Rescue Pharmacotherapy for OSA

NCT ID: NCT05293600

Last Updated: 2024-06-04

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 70 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-07-01
• Study Completion Date: 2026-10-30

Brief Summary

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.

Conditions

Obstructive Sleep Apnea

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Placebo

This is a two arm study. Patients will receive only one of the following drugs based on their altered sleep apnea trait. Patients with decreased arousal threshold will undergo treatment with placebo or Trazodone 100 mg in random order (one pill before 30 minutes before bedtime), patients with decreased pharyngeal muscle responsiveness will undergo treatment with placebo or Atomoxetine 80 mg + Eszopiclone 3 mg in random order (one pill before 30 minutes before bedtime), patients with increased loop gain will undergo treatment with placebo or Acetazolamide 500 mg in random order (one pill before 30 minutes before bedtime).

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo capsule 30 min before bedtime

Interventional arm

This is a two arm study. Patients will receive only one of the following drugs based on their altered sleep apnea trait. Patients with decreased arousal threshold will undergo treatment with placebo or Trazodone 100 mg in random order (one pill before 30 minutes before bedtime), patients with decreased pharyngeal muscle responsiveness will undergo treatment with placebo or Atomoxetine 80 mg + Eszopiclone 3 mg in random order (one pill before 30 minutes before bedtime), patients with increased loop gain will undergo treatment with placebo or Acetazolamide 500 mg in random order (one pill before 30 minutes before bedtime).

Group Type: ACTIVE_COMPARATOR

Acetazolamide

Intervention Type: DRUG

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.

Trazodone

Intervention Type: DRUG

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.

Atomoxetine and eszopiclone

Intervention Type: DRUG

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.

Interventions

Placebo

Placebo capsule 30 min before bedtime

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: DRUG

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

• Minimum Eligible Age: 21 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Brigham and Women's Hospital

OTHER

Sponsor Role: lead

Responsible Party

David Andrew Wellman

Associate Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Sleep Disorders Research Program Brigham and Women's Hospital

Boston, Massachusetts, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

David Andrew Wellman, MD

Role: CONTACT

awellman@bwh.harvard.edu

5089827401

Facility Contacts

Ludovico Messineo

Role: primary

lmessineo@bwh.harvard.edu

857-272-6188

Other Identifiers

2022p000430

Identifier Type: -

Identifier Source: org_study_id