Study of Cardiovascular Disease and Obstructive Sleep Apnea (CVD/OSA)

Pharmacologic Interventions for Cardiovascular Disease in Obstructive Sleep Apnea

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).

Study Overview

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

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 Type: Interventional
• Enrollment (Actual): 87
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Wisconsin
    • Green Bay, Wisconsin, United States, 54308
      • Aurora Bay Care
    • La Crosse, Wisconsin, United States, 54601
      • Gundersen Lutheran
    • Madison, Wisconsin, United States, 53705
      • University of Wisconsin Madison
    • Marshfield, Wisconsin, United States, 54449
      • Marshfield Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Losartan; Losartan 50 mg daily for two weeks, then increased to 100mg daily for 4 weeks if asymptomatic and blood pressure within range.	Drug: Losartan; Losartan 50 mg daily for two weeks, then increased to 100mg daily for 4 weeks if asymptomatic. Remain at 50 mg daily for 4 more weeks or removed from study if symptomatic.
Active Comparator: Allopurinol; Allopurinol 300 mg daily for 6 weeks	Drug: Allopurinol; Allopurinol 300 mg daily for 6 weeks
Placebo Comparator: Placebo; Placebo capsule daily for 6 weeks	Drug: Placebo; Placebo capsule daily for 6 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Muscle Sympathetic Nerve Activity Responses During Hypoxia	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.	baseline and 6 weeks

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: University of Wisconsin, Madison
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: John Dopp, Pharm.D., UW Madison School of Pharmacy; Principal Investigator: Barbara J Morgan, PhD, PT, UW Madison School of Medicine

Publications and helpful links

General Publications

• Morgan BJ, Teodorescu M, Pegelow DF, Jackson ER, Schneider DL, Plante DT, Gapinski JP, Hetzel SJ, Dopp JM. Effects of losartan and allopurinol on cardiorespiratory regulation in obstructive sleep apnoea. Exp Physiol. 2018 Jul;103(7):941-955. doi: 10.1113/EP087006. Epub 2018 Jun 8.

Study record dates

Study Major Dates

• Study Start: June 1, 2012
• Primary Completion (Actual): June 1, 2015
• Study Completion (Actual): June 1, 2015

Study Registration Dates

• First Submitted: June 29, 2012
• First Submitted That Met QC Criteria: July 6, 2012
• First Posted (Estimate): July 11, 2012

Study Record Updates

• Last Update Posted (Actual): August 14, 2020
• Last Update Submitted That Met QC Criteria: August 13, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Keywords: Hypertension; OSA; Obstructive Sleep Apnea; Sleep Apnea; High Blood Pressure
• Additional Relevant MeSH Terms: Vascular Diseases; Nervous System Diseases; Respiratory Tract Diseases; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Signs and Symptoms, Respiratory; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Hypertension; Cardiovascular Diseases; Apnea; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites; Protective Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Antioxidants; Free Radical Scavengers; Gout Suppressants; Losartan; Allopurinol
• Other Study ID Numbers: 2012-0026; A561000 (Other Identifier: UW Madison); PHARM/PHARMACY/PHARMACY (Other Identifier: UW Madison); U01HL105365 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No