nebhctz: Treatment of OSA Associated Hypertension With Nebivolol or Hydrochlorothiazide

• Sponsor: University of California, San Diego (Other)
• Overall Status: Completed
• CT.gov ID: NCT02710071
• Collaborator: (none)
• Enrollment: 41
• Arms: 2
• Duration (Months): 15

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Hypertension	Drug: Nebivolol; Drug: Hydrochlorothiazide	Phase 4

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 Design

• Study Type: Interventional
• Actual Enrollment: 41 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Blinded Crossover Study of the 24 Hour Blood Pressure Response to Treatment of Obstructive Sleep Apnea Associated Hypertension With Nebivolol or Hydrochlorothiazide
• Study Start Date: Jan 1, 2015
• Actual Primary Completion Date: Apr 1, 2016
• Actual Study Completion Date: Apr 1, 2016

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 24-h, Wake and Sleep Period Systolic and Diastolic Blood Pressure [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.]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 30 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• University of California, San Diego

Investigators

• Principal Investigator: Michael G. Ziegler, M.D., Professor of Medicine

Study Documents (Full-Text)

None provided.

More Information

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. Review.

• Responsible Party: Michael G. Ziegler, Professor of Medicine, University of California, San Diego
• ClinicalTrials.gov Identifier: NCT02710071
• Other Study ID Numbers: 110342
• First Posted: Mar 16, 2016
• Last Update Posted: Oct 19, 2020
• Last Verified: Sep 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Hypertension; Hydrochlorothiazide; Nebivolol

Study Results

Participant Flow

Pre-assignment Detail	41 of 405 participants were randomized. Of those not randomized, 364 did not meet inclusion criteria

Arm/Group Title	Placebo, Then Nebivolol, Then Hydrochlorothyazide	Placebo, Then Hydrochlorothiazide, Then Nebivolol
Arm/Group Description	The participants first received Placebo for 2 weeks. They then received nebivolol 5 mg for 2 weeks followed by nebivolol 10 mg for 4 weeks. They then received hydrochlorothyazide 12.5 mg for 2 weeks followed by hydrochlorothyazide 25 mg for 4 weeks.	The participants first received Placebo for 2 weeks. They then received hydrochlorothyazide 12.5 mg for 2 weeks followed by hydrochlorothyazide 25 mg for 4 weeks. They then received nebivolol 5 mg for 2 weeks followed by nebivolol 10 mg for 4 weeks.
Period Title: Placebo (2 Weeks).
STARTED	21	20
COMPLETED	21	20
NOT COMPLETED	0	0
Period Title: Placebo (2 Weeks).
STARTED	21	20
COMPLETED	18	16
NOT COMPLETED	3	4
Period Title: Placebo (2 Weeks).
STARTED	18	16
COMPLETED	17	14
NOT COMPLETED	1	2

Baseline Characteristics

Arm/Group Title	Placebo, Then Nebivolol, Then Hydrochlorothiazide	Placebo, Then Hydrochlorothiazide, Then Nebivolol	Total
Arm/Group Description	The participants first received Placebo for 2 weeks. They then received nebivolol 5 mg for 2 weeks followed by nebivolol 10 mg for 4 weeks. They then received hydrochlorothyazide 12.5 mg for 2 weeks followed by hydrochlorothyazide 25 mg for 4 weeks.	The participants first received Placebo for 2 weeks. They then received hydrochlorothyazide 12.5 mg for 2 weeks followed by hydrochlorothyazide 25 mg for 4 weeks. They then received nebivolol 5 mg for 2 weeks followed by nebivolol 10 mg for 4 weeks.	Total of all reporting groups
Overall Participants	21	20	41
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	18 85.7%	19 95%	37 90.2%
>=65 years	3 14.3%	1 5%	4 9.8%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50 (10)	54 (11)	52 (11)
Sex: Female, Male (Count of Participants)
Female	4 19%	2 10%	6 14.6%
Male	17 81%	18 90%	35 85.4%
Region of Enrollment (participants) [Number]
United States	21 100%	20 100%	41 100%
24-h Ambulatory Diastolic Blood Pressure (mmHg) [Mean (Standard Deviation) ]
24-h diastolic blood pressure	86 (11)	79 (11)	82 (10)
Wake diastolic blood pressure	89 (11)	83 (10)	86 (10)
Sleep diastolic blood pressure	78 (11)	74 (10)	76 (10)

Outcome Measures

1. Primary Outcome

Title	24-h, Wake and Sleep Period Systolic and Diastolic Blood Pressure
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

The overall Number of Analyzed Participants for primary outcome (27) differs from the Overall Number of Placebo (baseline) Participants (41) because 14 participants were excluded from the analysis due to either low quality of acquired data or due to missing data. Data Analysis was performed for the same 27 participants and for the each test period.

Arm/Group Title	Placebo	Nebivolol	Hydrochlorothiazide
Arm/Group Description	Placebo for 2 weeks.	Nebivolol 5 mg for 2 weeks followed by nebivolol 10 mg for 4 weeks.	Hydrochlorothiazide 12.5 mg for 2 weeks followed by hydrochlorothiazide 25 mg for 4 weeks.
Measure Participants	27	27	27
24-h systolic blood pressure	137 (3.1)	130 (2.5)	133 (2.9)
24-h diastolic blood pressure	82 (1.9)	77 (1.6)	80 (1.9)
Wake systolic blood pressure	141 (3.1)	135 (2.5)	138 (3.1)
Wake diastolic blood pressure	86 (1.9)	81 (1.7)	85 (2.1)
Sleep systolic blood pressure	129 (3.2)	123 (2.9)	127 (3.0)
Sleep diastolic blood pressure	76 (2.0)	71 (2.02)	75 (2.15)

Adverse Events

Time Frame	16 weeks.
Arm/Group Title	Placebo, Then Nebivolol, Then Hydrochlorothyazide		Placebo, Then Hydrochlorothyazide, Then Nebivolol
Arm/Group Description	Participants first received Placebo for 2 weeks. They then received nebivolol 5 mg for 2 weeks followed by nebivolol 10 mg for 4 weeks. They then received hydrochlorothyazide 12.5 mg for 2 weeks followed by hydrochlorothyazide 25 mg for 4 weeks.		Participants first received Placebo for 2 weeks. They then received hydrochlorothyazide 12.5 mg for 2 weeks followed by hydrochlorothyazide 25 mg for 4 weeks. They then received nebivolol 5 mg for 2 weeks followed by nebivolol 10 mg for 4 weeks.
All Cause Mortality
	Placebo, Then Nebivolol, Then Hydrochlorothyazide		Placebo, Then Hydrochlorothyazide, Then Nebivolol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/21 (0%)		0/20 (0%)
Serious Adverse Events
	Placebo, Then Nebivolol, Then Hydrochlorothyazide		Placebo, Then Hydrochlorothyazide, Then Nebivolol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/21 (0%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	Placebo, Then Nebivolol, Then Hydrochlorothyazide		Placebo, Then Hydrochlorothyazide, Then Nebivolol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/21 (0%)		0/20 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.