Pharyngeal Muscle Control Mechanisms of Atomoxetine-plus-oxybutynin in Obstructive Sleep Apnea
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ClinicalTrials.gov Identifier: NCT05944965 |
Recruitment Status :
Not yet recruiting
First Posted : July 14, 2023
Last Update Posted : October 17, 2023
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Condition or disease | Intervention/treatment | Phase |
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OSA | Drug: Atomoxetine 80 mg plus Oxybutynin 5 mg Drug: Atomoxetine 80 MG Drug: Placebo | Phase 1 Phase 2 |
Study Type : | Interventional (Clinical Trial) |
Estimated Enrollment : | 25 participants |
Allocation: | Randomized |
Intervention Model: | Crossover Assignment |
Masking: | Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) |
Masking Description: | placebo is open-label and optional |
Primary Purpose: | Treatment |
Official Title: | Pharyngeal Muscle Control Mechanisms of Atomoxetine-plus-oxybutynin in Obstructive Sleep Apnea |
Estimated Study Start Date : | October 22, 2023 |
Estimated Primary Completion Date : | September 1, 2024 |
Estimated Study Completion Date : | December 1, 2024 |
Arm | Intervention/treatment |
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Experimental: Atomoxetine-plus-Oxybutynin (AtoOxy)
80mg atomoxetine and 5mg of oxybutynin administered to participant, 30 min prior to bed.
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Drug: Atomoxetine 80 mg plus Oxybutynin 5 mg
80mg Atomoxetine and 5mg Oxybutynin administered 30mins prior to bed
Other Name: AtoOxy |
Active Comparator: Atomoxetine
80mg atomoxetine and placebo administered to participant, 30 min prior to bed.
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Drug: Atomoxetine 80 MG
80mg Atomoxetine administered 30 mins prior to bed
Other Name: Atomoxetine |
Placebo Comparator: Placebo
Placebo plus placebo administered to participant, 30mins prior to bed
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Drug: Placebo
Placebo and placebo (sugar pill) administered 30 mins prior to bed |
- Peak Genioglossus Activity [ Time Frame: 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.
- Tensor Palatini Activity [ Time Frame: 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 [ Time Frame: 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, baseline activation, i.e. at eupneic ventilatory drive (GGpassive) [ Time Frame: 1 night ]1st secondary outcome for genioglossus activation
- Peak genioglossus responsiveness (GG-Drive slope) [ Time Frame: 1 night ]2nd secondary outcome for genioglossus activation
- Tensor palatini, baseline activation, i.e. at eupneic ventilatory drive (TPpassive) [ Time Frame: 1 night ]1st secondary outcome for tensor palatini activation
- Tensor palatini responsiveness (TP-Drive slope) [ Time Frame: 1 night ]2nd secondary outcome for tensor palatini activation
- Ventilation, at eupneic ventilatory drive, reflecting collapsibility (Vpassive) [ Time Frame: 1 night ]1st secondary outcome for ventilation / functional pharyngeal airway mechanical improvement
- Muscle Effectiveness (V-Drive slope) [ Time Frame: 1 night ]2nd secondary outcome for ventilation / functional pharyngeal airway mechanical
- Ventilatory drive (Dmin) [ Time Frame: 1 night ]Ventilatory drive at the first decile drive level during sleep. Is expected to increase with the dual therapy, i.e. with improved arousal threshold. Measures are based on calibrated diaphragm EMG.
- Arousal Threshold [ Time Frame: 1 night ]Median level of ventliatory drive on the breath preceding arousal from sleep.
- Loop Gain [ Time Frame: 1 night ]Loop Gain
- Tonic genioglossus activity, unadjusted for ventilatory drive (GGtonic,min) [ Time Frame: 1 night ]Repeat of the GGmin but using tonic genioglossus activity (nadir value during each breath)
- Tonic genioglossus, baseline activation, i.e. at normal ventilatory drive (GGtonic,passive) [ Time Frame: 1 night ]Repeat of the GGpassive but using tonic genioglossus activity
- Tonic genioglossus responsiveness (GG-Drive slope) [ Time Frame: 1 night ]Repeat of the usual peak genioglossus responsiveness but using tonic genioglossus activity
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Ages Eligible for Study: | 21 Years to 70 Years (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | Yes |
Inclusion Criteria:
- 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)
Exclusion Criteria:
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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.
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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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05944965
Contact: Scott Sands, PhD | 8579280341 | sasands@bwh.harvard.edu | |
Contact: Atqiya Aishah, PhD | aaishah@bwh.harvard.edu |
United States, Massachusetts | |
Brigham and Womens Hospital | |
Boston, Massachusetts, United States, 02115 | |
Contact: Dillon Gilbertson 617-732-6488 dgilbertson@bwh.havad.edu |
Study Director: | Dillon Gilbertson | Brigham and Women's Hospital and Harvard Medical School | |
Principal Investigator: | Scott A Sands, PhD | Brigham and Women's Hospital and Harvard Medical School |
Responsible Party: | Scott Aaron Sands, Assistant Professor, Brigham and Women's Hospital |
ClinicalTrials.gov Identifier: | NCT05944965 |
Other Study ID Numbers: |
2023P001175 |
First Posted: | July 14, 2023 Key Record Dates |
Last Update Posted: | October 17, 2023 |
Last Verified: | October 2023 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | Yes |
Plan Description: | Deidentified data will be shared freely with collaborating scientists at any time and more broadly to other scientists 12 months following all planned publications using the data. |
Supporting Materials: |
Study Protocol Statistical Analysis Plan (SAP) Informed Consent Form (ICF) Clinical Study Report (CSR) Analytic Code |
Time Frame: | Deidentified data will be shared freely with collaborating scientists at any time and more broadly to other scientists 12 months following all planned publications using the data. |
Access Criteria: | Requests should be made in writing to the lead investigator. |
Studies a U.S. FDA-regulated Drug Product: | Yes |
Studies a U.S. FDA-regulated Device Product: | No |
Product Manufactured in and Exported from the U.S.: | No |
Sleep Apnea, Obstructive Sleep Apnea Syndromes Apnea Respiration Disorders Respiratory Tract Diseases Sleep Disorders, Intrinsic Dyssomnias Sleep Wake Disorders Nervous System Diseases Oxybutynin Atomoxetine Hydrochloride Adrenergic Uptake Inhibitors Neurotransmitter Uptake Inhibitors |
Membrane Transport Modulators Molecular Mechanisms of Pharmacological Action Adrenergic Agents Neurotransmitter Agents Physiological Effects of Drugs Parasympatholytics Autonomic Agents Peripheral Nervous System Agents Muscarinic Antagonists Cholinergic Antagonists Cholinergic Agents Urological Agents |