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Rescue Pharmacotherapy for OSA (RescOSA)

Primary Purpose

Obstructive Sleep Apnea

Status
Not yet recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Placebo
Acetazolamide
Trazodone
Atomoxetine and eszopiclone
Sponsored by
Brigham and Women's Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Obstructive Sleep Apnea

Eligibility Criteria

21 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Sleep Disorders Research Program Brigham and Women's Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Active Comparator

Arm Label

Placebo

Interventional arm

Arm Description

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).

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).

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Nadir oxygen saturation during sleep (LSpO2, %)
Based on previous studies the investigators anticipate that the interventional arm will reduce LSpO2 through a positive effect on the abnormal endotype.
Arousal Index (AI, Events/Hours of Sleep)
Based on previous studies the investigators anticipate that the interventional arm will reduce AI through inducing less fragmented sleep, which will be driven by a positive effect on the abnormal endotype.

Full Information

First Posted
February 23, 2022
Last Updated
July 18, 2022
Sponsor
Brigham and Women's Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT05293600
Brief Title
Rescue Pharmacotherapy for OSA
Acronym
RescOSA
Official Title
Treating Residual OSA With Endotype-directed Pharmacotherapy (Aim 3)
Study Type
Interventional

2. Study Status

Record Verification Date
July 2022
Overall Recruitment Status
Not yet recruiting
Study Start Date
September 1, 2022 (Anticipated)
Primary Completion Date
December 1, 2023 (Anticipated)
Study Completion Date
July 1, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Brigham and Women's Hospital

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Obstructive Sleep Apnea

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
70 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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).
Arm Title
Interventional arm
Arm Type
Active Comparator
Arm Description
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).
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo capsule 30 min before bedtime
Intervention Type
Drug
Intervention Name(s)
Acetazolamide
Intervention Description
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
Intervention Name(s)
Trazodone
Intervention Description
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
Intervention Name(s)
Atomoxetine and eszopiclone
Intervention Description
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 Measure Information:
Title
Apnea Hypopnea Index (AHI, Events/Hour of Sleep)
Description
Based on previous studies the investigators anticipate that the interventional arm will reduce AHI through a positive effect on the abnormal endotype.
Time Frame
1 night
Secondary Outcome Measure Information:
Title
Nadir oxygen saturation during sleep (LSpO2, %)
Description
Based on previous studies the investigators anticipate that the interventional arm will reduce LSpO2 through a positive effect on the abnormal endotype.
Time Frame
1 night
Title
Arousal Index (AI, Events/Hours of Sleep)
Description
Based on previous studies the investigators anticipate that the interventional arm will reduce AI through inducing less fragmented sleep, which will be driven by a positive effect on the abnormal endotype.
Time Frame
1 night

10. Eligibility

Sex
All
Minimum Age & Unit of Time
21 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
David Andrew Wellman, MD
Phone
5089827401
Email
awellman@bwh.harvard.edu
Facility Information:
Facility Name
Sleep Disorders Research Program Brigham and Women's Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ludovico Messineo
Phone
857-272-6188
Email
lmessineo@bwh.harvard.edu

12. IPD Sharing Statement

Plan to Share IPD
Yes

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Rescue Pharmacotherapy for OSA

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