Propranolol for Sleep Apnea Therapy

Phase 2

Completed

• Conditions: Obstructive Sleep Apnea
• Interventions: Drug: Propranolol Oral Tablet; Drug: Placebo Oral Tablet

• Registration Number: NCT03049306
• Lead Sponsor: Johns Hopkins University

Brief Summary

The primary objective in this study is to test whether propranolol lowers glucose and free fatty acid levels during sleep in obstructive sleep apnea (OSA), and preserves vascular function (EndoPAT) versus placebo. The secondary objective is to test whether propranolol influences sleep quality, architecture, and hemodynamics in OSA. OSA will be elicited by temporarily discontinuing CPAP therapy in patients with a history OSA accustomed to CPAP therapy (CPAP withdrawal).

Detailed Description

Free fatty acids and glucose elevations occur during the night in obstructive sleep apnea (OSA) patients, and these elevations may be responsible for adverse cardio-metabolic consequences of OSA. The sympathetic nervous system is well known to mediate adipose tissue lipolysis as well as "stress hyperglycemia". Thus, investigators may be able to mitigate these nocturnal metabolic changes with beta adrenergic blockade. 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 compare nocturnal metabolic profiles and hemodynamics on/off propranolol in the setting of CPAP withdrawal.

This study examines whether propranolol prevents changes in blood pressure, heart rate, and blood flow during sleep during CPAP withdrawal. Propranolol or placebo is given during the CPAP withdrawal visits.

Study Timeline

• Study First Submitted: 2016-12-06
• Study First Submitted QC: 2017-02-09
• Study First Posted: 2017-02-10
• Study Start: 2017-02-15
• Status Verified: 2024-05
• Primary Completion: 2024-05-01
• Study Completion: 2024-05-01
• Last Update Submitted: 2024-05-16
• Last Update Posted: 2024-05-20

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 23

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Placebo Oral Tablet	Propranolol 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.
Placebo Oral Tablet	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.
Propranolol Oral Tablet	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.
Propranolol Oral Tablet	Placebo 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.

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Reactive Hyperemia Index (RHI)	The morning after each intervention at 7:00 AM (approximately 11.5 hours post administration for each intervention)	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.
Diastolic Blood Pressure (mmHg)	The morning after each intervention at 7:00 AM (approximately 11.5 hours post administration for each intervention)	Measured in the morning (7 AM)
Augmentation Index (%)	The morning after each intervention at 7:00 AM (approximately 11.5 hours post administration for each intervention)	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%.
Systolic Blood Pressure (mmHg)	The morning after each intervention at 7:00 AM (approximately 11.5 hours post administration for each intervention)	Measured in the morning (7 AM)

Trial Locations

Locations (1)

Johns Hopkins Bayview Medical Center; 🇺🇸 Baltimore, Maryland, United States