Pharyngeal Muscle Control Mechanisms of Atomoxetine-plus-oxybutynin in Obstructive Sleep Apnea

NCT05944965 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: 2023P001175
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 1

Brief Summary

Current therapies available for obstructive sleep apnea (OSA) have varying degrees of efficacy due to the complex nature of the disorder. A reduction in pharyngeal muscle activity characterizes OSA, and recent research has shown that combining atomoxetine and oxybutynin improves OSA severity. Thus this may be a viable treatment option. However, the specific effects of these agents alone and in combination on pharyngeal muscle activity remain unknown. The current study will look at the impact of each drug on pharyngeal muscles to gain insight into the mechanisms of this combination.

Conditions

OSA

Outcome Measures

Primary Outcomes (3)

• Peak Genioglossus Activity

  Peak genioglossus activity will be calculated as % of maximum activity (inspiratory peak of respiratory phase), and is referred to as "GGmin". Values estimated specifically for the first decile of ventilatory drive, i.e. when the pharyngeal airway is most vulnerable. This primary analysis will be unadjusted for ventilatory drive. Note that primary outcomes for genioglossus (Aim 1), tensor palatini (Aim 2), and ventilation (Aim 3) are treated as distinct physiological questions, each assessed using a P-threshold of 0.05 for significance without adjustment for multiple comparisons. Primary analysis will compare atomoxetine-plus-oxybutynin versus atomoxetine alone. Comparisons will also be made between atomoxetine-plus-oxybutynin versus placebo, and atomoxetine versus placebo. Per-protocol analysis will be performed given that the study is mechanistic in nature.

  1 night

• Tensor Palatini Activity

  Tensor palatini activity will be calculated as % of maximum activity, and is referred to as "TPmin". Values estimated specifically for the first decile of ventilatory drive, i.e. when the pharyngeal airway is most vulnerable. This primary analysis will be unadjusted for ventilatory drive.

  1 night

• Ventilation

  Ventilation will be calculated as a %eupneic levels, and referred to as "Vmin". Ventilation is collected using a mask connected to a calibrated pneumotachograph. Values will be unadjusted for ventilatory drive. Increased ventilation is interpreted as an improved functional outcome of muscle activation, i.e. a composite product of all muscle activation, but is contingent on some level of neuromuscular efficiency.

  1 night

Secondary Outcomes (6)

• Peak genioglossus, baseline activation, i.e. at eupneic ventilatory drive (GGpassive)

  1 night

• Peak genioglossus responsiveness (GG-Drive slope)

  1 night

• Tensor palatini, baseline activation, i.e. at eupneic ventilatory drive (TPpassive)

  1 night

• Tensor palatini responsiveness (TP-Drive slope)

  1 night

• Ventilation, at eupneic ventilatory drive, reflecting collapsibility (Vpassive)

  1 night

Other Outcomes (6)

• Ventilatory drive (Dmin)

  1 night

• Arousal Threshold

  1 night

• Loop Gain

  1 night

Study Arms (3)

Atomoxetine-plus-Oxybutynin (AtoOxy)

EXPERIMENTAL

80mg atomoxetine and 5mg of oxybutynin administered to participant, 30 min prior to bed.

Drug: Atomoxetine 80 mg plus Oxybutynin 5 mg

Atomoxetine

ACTIVE COMPARATOR

80mg atomoxetine and placebo administered to participant, 30 min prior to bed.

Drug: Atomoxetine 80 MG

Placebo

PLACEBO COMPARATOR

Placebo plus placebo administered to participant, 30mins prior to bed

Drug: Placebo

Interventions

Atomoxetine 80 mg plus Oxybutynin 5 mg DRUG

80mg Atomoxetine and 5mg Oxybutynin administered 30mins prior to bed

Also known as: AtoOxy

Atomoxetine-plus-Oxybutynin (AtoOxy)

Atomoxetine 80 MG DRUG

80mg Atomoxetine administered 30 mins prior to bed

Also known as: Atomoxetine

Atomoxetine

Placebo DRUG

Placebo and placebo (sugar pill) administered 30 mins prior to bed

Placebo

Eligibility Criteria

• Age: 21 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• diagnosed OSA (AHI≥15 events/h reported in PSG performed within one year) or Suspected OSA (snoring, sleepiness, witness apneas, other clinical symptoms)
• not using CPAP (\>1 week)

You may not qualify if:

• 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 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 atomoxetine or oxybutynin (angioedema or urticaria)
• pheochromocytoma
• use of monoamine oxidase inhibitors
• diagnosed benign prostatic hypertrophy, urinary retention
• suspected benign prostatic hypertrophy / urinary retention based on a positive answer to either of the following questions:
• "During the last month, when urinating, have you had the sensation of not emptying your bladder completely more often than 1 out of 5 times?"

Sponsors & Collaborators

• Brigham and Women's Hospital: lead

Study Sites (1)

Brigham and Womens Hospital

Boston, Massachusetts, 02115, United States

Location

MeSH Terms

Interventions

Atomoxetine Hydrochloride; oxybutynin

Intervention Hierarchy (Ancestors)

Propylamines; Amines; Organic Chemicals

Study Officials

• Dillon Gilbertson

  Brigham and Women's Hospital and Harvard Medical School

  STUDY DIRECTOR

• Scott A Sands, PhD

  Brigham and Women's Hospital and Harvard Medical School

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: placebo is open-label and optional
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: July 6, 2023
• First Posted: July 14, 2023
• Study Start: December 1, 2023
• Primary Completion: June 17, 2025
• Study Completion: June 17, 2025
• Last Updated: December 17, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: Deidentified data will be shared freely with collaborating scientists at any time and more broadly to other scientists 12 months following all planned publications using the data.
• Access Criteria: Requests should be made in writing to the lead investigator.

Locations

US (1)