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.
調査の概要
状態
介入・治療
- 他の：Combination device and drug: Unilateral hypoglossal nerve stimulation & atomoxetine-plus-oxybutynin (HGNS+AtoOxy)
- デバイス：Unilateral hypoglossal nerve stimulation (HGNS), active comparator condition
- 薬：Atomoxetine-plus-oxybutynin (80/5 mg) (AtoOxy), active comparator condition
- 薬：Placebo; placebo comparator condition
詳細な説明
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.
研究の種類
入学 (推定)
段階
- フェーズ2
- フェーズ 1
連絡先と場所
研究連絡先
- 名前：Daniel P Vena, PhD
- 電話番号：617-852-0719
- メール：dvena@bwh.harvard.edu
研究連絡先のバックアップ
- 名前：Dillon Gilbertson, BASc
- 電話番号：617-732-6488
- メール：dgilbertson@bwh.harvard.edu
研究場所
-
-
Massachusetts
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Boston、Massachusetts、アメリカ、02115
- Brigham and Women's Hospital
-
コンタクト：
- Dillon Gilbertson, BASc
- 電話番号：617-732-6488
- メール：dgilbertson@bwh.harvard.edu
-
コンタクト：
- Natalie Lawrence, BASc
- 電話番号：7817076558
- メール：nvlawrence@bwh.harvard.edu
-
-
参加基準
適格基準
就学可能な年齢
- 大人
- 高齢者
健康ボランティアの受け入れ
説明
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
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：ランダム化
- 介入モデル：クロスオーバー割り当て
- マスキング：トリプル
武器と介入
参加者グループ / アーム |
介入・治療 |
|---|---|
|
他の：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.
他の名前：
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.
他の名前：
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
他の名前：
Matching placebo capsules administered orally at bedtime.
HGNS device off
他の名前：
|
|
他の：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.
他の名前：
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.
他の名前：
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
他の名前：
Matching placebo capsules administered orally at bedtime.
HGNS device off
他の名前：
|
|
他の：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.
他の名前：
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.
他の名前：
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
他の名前：
Matching placebo capsules administered orally at bedtime.
HGNS device off
他の名前：
|
|
他の：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.
他の名前：
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.
他の名前：
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
他の名前：
Matching placebo capsules administered orally at bedtime.
HGNS device off
他の名前：
|
この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Apnea-Hypopnea Index
時間枠：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
|
二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Hypoxic Burden
時間枠：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
時間枠：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
|
その他の成果指標
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Epworth Sleepiness Scale (ESS)
時間枠：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
時間枠：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)
時間枠：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
時間枠：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
時間枠：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
時間枠：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
|
協力者と研究者
捜査官
- 主任研究者：Scott A Sands, PhD、Brigham and Women's Hospital
出版物と役立つリンク
一般刊行物
- 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.
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- 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.
研究記録日
主要日程の研究
研究開始 (推定)
一次修了 (推定)
研究の完了 (推定)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (実際)
学習記録の更新
投稿された最後の更新 (実際)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
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