Rescue Pharmacotherapy for OSA

NCT05293600 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: 2022p000430
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 1

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

Outcome Measures

Primary Outcomes (1)

• Apnea Hypopnea Index (AHI, Events/Hour of Sleep)

  Based on previous studies the investigators anticipate that the interventional arm will reduce AHI through a positive effect on the abnormal endotype.

  1 night

Secondary Outcomes (2)

• Nadir oxygen saturation during sleep (LSpO2, %)

  1 night

• Arousal Index (AI, Events/Hours of Sleep)

  1 night

Study Arms (2)

Placebo

PLACEBO COMPARATOR

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

Interventional arm

ACTIVE COMPARATOR

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; Drug: Trazodone; Drug: Atomoxetine and eszopiclone

Interventions

Placebo DRUG

Placebo capsule 30 min before bedtime

Placebo

Acetazolamide 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.

Interventional arm

Trazodone 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.

Interventional arm

Atomoxetine and eszopiclone 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.

Interventional arm

Eligibility Criteria

• Age: 21 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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

Sponsors & Collaborators

• Brigham and Women's Hospital: lead

Study Sites (1)

Sleep Disorders Research Program Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

RECRUITING

MeSH Terms

Conditions

Sleep Apnea, Obstructive

Interventions

Acetazolamide; Trazodone; Atomoxetine Hydrochloride; Eszopiclone

Condition Hierarchy (Ancestors)

Sleep Apnea Syndromes; Apnea; Respiration Disorders; Respiratory Tract Diseases; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Thiadiazoles; Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Piperazines; Pyridones; Pyridines; Propylamines; Amines; Pyrazines

Central Study Contacts

David Andrew Wellman, MD

CONTACT

5089827401; awellman@bwh.harvard.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Medicine

Study Record Dates

• First Submitted: February 23, 2022
• First Posted: March 24, 2022
• Study Start: July 1, 2023
• Primary Completion (Estimated): October 30, 2026
• Study Completion (Estimated): October 30, 2026
• Last Updated: June 4, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will share

Locations

US (1)