<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/NCT02259686</url>
  </required_header>
  <id_info>
    <org_study_id>Apelin2014</org_study_id>
    <nct_id>NCT02259686</nct_id>
  </id_info>
  <brief_title>Cardiovascular Effects of Apelin In Healthy Volunteers</brief_title>
  <official_title>Cardiovascular Effects of Apelin In Healthy Volunteers</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Edinburgh</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>NHS Lothian</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Edinburgh</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Apelin is an endogenous peptide with physiological actions in the cardiovascular system.&#xD;
      Apelin can modulate vasomotor tone and is a potent endogenous inotrope. In a series of&#xD;
      clinical studies, we have shown that apelin causes peripheral and coronary vasodilatation and&#xD;
      increased cardiac contractility. We wish to study and compare the cardiovascular effects of&#xD;
      subcutaneous versus intravenous apelin. We specifically wish to determine how different&#xD;
      methods of apelin administration affect cardiac output and peripheral vascular resistance in&#xD;
      healthy volunteers&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study Protocols Groups of 5 subjects will be assigned to receive one of three protocols.&#xD;
&#xD;
      Protocol 1:&#xD;
&#xD;
      Five healthy volunteers will be asked to attend the clinical research facility on a total of&#xD;
      4 occasions as per the protocol below.&#xD;
&#xD;
      Visits 1 and 2 will occur over two consecutive days. Participants will attend at 07.30 and be&#xD;
      given a light breakfast. An intravenous sampling cannula will be inserted into the&#xD;
      antecubital vein of one arm. Blood samples (5 mL) will be taken immediately prior to&#xD;
      subcutaneous injection (t=0; 08.00) of 1 mg (Pyr1)apelin-13 and at 5, 10, 15, 20, 25, 30, 45,&#xD;
      60, 90, 120, 180, 240, 300, 360, 480 and 600 min after injection. Subjects will then be&#xD;
      discharged from the facility and reattend the following day at 08.00 for a single venous&#xD;
      sample. Approximately 85 mL of blood will be sampled in total over this time.&#xD;
&#xD;
      Visits 3 and 4 will also occur over two consecutive days, at least one week after visit 2.&#xD;
      Subjects will attend at 07.30 and be given a light breakfast. An intravenous sampling cannula&#xD;
      will be inserted into the antecubital vein of one arm. Blood samples (5 mL) will be taken&#xD;
      immediately prior to an intravenous bolus infusion (t=0; 08.00) of 1 mg (Pyr1)apelin-13 over&#xD;
      15 min and at 5, 10, 15, 20, 25, 30, 45, 60, 90, 120, 180, 240, 300, 360, 480 and 600 min&#xD;
      after injection. Subjects will then be discharged from the facility and reattend the&#xD;
      following day at 08.00 for a single venous sample.&#xD;
&#xD;
      Protocol 2:&#xD;
&#xD;
      Five healthy volunteers will be asked to attend the clinical research facility on a total of&#xD;
      4 occasions as per the protocol below.&#xD;
&#xD;
      Visits 1 and 2 will occur over two consecutive days. Participants will attend at 07.30 and be&#xD;
      given a light breakfast. An intravenous sampling cannula will be inserted into the&#xD;
      antecubital vein of one arm. Blood samples (5 mL) will be taken immediately prior to&#xD;
      subcutaneous injection (t=0; 08.00) of 5 mg (Pyr1)apelin-13 and at 5, 10, 15, 20, 25, 30, 45,&#xD;
      60, 90, 120, 180, 240, 300, 360, 480 and 600 min after injection. Subjects will then be&#xD;
      discharged from the facility and reattend the following day at 08.00 for a single venous&#xD;
      sample. Approximately 85 mL of blood will be sampled in total over this time.&#xD;
&#xD;
      Visits 3 and 4 will also occur over two consecutive days, at least one week after visit 2.&#xD;
      Subjects will attend at 07.30 and be given a light breakfast. An intravenous sampling cannula&#xD;
      will be inserted into the antecubital vein of one arm. Blood samples (5 mL) will be taken&#xD;
      immediately prior to an intravenous bolus infusion (t=0; 08.00) of 5 mg (Pyr1)apelin-13 over&#xD;
      15 min and at 5, 10, 15, 20, 25, 30, 45, 60, 90, 120, 180, 240, 300, 360, 480 and 600 min&#xD;
      after injection. Subjects will then be discharged from the facility and reattend the&#xD;
      following day at 08.00 for a single venous sample.&#xD;
&#xD;
      Protocol 3:&#xD;
&#xD;
      Five healthy volunteers will be asked to attend the clinical research facility for 2&#xD;
      consecutive days. Subjects will attend at 07.30 and be given a light breakfast. An&#xD;
      intravenous sampling cannula will be inserted into the antecubital vein of one arm. Blood&#xD;
      samples (5 mL) will be taken immediately prior to commencing a 24-h subcutaneous infusion of&#xD;
      (t=0; 08.00) of 10 mg (Pyr1)apelin-13 dissolved in 10 mL water for injection. Further venous&#xD;
      sampling will take place at 5, 10, 15, 20, 25, 30, 45, 60, 90, 120, 180, 240, 300, 360, 480&#xD;
      and 600 min after injection. Subjects will then be discharged from the facility and reattend&#xD;
      the following day at 08.00 for a single venous sample.&#xD;
&#xD;
      Measurements&#xD;
&#xD;
      Thoracic Bioimpedance Cardiography By virtue of changes in transthoracic electrical impedance&#xD;
      during cardiac ejection, thoracic bioimpedance cardiography allows the non-invasive&#xD;
      assessment of cardiac stroke volume and the calculation of cardiac output and cardiac index.&#xD;
      After skin preparation, four pairs of low-contact impedance 'sensing' and 'current injecting'&#xD;
      electrodes will be attached to the patient and connected to an impedance cardiograph. This&#xD;
      technique has been applied widely and compares favourably with both invasive and other&#xD;
      non-invasive (echocardiographic) measures of cardiac output. These variables will therefore&#xD;
      be recorded at regular intervals throughout the study in all 3 protocols. Heart rate and&#xD;
      blood pressure will also be monitored at regular intervals throughout each study using a&#xD;
      semi-automated oscillometric sphygmomanometer (Omron HEM-705CP, Omron, Matsusaka, Japan).&#xD;
      Mean arterial pressure (MAP) will be calculated as diastolic blood pressure plus a third of&#xD;
      the pulse pressure.&#xD;
&#xD;
      Assays Blood samples (5 mL) will be collected before and at the end of each drug infusion&#xD;
      into ethylene diamine tetraacetic acid (EDTA), centrifuged and plasma frozen in three 1-mL&#xD;
      aliquots to be stored at -80 °C until assay. Plasma concentrations of apelin will be measured&#xD;
      by collaborators at Bristol Myers Squibb, Princeton, USA.&#xD;
&#xD;
      Methods of Statistical Analysis&#xD;
&#xD;
      Outcome data will be analysed where appropriate, by analysis of variance (ANOVA) with&#xD;
      repeated measures, regression analysis, and paired and unpaired Student's t-test. Statistical&#xD;
      significance will be taken at the 5% level.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>November 2014</start_date>
  <completion_date type="Actual">May 2015</completion_date>
  <primary_completion_date type="Actual">May 2015</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>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in cardiac output between different methods of apelin administration.</measure>
    <time_frame>10 hours</time_frame>
    <description>Difference in cardiac output between different treatment arms. This will be assessed by recording cardiac index in L/min/m2 and Stroke volume index mL/min/m2</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in blood pressure between different methods of apelin administration.</measure>
    <time_frame>10 hours</time_frame>
    <description>Difference in blood pressure between different treatment arms assessed by measuring mean blood pressure in mmHg. Mean arterial pressure (MAP) will be calculated as diastolic blood pressure plus a third of the pulse pressure</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in apelin concentrations between the different methods of administration</measure>
    <time_frame>24 hours</time_frame>
    <description>Difference in temporal profile of apelin concentrations produced by different methods of apelin administration</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">14</enrollment>
  <condition>Healthy</condition>
  <arm_group>
    <arm_group_label>Protocol 1. Apelin 1mg doses</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>5 Healthy volunteers</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Protocol 2. Apelin 5mg doses</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>5 Healthy volunteers</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Protocol 3. Apelin 10mg single dose</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>5 Healthy volunteers</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Apelin 1mg subcutaneous</intervention_name>
    <description>single subcutaneous injection of Apelin 1mg subcutaneous</description>
    <arm_group_label>Protocol 1. Apelin 1mg doses</arm_group_label>
    <other_name>1mg Sc</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Apelin 1mg intravenous</intervention_name>
    <description>15 minute intravenous bolus of Apelin 1mg intravenous</description>
    <arm_group_label>Protocol 1. Apelin 1mg doses</arm_group_label>
    <other_name>1mg iv</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Apelin 5mg subcutaneous</intervention_name>
    <description>single subcutaneous injection of Apelin 5mg subcutaneous</description>
    <arm_group_label>Protocol 2. Apelin 5mg doses</arm_group_label>
    <other_name>5mg Sc</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Apelin 5mg intravenous</intervention_name>
    <description>15 minute intravenous infusion of Apelin 5mg intravenous</description>
    <arm_group_label>Protocol 2. Apelin 5mg doses</arm_group_label>
    <other_name>5mg iv</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Apelin 10 mg subcutaneous</intervention_name>
    <description>24 hour continuous subcutaneous infusion of Apelin 10 mg subcutaneous</description>
    <arm_group_label>Protocol 3. Apelin 10mg single dose</arm_group_label>
    <other_name>10mg sc</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Healthy males or females &gt;18 years old&#xD;
&#xD;
          -  Willing and able to complete an informed consent form&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Unable to give informed consent&#xD;
&#xD;
          -  Pregnant or lactating at screening&#xD;
&#xD;
          -  Use of any investigation product or device within 30 days prior to study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>David Newby</last_name>
    <role>Principal Investigator</role>
    <affiliation>British Heart Foundation</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Clinical Research Facility University of Edinburgh</name>
      <address>
        <city>Edinburgh</city>
        <zip>EH16 4SA</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Wellcome Trust Clinical Research Facility. Western General Hospital</name>
      <address>
        <city>Edinburgh</city>
        <zip>EH4 2XU</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>May 2015</verification_date>
  <study_first_submitted>October 1, 2014</study_first_submitted>
  <study_first_submitted_qc>October 7, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 8, 2014</study_first_posted>
  <last_update_submitted>May 29, 2015</last_update_submitted>
  <last_update_submitted_qc>May 29, 2015</last_update_submitted_qc>
  <last_update_posted type="Estimate">June 1, 2015</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Apelin</keyword>
  <keyword>volunteers</keyword>
  <!-- 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/NCT02259686
org study id: Apelin2014
nct id: NCT02259686
lead sponsor: 
collaborator: 
has dmc: No
Apelin is an endogenous peptide with physiological actions in the cardiovascular system.
      Apelin can modulate vasomotor tone and is a potent endogenous inotrope. In a series of
      clinical studies, we have shown that apelin causes peripheral and coronary vasodilatation and
      increased cardiac contractility. We wish to study and compare the cardiovascular effects of
      subcutaneous versus intravenous apelin. We specifically wish to determine how different
      methods of apelin administration affect cardiac output and peripheral vascular resistance in
      healthy volunteers
Study Protocols Groups of 5 subjects will be assigned to receive one of three protocols.

      Protocol 1:

      Five healthy volunteers will be asked to attend the clinical research facility on a total of
      4 occasions as per the protocol below.

      Visits 1 and 2 will occur over two consecutive days. Participants will attend at 07.30 and be
      given a light breakfast. An intravenous sampling cannula will be inserted into the
      antecubital vein of one arm. Blood samples (5 mL) will be taken immediately prior to
      subcutaneous injection (t=0; 08.00) of 1 mg (Pyr1)apelin-13 and at 5, 10, 15, 20, 25, 30, 45,
      60, 90, 120, 180, 240, 300, 360, 480 and 600 min after injection. Subjects will then be
      discharged from the facility and reattend the following day at 08.00 for a single venous
      sample. Approximately 85 mL of blood will be sampled in total over this time.

      Visits 3 and 4 will also occur over two consecutive days, at least one week after visit 2.
      Subjects will attend at 07.30 and be given a light breakfast. An intravenous sampling cannula
      will be inserted into the antecubital vein of one arm. Blood samples (5 mL) will be taken
      immediately prior to an intravenous bolus infusion (t=0; 08.00) of 1 mg (Pyr1)apelin-13 over
      15 min and at 5, 10, 15, 20, 25, 30, 45, 60, 90, 120, 180, 240, 300, 360, 480 and 600 min
      after injection. Subjects will then be discharged from the facility and reattend the
      following day at 08.00 for a single venous sample.

      Protocol 2:

      Five healthy volunteers will be asked to attend the clinical research facility on a total of
      4 occasions as per the protocol below.

      Visits 1 and 2 will occur over two consecutive days. Participants will attend at 07.30 and be
      given a light breakfast. An intravenous sampling cannula will be inserted into the
      antecubital vein of one arm. Blood samples (5 mL) will be taken immediately prior to
      subcutaneous injection (t=0; 08.00) of 5 mg (Pyr1)apelin-13 and at 5, 10, 15, 20, 25, 30, 45,
      60, 90, 120, 180, 240, 300, 360, 480 and 600 min after injection. Subjects will then be
      discharged from the facility and reattend the following day at 08.00 for a single venous
      sample. Approximately 85 mL of blood will be sampled in total over this time.

      Visits 3 and 4 will also occur over two consecutive days, at least one week after visit 2.
      Subjects will attend at 07.30 and be given a light breakfast. An intravenous sampling cannula
      will be inserted into the antecubital vein of one arm. Blood samples (5 mL) will be taken
      immediately prior to an intravenous bolus infusion (t=0; 08.00) of 5 mg (Pyr1)apelin-13 over
      15 min and at 5, 10, 15, 20, 25, 30, 45, 60, 90, 120, 180, 240, 300, 360, 480 and 600 min
      after injection. Subjects will then be discharged from the facility and reattend the
      following day at 08.00 for a single venous sample.

      Protocol 3:

      Five healthy volunteers will be asked to attend the clinical research facility for 2
      consecutive days. Subjects will attend at 07.30 and be given a light breakfast. An
      intravenous sampling cannula will be inserted into the antecubital vein of one arm. Blood
      samples (5 mL) will be taken immediately prior to commencing a 24-h subcutaneous infusion of
      (t=0; 08.00) of 10 mg (Pyr1)apelin-13 dissolved in 10 mL water for injection. Further venous
      sampling will take place at 5, 10, 15, 20, 25, 30, 45, 60, 90, 120, 180, 240, 300, 360, 480
      and 600 min after injection. Subjects will then be discharged from the facility and reattend
      the following day at 08.00 for a single venous sample.

      Measurements

      Thoracic Bioimpedance Cardiography By virtue of changes in transthoracic electrical impedance
      during cardiac ejection, thoracic bioimpedance cardiography allows the non-invasive
      assessment of cardiac stroke volume and the calculation of cardiac output and cardiac index.
      After skin preparation, four pairs of low-contact impedance 'sensing' and 'current injecting'
      electrodes will be attached to the patient and connected to an impedance cardiograph. This
      technique has been applied widely and compares favourably with both invasive and other
      non-invasive (echocardiographic) measures of cardiac output. These variables will therefore
      be recorded at regular intervals throughout the study in all 3 protocols. Heart rate and
      blood pressure will also be monitored at regular intervals throughout each study using a
      semi-automated oscillometric sphygmomanometer (Omron HEM-705CP, Omron, Matsusaka, Japan).
      Mean arterial pressure (MAP) will be calculated as diastolic blood pressure plus a third of
      the pulse pressure.

      Assays Blood samples (5 mL) will be collected before and at the end of each drug infusion
      into ethylene diamine tetraacetic acid (EDTA), centrifuged and plasma frozen in three 1-mL
      aliquots to be stored at -80 °C until assay. Plasma concentrations of apelin will be measured
      by collaborators at Bristol Myers Squibb, Princeton, USA.

      Methods of Statistical Analysis

      Outcome data will be analysed where appropriate, by analysis of variance (ANOVA) with
      repeated measures, regression analysis, and paired and unpaired Student's t-test. Statistical
      significance will be taken at the 5% level.
allocation: Randomized
intervention model: Crossover Assignment
masking: None (Open Label)
measure: Change in cardiac output between different methods of apelin administration.
time frame: 10 hours
description: Difference in cardiac output between different treatment arms. This will be assessed by recording cardiac index in L/min/m2 and Stroke volume index mL/min/m2
measure: Change in blood pressure between different methods of apelin administration.
time frame: 10 hours
description: Difference in blood pressure between different treatment arms assessed by measuring mean blood pressure in mmHg. Mean arterial pressure (MAP) will be calculated as diastolic blood pressure plus a third of the pulse pressure
measure: Change in apelin concentrations between the different methods of administration
time frame: 24 hours
description: Difference in temporal profile of apelin concentrations produced by different methods of apelin administration
arm group label: Protocol 1. Apelin 1mg doses
arm group type: Experimental
description: 5 Healthy volunteers
arm group label: Protocol 2. Apelin 5mg doses
arm group type: Experimental
description: 5 Healthy volunteers
arm group label: Protocol 3. Apelin 10mg single dose
arm group type: Experimental
description: 5 Healthy volunteers
intervention type: Drug
intervention name: Apelin 1mg subcutaneous
description: single subcutaneous injection of Apelin 1mg subcutaneous
arm group label: Protocol 1. Apelin 1mg doses
other name: 1mg Sc
intervention type: Drug
intervention name: Apelin 1mg intravenous
description: 15 minute intravenous bolus of Apelin 1mg intravenous
arm group label: Protocol 1. Apelin 1mg doses
other name: 1mg iv
intervention type: Drug
intervention name: Apelin 5mg subcutaneous
description: single subcutaneous injection of Apelin 5mg subcutaneous
arm group label: Protocol 2. Apelin 5mg doses
other name: 5mg Sc
intervention type: Drug
intervention name: Apelin 5mg intravenous
description: 15 minute intravenous infusion of Apelin 5mg intravenous
arm group label: Protocol 2. Apelin 5mg doses
other name: 5mg iv
intervention type: Drug
intervention name: Apelin 10 mg subcutaneous
description: 24 hour continuous subcutaneous infusion of Apelin 10 mg subcutaneous
arm group label: Protocol 3. Apelin 10mg single dose
other name: 10mg sc
criteria: 
gender: All
minimum age: 18 Years
maximum age: 85 Years
healthy volunteers: Accepts Healthy Volunteers
last name: David Newby
role: Principal Investigator
affiliation: British Heart Foundation
facility: 
facility: 
country: United Kingdom
responsible party type: Sponsor