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

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.

Study Overview

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

Detailed Description

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).

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

Contacts and Locations

• Study Contact: Name: Scott A Sands, PhD; Phone Number: 617-278-0911; Email: sasands@bwh.harvard.edu
• Study Contact Backup: Name: Laura K Gell, PhD; Phone Number: 617-525-9086; Email: lgell@bwh.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02141
      • Recruiting
      • Brigham and Women's Hospital
      • Contact: Scott A Sands, PhD; Phone Number: 857-928-0341; Email: sasands@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:

• 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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

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	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

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): May 5, 2022
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: September 19, 2022
• First Submitted That Met QC Criteria: September 19, 2022
• First Posted (Actual): September 22, 2022

Study Record Updates

• Last Update Posted (Actual): October 18, 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: 2022P001544

Plan for Individual participant data (IPD)

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

IPD Plan Description

Data will be available to researchers who provide a methodologically sound proposal.

All IPD collected during the study will be available after deidentification.

• 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