Propranolol for Sleep Apnea Therapy (ProSAT)

The primary objective of this study is to test whether a beta blocker, propranolol, lowers the overnight heart rate sleep in obstructive sleep apnea (OSA) during CPAP withdrawal. The secondary objectives are to test whether propranolol influences sleep architecture, morning blood pressure, and vascular function including reactive hyperemia index (RHI) and a marker of arterial stiffness, augmentation index (AIX).

Study Overview

• Status: Completed
• Conditions: Obstructive Sleep Apnea
• Intervention / Treatment: Drug: Propranolol Oral Tablet; Drug: Placebo Oral Tablet

Detailed Description

The overnight heart rate is increased in patients with obstructive sleep apnea (OSA), reflecting excessive sympathetic nervous system activity which may lead to long-term adverse cardiovascular consequences. Propranolol is a non-selective beta blocker that is used for a variety of indications including hypertension and anxiety. In this study investigators will administer propranolol or placebo to patients with OSA before sleep. Investigators will examine the effect of drug on nocturnal heart rate, morning blood pressure, and vascular health outcomes

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • Johns Hopkins Bayview Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• History of OSA (AHI>20, >50% events obstructive)
• Accustomed to CPAP use, and willing to discontinue CPAP temporarily for the study.
• If the participant has already completed "Metabolic Impact of Intermittent CPAP" (NA_00086830), they must have exhibited a >10% increase in nocturnal FFA or glucose during CPAP

Exclusion Criteria:

• Cardiovascular risks

  • Decompensated congestive heart failure
  • Atrial fibrillation, sick sinus syndrome, 2nd or 3rd degree heart block, pacemaker implantation, Wolff-Parkinson-White Syndrome (if not known, will check on a screening EKG)
  • Uncontrolled hypertension > 170/110
  • History of postural hypotension.
  • Resting systolic pressure <90 or heart rate < 50 on screening visit

• Drug interactions - currently taking any of the following drugs. (Subjects on these medications are excluded from participation and will not have the drug in question discontinued for the purposes of participation in the study. )

  • Calcium channel blockers that reduce heart rate (diltiazem, verapamil, fendiline, gallopamil)
  • Sympatholytic drugs: any other beta blocker; clonidine, terazosin or doxazosin; reserpine
  • Anti-arrhythmic drugs: (e.g. amiodarone, sotalol, digoxin, quinidine, lidocaine, propafenone)
  • Coumadin (propranolol may prolong INR)
  • Drugs that Inhibit CYP2D6, CYP1A2, or CYP2C19: amiodarone, ciprofloxacin, cimetidine, delavirdine, fluconazole, fluoxetine, fluvoxamine, imipramine, isoniazid, paroxetine, quinidine, ritonavir, rizatriptan, teniposide, theophylline, tolbutamide, zileuton, zolmitriptan
  • Drugs that increase hepatic metabolism of propranolol: rifampin, ethanol, phenytoin, and phenobarbital
  • Neuroleptics/anxiolytics: (thioridazine, chlorpromazine - may increase propranolol level), haloperidol, valium
  • Illicit drugs such as cocaine or amphetamines.

• Other medical conditions

  • Sleep disorder other than OSA, including: restless leg syndrome, parasomnia, or narcolepsy.
  • Shift work or circadian rhythm disorder that is expected to prevent good sleep as scheduled in the protocol
  • Insulin-dependent diabetes mellitus
  • Myasthenia gravis
  • Pheochromocytoma
  • Uncontrolled bronchospastic lung disease such as asthma or chronic obstructive pulmonary disease (COPD)
  • Current smoking
  • Chronic renal or liver failure
  • Known pregnancy, by urine testing in women of child-bearing age; nursing mothers
  • Known hypersensitivity to any beta blocker
• History of falling asleep while driving, near miss
• High risk occupation (pilot, commercial driver) Hemoglobin < 10 g/dL on point of care screening

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo Oral Tablet; Subjects will be admitted to the clinical research unit. On the CPAP withdrawal nights, placebo of propranolol LA (Inderal ® LA) 80 mg will be administered orally at 6:30 PM, after dinner. Blood pressure will be measured before administration, at 10:30 PM, and 6:30 AM. They will sleep from 10:30 PM to 6:30 AM. During sleep blood will be sampled from an indwelling IV for measurement of FFA, glucose, insulin, and triglycerides. This arm will is crossed-over with active drug 1 week before or after this study night.	Drug: Propranolol Oral Tablet; Patients will receive Propranolol LA 80 mg PO at 7 PM before sleep (on CPAP withdrawal nights only); Other Names: beta blocker; Drug: Placebo Oral Tablet; Patients will receive Placebo tablet at 7 PM before sleep (on CPAP withdrawal nights only); Other Names: placebo
Active Comparator: Propranolol Oral Tablet; Subjects will be admitted to the clinical research unit. On the CPAP withdrawal nights, Propranolol LA (Inderal ® LA) 80 mg will be administered orally before sleep, at 6:30 PM, after dinner. Blood pressure will be measured before administration, at 10:30 PM, and 6:30 AM. They will sleep from 10:30 Pm to 6:30 AM. During sleep blood will be sampled from an indwelling IV for measurement of FFA, glucose, insulin, and triglycerides. This arm will be crossed-over to placebo 1 week later. This arm will is crossed-over with active drug 1 week before or after this study night.	Drug: Propranolol Oral Tablet; Patients will receive Propranolol LA 80 mg PO at 7 PM before sleep (on CPAP withdrawal nights only); Other Names: beta blocker; Drug: Placebo Oral Tablet; Patients will receive Placebo tablet at 7 PM before sleep (on CPAP withdrawal nights only); Other Names: placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Nocturnal Heart Rate (Beats/Min, BPM)	Average overnight heart rate (10:30 PM to 06:30 AM)	1 Night (approximately 4 hours post administration for each intervention), from 10:30 PM to 06:30 AM

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reactive Hyperemia Index (RHI)	Reactive Hyperemia Index (RHI) is measured by assessing the change in pulse wave amplitude in the brachial artery before and after a period of occlusion (usually 5 minutes). RHI is unitless as it reflects the ratio of pulse wave amplitude after : before occlusion. A high RHI indicates good endothelial function (values >1.67) and healthy vascular reactivity, while a low RHI (values <1.67) suggest endothelial dysfunction, which may be a risk factor for cardiovascular disease.	The morning after each intervention at 7:00 AM (approximately 11.5 hours post administration for each intervention)
Systolic Blood Pressure (mmHg)	Measured in the morning (7 AM)	The morning after each intervention at 7:00 AM (approximately 11.5 hours post administration for each intervention)
Diastolic Blood Pressure (mmHg)	Measured in the morning (7 AM)	The morning after each intervention at 7:00 AM (approximately 11.5 hours post administration for each intervention)
Augmentation Index (%)	The Augmentation Index (AIx) is measured by analyzing the arterial pulse wave, which captures the pressure wave reflections in the arteries. A higher AIx indicates increased arterial stiffness and higher cardiovascular risk, while a lower AIx suggests more compliant, healthier arteries. AIx can theoretically range from negative values to over 100%, although clinical values usually are between -10% and +40%.	The morning after each intervention at 7:00 AM (approximately 11.5 hours post administration for each intervention)

Collaborators and Investigators

• Sponsor: Johns Hopkins University
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Jonathan C Jun, MD, Johns Hopkins University

Study record dates

Study Major Dates

• Study Start (Actual): February 15, 2017
• Primary Completion (Actual): May 1, 2024
• Study Completion (Actual): May 1, 2024

Study Registration Dates

• First Submitted: December 6, 2016
• First Submitted That Met QC Criteria: February 9, 2017
• First Posted (Actual): February 10, 2017

Study Record Updates

• Last Update Posted (Actual): September 5, 2024
• Last Update Submitted That Met QC Criteria: August 14, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: Obstructive sleep apnea; CPAP; Propranolol; Metabolism
• Additional Relevant MeSH Terms: Nervous System Diseases; Respiratory Tract Diseases; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Signs and Symptoms, Respiratory; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Apnea; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents; Propranolol
• Other Study ID Numbers: IRB00113241; 1R03HL138068-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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