Study of Cardiovascular Disease and Obstructive Sleep Apnea

Phase 2

Completed

• Conditions: Severe Obstructive Sleep Apnea (Apnea Hypopnea Index > 30 Events/Hour); Hypertension
• Interventions: Drug: Allopurinol; Drug: Placebo; Drug: Losartan

• Registration Number: NCT01637623
• Lead Sponsor: University of Wisconsin, Madison

Brief Summary

The purpose of this study is to determine if two medicines (allopurinol and losartan) can influence heart and blood vessel health compared to placebo in patients with sleep apnea who are using continuous positive airway pressure (CPAP).

Detailed Description

The specific aims of this research project are: 1) Determine if treatment with losartan, an angiotensin type I receptor (AT1R) antagonist, or allopurinol, a XO inhibitor, normalize chemoreflex control of sympathetic outflow and ventilation and improve local vascular regulation and stiffness; and 2) Determine if these interventions reduce the severity of sleep disordered breathing and lower diurnal blood pressure.

Study Timeline

• Study Start: 2012-06
• Study First Submitted: 2012-06-29
• Study First Submitted QC: 2012-07-06
• Study First Posted: 2012-07-11
• Primary Completion: 2015-06
• Study Completion: 2015-06
• Results First Submitted: 2018-08-06
• Status Verified: 2020-08
• Results First Submitted QC: 2020-08-13
• Last Update Submitted: 2020-08-13
• Results First Posted: 2020-08-14
• Last Update Posted: 2020-08-14

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 87

Inclusion Criteria

• Males and females between ages of 21 and 65 years
• Apnea hypopnea index or respiratory disturbance index greater than or equal to 25 events per hour
• Subjects eligible for CPAP or BiPAP therapy
• Hypertension by clinical history/diagnosis (may be controlled with non- exclusionary medications) or average blood pressure > 140/90 mm Hg (using last two measurements in prior 12 months - or 1 prior blood pressure and 1 blood pressure at screening)

Exclusion Criteria

• If subject not using CPAP, having AHI > 60 events/hour or oxygen saturation ≤ 65% during sleep
• Presence of clinical CV disease (coronary artery disease, angina, arrhythmias (subjects with sinus arrhythmias will be reviewed by PI for enrollment), stroke, TIA, cor pulmonale, etc.), heart failure, bruits, or diabetes mellitus by clinical diagnosis/history
• Presence of pulmonary disease that results in significant hypoxemia (resting SaO2 < 88%)
• Hypertriglyceridemia (triglycerides >300 mg/dL), diabetes or impaired glucose tolerance (fasting plasma glucose > 125 mg/dL)
• Patients taking angiotensin converting enzyme inhibitors, angiotensin receptor antagonists, potassium-sparing diuretics (without accompanying loop/thiazide diuretic), allopurinol, oxypurinol, febuxostat, amoxicillin, ampicillin, azathioprine or mercaptopurine.
• Patients with chronic kidney disease (Serum creatinine >1.5 mg/dL) or history of significant hyperkalemia (Serum potassium > 5.2 mEq/L) with ARB therapy
• Patients with history of angioedema
• Patients with bilateral,modified radical or radical mastectomies
• Patients who have a Serum potassium > 5.0 mEq/L at the screening visit
• Female patients who are pregnant (determined by urine pregnancy test) or breastfeeding
• Patients with active MRSA or VRE (vancomycin resistant enterococcus) infection
• History of adverse reaction to allopurinol,losartan, or zolpidem**
• Patients who cannot swallow oral capsules
• Patients who are hospitalized or who have been recently hospitalized (last 2 weeks)
• Inability to comply with or complete the protocol or other reasons at the discretion of the investigators

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Allopurinol	Allopurinol	Allopurinol 300 mg daily for 6 weeks
Placebo	Placebo	Placebo capsule daily for 6 weeks
Losartan	Losartan	Losartan 50 mg daily for two weeks, then increased to 100mg daily for 4 weeks if asymptomatic and blood pressure within range.

Primary Outcome Measures

Name	Time	Method
Change in Muscle Sympathetic Nerve Activity Responses During Hypoxia	baseline and 6 weeks	The primary outcome variable is the change in the individual slope of the MSNA - SaO2 response curve at 6 weeks and baseline between treatment groups.

Secondary Outcome Measures

Name	Time	Method
Change in Aortic Pulse Wave Velocity	baseline and 6 weeks	measurement of vascular stiffness assessed before and after study drug treatment
Cerebrovascular Conductance	baseline and 6 weeks	Assessment measures of cerebral blood flow during basal conditions and during graded hypoxia before and after study drug treatment. Cerebrovascular conductance (CVC) was calculated as velocity-time integral/mean arterial pressure.
Forearm Vascular Conductance	baseline and 6 weeks	Assessment measurements of forearm vascular conductance during basal conditions and during graded hypoxia before and after study drug treatment.
Change in Minute Ventilation at Normoxia	baseline and 6 weeks	assessed before and after study drug treatment
Change in Minute Ventilation During Hypoxia	baseline and 6 weeks	assessed before and after study drug treatment
Aortic Augmentation Index	baseline and 6 weeks	assessed before and after study drug treatment
Mean Change in PERCENT Vasodilation	baseline and 6 weeks	Flow-mediated vasodilation (FMD) (measurement of vascular endothelial function) assessed before and after study drug treatment
Apnea-Hypopnea Index	baseline and 6 weeks	Severity of sleep apnea assessed before and after study drug treatment
PERCENT Time Spent Below 88 PERCENT Oxygen Saturation	baseline and 6 weeks	assessed before and after study drug treatment
Change in Mean 24-Hour Blood Pressure (Mean Arterial Pressure)	baseline and 6 weeks	Change in mean 24 hour blood pressure (mean arterial pressure)

Trial Locations

Locations (4)

Marshfield Clinic; 🇺🇸 Marshfield, Wisconsin, United States

Gundersen Lutheran; 🇺🇸 La Crosse, Wisconsin, United States

Aurora Bay Care; 🇺🇸 Green Bay, Wisconsin, United States

University of Wisconsin Madison; 🇺🇸 Madison, Wisconsin, United States