Contribution of Angiotensin II to Supine Hypertension in Autonomic Failure
Primary Purpose
Hypertension, Pure Autonomic Failure, Multiple System Atrophy
Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Losartan
Captopril
Placebo
Sponsored by
About this trial
This is an interventional basic science trial for Hypertension focused on measuring supine hypertension, autonomic failure, angiotensin, losartan, captopril
Eligibility Criteria
Inclusion Criteria:
- Patients with autonomic failure who exhibit supine hypertension and are in the hospital already participating in the study "The Evaluation and Treatment of Autonomic Failure [IRB # 000814]
- Supine hypertension, defined as systolic blood pressure > 150 mm Hg and/or diastolic blood pressure > 90 mm Hg
- Males and females of all races, between 18 to 85 years of age
- Able and willing to provide informed consent with the understanding that they may withdraw consent at any time without prejudice to future medical care
Exclusion Criteria:
- All medical students
- Pregnant women
- Patients with a history of angioedema
- Patients with a known allergy to any ACE inhibitor or angiotensin receptor blocker
- High-risk patients [e.g. heart failure, symptomatic coronary artery disease, liver impairment, history of stroke or myocardial infarction]
- Patients with hemoglobin < 10.5 [or hematocrit < 32]
- Inability to give, or withdraw, informed consent
- Other factors which in the investigator's opinion would prevent the patient from completing the protocol including clinically significant abnormalities in clinical, mental or laboratory testing
Sites / Locations
- Vanderbilt University
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Experimental
Placebo Comparator
Arm Label
Losartan
Captopril
Placebo Tablet
Arm Description
Angiotensin II AT1 receptor antagonist which blocks the actions of angiotensin II
ACE inhibitor which blocks the formation of angiotensin II
A placebo tablet will be provided by the Vanderbilt Investigational Drug Service for these studies.
Outcomes
Primary Outcome Measures
Changes in plasma renin activity and subsequent components of the circulating renin-angiotensin system
Changes in supine plasma renin activity and aldosterone following drug administration
Secondary Outcome Measures
Changes in blood pressure
Changes in supine blood pressure following drug administration
Changes in heart rate, cardiac output, stroke volume and systemic vascular resistance
Changes in supine systemic hemodynamics following drug administration
Full Information
NCT ID
NCT01292694
First Posted
February 8, 2011
Last Updated
August 22, 2018
Sponsor
Vanderbilt University
1. Study Identification
Unique Protocol Identification Number
NCT01292694
Brief Title
Contribution of Angiotensin II to Supine Hypertension in Autonomic Failure
Official Title
Contribution of Angiotensin II to Supine Hypertension in Autonomic Failure
Study Type
Interventional
2. Study Status
Record Verification Date
August 2018
Overall Recruitment Status
Terminated
Why Stopped
Could not enroll enough participants, and lost funding.
Study Start Date
March 2011 (Actual)
Primary Completion Date
March 2017 (Actual)
Study Completion Date
March 2017 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Vanderbilt University
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
The purpose of this study is to test the hypothesis that angiotensin II plays a role in the supine hypertension of primary autonomic failure. To determine the contribution of angiotensin II to renin and blood pressure regulation in autonomic failure, patients with multiple system atrophy [MSA] or pure autonomic failure [PAF] and supine hypertension will undergo medication testing with the angiotensin II receptor blocker losartan. The investigators will compare the biochemical and hemodynamic effects between MSA and PAF patients. In a subset of patients, the investigators will also give the ACE inhibitor captopril. Our primary endpoint will be changes in plasma renin activity, and subsequent components of the circulating renin-angiotensin system, in response to angiotensin II blockade. Our secondary outcome will be changes in hemodynamic measures during administration of these drugs.
Detailed Description
Primary autonomic failure is a disabling condition characterized by orthostatic hypotension. It is less well appreciated that at least 50% of these patients have high blood pressure when lying down [supine hypertension]. The mechanisms underlying supine hypertension in autonomic failure remain poorly understood. The hypertension in MSA patients may be explained by residual sympathetic tone, possibly acting on hypersensitive adrenoreceptors and unrestrained by the lack of baroreflex modulation. In contrast, the hypertension in PAF is associated with increased vascular resistance in the absence of residual sympathetic tone. However, the factors driving an elevation in either sympathetic or vascular tone in these patients remain unclear.
The investigators hypothesize that angiotensin II, a hormone widely implicated in blood pressure regulation, plays a role in the supine hypertension of autonomic failure. To determine the contribution of angiotensin II to renin and blood pressure regulation in autonomic failure, the investigators will administer the angiotensin II receptor blocker losartan to MSA and PAF patients with supine hypertension. The primary endpoint will be changes in plasma renin activity, and subsequent components of the circulating renin-angiotensin system, in response to angiotensin II blockade. The secondary outcomes will be the decrease in blood pressure and changes in heart rate, cardiac output, stroke volume and systemic vascular resistance during administration of these drugs.
Subjects will be studied on 2 separate days, one with oral administration of placebo and the other with losartan [50 mg]. The order of administration will be randomized in a single-blind manner. The investigators will collect blood samples before and every 2 hours after administration for up to 6 hours to determine if angiotensin II regulates plasma renin activity, and other components of the circulating renin-angiotensin system, in autonomic failure. The investigators will also obtain hemodynamic measurements before and every 1 hour (blood pressure and heart rate) or 2 hours (cardiac output, stroke volume and systemic vascular resistance) after drug administration.
In a subset of patients the investigators will also administer the ACE inhibitor captopril [50 mg] on a separate study day using the same methods. Captopril is less specific for assessing the role of angiotensin II to hypertension. However, it may provide important information on the mechanism for angiotensin II formation in these patients.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypertension, Pure Autonomic Failure, Multiple System Atrophy
Keywords
supine hypertension, autonomic failure, angiotensin, losartan, captopril
7. Study Design
Primary Purpose
Basic Science
Study Phase
Phase 1
Interventional Study Model
Crossover Assignment
Masking
Participant
Allocation
Randomized
Enrollment
12 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Losartan
Arm Type
Experimental
Arm Description
Angiotensin II AT1 receptor antagonist which blocks the actions of angiotensin II
Arm Title
Captopril
Arm Type
Experimental
Arm Description
ACE inhibitor which blocks the formation of angiotensin II
Arm Title
Placebo Tablet
Arm Type
Placebo Comparator
Arm Description
A placebo tablet will be provided by the Vanderbilt Investigational Drug Service for these studies.
Intervention Type
Drug
Intervention Name(s)
Losartan
Other Intervention Name(s)
Cozaar
Intervention Description
Oral, single-dose, 50 mg tablet
Intervention Type
Drug
Intervention Name(s)
Captopril
Other Intervention Name(s)
Capoten
Intervention Description
Oral, single-dose, 50 mg tablet
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Oral, single administration, gelatin capsule filled with microcrystalline cellulose
Primary Outcome Measure Information:
Title
Changes in plasma renin activity and subsequent components of the circulating renin-angiotensin system
Description
Changes in supine plasma renin activity and aldosterone following drug administration
Time Frame
0 - 6 hours post administration
Secondary Outcome Measure Information:
Title
Changes in blood pressure
Description
Changes in supine blood pressure following drug administration
Time Frame
0 - 6 hours post administration
Title
Changes in heart rate, cardiac output, stroke volume and systemic vascular resistance
Description
Changes in supine systemic hemodynamics following drug administration
Time Frame
0 - 6 hours post administration
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Patients with autonomic failure who exhibit supine hypertension and are in the hospital already participating in the study "The Evaluation and Treatment of Autonomic Failure [IRB # 000814]
Supine hypertension, defined as systolic blood pressure > 150 mm Hg and/or diastolic blood pressure > 90 mm Hg
Males and females of all races, between 18 to 85 years of age
Able and willing to provide informed consent with the understanding that they may withdraw consent at any time without prejudice to future medical care
Exclusion Criteria:
All medical students
Pregnant women
Patients with a history of angioedema
Patients with a known allergy to any ACE inhibitor or angiotensin receptor blocker
High-risk patients [e.g. heart failure, symptomatic coronary artery disease, liver impairment, history of stroke or myocardial infarction]
Patients with hemoglobin < 10.5 [or hematocrit < 32]
Inability to give, or withdraw, informed consent
Other factors which in the investigator's opinion would prevent the patient from completing the protocol including clinically significant abnormalities in clinical, mental or laboratory testing
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Italo Biaggioni, MD
Organizational Affiliation
Vanderbilt University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Vanderbilt University
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States
12. IPD Sharing Statement
Learn more about this trial
Contribution of Angiotensin II to Supine Hypertension in Autonomic Failure
We'll reach out to this number within 24 hrs