<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/NCT03240068</url>
  </required_header>
  <id_info>
    <org_study_id>6189</org_study_id>
    <nct_id>NCT03240068</nct_id>
  </id_info>
  <brief_title>Angiotensin-(1-7) in Peripheral Arterial Disease</brief_title>
  <official_title>Protective Effects of Angiotensin-(1-7) in Peripheral Arterial Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Milton S. Hershey Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Milton S. Hershey Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Peripheral arterial disease (PAD) affects over 8 million individuals in the United States&#xD;
      alone. This is a form of atherosclerosis in which plaques preferentially build up inside the&#xD;
      arteries of the legs to limit blood flow. These patients are at high risk for heart attack&#xD;
      and stroke, with at least half dying from coronary artery disease. Our understanding of the&#xD;
      causes of PAD remains incomplete. The renin-angiotensin hormone system is one mechanism known&#xD;
      to contribute to atherosclerosis. Pharmacologic blockade of the hormone angiotensin II is&#xD;
      beneficial in forms of atherosclerosis, including peripheral arterial disease, to improve&#xD;
      blood vessel damage and functional outcomes. These therapies also increase circulating levels&#xD;
      of angiotensin-(1-7), a hormone that dilates blood vessels. Angiotensin-(1-7) improves blood&#xD;
      vessel function and reduces inflammation to protect against atherosclerosis in animal models;&#xD;
      however, there are no clinical data in patients with atherosclerosis. The overall goal of&#xD;
      this project is to examine the cardiovascular effects of angiotensin-(1-7) in PAD.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a randomized, double blind, placebo-controlled, crossover study to determine if acute&#xD;
      intravenous Ang-(1-7) infusion can reduce systemic inflammation and improve measures of leg&#xD;
      blood flow in subjects with PAD. The investigators will also measure for changes in blood&#xD;
      pressure and circulating hormones in response to angiotensin-(1-7) infusion. This is an&#xD;
      outpatient study that will be conducted in the Clinical Research Center at the Penn State&#xD;
      Milton S. Hershey Medical Center.&#xD;
&#xD;
      Subjects with PAD will participate in a screening visit, and if eligible, in two separate&#xD;
      study visits in which they will receive intravenous angiotensin-(1-7) or saline infusion.&#xD;
      Each study visit will last approximately 4 hours, with at least one week of washout between&#xD;
      study visits. During study visits, subjects will be instrumented with two intravenous&#xD;
      catheters (one for drug infusion and one for blood sampling), arm and finger blood pressure&#xD;
      cuffs, sticky patches to measure heart rate, a belt around the stomach to measure breathing,&#xD;
      an ultrasound probe on each leg to measure blood flow, a probe on the ear to measure blood&#xD;
      oxygen saturation, a probe on each calf muscle to measure oxygen levels, and probes on the&#xD;
      skin to measure temperature and blood flow. The investigators will obtain baseline measures&#xD;
      of blood pressure and heart rate and collect blood samples to measure hormones in the blood.&#xD;
      After baseline measurements, the investigators will infuse angiotensin-(1-7) or saline for 50&#xD;
      minutes. Finger cuff blood pressure, leg blood flow, and calf muscle oxygen levels will be&#xD;
      measured continuously during infusions. The investigators will measure blood pressure and&#xD;
      heart rate and collect blood samples at the end of the infusion period.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Study funding ended prior to completion.&#xD;
  </why_stopped>
  <start_date type="Actual">September 1, 2017</start_date>
  <completion_date type="Actual">August 30, 2023</completion_date>
  <primary_completion_date type="Actual">August 30, 2023</primary_completion_date>
  <phase>Early 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>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Leg Blood Flow</measure>
    <time_frame>50 minutes</time_frame>
    <description>The change in measures of leg blood flow (e.g. femoral blood flow and conductance, calf muscle oxygen saturation) following angiotensin-(1-7) versus saline infusion.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Inflammatory Markers</measure>
    <time_frame>50 minutes</time_frame>
    <description>The change in blood levels of inflammatory markers C-Reactive Protein and Interleukin-6 following angiotensin-(1-7) versus saline infusion.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Blood Pressure</measure>
    <time_frame>50 minutes</time_frame>
    <description>The change in arm and finger cuff blood pressure following angiotensin-(1-7) versus saline infusion.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Heart Rate</measure>
    <time_frame>50 minutes</time_frame>
    <description>The change in heart rate following angiotensin-(1-7) versus saline infusion.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Renin-Angiotensin System Hormones</measure>
    <time_frame>50 minutes</time_frame>
    <description>The change in circulating levels of renin-angiotensin system hormones (e.g. plasma renin activity, angiotensin peptides, aldosterone) following angiotensin-(1-7) versus saline infusion.</description>
  </other_outcome>
  <other_outcome>
    <measure>Nitric Oxide Bioavailability</measure>
    <time_frame>50 minutes</time_frame>
    <description>The change in circulating levels of nitrate and nitrite following angiotensin-(1-7) versus saline infusion.</description>
  </other_outcome>
  <other_outcome>
    <measure>Lipids</measure>
    <time_frame>50 minutes</time_frame>
    <description>The change in circulating lipids (e.g. cholesterol, triglycerides) following angiotensin-(1-7) versus saline infusion.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">6</enrollment>
  <condition>Peripheral Arterial Disease</condition>
  <arm_group>
    <arm_group_label>Angiotensin-(1-7)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will receive intravenous infusion of five ascending doses of angiotensin-(1-7). The doses are: 1, 2, 4, 8, and 12 ng/kg/min. Each dose will be maintained for 10 minutes, for a total infusion period of 50 minutes.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Saline</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Subjects will receive intravenous infusion of saline that is matched in volume to the angiotensin-(1-7) arm. Saline infusion will be maintained for a total infusion period of 50 minutes.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Angiotensin 1-7</intervention_name>
    <description>This is a biologically active hormone of the renin-angiotensin system. It may play a beneficial role in regulation of blood pressure by dilating blood vessels and reducing inflammation.</description>
    <arm_group_label>Angiotensin-(1-7)</arm_group_label>
    <other_name>Angiotensin I (1-7)</other_name>
    <other_name>Angiotensin I/II (1-7) Acetate</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Saline</intervention_name>
    <description>Normal saline will be used as the placebo comparator.</description>
    <arm_group_label>Saline</arm_group_label>
    <other_name>normal saline</other_name>
    <other_name>0.9% sodium chloride</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Sex: Male or Female&#xD;
&#xD;
          -  Age: 21-80 years of age&#xD;
&#xD;
          -  Diagnosed with PAD (e.g. ankle-brachial index below 0.9)&#xD;
&#xD;
          -  Fontaine stage II or less (no rest pain)&#xD;
&#xD;
          -  Capable of giving informed consent&#xD;
&#xD;
          -  Fluent in written and spoken English&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Age less than or equal to 20 years or greater than or equal to 81 years&#xD;
&#xD;
          -  Pregnant or nursing woman&#xD;
&#xD;
          -  Decisional impairment&#xD;
&#xD;
          -  Prisoners&#xD;
&#xD;
          -  Alcohol or drug abuse&#xD;
&#xD;
          -  Evidence of type I or type II diabetes (fasting glucose &gt;126 mg/dl or use of&#xD;
             anti-diabetic medications)&#xD;
&#xD;
          -  History of serious cardiovascular disease (e.g. myocardial infarction within 6 months,&#xD;
             symptomatic coronary artery disease, presence of angina pectoris, significant&#xD;
             arrhythmia, congestive heart failure, deep vein thrombosis, pulmonary embolism, second&#xD;
             or third degree heart block, mitral valve stenosis, aortic stenosis, hypertrophic&#xD;
             cardiomyopathy) or cerebrovascular disease (e.g. cerebral hemorrhage, stroke,&#xD;
             transient ischemic attack).&#xD;
&#xD;
          -  History or presence of immunological or hematological disease&#xD;
&#xD;
          -  Impaired hepatic function [aspartate aminotransferase (AST) or alanine&#xD;
             aminotransferase (ALT) levels &gt; 2 times the upper limit of normal range)&#xD;
&#xD;
          -  Impaired renal function (serum creatinine &gt;2.0 mg/dl)&#xD;
&#xD;
          -  Anemia&#xD;
&#xD;
          -  Treatment with serotonin-norepinephrine reuptake inhibitors (SNRI) or norepinephrine&#xD;
             transporter (NET) inhibitors&#xD;
&#xD;
          -  Treatment with phosphodiesterase-5 inhibitors&#xD;
&#xD;
          -  Treatment with anticoagulants&#xD;
&#xD;
          -  Treatment with chronic systemic glucocorticoid therapy (&gt;7 consecutive days in 1&#xD;
             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;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Amy C Arnold, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Penn State College of Medicine</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Penn State Milton S. Hershey Medical Center</name>
      <address>
        <city>Hershey</city>
        <state>Pennsylvania</state>
        <zip>17033</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>August 2, 2017</study_first_submitted>
  <study_first_submitted_qc>August 3, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 4, 2017</study_first_posted>
  <last_update_submitted>August 31, 2023</last_update_submitted>
  <last_update_submitted_qc>August 31, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 6, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Milton S. Hershey Medical Center</investigator_affiliation>
    <investigator_full_name>Amy Arnold</investigator_full_name>
    <investigator_title>Associate Professor</investigator_title>
  </responsible_party>
  <keyword>Renin-Angiotensin System</keyword>
  <keyword>Inflammation</keyword>
  <keyword>Cardiovascular</keyword>
  <keyword>Atherosclerosis</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Peripheral Arterial Disease</mesh_term>
    <mesh_term>Peripheral Vascular Diseases</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>Angiotensin II</mesh_term>
    <mesh_term>Angiotensinogen</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/NCT03240068
org study id: 6189
nct id: NCT03240068
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
Peripheral arterial disease (PAD) affects over 8 million individuals in the United States
      alone. This is a form of atherosclerosis in which plaques preferentially build up inside the
      arteries of the legs to limit blood flow. These patients are at high risk for heart attack
      and stroke, with at least half dying from coronary artery disease. Our understanding of the
      causes of PAD remains incomplete. The renin-angiotensin hormone system is one mechanism known
      to contribute to atherosclerosis. Pharmacologic blockade of the hormone angiotensin II is
      beneficial in forms of atherosclerosis, including peripheral arterial disease, to improve
      blood vessel damage and functional outcomes. These therapies also increase circulating levels
      of angiotensin-(1-7), a hormone that dilates blood vessels. Angiotensin-(1-7) improves blood
      vessel function and reduces inflammation to protect against atherosclerosis in animal models;
      however, there are no clinical data in patients with atherosclerosis. The overall goal of
      this project is to examine the cardiovascular effects of angiotensin-(1-7) in PAD.
This is a randomized, double blind, placebo-controlled, crossover study to determine if acute
      intravenous Ang-(1-7) infusion can reduce systemic inflammation and improve measures of leg
      blood flow in subjects with PAD. The investigators will also measure for changes in blood
      pressure and circulating hormones in response to angiotensin-(1-7) infusion. This is an
      outpatient study that will be conducted in the Clinical Research Center at the Penn State
      Milton S. Hershey Medical Center.

      Subjects with PAD will participate in a screening visit, and if eligible, in two separate
      study visits in which they will receive intravenous angiotensin-(1-7) or saline infusion.
      Each study visit will last approximately 4 hours, with at least one week of washout between
      study visits. During study visits, subjects will be instrumented with two intravenous
      catheters (one for drug infusion and one for blood sampling), arm and finger blood pressure
      cuffs, sticky patches to measure heart rate, a belt around the stomach to measure breathing,
      an ultrasound probe on each leg to measure blood flow, a probe on the ear to measure blood
      oxygen saturation, a probe on each calf muscle to measure oxygen levels, and probes on the
      skin to measure temperature and blood flow. The investigators will obtain baseline measures
      of blood pressure and heart rate and collect blood samples to measure hormones in the blood.
      After baseline measurements, the investigators will infuse angiotensin-(1-7) or saline for 50
      minutes. Finger cuff blood pressure, leg blood flow, and calf muscle oxygen levels will be
      measured continuously during infusions. The investigators will measure blood pressure and
      heart rate and collect blood samples at the end of the infusion period.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Leg Blood Flow
time frame: 50 minutes
description: The change in measures of leg blood flow (e.g. femoral blood flow and conductance, calf muscle oxygen saturation) following angiotensin-(1-7) versus saline infusion.
measure: Inflammatory Markers
time frame: 50 minutes
description: The change in blood levels of inflammatory markers C-Reactive Protein and Interleukin-6 following angiotensin-(1-7) versus saline infusion.
measure: Blood Pressure
time frame: 50 minutes
description: The change in arm and finger cuff blood pressure following angiotensin-(1-7) versus saline infusion.
measure: Heart Rate
time frame: 50 minutes
description: The change in heart rate following angiotensin-(1-7) versus saline infusion.
measure: Renin-Angiotensin System Hormones
time frame: 50 minutes
description: The change in circulating levels of renin-angiotensin system hormones (e.g. plasma renin activity, angiotensin peptides, aldosterone) following angiotensin-(1-7) versus saline infusion.
measure: Nitric Oxide Bioavailability
time frame: 50 minutes
description: The change in circulating levels of nitrate and nitrite following angiotensin-(1-7) versus saline infusion.
measure: Lipids
time frame: 50 minutes
description: The change in circulating lipids (e.g. cholesterol, triglycerides) following angiotensin-(1-7) versus saline infusion.
arm group label: Angiotensin-(1-7)
arm group type: Experimental
description: Subjects will receive intravenous infusion of five ascending doses of angiotensin-(1-7). The doses are: 1, 2, 4, 8, and 12 ng/kg/min. Each dose will be maintained for 10 minutes, for a total infusion period of 50 minutes.
arm group label: Saline
arm group type: Placebo Comparator
description: Subjects will receive intravenous infusion of saline that is matched in volume to the angiotensin-(1-7) arm. Saline infusion will be maintained for a total infusion period of 50 minutes.
intervention type: Drug
intervention name: Angiotensin 1-7
description: This is a biologically active hormone of the renin-angiotensin system. It may play a beneficial role in regulation of blood pressure by dilating blood vessels and reducing inflammation.
arm group label: Angiotensin-(1-7)
other name: Angiotensin I (1-7)
other name: Angiotensin I/II (1-7) Acetate
intervention type: Drug
intervention name: Saline
description: Normal saline will be used as the placebo comparator.
arm group label: Saline
other name: normal saline
other name: 0.9% sodium chloride
criteria: 
gender: All
minimum age: 21 Years
maximum age: 80 Years
healthy volunteers: No
last name: Amy C Arnold, PhD
role: Principal Investigator
affiliation: Penn State College of Medicine
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Milton S. Hershey Medical Center
investigator full name: Amy Arnold
investigator title: Associate Professor
mesh term: Peripheral Arterial Disease
mesh term: Peripheral Vascular Diseases
mesh term: Angiotensin I (1-7)
mesh term: Angiotensin II
mesh term: Angiotensinogen
sharing ipd: No