<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/NCT03787082</url>
  </required_header>
  <id_info>
    <org_study_id>STUDY19120104</org_study_id>
    <secondary_id>5P01HL103455</secondary_id>
    <nct_id>NCT03787082</nct_id>
  </id_info>
  <brief_title>Chlorhexidine Mouthwash and Oral Nitrate in Adults With Pulmonary Hypertension</brief_title>
  <official_title>A Randomized Trial of Chlorhexidine Mouthwash and Oral Nitrate in Adults With Pulmonary Hypertension</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Gladwin, Mark, MD</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institutes of Health (NIH)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Heart, Lung, and Blood Institute (NHLBI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Pittsburgh</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Pittsburgh</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>
      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 volunteers with PH in the breakdown&#xD;
      of oral nitrate and effect on hemodynamics.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <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 volunteers with PH in the breakdown&#xD;
      of oral nitrate and effect on hemodynamics.&#xD;
&#xD;
      The investigators will enroll 40 PH patients over three years. 5 healthy participants will be&#xD;
      enrolled as controls. Participants will receive a single dose of the study drug,:14N Sodium&#xD;
      Nitrate(1000mg): standard sodium nitrate, and all will receive one dose of CLA 3g. CLA will&#xD;
      be obtained from GNC (General Nutrition Corporation) and given once. Participants will be&#xD;
      randomized to receive chlorhexidine gluconate 0.12% (15mL) or placebo to rinse their mouth&#xD;
      with for 1 minute.&#xD;
&#xD;
      Oral samples will be collected pre- and post-chlorhexidine treatments and stool samples will&#xD;
      be collected post-chlorhexidine treatment.&#xD;
&#xD;
      Right heart catheterization will be performed for clinical or research purposes.&#xD;
&#xD;
      The RHC done (in the last 5 years) that establishes inclusion is not the same RHC done as&#xD;
      part of the study in most cases. If there is a strong suspicion of PH based on&#xD;
      echocardiography in a patient who has not had a clinical RHC, the first hemodynamic&#xD;
      measurements obtained in the clinical RHC will establish inclusion and the RHC study&#xD;
      procedures will be performed following confirmation of inclusion.&#xD;
&#xD;
      Participants for whom the RHC done in the study is considered a clinical RHC will be&#xD;
      participants who do have an additional follow up RHC scheduled.&#xD;
&#xD;
      Participants for whom the RHC done in the study is considered a research RHC will be those&#xD;
      who do not have an additional follow RHC scheduled or who are considered healthy and have not&#xD;
      had an RHC before.&#xD;
&#xD;
      Catheterization will generally be performed via the right internal jugular vein access with&#xD;
      the assistance of fluoroscopy, if needed. Once the pulmonary arterial (PA) catheter has been&#xD;
      placed in proper position, measured values will be obtained. The investigators often perform&#xD;
      simultaneous measurement of right atrial pressure and distal pressure (PAP/PAWP) using two&#xD;
      transducers in order to assess both pressures during vasodilator challenge, or other&#xD;
      confrontational testing. An initial hemodynamic profile will be obtained.&#xD;
&#xD;
      With the right heart catheter still in place, participants will be randomized to either&#xD;
      chlorhexidine mouthwash or placebo, then after 30 minutes, all will receive 14N oral nitrate&#xD;
      and CLA. A repeat hemodynamic profile will be performed after two hours. Nitrate metabolites&#xD;
      in plasma will be measured at time 0, 2, and 6 hrs after 14N nitrate dose. Urine nitrite and&#xD;
      nitrate will be measured at 0 and 6 hours. Participants will be monitored with continuous&#xD;
      pulse oximetry and EKG monitoring. Blood pressure measurements will be performed every 15&#xD;
      minutes during the catheterization. Pressure-volume loop and impedance analysis will be&#xD;
      performed at the time of the right heart catheterization (RHC) using the micromanometer&#xD;
      catheter technique to simultaneously measure RV pressure and pulmonary blood flow.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Study was never able to start after the pandemic restrictions lifted&#xD;
  </why_stopped>
  <start_date type="Anticipated">December 2022</start_date>
  <completion_date type="Anticipated">December 2023</completion_date>
  <primary_completion_date type="Anticipated">December 2023</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>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
    <masking_description>Participants will receive open label nitrate and be randomly assigned to either chlorhexidine mouthwash or placebo mouthwash. The participant and investigator will be blinded to which mouthwash the participant is randomized.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Plasma Nitrate</measure>
    <time_frame>At baseline and 2 hours post drug administration</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in Urine Nitrate</measure>
    <time_frame>At baseline and 2 hours post drug administration</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in Plasma Nitrate</measure>
    <time_frame>At baseline and 6 hours post drug administration</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in Urine Nitrate</measure>
    <time_frame>At baseline and 6 hours post drug administration</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in Plasma Nitrate</measure>
    <time_frame>At 2 hours post drug administration and 6 hours post drug administration</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in Urine Nitrate</measure>
    <time_frame>At 2 hours post drug administration and 6 hours post drug administration</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Pulmonary Vascular Resistance (PVR)</measure>
    <time_frame>At baseline and 2 hours post drug administration</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Pulmonary Hypertension</condition>
  <condition>Heart Failure With Normal Ejection Fraction</condition>
  <condition>Pulmonary Heart Disease and Diseases of Pulmonary Circulation</condition>
  <arm_group>
    <arm_group_label>Chlorhexidine Gluconate Mouthwash</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>rinse with chlorhexidine gluconate 0.12% (15mL) mouthwash before administration of 14N Sodium Nitrate 1,000 mg/11.18 mmol, oral</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo Mouthwash</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>rinse with placebo mouthwash (15mL) before administration of 14N Sodium Nitrate 1,000 mg/11.18 mmol, oral</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nitrates</intervention_name>
    <description>1,000 mg/11.18 mmol, oral</description>
    <arm_group_label>Chlorhexidine Gluconate Mouthwash</arm_group_label>
    <arm_group_label>Placebo Mouthwash</arm_group_label>
    <other_name>14N Sodium Nitrate</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Chlorhexidine Gluconate Mouthwash</intervention_name>
    <description>chlorhexidine gluconate 0.12% (15mL) mouth rinse for 1 minute</description>
    <arm_group_label>Chlorhexidine Gluconate Mouthwash</arm_group_label>
    <other_name>Chlorhexidine mouthwash</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo Mouthwash</intervention_name>
    <description>sterile water (15mL) mouth rinse for 1 minute</description>
    <arm_group_label>Placebo Mouthwash</arm_group_label>
    <other_name>Sterile Water</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male or female, 18 years of age or older&#xD;
&#xD;
          -  Undergoing clinical right heart catheterization or had a RHC in past 5 years if in PH&#xD;
             group&#xD;
&#xD;
          -  Pulmonary Hypertension: hemodynamically defined by a mean PAP ≥ 25 mm Hg and have a&#xD;
             PVR &gt; 3 Woods units and normal cardiac index (&gt;2.0 L/min/m2)&#xD;
&#xD;
          -  Healthy Control group: no history of or active cardiac or pulmonary disease&#xD;
&#xD;
          -  Ability to provide written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#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&#xD;
&#xD;
          -  Has chronic renal insufficiency as defined by serum creatinine &gt;3 mg/dL in the last 6&#xD;
             months or requiring dialytic support as reported in the medical record&#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>
  <overall_official>
    <last_name>Alison Morris, MD, MS</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Pittsburgh</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Cathy Kessinger</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>July 2022</verification_date>
  <study_first_submitted>December 24, 2018</study_first_submitted>
  <study_first_submitted_qc>December 24, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 26, 2018</study_first_posted>
  <last_update_submitted>July 5, 2022</last_update_submitted>
  <last_update_submitted_qc>July 5, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">July 7, 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 Diseases</mesh_term>
    <mesh_term>Pulmonary Heart Disease</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Chlorhexidine</mesh_term>
    <mesh_term>Chlorhexidine gluconate</mesh_term>
  </intervention_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/NCT03787082
org study id: STUDY19120104
secondary id: 5P01HL103455
nct id: NCT03787082
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
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 volunteers with PH in the breakdown
      of oral nitrate and effect on hemodynamics.
This is an open-label, single-center study to examine distinguishing features of the
      structure and function of the oral and gut microbiome in volunteers with PH in the breakdown
      of oral nitrate and effect on hemodynamics.

      The investigators will enroll 40 PH patients over three years. 5 healthy participants will be
      enrolled as controls. Participants will receive a single dose of the study drug,:14N Sodium
      Nitrate(1000mg): standard sodium nitrate, and all will receive one dose of CLA 3g. CLA will
      be obtained from GNC (General Nutrition Corporation) and given once. Participants will be
      randomized to receive chlorhexidine gluconate 0.12% (15mL) or placebo to rinse their mouth
      with for 1 minute.

      Oral samples will be collected pre- and post-chlorhexidine treatments and stool samples will
      be collected post-chlorhexidine treatment.

      Right heart catheterization will be performed for clinical or research purposes.

      The RHC done (in the last 5 years) that establishes inclusion is not the same RHC done as
      part of the study in most cases. If there is a strong suspicion of PH based on
      echocardiography in a patient who has not had a clinical RHC, the first hemodynamic
      measurements obtained in the clinical RHC will establish inclusion and the RHC study
      procedures will be performed following confirmation of inclusion.

      Participants for whom the RHC done in the study is considered a clinical RHC will be
      participants who do have an additional follow up RHC scheduled.

      Participants for whom the RHC done in the study is considered a research RHC will be those
      who do not have an additional follow RHC scheduled or who are considered healthy and have not
      had an RHC before.

      Catheterization will generally be performed via the right internal jugular vein access with
      the assistance of fluoroscopy, if needed. Once the pulmonary arterial (PA) catheter has been
      placed in proper position, measured values will be obtained. The investigators often perform
      simultaneous measurement of right atrial pressure and distal pressure (PAP/PAWP) using two
      transducers in order to assess both pressures during vasodilator challenge, or other
      confrontational testing. An initial hemodynamic profile will be obtained.

      With the right heart catheter still in place, participants will be randomized to either
      chlorhexidine mouthwash or placebo, then after 30 minutes, all will receive 14N oral nitrate
      and CLA. A repeat hemodynamic profile will be performed after two hours. Nitrate metabolites
      in plasma will be measured at time 0, 2, and 6 hrs after 14N nitrate dose. Urine nitrite and
      nitrate will be measured at 0 and 6 hours. Participants will be monitored with continuous
      pulse oximetry and EKG monitoring. Blood pressure measurements will be performed every 15
      minutes during the catheterization. Pressure-volume loop and impedance analysis will be
      performed at the time of the right heart catheterization (RHC) using the micromanometer
      catheter technique to simultaneously measure RV pressure and pulmonary blood flow.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
masking description: Participants will receive open label nitrate and be randomly assigned to either chlorhexidine mouthwash or placebo mouthwash. The participant and investigator will be blinded to which mouthwash the participant is randomized.
measure: Change in Plasma Nitrate
time frame: At baseline and 2 hours post drug administration
measure: Change in Urine Nitrate
time frame: At baseline and 2 hours post drug administration
measure: Change in Plasma Nitrate
time frame: At baseline and 6 hours post drug administration
measure: Change in Urine Nitrate
time frame: At baseline and 6 hours post drug administration
measure: Change in Plasma Nitrate
time frame: At 2 hours post drug administration and 6 hours post drug administration
measure: Change in Urine Nitrate
time frame: At 2 hours post drug administration and 6 hours post drug administration
measure: Change in Pulmonary Vascular Resistance (PVR)
time frame: At baseline and 2 hours post drug administration
arm group label: Chlorhexidine Gluconate Mouthwash
arm group type: Experimental
description: rinse with chlorhexidine gluconate 0.12% (15mL) mouthwash before administration of 14N Sodium Nitrate 1,000 mg/11.18 mmol, oral
arm group label: Placebo Mouthwash
arm group type: Placebo Comparator
description: rinse with placebo mouthwash (15mL) before administration of 14N Sodium Nitrate 1,000 mg/11.18 mmol, oral
intervention type: Drug
intervention name: Nitrates
description: 1,000 mg/11.18 mmol, oral
arm group label: Chlorhexidine Gluconate Mouthwash
arm group label: Placebo Mouthwash
other name: 14N Sodium Nitrate
intervention type: Drug
intervention name: Chlorhexidine Gluconate Mouthwash
description: chlorhexidine gluconate 0.12% (15mL) mouth rinse for 1 minute
arm group label: Chlorhexidine Gluconate Mouthwash
other name: Chlorhexidine mouthwash
intervention type: Drug
intervention name: Placebo Mouthwash
description: sterile water (15mL) mouth rinse for 1 minute
arm group label: Placebo Mouthwash
other name: Sterile Water
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Alison Morris, MD, MS
role: Principal Investigator
affiliation: University of Pittsburgh
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 Diseases
mesh term: Pulmonary Heart Disease
mesh term: Chlorhexidine
mesh term: Chlorhexidine gluconate
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.