Rescue Pharmacotherapy for OSA

Official title

Treating Residual OSA With Endotype-directed Pharmacotherapy (Aim 3)

Overview

Persistent obstructive sleep apnea (OSA) is common in people treated with mandibular advancement device (MAD) or hypoglossal nerve stimulation (HGNS). For most patients, these treatments are the last line of defense. If MAD or HGNS do not work, then patients are left to suffer the consequences of undertreated OSA. In this study, the investigators want to test the addition of a drug treatment to their regimen. Endotypes will be targeted pharmacologically with one of the following drugs: acetazolamide for a high loop gain, atomoxetine-plus-eszopiclone for poor pharyngeal muscle compensation, or trazodone for a low arousal threshold. This aim is expected to provide treatment strategies for rescuing non-responders to MAD or HGNS therapy.

Interventions

• Drug Placebo
  Placebo capsule 30 min before bedtime
• Drug Acetazolamide
  The intervention drug will be determined based on altered endotype and administered 30 min before bedtime. Patients will only take one drug of this intervention, which will be subsequently compared to placebo. Patients with increased loop gain will be given Acetazolamide 500 mg.
• Drug Trazodone
  The intervention drug will be determined based on altered endotype and administered 30 min before bedtime. Patients will only take one drug of this intervention, which will be subsequently compared to placebo. Patients with decreased arousal threshold will be given Trazodone 100 mg.
• Drug Atomoxetine and eszopiclone
  The intervention drug will be determined based on altered endotype and administered 30 min before bedtime. Patients will only take one drug of this intervention, which will be subsequently compared to placebo. Patients with decreased muscle responsiveness will be given Atomoxetine and Eszopiclone 80 + 3 mg.

Primary outcome measures

• Apnea Hypopnea Index (AHI, Events/Hour of Sleep) [Time frame: 1 night]

Secondary outcome measures (2)

• Nadir oxygen saturation during sleep (LSpO2, %) [Time frame: 1 night]
• Arousal Index (AI, Events/Hours of Sleep) [Time frame: 1 night]

Eligibility criteria

Inclusion criteria

• Individuals who have failed MAD or HGNS therapy, defined as a residual AHI ≥ 15 events/hr on MAD or HGNS therapy.

Exclusion criteria

• Sleep disordered breathing or respiratory disorders other than obstructive sleep apnea:

central sleep apnea (>50% of respiratory events scored as central), 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 index > 20/hr), narcolepsy, or parasomnias.
• Any unstable major medical condition.
• Medications expected to stimulate or depress respiration (including opioids, barbiturates, benzodiazepines, doxapram, almitrine, theophylline, 4-hydroxybutanoic acid).
• Use of SSRIs/SNRIs.
• Contraindications for atomoxetine, including:
• pheochromocytoma
• use of monoamine oxidase inhibitors
• benign prostatic hypertrophy, urinary retention
• untreated narrow angle glaucoma
• bipolar disorder, mania, psychosis
• clinically significant constipation, gastric retention
• pre-existing seizure disorders
• clinically-significant kidney disorders
• 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 atherosclerosi
• 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
• Contraindications for eszopiclone, including:
• Hypersensitivity to eszopiclone
• Chronic Obstructive Pulmonary Disease (COPD)
• Pregnancy
• Breast feeding
• Liver disease
• Contraindications for acetazolamide, including:
• Hyperchloremic acidosis
• Hypokalemia
• Hyponatremia
• Adrenal insufficiency
• Impaired kidney function
• Hypersensitivity to acetazolamide or other sulfonamides.
• Marked liver disease or impairment of liver function, including cirrhosis.
• Contraindications for trazodone, including:
• suicidal ideation
• bipolar disorder, mania
• use of monoamine oxidase inhibitors
• coronary artery disease
• cardiac arrhythmias
• QT prolongation
• hepatic disease
• renal failure or impairment
• closed angle glaucoma
• priapism
• 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

Quadruple blind

Primary purpose

Treatment

Study locations

United States · 1 center

• Sleep Disorders Research Program Brigham and Women's Hospital — Boston

Identifiers

NCT: NCT05293600 · 2022p000430

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗