Treatment of OSA Associated Hypertension With Nebivolol or Hydrochlorothiazide (nebhctz)

A Blinded Crossover Study of the 24 Hour Blood Pressure Response to Treatment of Obstructive Sleep Apnea Associated Hypertension With Nebivolol or Hydrochlorothiazide

Patients who have obstructive sleep apnea (OSA) frequently stop breathing while they sleep. They often develop high blood pressure. We are not sure what drug is best to treat the high blood pressure. This study will give the patients nebivolol or hydrochlorothiazide (HCTZ) for 6 weeks after 2 weeks of placebo. The blood pressure response will be evaluated by 24 hour monitoring.

Study Overview

• Status: Completed
• Conditions: Hypertension
• Intervention / Treatment: Drug: Nebivolol; Drug: Hydrochlorothiazide

Detailed Description

This is a blinded crossover study measuring the antihypertensive efficacy of nebivolol vs HCTZ in up to 34 subjects. Subjects with an apnea-hypopnea index (AHI) > 10 and hypertension can enter the study. Hypertension is defined as a systolic blood pressure (SBP) > 140 or a diastolic blood pressure (DBP) > 90 on the average of three seated blood pressure measurements or a history of medical therapy for hypertension. Subjects who have tried and abandoned continuous positive airway pressure (CPAP) therapy for sleep apnea are eligible for this study. All others will be advised that CPAP is preferred treatment for sleep apnea and are eligible only if they decline CPAP or use it for too short a time at night to be effective.

Then patients will have their antihypertensive drugs tapered off and receive single blind placebo for two weeks. After that, all subjects receive nebivolol or HCTZ for six weeks with a full evaluation at that time. Subjects are crossed over to HCTZ 12.5 mg for 2 weeks followed by HCTZ 25 mg for 4 more weeks. Nebivolol 5 mg will be taken daily at bedtime for 2 weeks and then as a dose of 10 mg for the remaining 4 weeks. Subjects will receive a telephone call at the time of increased dosage as a reminder. Blood, urine and 24-hour blood pressure measurements, hemodynamic measurements, questionnaires and drug accountability are measured in the same manner toward at the the end of placebo and each drug treatment. The entire study will take 14 weeks, although each study period may be lengthened by one week if necessary for the convenience of the subject's personal schedule.

Patients will provide blood pressure readings from their home monitor or in clinic and will not have the dose increased if they have systolic blood pressure below 105 mm Hg or side effects suggesting that an increased dose might worsen side effects

At the end of each treatment period, subjects will undergo noninvasive hemodynamic testing. Ultrasound will be used to measure aortic diameter and blood velocity in the ascending aorta in order to better estimate cardiac output. Then, finger plethysmography will be used to acquire beat-to-beat finger blood pressure and pulse rate. Beat-to-beat derived hemodynamic variables will be calculated by a model flow algorithm (e.g. brachial artery flow, stroke volume, cardiac output, ejection time, blood pressure rate of change, peripheral resistance). Applanation tonometry will be used to obtain pulse wave velocity and central arterial pressure. ECG will be recorded with standard ECG leads to determine heart rate variability in both time and frequency domains. Spontaneous baroreflex will be determined from beat-to-beat changes in blood pressure and pulse pressure interval. Forearm reactive hyperemia will be used to quantify endothelial dysfunction during 4 minutes of post-ischemic change. Subjects will then complete an Epworth Sleepiness Scale questionnaire (ESS) and a Functional Outcomes of Sleep Questionnaire (FOSQ) to find whether they are drowsy in the daytime and if they feel that they are compromised by not having adequate rest. Any adverse event will be recorded. They are asked about any concurrent medication over the prior period, including prescription medication, over the counter medication, and caffeine intake. Medication compliance is evaluated by pill count. Those who fail to return their pill bottle are requested to bring it in. Finally, a 24-hour ambulatory blood pressure monitor (ABPM) will be attached to automatically collect blood pressure and heart rate values every 15 minutes during the wake period and every 30 minutes during the sleep period.

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 4

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients ranging from 20 - 80 years
• Body mass index (BMI) of 20-38 to include the typical obese OSA patients
• Hypertension with blood pressures > 140/90 but less than 180/105 mmHg.
• Apnea-hypopnea index above 10

Exclusion Criteria:

• Receiving sleep medicines (including heavy alcohol use) or drugs with adverse interactions with study medication.
• Women who have premenstrual syndrome, or those who are pregnant or capable of pregnancy and unwilling to use effective non-hormonal contraception
• Shift workers or have symptoms of narcolepsy, restless legs syndrome or insomnia, in order to minimize confounding effects of other sleep disorders
• Have apneas which are primarily central
• Have sleep fragmentation caused by syndromes such as chronic pain or movement disorders
• Have diseases such as asthma or chronic obstructive pulmonary disease that compromises respiration.
• Have known coronary or cerebral vascular disease, history of arrhythmias, cardiomyopathy, history of psychosis, current alcohol or drug abuse.
• Have any contraindications to any study materials, such as heart block.
• Have secondary hypertension
• Have creatinine levels above 2.5 mg %, more than 1+ proteinuria by dipstick, hematuria or electrolyte disorders.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Placebo, Nebivolol, Hydrochlorothyazide; Sequence: Placebo, Then Nebivolol 5mg for 2 weeks followed by nebivolol 10 mg for 4 weeks,Then Hydrochlorothiazide 12.5 mg for 2 weeks followed by hydrochlorothiazide 25 mg for 4 weeks.	Drug: Nebivolol; Nebivolol 5mg then nebivolol 10 mg; Other Names: Bystolic; Drug: Hydrochlorothiazide; Hydrochlorothiazide 12.5 mg then hydrochlorothiazide 25 mg; Other Names: Hydrodiuril
Experimental: Placebo, Hydrochlorothyazide, Nebivolol; Sequence: Placebo, Then Hydrochlorothiazide 12.5 mg for 2 weeks followed by hydrochlorothiazide 25 mg for 4 weeks, Then Nebivolol 5mg for 2 weeks followed by nebivolol 10 mg for 4 weeks.	Drug: Nebivolol; Nebivolol 5mg then nebivolol 10 mg; Other Names: Bystolic; Drug: Hydrochlorothiazide; Hydrochlorothiazide 12.5 mg then hydrochlorothiazide 25 mg; Other Names: Hydrodiuril

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
24-h, Wake and Sleep Period Systolic and Diastolic Blood Pressure	24-h Systolic Blood Pressure is the average of all 24-h Ambulatory Systolic Blood Pressure recordings. The Wake Period Systolic Blood Pressure is the average of all Systolic Blood Pressures recorded every 15 minutes during the wake period. The Sleep Period Systolic Blood pressure is the average of all Systolic Blood Pressures recorded every 30 minutes during the sleep period. 24-h Diastolic Blood Pressure is the average of all 24-h Ambulatory Diastolic Blood Pressure recordings. The Wake Period Diastolic Blood Pressure is the average of all Diastolic Blood Pressures recorded every 15 minutes during the wake period. The Sleep Period Diastolic Blood pressure is the average of all Diastolic Blood Pressures recorded every 30 minutes during the sleep period.	At the end of 2 weeks of placebo therapy, at the end of 6 weeks of Nebivolol therapy and at the end of 6 weeks of hydrochlorothiazide therapy.

Collaborators and Investigators

• Sponsor: University of California, San Diego
• Investigators: Principal Investigator: Michael G. Ziegler, M.D., Professor of Medicine

Publications and helpful links

General Publications

• Ziegler MG, Milic M, Sun P. Antihypertensive therapy for patients with obstructive sleep apnea. Curr Opin Nephrol Hypertens. 2011 Jan;20(1):50-5. doi: 10.1097/MNH.0b013e3283402eb5.

Study record dates

Study Major Dates

• Study Start: January 1, 2015
• Primary Completion (Actual): April 1, 2016
• Study Completion (Actual): April 1, 2016

Study Registration Dates

• First Submitted: March 7, 2016
• First Submitted That Met QC Criteria: March 11, 2016
• First Posted (Estimate): March 16, 2016

Study Record Updates

• Last Update Posted (Actual): October 19, 2020
• Last Update Submitted That Met QC Criteria: September 22, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Adrenergic Agonists; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Adrenergic beta-Agonists; Sodium Chloride Symporter Inhibitors; Adrenergic beta-1 Receptor Agonists; Hydrochlorothiazide; Nebivolol
• Other Study ID Numbers: 110342

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: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No