A Novel Pharmacological Therapy for Obstructive Sleep Apnea

• Sponsor: Brigham and Women's Hospital (Other)
• Overall Status: Recruiting
• CT.gov ID: NCT03919955
• Collaborator: (none)
• Enrollment: 75
• Location: 1
• Arms: 2
• Anticipated Duration (Months): 55.9
• Patients Per Site Per Month: 1.3

Study Details

Study Description

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 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, Short Form).

• Disease-specific quality of life (Sleep Apnea Quality of Life Index, Short Form)

Additional pre-specified exploratory outcome measures will be assessed, including Visual Analog Scales (Sleep Quality, 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.

Study Design

• Study Type: Interventional
• Anticipated 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: Sep 3, 2019
• Anticipated Primary Completion Date: May 1, 2024
• Anticipated Study Completion Date: May 1, 2024

Arms and Interventions

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 Names: Strattera ; Drug: Oxybutynin; Oxybutynin 5 mg, per mouth, before bed; Other Names: 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

Outcome Measures

Primary Outcome Measures

1. Apnea-hypopnea index [AHI] [one month]

   Apneas and hypopneas per hour (3% desat and/or arousal), % change from baseline

Secondary Outcome Measures

1. Hypoxic Burden [one month]

   Desaturation area under curve × event frequency

2. Arousal index [one month]

   Scored EEG arousals per hour (>3 s), % change from baseline

3. Epworth Sleepiness Scale [one month]

   Self-reported sleepiness on scale of 0-24, higher being more sleepy

4. Functional Outcomes of Sleep Questionnaire, Short Form [one month]

   Disease-specific quality of life

5. Sleep Apnea Quality of Life Index, Short Form [one month]

   Disease-specific quality of life

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115

Sponsors and Collaborators

• Brigham and Women's Hospital

Investigators

• Principal Investigator: Scott A Sands, PhD, Brigham and Women's Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Scott Aaron Sands, Assistant Professor of Medicine, Brigham and Women's Hospital
• ClinicalTrials.gov Identifier: NCT03919955
• Other Study ID Numbers: 2019P000666
• First Posted: Apr 18, 2019
• Last Update Posted: Mar 29, 2021
• Last Verified: Mar 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• 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: Apnea; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Oxybutynin; Atomoxetine Hydrochloride

Study Results

No Results Posted as of Mar 29, 2021