a methodologically sound proposal for any purpose.
• IPD Sharing Time Frame: Immediately after publication. No end date.
• IPD Sharing Access Criteria: 1-page proposals should be directed to Dr. Scott Sands (sasands@bwh.harvard.edu). To gain access, requestors will be asked to sign a data use agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes