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Blood Pressure Lowering Effects of Angiotensin-(1-7) in Primary Autonomic Failure

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ClinicalTrials.gov Identifier: NCT02591173
Recruitment Status : Recruiting
First Posted : October 29, 2015
Last Update Posted : January 25, 2018
Sponsor:
Information provided by (Responsible Party):
Amy Arnold, Vanderbilt University

Brief Summary:
Pharmacologic approaches to increase levels or actions of the vasodilatory peptide angiotensin-(1-7) are currently in development for the treatment of hypertension based on findings from animal models. There are limited and contradictory clinical studies, however, and it is not clear if this peptide regulates blood pressure in humans. The purpose of this study is to better understand the cardiovascular effects angiotensin-(1-7) in human hypertension, and to examine interactions of this peptide with the autonomic nervous system. The investigators propose that the difficulties in showing angiotensin-(1-7) cardiovascular effects in previous clinical studies relates to the buffering capacity of the baroreceptor reflex to prevent changes in blood pressure. Autonomic failure provides the ideal patient population to test this hypothesis. These patients have loss of baroreflex buffering and have low levels of angiotensin-(1-7) in blood. The investigators will test if angiotensin-(1-7) infusion can lower blood pressure in patients with autonomic failure, and will determine the hemodynamic and hormonal mechanisms involved in this effect.

Condition or disease Intervention/treatment Phase
Autonomic Nervous System Disorders Pure Autonomic Failure Shy-Drager Syndrome Orthostatic Hypotension, Dysautonomic Drug: Angiotensin-(1-7) Drug: Saline Early Phase 1

Detailed Description:
This is an inpatient study that requires at least four days of admission to the Vanderbilt Clinical Research Center. Autonomic failure patients will be placed on a fixed diet during the admission and will have routine tests performed for screening and clinical characterization. Patients will then receive intravenous angiotensin-(1-7) or saline infusion on two separate study days, with each study day lasting approximately 3 hours. There will be at least one washout day between study days. Patients will be instrumented with two intravenous catheters (one for blood sampling and one for drug infusion), arm and finger blood pressure cuffs, and sticky patches to measure heart rate during the study. The investigators will take baseline measurements of blood pressure and heart rate and collect blood samples. The investigators will also perform a rebreathing test to measure the heart's pumping capacity. After baseline measurements, the investigators will infusion angiotensin-(1-7) or saline for 50 minutes. There will be five doses of angiotensin-(1-7). Each dose will be maintained for 10 minutes. The investigators will measure blood pressure and heart rate, repeat the rebreathing test, and collect blood samples at the end of each dosing period.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 22 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Blood Pressure Lowering Effects of Angiotensin-(1-7) in Primary Autonomic Failure
Actual Study Start Date : February 2016
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : December 2018


Arm Intervention/treatment
Experimental: Angiotensin-(1-7)
Patients will receive an intravenous infusion of five ascending doses of Angiotensin-(1-7). The doses are: 1, 2, 4, 8 and 16 ng/kg/min. Each dose will be maintained for 10 minutes, for a total of 50 minutes.
Drug: Angiotensin-(1-7)
This is a biologically active endogenous angiotensin peptide. It may play an important role in the regulation of blood pressure by dilating blood vessels.
Other Names:
  • Angiotensin I (1-7)
  • Angiotensin I/II (1-7) Acetate

Placebo Comparator: Saline
Patients will receive an intravenous infusion of saline that is matched in volume to the Angiotensin-(1-7) study day. The saline infusion will be maintained for 50 minutes.
Drug: Saline
Normal saline will be used as the placebo comparator.
Other Names:
  • normal saline
  • 0.9% sodium chloride




Primary Outcome Measures :
  1. Blood Presure [ Time Frame: 50 minutes ]
    The decrease in blood pressure following angiotensin-(1-7) versus saline infusion.


Secondary Outcome Measures :
  1. Heart Rate [ Time Frame: 50 minutes ]
    The change in heart rate following angiotensin-(1-7) versus saline infusion.

  2. Cardiac Output [ Time Frame: 50 minutes ]
    The change in cardiac output following angiotensin-(1-7) versus saline infusion.

  3. Stroke Volume [ Time Frame: 50 minutes ]
    The change in stroke volume following angiotensin-(1-7) versus saline infusion.

  4. Systemic Vascular Resistance [ Time Frame: 50 minutes ]
    The change in systemic vascular resistance following angiotensin-(1-7) versus saline infusion.

  5. Renin Activity [ Time Frame: 50 minutes ]
    The change in plasma renin activity following angiotensin-(1-7) versus placebo infusion.

  6. Angiotensin Peptides [ Time Frame: 50 minutes ]
    The change in plasma angiotensin peptides following angiotensin-(1-7) versus placebo infusion.

  7. Aldosterone [ Time Frame: 50 minutes ]
    The change in plasma aldosterone following angiotensin-(1-7) versus placebo infusion.



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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Males and females of all races between 18 to 80 years of age.
  • Diagnosed with primary autonomic failure and supine hypertension. Supine hypertension will be defined as systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 90 mmHg while lying down.
  • Able and willing to provide informed consent.

Exclusion Criteria:

  • Pregnancy or breast feeding.
  • Hemoglobin < 10.5 or hematocrit < 32.
  • High-risk patients (e.g. heart failure, symptomatic coronary artery disease, liver impairment, renal failure, history of stroke or myocardial infarction).
  • Inability to give or withdraw informed consent.
  • Other factors which in the investigator's opinion would prevent the patient from completing the protocol (e.g. clinically significant abnormalities on clinical, mental examination, or laboratory testing or inability to comply with the protocol).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02591173


Contacts
Contact: Bonnie K Black, RN adcresearch@vanderbilt.edu

Locations
United States, Tennessee
Vanderbilt University Recruiting
Nashville, Tennessee, United States, 37211
Contact: Bonnie K Black, RN       adcresearch@vanderbilt.edu   
Principal Investigator: Amy C Arnold, Ph.D.         
Sub-Investigator: Italo Biaggioni, M.D.         
Sub-Investigator: David Robertson, M.D.         
Sub-Investigator: Cyndya A Shibao, M.D.         
Sub-Investigator: Alfredo Gamboa, M.D.         
Sub-Investigator: Amanda Peltier, M.D.         
Sub-Investigator: Luis E Okamoto, M.D.         
Sub-Investigator: Jorge Celedonio Colquicocha, M.D.         
Sponsors and Collaborators
Vanderbilt University
Investigators
Principal Investigator: Amy C Arnold, PhD Vanderbilt University

Responsible Party: Amy Arnold, Research Instructor, Vanderbilt University
ClinicalTrials.gov Identifier: NCT02591173     History of Changes
Other Study ID Numbers: 151461
First Posted: October 29, 2015    Key Record Dates
Last Update Posted: January 25, 2018
Last Verified: January 2018

Keywords provided by Amy Arnold, Vanderbilt University:
Autonomic
Hypertension
Renin-Angiotensin System

Additional relevant MeSH terms:
Hypotension, Orthostatic
Hypotension
Pure Autonomic Failure
Nervous System Diseases
Shy-Drager Syndrome
Multiple System Atrophy
Autonomic Nervous System Diseases
Primary Dysautonomias
Vascular Diseases
Cardiovascular Diseases
Orthostatic Intolerance
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases
Angiotensin I (1-7)
Angiotensin II
Angiotensinogen
Antihypertensive Agents
Vasodilator Agents
Vasoconstrictor Agents
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action