<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02245230</url>
  </required_header>
  <id_info>
    <org_study_id>140958</org_study_id>
    <nct_id>NCT02245230</nct_id>
  </id_info>
  <brief_title>Cardiovascular Effects of Angiotensin (1-7) in Essential Hypertension</brief_title>
  <official_title>Cardiovascular Effects of Angiotensin (1-7) in Essential Hypertension</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Vanderbilt University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Vanderbilt University Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to better understand the cardiovascular effects of the&#xD;
      vasodilatory peptide Angiotensin (1-7) in human hypertension. In this study, the&#xD;
      investigators will test the hypothesis that systemic Angiotensin (1-7) infusion produces&#xD;
      negligible effects with intact baroreceptors, and that the cardiovascular effects of this&#xD;
      peptide are unmasked following elimination of baroreflex buffering.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Pharmacologic approaches to increase levels or actions of the vasodilatory peptide&#xD;
      Angiotensin (1-7) are currently in development for the treatment of hypertension based on&#xD;
      findings from animal studies. There are limited and contradictory clinical studies, however,&#xD;
      and it is unclear if this peptide even contributes to blood pressure regulation in humans.&#xD;
      The purpose of this study is to learn more about the cardiovascular effects of Angiotensin&#xD;
      (1-7) in essential hypertension, and to examine interactions of this peptide with the&#xD;
      autonomic nervous system for blood pressure regulation. The investigators propose that the&#xD;
      difficulties in showing Angiotensin (1-7) cardiovascular effects in previous clinical studies&#xD;
      relates to the buffering capacity of the baroreceptor reflex to prevent changes in blood&#xD;
      pressure. In this study, the investigators will test the hypothesis that Angiotensin (1-7)&#xD;
      produces negligible effects with intact baroreceptors, and that the cardiovascular effects of&#xD;
      this peptide are unmasked following elimination of baroreflex buffering. To test this&#xD;
      hypothesis, the investigators will examine the effects of acute intravenous Angiotensin (1-7)&#xD;
      infusion on blood pressure in subjects with essential hypertension under intact conditions&#xD;
      and following acute autonomic withdrawal with the ganglionic blocker trimethaphan. The&#xD;
      primary outcome will be the decrease in systolic blood pressure produced by Angiotensin (1-7)&#xD;
      infusion, with comparisons made between intact and blocked study days. As a secondary&#xD;
      objective, the investigators will examine for changes in systemic hemodynamics and&#xD;
      circulating hormones in response to the Angiotensin (1-7) infusion, to determine potential&#xD;
      mechanisms underlying any changes in blood pressure.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">January 2015</start_date>
  <completion_date type="Anticipated">December 2026</completion_date>
  <primary_completion_date type="Anticipated">December 2025</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Systolic Blood Pressure</measure>
    <time_frame>Change from baseline in systolic blood pressure over the 50-minute infusion period</time_frame>
    <description>The primary outcome will be the change in systolic blood pressure from baseline produced by the Angiotensin (1-7) infusion, with comparisons made between intact and autonomic blockade study days.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Hemodynamic Measures</measure>
    <time_frame>Change from baseline in hemodynamic measures over the 50-minute infusion period</time_frame>
    <description>We will examine for changes in cardiac output, stroke volume, and systemic vascular resistance to determine hemodynamic mechanisms underlying any changes in blood pressure during Angiotensin (1-7) infusion.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Circulating Renin-Angiotensin System Components</measure>
    <time_frame>Change from baseline in circulating renin-angiotensin system components over the 50-minute infusion period</time_frame>
    <description>We will examine for changes in plasma renin activity, angiotensin II, Angiotensin (1-7), and aldosterone levels to determine renin-angiotensin system hormonal mechanisms underlying any changes in blood pressure during Angiotensin (1-7) infusion.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">34</enrollment>
  <condition>Hypertension</condition>
  <condition>Hypertension, Essential</condition>
  <arm_group>
    <arm_group_label>Intact Study Day</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Subjects will receive saline infusion for 60 minutes followed by five ascending doses of Angiotensin (1-7) ranging from 0.5 to 20 ng/kg/min. Each dose will be maintained for 10 minutes with hemodynamic measurements and blood samples collected at the end of each dosing period.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Autonomic Blockade Study Day</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Autonomic blockade will be induced by continuous intravenous infusion of trimethaphan starting at 0.5-1.0 mg/min and increasing by 1.0 mg/min every 2 to 6 minutes up to an infusion rate of 5 mg/min. Blood pressure will be restored to pre-trimethaphan levels with intravenous phenylephrine infusion at individually titrated doses, starting with 0.1 ug/kg/min. Angiotensin (1-7) will then be infused in five ascending doses ranging from 0.5 to 20 ng/kg/min. Each dose will be maintained for 10 minutes with hemodynamic measurements and blood samples collected at the end of each dosing period.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Angiotensin (1-7)</intervention_name>
    <description>Angiotensin (1-7) is a peptide produced by the body. It will be administered as an acute intravenous infusion with doses ranging from 0.5 to 20 ng/kg/min.</description>
    <arm_group_label>Autonomic Blockade Study Day</arm_group_label>
    <arm_group_label>Intact Study Day</arm_group_label>
    <other_name>Angiotensin-(1-7)</other_name>
    <other_name>Angiotensin I (1-7)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Trimethaphan</intervention_name>
    <description>Trimethaphan is a Nn-nicotinic receptor antagonist that blocks sympathetic and parasympathetic transmission at the level of the autonomic ganglia. It will be administered as an acute intravenous infusion with doses ranging from 0.5 to 5.0 mg/min.</description>
    <arm_group_label>Autonomic Blockade Study Day</arm_group_label>
    <other_name>Trimethaphan Camsylate</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Phenylephrine</intervention_name>
    <description>Phenylephrine is an alpha 1-adrenergic agonist. It will be administered as an acute intravenous infusion to restore blood pressure following trimethaphan with doses ranging from 0.1 to 0.5 ug/kg/min.</description>
    <arm_group_label>Autonomic Blockade Study Day</arm_group_label>
    <other_name>Phenylephrine Hydrochloride</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Males and females of all races between 18 and 60 years of age&#xD;
&#xD;
          -  Hypertension defined by two or more properly measured seated blood pressure readings&#xD;
             &gt;130/85 mmHg. This will allow us to include subjects with &quot;pre-hypertension.&quot;&#xD;
&#xD;
          -  Able and willing to provide informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnancy or breast feeding&#xD;
&#xD;
          -  Current smokers or history of heavy smoking (&gt;2 packs/day)&#xD;
&#xD;
          -  History of alcohol or drug abuse&#xD;
&#xD;
          -  Previous allergic reaction to study medications&#xD;
&#xD;
          -  Evidence of type I or type II diabetes (i.e. fasting glucose &gt;126 mg/dl, use of&#xD;
             anti-diabetic medications)&#xD;
&#xD;
          -  Cardiovascular disease other than hypertension such as myocardial infarction within 6&#xD;
             months prior to enrollment, presence of angina pectoris, significant arrhythmia,&#xD;
             congestive heart failure (LV hypertrophy acceptable), deep vein thrombosis, pulmonary&#xD;
             embolism, second or third degree heart block, mitral valve stenosis, aortic stenosis,&#xD;
             or hypertrophic cardiomyopathy&#xD;
&#xD;
          -  History of serious cerebrovascular disease such as cerebral hemorrhage, stroke, or&#xD;
             transient ischemic attack&#xD;
&#xD;
          -  History or presence of immunological or hematological disorders&#xD;
&#xD;
          -  Impaired hepatic function [aspartate amino transaminase (AST) and/or alanine amino&#xD;
             transaminase (ALT) &gt; 2.0 x upper limit of normal range]&#xD;
&#xD;
          -  Impaired renal function (serum creatinine &gt;1.5 mg/dl)&#xD;
&#xD;
          -  Anemia (hemoglobin &lt;13.5 g/dl in males or &lt;12.5 g/dl in females)&#xD;
&#xD;
          -  Treatment with phosphodiesterase 5 inhibitors&#xD;
&#xD;
          -  Treatment with anticoagulants&#xD;
&#xD;
          -  Treatment with chronic systemic glucocorticoid therapy (more than 7 consecutive days&#xD;
             in 1 month)&#xD;
&#xD;
          -  Treatment with any investigational drug in the 1 month preceding the study&#xD;
&#xD;
          -  Inability to give, or withdraw, informed consent&#xD;
&#xD;
          -  Other factors which in the investigator's opinion would prevent the subject from&#xD;
             completing the protocol (i.e. clinically significant abnormalities on clinical, mental&#xD;
             examination or laboratory testing or inability to comply with protocol)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Italo Biaggioni, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Vanderbilt University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Vanderbilt University</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>January 2023</verification_date>
  <study_first_submitted>September 17, 2014</study_first_submitted>
  <study_first_submitted_qc>September 18, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 19, 2014</study_first_posted>
  <last_update_submitted>January 2, 2023</last_update_submitted>
  <last_update_submitted_qc>January 2, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">January 4, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Vanderbilt University</investigator_affiliation>
    <investigator_full_name>Italo Biaggioni</investigator_full_name>
    <investigator_title>Professor of Medicine</investigator_title>
  </responsible_party>
  <keyword>Hypertension</keyword>
  <keyword>Autonomic Nervous System</keyword>
  <keyword>Renin-Angiotensin System</keyword>
  <keyword>Angiotensin (1-7)</keyword>
  <keyword>Ganglionic Blockers</keyword>
  <keyword>Trimethaphan</keyword>
  <keyword>Blood Pressure</keyword>
  <keyword>Hemodynamics</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hypertension</mesh_term>
    <mesh_term>Essential Hypertension</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Angiotensin I (1-7)</mesh_term>
    <mesh_term>Trimethaphan</mesh_term>
    <mesh_term>Phenylephrine</mesh_term>
    <mesh_term>Oxymetazoline</mesh_term>
    <mesh_term>Trimethaphan camsylate</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02245230
org study id: 140958
nct id: NCT02245230
lead sponsor: 
has dmc: Yes
The purpose of this study is to better understand the cardiovascular effects of the
      vasodilatory peptide Angiotensin (1-7) in human hypertension. In this study, the
      investigators will test the hypothesis that systemic Angiotensin (1-7) infusion produces
      negligible effects with intact baroreceptors, and that the cardiovascular effects of this
      peptide are unmasked following elimination of baroreflex buffering.
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 studies. There are limited and contradictory clinical studies, however,
      and it is unclear if this peptide even contributes to blood pressure regulation in humans.
      The purpose of this study is to learn more about the cardiovascular effects of Angiotensin
      (1-7) in essential hypertension, and to examine interactions of this peptide with the
      autonomic nervous system for blood pressure regulation. 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. In this study, the investigators will test the hypothesis that Angiotensin (1-7)
      produces negligible effects with intact baroreceptors, and that the cardiovascular effects of
      this peptide are unmasked following elimination of baroreflex buffering. To test this
      hypothesis, the investigators will examine the effects of acute intravenous Angiotensin (1-7)
      infusion on blood pressure in subjects with essential hypertension under intact conditions
      and following acute autonomic withdrawal with the ganglionic blocker trimethaphan. The
      primary outcome will be the decrease in systolic blood pressure produced by Angiotensin (1-7)
      infusion, with comparisons made between intact and blocked study days. As a secondary
      objective, the investigators will examine for changes in systemic hemodynamics and
      circulating hormones in response to the Angiotensin (1-7) infusion, to determine potential
      mechanisms underlying any changes in blood pressure.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Other
masking: None (Open Label)
measure: Systolic Blood Pressure
time frame: Change from baseline in systolic blood pressure over the 50-minute infusion period
description: The primary outcome will be the change in systolic blood pressure from baseline produced by the Angiotensin (1-7) infusion, with comparisons made between intact and autonomic blockade study days.
measure: Hemodynamic Measures
time frame: Change from baseline in hemodynamic measures over the 50-minute infusion period
description: We will examine for changes in cardiac output, stroke volume, and systemic vascular resistance to determine hemodynamic mechanisms underlying any changes in blood pressure during Angiotensin (1-7) infusion.
measure: Circulating Renin-Angiotensin System Components
time frame: Change from baseline in circulating renin-angiotensin system components over the 50-minute infusion period
description: We will examine for changes in plasma renin activity, angiotensin II, Angiotensin (1-7), and aldosterone levels to determine renin-angiotensin system hormonal mechanisms underlying any changes in blood pressure during Angiotensin (1-7) infusion.
arm group label: Intact Study Day
arm group type: Active Comparator
description: Subjects will receive saline infusion for 60 minutes followed by five ascending doses of Angiotensin (1-7) ranging from 0.5 to 20 ng/kg/min. Each dose will be maintained for 10 minutes with hemodynamic measurements and blood samples collected at the end of each dosing period.
arm group label: Autonomic Blockade Study Day
arm group type: Experimental
description: Autonomic blockade will be induced by continuous intravenous infusion of trimethaphan starting at 0.5-1.0 mg/min and increasing by 1.0 mg/min every 2 to 6 minutes up to an infusion rate of 5 mg/min. Blood pressure will be restored to pre-trimethaphan levels with intravenous phenylephrine infusion at individually titrated doses, starting with 0.1 ug/kg/min. Angiotensin (1-7) will then be infused in five ascending doses ranging from 0.5 to 20 ng/kg/min. Each dose will be maintained for 10 minutes with hemodynamic measurements and blood samples collected at the end of each dosing period.
intervention type: Drug
intervention name: Angiotensin (1-7)
description: Angiotensin (1-7) is a peptide produced by the body. It will be administered as an acute intravenous infusion with doses ranging from 0.5 to 20 ng/kg/min.
arm group label: Autonomic Blockade Study Day
arm group label: Intact Study Day
other name: Angiotensin-(1-7)
other name: Angiotensin I (1-7)
intervention type: Drug
intervention name: Trimethaphan
description: Trimethaphan is a Nn-nicotinic receptor antagonist that blocks sympathetic and parasympathetic transmission at the level of the autonomic ganglia. It will be administered as an acute intravenous infusion with doses ranging from 0.5 to 5.0 mg/min.
arm group label: Autonomic Blockade Study Day
other name: Trimethaphan Camsylate
intervention type: Drug
intervention name: Phenylephrine
description: Phenylephrine is an alpha 1-adrenergic agonist. It will be administered as an acute intravenous infusion to restore blood pressure following trimethaphan with doses ranging from 0.1 to 0.5 ug/kg/min.
arm group label: Autonomic Blockade Study Day
other name: Phenylephrine Hydrochloride
criteria: 
gender: All
minimum age: 18 Years
maximum age: 60 Years
healthy volunteers: No
last name: Italo Biaggioni, MD
role: Principal Investigator
affiliation: Vanderbilt University
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Vanderbilt University
investigator full name: Italo Biaggioni
investigator title: Professor of Medicine
mesh term: Hypertension
mesh term: Essential Hypertension
mesh term: Angiotensin I (1-7)
mesh term: Trimethaphan
mesh term: Phenylephrine
mesh term: Oxymetazoline
mesh term: Trimethaphan camsylate
sharing ipd: No