<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/NCT02980068</url>
  </required_header>
  <id_info>
    <org_study_id>STUDY19120066</org_study_id>
    <secondary_id>5P01HL103455</secondary_id>
    <nct_id>NCT02980068</nct_id>
  </id_info>
  <brief_title>A Study of Oral Nitrate in Adults With Pulmonary Hypertension With Heart Failure and Preserved Ejection Fraction</brief_title>
  <acronym>PMED</acronym>
  <official_title>An Open Label Study of Oral Nitrate in Adults With Pulmonary Hypertension With Heart Failure and Preserved Ejection Fraction (PH-HFpEF) and Normal Healthy Adults</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Gladwin, Mark, MD</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Heart, Lung, and Blood Institute (NHLBI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Pittsburgh</source>
  <oversight_info>
    <has_dmc>No</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>
      This is an open-label, single-center study to examine distinguishing features of the&#xD;
      structure and function of the oral and gut microbiome in healthy adult normal volunteers&#xD;
      compared to volunteers with PH-HFpEF in the breakdown of oral nitrate.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      We will enroll 60 Group II PH (PH-HFpEF) or Group I PAH patients and 60 matched healthy&#xD;
      controls over three years. The Subjects will receive a single dose of one of the two study&#xD;
      drugs, determined by whether they will participate in one study visit or two: 15N nitrate&#xD;
      (1,000 mg) or 14N Sodium Nitrate: standard sodium nitrate, and all will receive one dose of&#xD;
      CLA 3g. Twenty of the PH or PAH subjects and 20 of the control subjects willing to return for&#xD;
      a follow up visit 24 hours after drug administration will receive 15N nitrate. All others&#xD;
      will receive standard sodium nitrate. CLA will be obtained from GNC (General Nutrition&#xD;
      Corporation) and given once.&#xD;
&#xD;
      Throughout the experiment, we will measure blood pressure, heart rate, and respiratory rate&#xD;
      as well as co-oximetry. Plasma samples are collected at approximate times 0, 2, and 6 hrs&#xD;
      post-drug administration. Urine will be collected at approximate times 0 and 6 hrs. We will&#xD;
      examine plasma and urine nitrate and nitrite. The 40 subjects who return for a second visit&#xD;
      24 hours post-drug administration will provide an additional plasma and urine sample.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 28, 2017</start_date>
  <completion_date type="Actual">February 25, 2022</completion_date>
  <primary_completion_date type="Actual">February 25, 2022</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in nitrate level in urine</measure>
    <time_frame>Urine collected approx 0 &amp; 6 hours after drug administration</time_frame>
    <description>The investigators will examine urine nitrate</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in nitrate level in plasma</measure>
    <time_frame>Approx 50cc of blood drawn approx 0, 2, &amp; 6 hours after drug administration</time_frame>
    <description>The investigators will examine plasma nitrate</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Bacterial content of gut microbiome</measure>
    <time_frame>Stool collected before drug administration</time_frame>
    <description>Stool will be analyzed for bacterial makeup</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Bacterial content of the oral microbiome</measure>
    <time_frame>Saliva and tongue scraping will occur preceding administration of drug</time_frame>
    <description>Saliva and tongue scraping will be analyzed for bacterial makeup</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in nitrite level in urine</measure>
    <time_frame>Urine collected approx 0 &amp; 6 hours after drug administration</time_frame>
    <description>The investigators will examine urine nitrite</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in nitrite level in plasma</measure>
    <time_frame>Approx 50cc of blood drawn approx 0, 2, &amp; 6 hours after drug administration</time_frame>
    <description>The investigators will examine plasma nitrite</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in blood pressure</measure>
    <time_frame>Frequently over 6 hour study visit</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in heart rate</measure>
    <time_frame>Continuous over 6 hour study visit</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in respiratory rate</measure>
    <time_frame>Continuous over 6 hour study visit</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in hemoglobin concentration</measure>
    <time_frame>Continuous over 6 hour study visit</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">77</enrollment>
  <condition>Pulmonary; Hypertension</condition>
  <condition>Heart Failure</condition>
  <condition>Preserved Ejection Fraction</condition>
  <arm_group>
    <arm_group_label>15N Nitrate</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>single 1,000mg dose of 15N nitrate with 3g of conjugated linoleic acid (CLA).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>14N Sodium Nitrate</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>single 1,000mg dose of 14N sodium nitrate with 3g of conjugated linoleic acid (CLA)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>15N Nitrate</intervention_name>
    <description>1,000 mg/11.8 mmol, oral, on day one, hour zero</description>
    <arm_group_label>15N Nitrate</arm_group_label>
    <other_name>15N Sodium Nitrate</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>14N Nitrate</intervention_name>
    <description>1,000 mg/11.18 mmol, oral, on day hour, hour zero</description>
    <arm_group_label>14N Sodium Nitrate</arm_group_label>
    <other_name>14N Sodium Nitrate</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        INCLUSION:&#xD;
&#xD;
          -  Male or female, 18 years of age or older&#xD;
&#xD;
          -  PH group: Pulmonary hypertension, hemodynamically defined by a mean PAP ≥ 25 mm Hg,&#xD;
             and a TPG &gt;= 12 at rest or during exercise as demonstrated on a right heart&#xD;
             catheterization in the last 10 years&#xD;
&#xD;
          -  RHC Control group: Normal hemodynamics (mean PAP &lt; 25 mm Hg, PCWP ≤ 15 mm Hg) on&#xD;
             clinical right heart catheterization&#xD;
&#xD;
          -  Healthy Control group: Healthy patients with no evidence of pulmonary hypertension,&#xD;
             respiratory or cardiac disease&#xD;
&#xD;
          -  Ability to provide written informed consent&#xD;
&#xD;
        EXCLUSION:&#xD;
&#xD;
          -  Use of systemic antibiotics and/or chlorhexidine mouthwash, within the previous three&#xD;
             months&#xD;
&#xD;
          -  Use of immune suppression (chemotherapy, oral prednisone greater than 20mg per day,&#xD;
             etc) with in the previous three months&#xD;
&#xD;
          -  Use of phosphodiesterase-5 inhibitors (tadalafil, sildenafil, etc) within 7 days&#xD;
             before study drug administration&#xD;
&#xD;
          -  Current pregnancy or lactation&#xD;
&#xD;
          -  Uncontrolled systemic hypertension based on repeated measurement of sitting systolic&#xD;
             blood pressure &gt;185 mm Hg or sitting diastolic blood pressure &gt;110 mm Hg at screening&#xD;
&#xD;
          -  Has chronic renal insufficiency as defined by serum creatinine &gt;3 mg/dL at screening&#xD;
             or requires dialytic support&#xD;
&#xD;
          -  Known history of left ventricular ejection fraction &lt; 40% by multiple gated&#xD;
             acquisition scan (MUGA), angiography, or echocardiography&#xD;
&#xD;
          -  History of atrial septostomy&#xD;
&#xD;
          -  Repaired or unrepaired congenital heart disease&#xD;
&#xD;
          -  Pericardial constriction&#xD;
&#xD;
          -  Restrictive or constrictive cardiomyopathy&#xD;
&#xD;
          -  Symptomatic coronary disease with demonstrable ischemia&#xD;
&#xD;
          -  Addition or change in dosing of hormonal contraception medications (OCP, IUD,&#xD;
             Depo-Provera) in the past 4 weeks.&#xD;
&#xD;
          -  Other severe acute or chronic medical or laboratory abnormality that may increase the&#xD;
             risk associated with study participation or investigational product administration,&#xD;
             that may interfere with the interpretation of study results and, in the judgment of&#xD;
             the investigator, would make the subject inappropriate for entry into this study or&#xD;
             would prevent completion of the study&#xD;
&#xD;
          -  Active participation in other research studies with investigational drugs&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Nydia Chien</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15213</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Pittsburgh</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15213</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2022</verification_date>
  <study_first_submitted>November 17, 2016</study_first_submitted>
  <study_first_submitted_qc>December 1, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 2, 2016</study_first_posted>
  <last_update_submitted>March 21, 2022</last_update_submitted>
  <last_update_submitted_qc>March 21, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">March 22, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Pittsburgh</investigator_affiliation>
    <investigator_full_name>Alison Morris</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hypertension, Pulmonary</mesh_term>
    <mesh_term>Hypertension</mesh_term>
    <mesh_term>Heart Failure</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>After de-identification, all participant data collected during the trial will be made available.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_info_type>Analytic Code</ipd_info_type>
    <ipd_time_frame>Data will be made following publication.</ipd_time_frame>
    <ipd_access_criteria>Data will be available publicly.</ipd_access_criteria>
  </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/NCT02980068
org study id: STUDY19120066
secondary id: 5P01HL103455
nct id: NCT02980068
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
This is an open-label, single-center study to examine distinguishing features of the
      structure and function of the oral and gut microbiome in healthy adult normal volunteers
      compared to volunteers with PH-HFpEF in the breakdown of oral nitrate.
We will enroll 60 Group II PH (PH-HFpEF) or Group I PAH patients and 60 matched healthy
      controls over three years. The Subjects will receive a single dose of one of the two study
      drugs, determined by whether they will participate in one study visit or two: 15N nitrate
      (1,000 mg) or 14N Sodium Nitrate: standard sodium nitrate, and all will receive one dose of
      CLA 3g. Twenty of the PH or PAH subjects and 20 of the control subjects willing to return for
      a follow up visit 24 hours after drug administration will receive 15N nitrate. All others
      will receive standard sodium nitrate. CLA will be obtained from GNC (General Nutrition
      Corporation) and given once.

      Throughout the experiment, we will measure blood pressure, heart rate, and respiratory rate
      as well as co-oximetry. Plasma samples are collected at approximate times 0, 2, and 6 hrs
      post-drug administration. Urine will be collected at approximate times 0 and 6 hrs. We will
      examine plasma and urine nitrate and nitrite. The 40 subjects who return for a second visit
      24 hours post-drug administration will provide an additional plasma and urine sample.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Change in nitrate level in urine
time frame: Urine collected approx 0 & 6 hours after drug administration
description: The investigators will examine urine nitrate
measure: Change in nitrate level in plasma
time frame: Approx 50cc of blood drawn approx 0, 2, & 6 hours after drug administration
description: The investigators will examine plasma nitrate
measure: Bacterial content of gut microbiome
time frame: Stool collected before drug administration
description: Stool will be analyzed for bacterial makeup
measure: Bacterial content of the oral microbiome
time frame: Saliva and tongue scraping will occur preceding administration of drug
description: Saliva and tongue scraping will be analyzed for bacterial makeup
measure: Change in nitrite level in urine
time frame: Urine collected approx 0 & 6 hours after drug administration
description: The investigators will examine urine nitrite
measure: Change in nitrite level in plasma
time frame: Approx 50cc of blood drawn approx 0, 2, & 6 hours after drug administration
description: The investigators will examine plasma nitrite
measure: Change in blood pressure
time frame: Frequently over 6 hour study visit
measure: Change in heart rate
time frame: Continuous over 6 hour study visit
measure: Change in respiratory rate
time frame: Continuous over 6 hour study visit
measure: Change in hemoglobin concentration
time frame: Continuous over 6 hour study visit
arm group label: 15N Nitrate
arm group type: Experimental
description: single 1,000mg dose of 15N nitrate with 3g of conjugated linoleic acid (CLA).
arm group label: 14N Sodium Nitrate
arm group type: Experimental
description: single 1,000mg dose of 14N sodium nitrate with 3g of conjugated linoleic acid (CLA)
intervention type: Drug
intervention name: 15N Nitrate
description: 1,000 mg/11.8 mmol, oral, on day one, hour zero
arm group label: 15N Nitrate
other name: 15N Sodium Nitrate
intervention type: Drug
intervention name: 14N Nitrate
description: 1,000 mg/11.18 mmol, oral, on day hour, hour zero
arm group label: 14N Sodium Nitrate
other name: 14N Sodium Nitrate
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
facility: 
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of Pittsburgh
investigator full name: Alison Morris
investigator title: Professor
mesh term: Hypertension, Pulmonary
mesh term: Hypertension
mesh term: Heart Failure
sharing ipd: Yes
ipd description: After de-identification, all participant data collected during the trial will be made available.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd info type: Clinical Study Report (CSR)
ipd info type: Analytic Code
ipd time frame: Data will be made following publication.
ipd access criteria: Data will be available publicly.