Propranolol for Sleep Apnea Therapy

Study Overview
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Brief Summary
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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
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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 involves 3 visits, one visit on CPAP and the other 2 visits after CPAP withdrawal. Propranolol or placebo is given during the CPAP withdrawal visits. A sub-study called PROSAT 2 examines whether propranolol prevents changes in blood pressure, heart rate, and blood flow during sleep. PROSAT 2 involves only 2 visits, both after CPAP withdrawal. Propranolol or placebo is given during the CPAP withdrawal visits.

Official Title
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Propranolol for Sleep Apnea Therapy

Conditions
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Obstructive Sleep Apnea

Intervention / Treatment
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* Drug: Propranolol Oral Tablet
* Drug: Placebo Oral Tablet
* Device: CPAP


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo Oral Tablet<br>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 7 PM, after dinner. Blood pressure will be measured before administration, at 11 PM, and 7 AM. They will sleep from 11 Pm to 7 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. This visit is part of both the PROSAT 1.0 and PROSAT 2.0 study. | Drug: Propranolol Oral Tablet<br>* Patients will receive Propranolol LA 80 mg PO at 7 PM before sleep (on CPAP withdrawal nights only)<br>* Other names: beta blocker;Drug: Placebo Oral Tablet<br>* Patients will receive Placebo tablet at 7 PM before sleep (on CPAP withdrawal nights only)<br>* Other names: placebo;|
| Active Comparator: Propranolol Oral Tablet<br>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 7 PM, after dinner. Blood pressure will be measured before administration, at 11 PM, and 7 AM. They will sleep from 11 Pm to 7 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. This visit is part of both the PROSAT 1.0 and PROSAT 2.0 study. | Drug: Propranolol Oral Tablet<br>* Patients will receive Propranolol LA 80 mg PO at 7 PM before sleep (on CPAP withdrawal nights only)<br>* Other names: beta blocker;Drug: Placebo Oral Tablet<br>* Patients will receive Placebo tablet at 7 PM before sleep (on CPAP withdrawal nights only)<br>* Other names: placebo;|
| Active Comparator: CPAP<br>Subjects will be admitted to the clinical research unit. They will sleep wearing CPAP according to their usual home settings. Blood pressure will be measured before administration, at 11 PM, and 7 AM. They will sleep from 11 Pm to 7 AM. During sleep blood will be sampled from an indwelling IV for measurement of FFA, glucose, insulin, and triglycerides. This visit part of the PROSAT 1.0 study. | Device: CPAP<br>* Patients will sleep in the lab wearing CPAP<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Free fatty acid (FFA, mmol/L) | Serial blood samples taken before, during, and after sleep, 27 time points per night on 3 separate study visits. | 3 nights, <3 weeks apart completed within 1 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oral Glucose Tolerance Test (OGTT) | Serial blood samples taken before, during, and after sleep, 27 time points per night on 3 separate study visits. | 3 nights, <3 weeks apart completed within 1 month | 
| Reactive hyperemia Index | Measured in the morning after each sleep study (around 7 :30 am), using Itamar EndoPAT device. The data will be presented upon study completion. | 3 nights, <3 weeks apart completed within 1 month | 
| Blood pressure, mmHg | Measured before drug administration (7 PM), before sleep (9 PM, 11 PM) and in the morning (7 AM) on 3 separate visits. | 3 nights, <3 weeks apart completed within 1 month | 
| Heart rate | Measured before drug administration (7 PM), before sleep (9 PM, 11 PM) and in the morning (7 AM) on 3 separate visits. | 3 nights, <3 weeks apart completed within 1 month | 
| Sleep quality and side effect questionnaire | Questionnaire including questions about sleep quality and possible side effects from study drug on 3 separate visits. | 3 nights, <3 weeks apart completed within 1 month | 
| Glucose (mg/dl) | Serial blood samples taken before, during, and after sleep, 27 time points per night on 3 separate study visits. | 3 nights, <3 weeks apart completed within 1 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Obstructive sleep apnea, CPAP, Propranolol, Metabolism