Combination Upper-Airway Electrical and Pharmacological Stimulation for Obstructive Sleep Apnea
Combination Upper-Airway Electrical and Pharmacological Stimulation for Obstructive Sleep Apnea: A Randomized-Controlled Trial.
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.
Visão geral do estudo
Status
Intervenção / Tratamento
- Outro: Combination device and drug: Unilateral hypoglossal nerve stimulation & atomoxetine-plus-oxybutynin (HGNS+AtoOxy)
- Dispositivo: Unilateral hypoglossal nerve stimulation (HGNS), active comparator condition
- Medicamento: Atomoxetine-plus-oxybutynin (80/5 mg) (AtoOxy), active comparator condition
- Medicamento: Placebo; placebo comparator condition
Descrição detalhada
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.
Tipo de estudo
Inscrição (Estimado)
Estágio
- Fase 2
- Fase 1
Contactos e Locais
Contato de estudo
- Nome: Daniel P Vena, PhD
- Número de telefone: 617-852-0719
- E-mail: dvena@bwh.harvard.edu
Estude backup de contato
- Nome: Dillon Gilbertson, BASc
- Número de telefone: 617-732-6488
- E-mail: dgilbertson@bwh.harvard.edu
Locais de estudo
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Massachusetts
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Boston, Massachusetts, Estados Unidos, 02115
- Brigham and Women's Hospital
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Contato:
- Dillon Gilbertson, BASc
- Número de telefone: 617-732-6488
- E-mail: dgilbertson@bwh.harvard.edu
-
Contato:
- Natalie Lawrence, BASc
- Número de telefone: 7817076558
- E-mail: nvlawrence@bwh.harvard.edu
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-
Critérios de participação
Critérios de elegibilidade
Idades elegíveis para estudo
- Adulto
- Adulto mais velho
Aceita Voluntários Saudáveis
Descrição
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
Plano de estudo
Como o estudo é projetado?
Detalhes do projeto
- Finalidade Principal: Tratamento
- Alocação: Randomizado
- Modelo Intervencional: Atribuição cruzada
- Mascaramento: Triplo
Armas e Intervenções
Grupo de Participantes / Braço |
Intervenção / Tratamento |
|---|---|
|
Outro: Sequence 1
HGNS+AtoOxy -> Placebo -> HGNS -> AtoOxy Each participant receives all four treatment conditions ("periods") in randomized order; outcomes are analyzed as within-subject comparisons, not between sequence arms. |
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.
Outros nomes:
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.
Outros nomes:
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
Outros nomes:
Matching placebo capsules administered orally at bedtime.
HGNS device off
Outros nomes:
|
|
Outro: Sequence 2
HGNS -> AtoOxy -> HGNS+AtoOxy -> Placebo Each participant receives all four treatment conditions ("periods") in randomized order; outcomes are analyzed as within-subject comparisons, not between sequence arms. |
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.
Outros nomes:
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.
Outros nomes:
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
Outros nomes:
Matching placebo capsules administered orally at bedtime.
HGNS device off
Outros nomes:
|
|
Outro: Sequence 3
AtoOxy -> HGNS -> Placebo -> HGNS+AtoOxy Each participant receives all four treatment conditions ("periods") in randomized order; outcomes are analyzed as within-subject comparisons, not between sequence arms. |
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.
Outros nomes:
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.
Outros nomes:
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
Outros nomes:
Matching placebo capsules administered orally at bedtime.
HGNS device off
Outros nomes:
|
|
Outro: Sequence 4
Placebo -> HGNS+AtoOxy -> AtoOxy -> HGNS Each participant receives all four treatment conditions ("periods") in randomized order; outcomes are analyzed as within-subject comparisons, not between sequence arms. |
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.
Outros nomes:
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.
Outros nomes:
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
Outros nomes:
Matching placebo capsules administered orally at bedtime.
HGNS device off
Outros nomes:
|
O que o estudo está medindo?
Medidas de resultados primários
Medida de resultado |
Descrição da medida |
Prazo |
|---|---|---|
|
Apnea-Hypopnea Index
Prazo: 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. |
2 Weeks
|
Medidas de resultados secundários
Medida de resultado |
Descrição da medida |
Prazo |
|---|---|---|
|
Hypoxic Burden
Prazo: 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. |
2 Weeks
|
|
Visual Analog Scale for Sleep Quality
Prazo: 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).
|
2 Weeks
|
Outras medidas de resultado
Medida de resultado |
Descrição da medida |
Prazo |
|---|---|---|
|
Epworth Sleepiness Scale (ESS)
Prazo: 2 Weeks
|
Daytime sleepiness assessed using the Epworth Sleepiness Scale (range 0-24, higher scores indicate greater sleepiness). Quantitative outcome variable: absolute change from baseline. |
2 Weeks
|
|
Visual Analog Scale for Treatment Satisfaction
Prazo: 2 Weeks
|
Self-reported treatment satisfaction measured using a visual analog scale.
Quantitative outcome variable: absolute value on treatment.
Range: 0-10 (higher values indicate greater treatment satisfaction).
|
2 Weeks
|
|
Sleep Apnea Quality of Life Index (SAQLI)
Prazo: 2 Weeks
|
Disease-specific quality of life assessed using the Sleep Apnea Quality of Life Index. Quantitative outcome variable: absolute change from baseline. Range: 1-7 (higher values indicate greater sleep apnea-related quality of life). |
2 Weeks
|
|
PROMIS Sleep-Related Impairment
Prazo: 2 Weeks
|
Patient-reported outcomes assessing sleep-related impairment: Quantitative outcome variable: absolute change from baseline. Range: 0-100 (mean 50, SD 10; higher T-scores indicate greater impairment). |
2 Weeks
|
|
PROMIS Fatigue
Prazo: 2 Weeks
|
Patient-reported outcomes assessing fatigue: Quantitative outcome variable: absolute change from baseline. Range: 0-100 (mean 50, SD 10; higher T-scores indicate greater fatigue). |
2 Weeks
|
|
PROMIS Sleep Disturbance
Prazo: 2 Weeks
|
Patient-reported outcomes assessing sleep disturbance: Quantitative outcome variable: absolute change from baseline. Range: 0-100 (mean 50, SD 10; higher T-scores indicate greater sleep disturbance). |
2 Weeks
|
Colaboradores e Investigadores
Patrocinador
Investigadores
- Investigador principal: Scott A Sands, PhD, Brigham and Women's Hospital
Publicações e links úteis
Publicações Gerais
- Phillips CL, Grunstein RR, Darendeliler MA, Mihailidou AS, Srinivasan VK, Yee BJ, Marks GB, Cistulli PA. Health outcomes of continuous positive airway pressure versus oral appliance treatment for obstructive sleep apnea: a randomized controlled trial. Am J Respir Crit Care Med. 2013 Apr 15;187(8):879-87. doi: 10.1164/rccm.201212-2223OC.
- Strollo PJ Jr, Soose RJ, Maurer JT, de Vries N, Cornelius J, Froymovich O, Hanson RD, Padhya TA, Steward DL, Gillespie MB, Woodson BT, Van de Heyning PH, Goetting MG, Vanderveken OM, Feldman N, Knaack L, Strohl KP; STAR Trial Group. Upper-airway stimulation for obstructive sleep apnea. N Engl J Med. 2014 Jan 9;370(2):139-49. doi: 10.1056/NEJMoa1308659.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Gold AR, Schwartz AR, Bleecker ER, Smith PL. The effect of chronic nocturnal oxygen administration upon sleep apnea. Am Rev Respir Dis. 1986 Nov;134(5):925-9. doi: 10.1164/arrd.1986.134.5.925.
- Azarbarzin A, Sands SA, Stone KL, Taranto-Montemurro L, Messineo L, Terrill PI, Ancoli-Israel S, Ensrud K, Purcell S, White DP, Redline S, Wellman A. The hypoxic burden of sleep apnoea predicts cardiovascular disease-related mortality: the Osteoporotic Fractures in Men Study and the Sleep Heart Health Study. Eur Heart J. 2019 Apr 7;40(14):1149-1157. doi: 10.1093/eurheartj/ehy624.
- Taylor KS, Murai H, Millar PJ, Haruki N, Kimmerly DS, Morris BL, Tomlinson G, Bradley TD, Floras JS. Arousal From Sleep and Sympathetic Excitation During Wakefulness. Hypertension. 2016 Dec;68(6):1467-1474. doi: 10.1161/HYPERTENSIONAHA.116.08212. Epub 2016 Oct 3.
- Winslow DH, Bowden CH, DiDonato KP, McCullough PA. A randomized, double-blind, placebo-controlled study of an oral, extended-release formulation of phentermine/topiramate for the treatment of obstructive sleep apnea in obese adults. Sleep. 2012 Nov 1;35(11):1529-39. doi: 10.5665/sleep.2204.
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- 2026P000970
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