Pharyngeal Muscle Control Mechanisms of Atomoxetine-plus-oxybutynin in Obstructive Sleep Apnea
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 27
- 试验地点
- 1
- 主要终点
- Tensor Palatini Activity
研究概览
简要总结
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.
详细描述
The goal of this randomized controlled double-blind crossover physiology study is to examine the pathophysiological mechanisms of how atomoxetine-oxybutynin (AtoOxy) versus atomoxetine alone effect pharyngeal dilator muscle activity in people with obstructive sleep apnea (OSA). Subjects will attend a virtual Screening and Consent visit to assess eligibility for enrollment. Participants will take part in a video call with the consenting doctor to obtain consent (Zoom).
After consent, eligible subjects will be randomized to receive the first period of study medication for 1 night. Allocations will be concealed from the subjects, investigators, physicians, and outcomes assessors. Patients will perform in random order the two study interventions:
A) atomoxetine 80 mg plus oxybutynin 5 mg (full doses described) B) atomoxetine 80 mg plus placebo (encapsulated to mimic oxybutynin) There will be a 1-week washout between periods. Subjects will undergo acute administration of the drugs. The treatment will be administered after the first sleep cycle (60-90 minutes after sleep onset), to provide within-night control data. An additional night (open-label placebo) will be performed at the end of the first two study arms.
In addition to the listed outcome, we will also examine effects of each treatment on clinical parameters: apnea hypopnea index, hypoxic burden, arousal index, within the caveats that the studies are physiological in nature (per experimental equipment).
Data analysis
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
placebo is open-label and optional
入排标准
- 年龄范围
- 21 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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)
排除标准
- •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?"
- •"During the last month, have you had a weak urinary stream more often than 1 out of 5 times?
- •untreated narrow angle glaucoma
- •bipolar disorder, mania, psychosis
- •history of major depressive disorder (age<24).
- •history of attempted suicide or suicidal ideation within one year prior to screening
- •clinically significant constipation, gastric retention
- •pre-existing seizure disorders
- •clinically-significant kidney disorders (eGFR<60 ml/min/1.73m2)
- •clinically-significant liver disorders
- •clinically-significant cardiovascular conditions
- •severe hypertension (SBP>180 mmHg or DBP>110 mmHg measured at baseline)
- •cardiomyopathy (LVEF<50%) or heart failure
- •advanced atherosclerosis
- •history of cerebrovascular events
- •history of cardiac arrhythmias e.g., atrial fibrillation, QT prolongation
- •other serious cardiac conditions that would raise the consequences of an increase in blood pressure or heart rate
- •myasthenia gravis
- •pregnancy/breast-feeding
- •Allergy to lidocaine
- •Use of oral anti-coagulants
- •Claustrophobia
- •Pregnancy or nursing
研究组 & 干预措施
Atomoxetine-plus-Oxybutynin (AtoOxy)
80mg atomoxetine and 5mg of oxybutynin administered to participant, 30 min prior to bed.
干预措施: Atomoxetine 80 mg plus Oxybutynin 5 mg (Drug)
Atomoxetine
80mg atomoxetine and placebo administered to participant, 30 min prior to bed.
干预措施: Atomoxetine 80 MG (Drug)
Placebo
Placebo plus placebo administered to participant, 30mins prior to bed
干预措施: Placebo (Drug)
结局指标
主要结局
Tensor Palatini Activity
时间窗: 1 night
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.
Ventilation
时间窗: 1 night
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.
Peak Genioglossus Activity
时间窗: 1 night
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.
次要结局
- 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)
- Muscle Effectiveness (V-Drive slope)(1 night)
研究者
Scott Aaron Sands
Assistant Professor
Brigham and Women's Hospital