Obstructive Sleep Apnea, Sleep-disordered Breathing
Conditions
Keywords
Obstructive sleep apnea, Pharmacotherapy, Hypoglossal nerve stimulation, Oxybutynin, Atomoxetine
Brief summary
Obstructive sleep apnea (OSA) is a common condition in which the airway repeatedly collapses during sleep, leading to poor sleep quality and reduced oxygen levels. Hypoglossal nerve stimulation (HGNS) is an approved treatment that uses a small implanted device to stimulate the genioglossus muscle and keep the airway open. However, some patients continue to have OSA despite using HGNS. Atomoxetine and oxybutynin, "AtoOxy", is a promising pharmacologcal therapy under investigation that has been shown to activate pharyngeal muscles-in particular non-genioglossus muscles--but appears more efficacious in some patients than others. This study will test whether the combination of AtoOxy and HGNS can further improve breathing during sleep compared to either monotherapy alone. Participants with OSA and an HGNS device will be randomized to receive, in random order: HGNS+AtoOxy, HGNS alone (plus placebo), AtoOxy alone (HGNS device off), and placebo (HGNS device off), in a cross-over trial. The main goal is to determine whether the combined treatment reduces the number of breathing events during sleep; the primary outcome test will compare HGNS+AtoOxy versus HGNS alone. The effect of each intervention versus placebo will also be presented. The study will also examine how individual patient characteristics influence response to treatment.
Detailed description
Residual obstructive sleep apnea (OSA) is common among patients treated with hypoglossal nerve stimulation (HGNS), reflecting incomplete correction of underlying pathophysiological traits. In addition to upper airway collapsibility, non-anatomical factors such as a low arousal threshold may contribute to persistent disease despite HGNS therapy. Pharmacologic modulation of these traits represents a potential strategy to enhance treatment efficacy. Atomoxetine (a norepinephrine re-uptake inhibitor) and oxybutynin (an anti-muscarinic agent) have been shown to increase upper airway muscle tone and raise the arousal threshold, leading to reductions in OSA severity in prior studies. However, their combined effect when added to ongoing HGNS therapy has not been systematically evaluated. This study is a randomized, placebo-controlled, crossover trial designed to assess the acute effects of combined pharmacologic and electrical stimulation on OSA severity. Participants with OSA who are already implanted with HGNS, or pending clinical implantation, will be enrolled in a four-period randomized placebo-controlled cross-over trial assessing HGNS+AtoOxy, HGNS alone (plus placebo), AtoOxy alone (HGNS device off), and placebo (HGNS device off). The main goal is to determine whether the combined treatment reduces the number of breathing events during sleep; the primary outcome test will compare HGNS+AtoOxy versus HGNS alone. The effect of each intervention versus placebo will also be presented. Polysomnographic measurements will be also be used to explore mechanisms underlying response, including the interaction between pharmacologically modifiable traits and HGNS-mediated airway stabilization. Additional analyses will evaluate whether baseline physiological characteristics predict treatment response, with the goal of informing personalized treatment strategies for patients with residual OSA. Patient-reported outcomes, including sleepiness, sleep-related quality of life, fatigue, and treatment satisfaction, will also be assessed to evaluate the broader clinical impact of the combination intervention.
Interventions
OTHERCombination device and drug: Unilateral hypoglossal nerve stimulation & atomoxetine-plus-oxybutynin (HGNS+AtoOxy)
Electrical stimulation of the hypoglossal nerve using an implanted device (Inspire Medical Systems) to activate upper airway dilator muscles during sleep at prescribed therapeutic settings. Atomoxetine 80 mg administered orally at bedtime. Oxybutynin 5 mg administered orally at bedtime. Dose escalation with half-dose for initial 3 nights followed by full dose.
DEVICEUnilateral hypoglossal nerve stimulation (HGNS), active comparator condition
Electrical stimulation of the hypoglossal nerve using an implanted device (Inspire Medical Systems) to activate upper airway dilator muscles during sleep at prescribed therapeutic settings. Matching placebo capsules administered orally at bedtime.
DRUGAtomoxetine-plus-oxybutynin (80/5 mg) (AtoOxy), active comparator condition
Atomoxetine 80 mg administered orally at bedtime. Oxybutynin 5 mg administered orally at bedtime. Dose escalation with half-dose for initial 3 nights followed by full dose. HGNS device off
DRUGPlacebo; placebo comparator condition
Matching placebo capsules administered orally at bedtime. HGNS device off
Sponsors
Brigham and Women's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
Medication (atomoxetine plus oxybutynin vs placebo) is double-blinded to participants, investigators, and outcomes assessors. Hypoglossal nerve stimulation (HGNS) cannot be blinded, as device activation status must be known to study staff and participants. Randomization procedures are designed to maintain blinding of medication assignment while allowing appropriate administration of HGNS.
Intervention model description
Randomized, double-blind (medication), crossover trial with four treatment conditions: hypoglossal nerve stimulation (HGNS) alone, pharmacotherapy alone (atomoxetine plus oxybutynin), combination therapy (HGNS plus pharmacotherapy), and placebo (HGNS off). Each participant undergoes four 2-week treatment periods with 1-week washout intervals between periods. Treatment order is randomized.
Eligibility
Sex/Gender
ALL
Age
18 Years to 79 Years
Healthy volunteers
No
Inclusion criteria
for Enrolment: * Ages 18 - 79 years * Diagnosed OSA * Implantation of a hypoglossal nerve stimulation device (HGNS, Inspire Medical) or scheduled for implantation (implantation required for randomization) * Willingness to withhold HGNS while testing therapies (up to 6 weeks with HGNS off \[with/without pharmacotherapy\] to assess benefits of HGNS therapy).
Exclusion criteria
* Any uncontrolled medical condition * Current use of the medications under investigation. * Issues relating to short-term withdrawal of HGNS therapy * Excluded: Occupational driving (truck drivers, fork-lift operation, taxi/uber drivers) * Excluded: History of traffic accidents attributable to sleepiness or fatigue (\<2 years). * Use of SNRIs/SSRIs or anticholinergic medications during the study. * 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: narcolepsy, parasomnias. Insomnia * 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: 1. "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?" 2. "During the last month, have you had a weak urinary stream more often than 1 out of 5 times? * known untreated narrow angle glaucoma * known bipolar disorder, mania, psychosis * known history of major depressive disorder (age\<24). * known history of attempted suicide or suicidal ideation within one year prior to screening * known clinically significant constipation, gastric retention * known pre-existing seizure disorders * known clinically-significant kidney disorders (eGFR\<60 ml/min/1.73m2) * known clinically-significant liver disorders * known clinically-significant cardiovascular conditions * moderate-to-severe hypertension (SBP\>160 mmHg or DBP\>100 mmHg measured at baseline; average of evening and morning measures) * known cardiomyopathy (LVEF\<50%) or heart failure * known advanced atherosclerosis * recent cerebrovascular events (within 2 years) * recent history of cardiac arrhythmias e.g., atrial fibrillation, QT prolongation (within 2 years) * other serious cardiac conditions that would raise the consequences of an increase in blood pressure or heart rate * myasthenia gravis * pregnancy/breast-feeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Apnea-Hypopnea Index | 2 Weeks | Apnea-hypopnea index (AHI), defined as the number of apneas and hypopneas per hour of sleep, measured by overnight polysomnography at the end of each treatment period. Quantitative outcome variable: percent change (symmetrized) from baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hypoxic Burden | 2 Weeks | Hypoxic burden, defined as the area under the oxygen desaturation curve associated with respiratory events multiplied by event frequency, measured during overnight polysomnography. Quantitative outcome variable: percent change (symmetrized) from baseline. |
| Visual Analog Scale for Sleep Quality | 2 Weeks | Self-reported sleep quality measured using a visual analog scale. Quantitative outcome variable: absolute change from baseline. Range: 0-10 (higher values indicate greater sleep quality). |
Countries
United States
Contacts
CONTACTDaniel P Vena, PhD
CONTACTDillon Gilbertson, BASc
PRINCIPAL_INVESTIGATORScott A Sands, PhD
Brigham and Women's Hospital
Outcome results
None listed