Combination Upper-Airway Electrical and Pharmacological Stimulation for Obstructive Sleep Apnea

Official title

Combination Upper-Airway Electrical and Pharmacological Stimulation for Obstructive Sleep Apnea: A Randomized-Controlled Trial.

Overview

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

• Other Combination 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.
• Device Unilateral 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.
• Drug Atomoxetine-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
• Drug Placebo; placebo comparator condition
  Matching placebo capsules administered orally at bedtime. HGNS device off

Primary outcome measures

• Apnea-Hypopnea Index [Time frame: 2 Weeks]

Secondary outcome measures (2)

• Hypoxic Burden [Time frame: 2 Weeks]
• Visual Analog Scale for Sleep Quality [Time frame: 2 Weeks]

Eligibility criteria

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:

• "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?"
• "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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Crossover

Masking

Triple blind

Primary purpose

Treatment

Study locations

United States · 1 center

• Brigham and Women's Hospital — Boston

Publications

• Edwards BA, Sands SA, Eckert DJ, White DP, Butler JP, Owens RL, Malhotra A, Wellman A. Acetazolamide improves loop gain but not the other physiological traits causing obstructive sleep apnoea. J Physiol. 2012 Mar 1;590(5):1199-211. doi: 10.1113/jphysiol.2011.223925. Epub 2012 Jan 4. PMID 22219335
• Sands SA, Terrill PI, Edwards BA, Taranto Montemurro L, Azarbarzin A, Marques M, de Melo CM, Loring SH, Butler JP, White DP, Wellman A. Quantifying the Arousal Threshold Using Polysomnography in Obstructive Sleep Apnea. Sleep. 2018 Jan 1;41(1):zsx183. doi: 10.1093/sleep/zsx183. PMID 29228393
• Sands SA, Edwards BA, Terrill PI, Taranto-Montemurro L, Azarbarzin A, Marques M, Hess LB, White DP, Wellman A. Phenotyping Pharyngeal Pathophysiology using Polysomnography in Patients with Obstructive Sleep Apnea. Am J Respir Crit Care Med. 2018 May 1;197(9):1187-1197. doi: 10.1164/rccm.201707-1435OC. PMID 29327943
• Terrill PI, Edwards BA, Nemati S, Butler JP, Owens RL, Eckert DJ, White DP, Malhotra A, Wellman A, Sands SA. Quantifying the ventilatory control contribution to sleep apnoea using polysomnography. Eur Respir J. 2015 Feb;45(2):408-18. doi: 10.1183/09031936.00062914. Epub 2014 Oct 16. PMID 25323235
• Sands SA, Edwards BA, Terrill PI, Butler JP, Owens RL, Taranto-Montemurro L, Azarbarzin A, Marques M, Hess LB, Smales ET, de Melo CM, White DP, Malhotra A, Wellman A. Identifying obstructive sleep apnoea patients responsive to supplemental oxygen therapy. Eur Respir J. 2018 Sep 27;52(3):1800674. doi: 10.1183/13993003.00674-2018. Print 2018 Sep. PMID 30139771
• Pepperell JC, Maskell NA, Jones DR, Langford-Wiley BA, Crosthwaite N, Stradling JR, Davies RJ. A randomized controlled trial of adaptive ventilation for Cheyne-Stokes breathing in heart failure. Am J Respir Crit Care Med. 2003 Nov 1;168(9):1109-14. doi: 10.1164/rccm.200212-1476OC. Epub 2003 Aug 19. PMID 12928310
• Pepperell JC, Ramdassingh-Dow S, Crosthwaite N, Mullins R, Jenkinson C, Stradling JR, Davies RJ. Ambulatory blood pressure after therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomised parallel trial. Lancet. 2002 Jan 19;359(9302):204-10. doi: 10.1016/S0140-6736(02)07445-7. PMID 11812555
• Ryan CM, Usui K, Floras JS, Bradley TD. Effect of continuous positive airway pressure on ventricular ectopy in heart failure patients with obstructive sleep apnoea. Thorax. 2005 Sep;60(9):781-5. doi: 10.1136/thx.2005.040972. Epub 2005 Jun 30. PMID 15994252

Identifiers

NCT: NCT07577661 · 2026P000970

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗