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A Novel Pharmacological Therapy for Obstructive Sleep Apnea

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ClinicalTrials.gov Identifier: NCT03919955
Recruitment Status : Recruiting
First Posted : April 18, 2019
Last Update Posted : July 31, 2019
Sponsor:
Information provided by (Responsible Party):
Scott Aaron Sands, Brigham and Women's Hospital

Brief Summary:
A pharmacological, non-mechanical therapy for OSA that is efficacious and tolerable remains elusive. Here the investigators study the effect on sleep apnea severity of a combination of pharmacological agents (atomoxetine and oxybutynin, "AtoOxy") over a 1 month period of time. The current study will answer the following questions: Does ongoing, repeated-dose administration of atomoxetine-plus-oxybutynin (referred to as "AtoOxy") improve OSA severity, and do patients exhibit signs of symptomatic relief? Most importantly, which phenotypic subgroup of patients preferentially benefit from this intervention?

Condition or disease Intervention/treatment Phase
Sleep Apnea Drug: Atomoxetine Drug: Oxybutynin Drug: Placebo Phase 1 Phase 2

Detailed Description:

Aim 1 - Effect of AtoOxy on sleep apnea severity. In a randomized controlled double-blind crossover study, 48 patients with moderate-to-severe OSA will take atomoxetine-plus-oxybutynin ("AtoOxy") versus placebo nightly for 1 month, with a 2-week washout in between. The investigators will test the hypothesis that AtoOxy reduces the Apnea-hypopnea index (primary outcome measure), and improves the following secondary outcomes:

  • Nocturnal oxygenation, per "hypoxic burden of sleep apnea"
  • Frequency of arousals from sleep (Arousal index)
  • Self-reported sleepiness (Epworth Sleepiness Scale)
  • Disease-specific quality of life (Functional Outcomes of Sleep Questionnaire).

Additional pre-specified exploratory outcome measures will be assessed, including Visual Analog Scales (Sleep Quality, Excessive Fatigue, Waking Unrefreshed, Low Energy, Treatment Satisfaction) and additional polysomnographic measures of sleep (Stage 1 sleep, %total sleep time). Adherence and adverse events will also be carefully monitored to assess repeated-dose tolerance of the intervention.

Aim 2 - Determine which patient phenotypes respond best to AtoOxy. Patients will also take part in an additional night before initiating study medication to measure the key mechanisms causing OSA. The investigators will prospectively test the hypothesis that greater pharyngeal collapsibility determines a reduced response to therapy. They will also separately test the hypotheses that a reduced muscle responsiveness, reduced baseline muscle activation, a higher arousal threshold, and a lower loop gain will facilitate a greater response to therapy.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 75 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Novel Pharmacological Therapy for Obstructive Sleep Apnea
Actual Study Start Date : April 30, 2019
Estimated Primary Completion Date : May 2020
Estimated Study Completion Date : May 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Sleep Apnea

Arm Intervention/treatment
Experimental: Atomoxetine and Oxybutynin
Participants will take Atomoxetine and Oxybutynin nightly for one month. Half doses will be given on the first three nights.
Drug: Atomoxetine
Atomoxetine 80 mg, per mouth, before bed
Other Name: Strattera

Drug: Oxybutynin
Oxybutynin 5 mg, per mouth, before bed
Other Name: Ditropan

Placebo Comparator: Placebo
Participants will take Placebos nightly for one month. Half doses will be given on the first three nights.
Drug: Placebo
Placebo, per mouth, before bed




Primary Outcome Measures :
  1. Apnea-hypopnea index [AHI] [ Time Frame: one month ]
    Apneas and hypopneas per hour (3% desat and/or arousal), % change from baseline


Secondary Outcome Measures :
  1. Hypoxic Burden [ Time Frame: one month ]
    Desaturation area under curve × event frequency

  2. Arousal index [ Time Frame: one month ]
    Scored EEG arousals per hour (>3 s), % change from baseline

  3. Epworth Sleepiness Scale [ Time Frame: one month ]
    Self-reported sleepiness on scale of 0-3, higher being more sleepy

  4. Functional Outcomes of Sleep Questionnaire [ Time Frame: one month ]
    Disease-specific quality of life



Information from the National Library of Medicine

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Ages Eligible for Study:   21 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  • Ages 21-70 years
  • Diagnosed OSA or clinically-suspected OSA
  • Not using CPAP (>1 month).

Exclusion criteria:

  • Any uncontrolled medical condition
  • Current use of the medications under investigation
  • Use of medications expected to stimulate or depress respiration (including opioids, barbiturates, doxapram, almitrine, theophylline, 4-hydroxybutanoic acid).
  • Current use of hypnotic medications (trazodone, eszopiclone, benzodiazepines).
  • Current use of SNRIs/SSRIs or anticholinergic medications.
  • Conditions likely to affect obstructive sleep apnea physiology: neuromuscular disease or other major neurological disorder, heart failure (also below), or any other unstable major medical condition.
  • Respiratory disorders other than sleep disordered breathing:

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 arousal index > 10/hr), narcolepsy, or parasomnias.
  • Contraindications for atomoxetine and oxybutynin, including:

    • hypersensitivity to study drugs (angioedema or urticaria)
    • pheochromocytoma
    • use of monoamine oxidase inhibitors
    • benign prostatic hypertrophy, urinary retention
    • untreated narrow angle glaucoma
    • bipolar disorder, mania, psychosis
    • history of major depressive disorder (age<24).
    • history of attempted suicide or suicidal ideation within one year prior to screening
    • clinically significant constipation, gastric retention
    • pre-existing seizure disorders
    • clinically-significant kidney disorders (eGFR<60 ml/min/1.73m2)
    • 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 atherosclerosis
    • 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
  • Allergy to lidocaine (Aim 2 only)
  • Claustrophobia
  • Pregnancy or nursing

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03919955


Contacts
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Contact: Scott A Sands, PhD 6172780911 sasands@bwh.harvard.edu

Locations
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United States, Massachusetts
Brigham and Women's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Lauren Hess    617-732-8976    lhess1@bwh.harvard.edu   
Sponsors and Collaborators
Brigham and Women's Hospital
Investigators
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Principal Investigator: Scott A Sands, PhD Brigham and Women's Hospital

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Responsible Party: Scott Aaron Sands, Assistant Professor of Medicine, Brigham and Women's Hospital
ClinicalTrials.gov Identifier: NCT03919955     History of Changes
Other Study ID Numbers: 2019P000666
First Posted: April 18, 2019    Key Record Dates
Last Update Posted: July 31, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: All IPD collected during the study, after deidentification, will be available immediately after publication to researchers who provide a methodologically sound proposal for any purpose.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: Immediately after publication. No end date.
Access Criteria: 1-page proposals should be directed to Dr. Scott Sands (sasands@bwh.harvard.edu). To gain access, requestors will be asked to sign a data use agreement.

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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.: Yes

Additional relevant MeSH terms:
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Apnea
Sleep Apnea Syndromes
Sleep Apnea, Obstructive
Respiration Disorders
Respiratory Tract Diseases
Signs and Symptoms, Respiratory
Signs and Symptoms
Sleep Disorders, Intrinsic
Dyssomnias
Sleep Wake Disorders
Nervous System Diseases
Mandelic Acids
Oxybutynin
Atomoxetine Hydrochloride
Adrenergic Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Adrenergic Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Parasympatholytics
Autonomic Agents
Peripheral Nervous System Agents
Muscarinic Antagonists
Cholinergic Antagonists
Cholinergic Agents
Urological Agents
Anti-Infective Agents, Urinary
Anti-Infective Agents