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Purpose

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.

Condition

Eligibility

Eligible Ages
Between 21 Years and 70 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

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

Study Design

Phase
Phase 1/Phase 2
Study Type
Interventional
Allocation
Randomized
Intervention Model
Crossover Assignment
Primary Purpose
Treatment
Masking
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Arm Groups

ArmDescriptionAssigned Intervention
Placebo Comparator
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).
  • Drug: Placebo
    Placebo capsule 30 min before bedtime
Active Comparator
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).
  • 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.

Recruiting Locations

Sleep Disorders Research Program Brigham and Women's Hospital
Boston, Massachusetts 02115
Contact:
Ludovico Messineo
857-272-6188
lmessineo@bwh.harvard.edu

More Details

Status
Recruiting
Sponsor
Brigham and Women's Hospital

Study Contact

David Andrew Wellman, MD
5089827401
awellman@bwh.harvard.edu

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.