<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/NCT02256345</url>
  </required_header>
  <id_info>
    <org_study_id>01340</org_study_id>
    <nct_id>NCT02256345</nct_id>
  </id_info>
  <brief_title>Pharmacokinetics, Pharmacodynamics, and Impact of Inorganic Nitrate on Exercise in HFpEF</brief_title>
  <official_title>Pharmacokinetics, Pharmacodynamics, and Impact of Inorganic Nitrate on Exercise in HFpEF</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Pennsylvania</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Pennsylvania</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study will be performed to determine the safety, tolerability, and dose-response to&#xD;
      inorganic nitrate on exercise capacity in HFpEF. There are two primary goals for this study:&#xD;
&#xD;
        1. Determine the population-specific pharmacokinetics and dose of KNO3 that can be safely&#xD;
           given to subjects with HFpEF.&#xD;
&#xD;
        2. Determine if there is a dose-response effect of nitrate supplementation on exercise&#xD;
           capacity, evidenced by peak oxygen consumption (peak VO2), and physiologic adaptations&#xD;
           to exercise.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This study randomized subjects to either placebo (n=3) or KNO3 (n=9) given a sequential&#xD;
      dosing regimen: 6 mmol twice daily for 1 week followed by dose escalation to 6 mmol thrice&#xD;
      daily for 1 week). Although a primary goal of the study was to assess the safety of KNO3 and&#xD;
      within-group changes in various end points in KNO3-treated subjects, a small number of&#xD;
      placebo-treated (PB, n=3) subjects were included only to assess for any potential training&#xD;
      effect on repeated exercise and Kansas City Cardiomyopathy Questionnaire (KCCQ) measurements.&#xD;
      Potassium chloride, given in equivalent doses, was used as the PB to account for differences&#xD;
      in blood pressure or flow that could be attributed to potassium.&#xD;
&#xD;
      The study was initially designed to be single-blinded to allow the principal investigator to&#xD;
      be aware of arm allocation because of potential concerns for methemoglobinemia with drug&#xD;
      administration. One investigator, who was the primary investigator responsible for&#xD;
      supervising all visits and measurements during the study, remained blinded to treatment&#xD;
      allocation throughout the entirety of the study. All physiological and imaging data were&#xD;
      analyzed in a double-blind manner.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>January 2015</start_date>
  <completion_date type="Actual">June 2016</completion_date>
  <primary_completion_date type="Actual">June 2016</primary_completion_date>
  <phase>Phase 2</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>Single (Participant)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Peak Oxygen Uptake (VO2) From Baseline Upto 1 Week of Administration for Each Dose</measure>
    <time_frame>Baseline, end of week 1, end of week 2</time_frame>
    <description>Peak oxygen uptake (VO2) defined as the average value obtained during the last 30 seconds of exercise.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Vasodilatory Reserve for Each Dose</measure>
    <time_frame>Baseline, end of week 1, end of week 2</time_frame>
    <description>Percent change in peak vascular resistance from rest to peak exercise</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Mitochondrial Oxidative Capacity for Each Dose</measure>
    <time_frame>Baseline, end of week 1, end of week 2</time_frame>
    <description>Percent change in oxidative capacity (oxyhemoglobin levels) before and after occlusion</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Aortic Augmentation Index</measure>
    <time_frame>Baseline, end of week 1, end of week 2</time_frame>
    <description>Percent change in augmentation index, whereas augmentation index at each time point (visit) is defined as the amplitude of the second peak to the first peak of the aortic pulse wave form multiplied by 100: augmentation index = (P2/P1)×100.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">12</enrollment>
  <condition>Heart Failure</condition>
  <condition>Diastolic Heart Failure</condition>
  <arm_group>
    <arm_group_label>KNO3 active comparator</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>KNO3 will be given at a dose of 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if well tolerated</description>
  </arm_group>
  <arm_group>
    <arm_group_label>KCl placebo comparator</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>KCl will be used as a placebo and will be given as 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if well tolerated</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>KNO3</intervention_name>
    <description>Active Comparator</description>
    <arm_group_label>KNO3 active comparator</arm_group_label>
    <other_name>Potassium Nitrate</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>KCl</intervention_name>
    <description>Placebo Comparator</description>
    <arm_group_label>KCl placebo comparator</arm_group_label>
    <other_name>Potassium Chloride</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. NYHA Class II-III symptoms.&#xD;
&#xD;
          2. LV EF &gt; 50%.&#xD;
&#xD;
          3. Stable medical therapy for at least 1 month.&#xD;
&#xD;
          4. Evidence of significant diastolic dysfunction, meeting the European Society of&#xD;
             Echocardiography criteria for HFpEF.&#xD;
&#xD;
        Exclusion Criteria&#xD;
&#xD;
          1. Any rhythm other than sinus with native conduction.&#xD;
&#xD;
          2. Inability to exercise.&#xD;
&#xD;
          3. Moderate or greater valvular disease.&#xD;
&#xD;
          4. Hypertrophic, infiltrative, or inflammatory cardiomyopathy.&#xD;
&#xD;
          5. Pericardial disease.&#xD;
&#xD;
          6. Current angina.&#xD;
&#xD;
          7. Acute coronary syndrome or coronary intervention within the past 2 months.&#xD;
&#xD;
          8. Primary pulmonary arteriopathy.&#xD;
&#xD;
          9. Clinically significant lung disease.&#xD;
&#xD;
         10. Ischemia on stress testing without subsequent revascularization.&#xD;
&#xD;
         11. Treatment with phosphodiesterase inhibitors that cannot be withheld.&#xD;
&#xD;
         12. Treatment with organic nitrates or allopurinol.&#xD;
&#xD;
         13. Significant liver disease impacting synthetic function or volume control.&#xD;
&#xD;
         14. Poor echocardiographic windows.&#xD;
&#xD;
         15. eGFR &lt; 30 mL/min/m2 or Cr &gt;2.5.&#xD;
&#xD;
         16. Current smoking.&#xD;
&#xD;
         17. Alcohol dependency.&#xD;
&#xD;
         18. History of Barret's esophagus.&#xD;
&#xD;
         19. G6PD deficiency&#xD;
&#xD;
         20. Methemoglobinemia - baseline methemoglobin level &gt;3% prior to any study medication.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Julio A Chirinos, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Pennsylvania</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hospital of the University of Pennsylvania</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2017</verification_date>
  <study_first_submitted>September 30, 2014</study_first_submitted>
  <study_first_submitted_qc>September 30, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 3, 2014</study_first_posted>
  <results_first_submitted>June 14, 2017</results_first_submitted>
  <results_first_submitted_qc>August 30, 2017</results_first_submitted_qc>
  <results_first_posted type="Actual">October 3, 2017</results_first_posted>
  <last_update_submitted>August 30, 2017</last_update_submitted>
  <last_update_submitted_qc>August 30, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">October 3, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heart Failure</mesh_term>
    <mesh_term>Heart Failure, Diastolic</mesh_term>
  </condition_browse>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Randomized to KNO3</title>
          <description>KNO3 will be given at a dose of 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if well tolerated.&#xD;
Active Comparator: Potassium Nitrate (KNO3)</description>
        </group>
        <group group_id="P2">
          <title>Randomized to KCl</title>
          <description>KCl will be used as a placebo and will be given as 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if well tolerated.&#xD;
Placebo Comparator: Potassium Chloride (KCl)</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
                <participants group_id="P2" count="3"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
                <participants group_id="P2" count="3"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Randomized to KNO3</title>
          <description>KNO3 will be given at a dose of 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if well tolerated&#xD;
Active Comparator: Potassium Nitrate</description>
        </group>
        <group group_id="B2">
          <title>Randomized to KCl</title>
          <description>KCl will be used as a placebo and will be given as 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if tolerating well.&#xD;
Placebo Comparator: Potassium Chloride</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="9"/>
            <count group_id="B2" value="3"/>
            <count group_id="B3" value="12"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="62.4" spread="5.5"/>
                    <measurement group_id="B2" value="62.7" spread="8.0"/>
                    <measurement group_id="B3" value="62.5" spread="5.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="8"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Race, n (%)</title>
              <category_list>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="8"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>New York Heart Association Heart failure classification (NYHA Class) n (%)</title>
          <description>Class II- Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea (shortness of breath).&#xD;
Class III- Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, palpitation, or dyspnea.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Class II</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Class III</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Body Mass Index, kg/m^2, mean (SD)</title>
          <units>kg/m^2</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="33.4" spread="6.3"/>
                    <measurement group_id="B2" value="37.4" spread="9.9"/>
                    <measurement group_id="B3" value="34.4" spread="7.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Number of Obese Participants, n(%)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Number of Hypertensive Participants, n(%)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Number of Participants with Hyperlipidemia, n (%)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Number of Participants with Coronary Artery Disease, n (%)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Number of Participants with History of atrial fibrillation, n (%)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Number of Participants with Diabetes Mellitus, n (%)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Number of Participants with Obstructive sleep apnea, n (%)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Number of Participants with Current Continuous Positive Airway Pressure (CPAP) use, n (%)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Number of Participants with Obstructive lung disease, n (%)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Number of Participants on Beta-blockers, n (%)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Number of Participants onACEI/ARB, n (%)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Number of Participants on Mineralocorticoid receptor antagonists, n (%)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Number of Participants on Calcium-channel blockers, n (%)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Number of Participants on Loop diuretics, n (%)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Number of Participants on Thiazide diuretic, n (%)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Number of Participants on Statin, n (%)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Estimated Glomerular Filtration Rate (eGFR), mL/min per 1.73m^2, mean (SD)</title>
          <units>mL/min per 1.73m^2</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="71.0" spread="14.1"/>
                    <measurement group_id="B2" value="64.7" spread="5.9"/>
                    <measurement group_id="B3" value="69.4" spread="12.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Estimated Glomerular Filtration Rate (eGFR) &lt;60 mL/min per 1.73m^2, n (%)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>N-terminal pro-brain natriuretic peptide (NT-proBNP), pg/ml, mean (SD)</title>
          <units>pg/ml</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="108.3" spread="94.7"/>
                    <measurement group_id="B2" value="119" spread="87.0"/>
                    <measurement group_id="B3" value="111" spread="89.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Number of Participants with high N-terminal pro-brain natriuretic peptide (NT-proBNP), pg/ml, n (%)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Hemoglobin, g/dL, mean (SD)</title>
          <units>g/dL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="13.6" spread="0.8"/>
                    <measurement group_id="B2" value="13.5" spread="1.0"/>
                    <measurement group_id="B3" value="13.6" spread="0.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Methemoglobin, %, mean (SD)</title>
          <units>percent of total hemoglobin</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1.0" spread="0.2"/>
                    <measurement group_id="B2" value="1.0" spread="0.5"/>
                    <measurement group_id="B3" value="1.0" spread="0.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Left Ventricular (LV) mass,g, mean (SD)</title>
          <units>g</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="174.43" spread="77.09"/>
                    <measurement group_id="B2" value="165.98" spread="19.27"/>
                    <measurement group_id="B3" value="172.32" spread="66.36"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Left Ventricular (LV) mass index, g/m^2, mean (SD)</title>
          <units>g/m^2</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="79.78" spread="26.01"/>
                    <measurement group_id="B2" value="76.18" spread="7.33"/>
                    <measurement group_id="B3" value="78.88" spread="22.46"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Relative wall thickness, mean (SD)</title>
          <description>The ratio of twice LV diastolic posterior wall thickness to left ventricular end-diastolic dimension</description>
          <units>ratio</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0.47" spread="0.09"/>
                    <measurement group_id="B2" value="0.46" spread="0.09"/>
                    <measurement group_id="B3" value="0.47" spread="0.09"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Mitral early inflow velocity (E), cm/s, mean (SD)</title>
          <units>cm/s</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="74.53" spread="24.75"/>
                    <measurement group_id="B2" value="85.73" spread="7.04"/>
                    <measurement group_id="B3" value="77.33" spread="21.91"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Mitral atrial inflow velocity (E), cm/s, mean (SD)</title>
          <units>cm/s</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="70.74" spread="20.06"/>
                    <measurement group_id="B2" value="88.61" spread="21.28"/>
                    <measurement group_id="B3" value="75.21" spread="20.99"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Septal tissue doppler early velocity (e'), mm/s, mean (SD)</title>
          <units>mm/s</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="70.64" spread="12.45"/>
                    <measurement group_id="B2" value="93.71" spread="28.65"/>
                    <measurement group_id="B3" value="76.41" spread="19.26"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Septal E/e' ratio, mean (SD)</title>
          <units>ratio</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="10.70" spread="3.76"/>
                    <measurement group_id="B2" value="9.60" spread="2.39"/>
                    <measurement group_id="B3" value="10.42" spread="3.40"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Left atrial volume index, mL/m^2, mean (SD)</title>
          <units>mL/m^2</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="27.20" spread="7.87"/>
                    <measurement group_id="B2" value="29.38" spread="5.33"/>
                    <measurement group_id="B3" value="27.74" spread="7.15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Left ventricular ejection fraction, %, mean (SD)</title>
          <units>% (stroke volume/ end-diastolic vol)x100</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="65.84" spread="7.74"/>
                    <measurement group_id="B2" value="59.41" spread="13.66"/>
                    <measurement group_id="B3" value="64.23" spread="9.27"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change in Peak Oxygen Uptake (VO2) From Baseline Upto 1 Week of Administration for Each Dose</title>
        <description>Peak oxygen uptake (VO2) defined as the average value obtained during the last 30 seconds of exercise.</description>
        <time_frame>Baseline, end of week 1, end of week 2</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Randomized to KNO3</title>
            <description>KNO3 will be given at a dose of 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if well tolerated&#xD;
Active Comparator: Potassium Nitrate</description>
          </group>
          <group group_id="O2">
            <title>Randomized to KCl</title>
            <description>KCl will be used as a placebo and will be given as 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if tolerating well.&#xD;
Placebo Comparator: Potassium Chloride</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Peak Oxygen Uptake (VO2) From Baseline Upto 1 Week of Administration for Each Dose</title>
          <description>Peak oxygen uptake (VO2) defined as the average value obtained during the last 30 seconds of exercise.</description>
          <units>L/min</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="9"/>
                <count group_id="O2" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline Viist</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.16" lower_limit="1.13" upper_limit="1.19"/>
                    <measurement group_id="O2" value="1.49" lower_limit="1.43" upper_limit="1.54"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>End of week 1 visit</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.20" lower_limit="1.17" upper_limit="1.24"/>
                    <measurement group_id="O2" value="1.44" lower_limit="1.39" upper_limit="1.49"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>End of week 2 visit</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.20" lower_limit="1.17" upper_limit="1.23"/>
                    <measurement group_id="O2" value="1.44" lower_limit="1.39" upper_limit="1.50"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Vasodilatory Reserve for Each Dose</title>
        <description>Percent change in peak vascular resistance from rest to peak exercise</description>
        <time_frame>Baseline, end of week 1, end of week 2</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Randomized to KNO3</title>
            <description>KNO3 will be given at a dose of 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if well tolerated&#xD;
Active Comparator: Potassium Nitrate</description>
          </group>
          <group group_id="O2">
            <title>Randomized to KCl</title>
            <description>KCl will be used as a placebo and will be given as 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if tolerating well.&#xD;
Placebo Comparator: Potassium Chloride</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Vasodilatory Reserve for Each Dose</title>
          <description>Percent change in peak vascular resistance from rest to peak exercise</description>
          <units>%change in peak vascular resistance</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="9"/>
                <count group_id="O2" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-25.6" lower_limit="-40.9" upper_limit="-10.4"/>
                    <measurement group_id="O2" value="-25.8" lower_limit="-31.4" upper_limit="-20.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>End of week 1 visit</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-27.1" lower_limit="-43.6" upper_limit="-10.5"/>
                    <measurement group_id="O2" value="-30.6" lower_limit="-36.2" upper_limit="-25.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>End of week 2 visit</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-34.2" lower_limit="-49.4" upper_limit="-18.9"/>
                    <measurement group_id="O2" value="-20.0" lower_limit="-24.2" upper_limit="-15.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Mitochondrial Oxidative Capacity for Each Dose</title>
        <description>Percent change in oxidative capacity (oxyhemoglobin levels) before and after occlusion</description>
        <time_frame>Baseline, end of week 1, end of week 2</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Randomized to KNO3</title>
            <description>KNO3 will be given at a dose of 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if well tolerated&#xD;
Active Comparator: Potassium Nitrate</description>
          </group>
          <group group_id="O2">
            <title>Randomized to KCl</title>
            <description>KCl will be used as a placebo and will be given as 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if tolerating well.&#xD;
Placebo Comparator: Potassium Chloride</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Mitochondrial Oxidative Capacity for Each Dose</title>
          <description>Percent change in oxidative capacity (oxyhemoglobin levels) before and after occlusion</description>
          <units>Percent change in oxidative capacity</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="9"/>
                <count group_id="O2" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="63.2" lower_limit="47.6" upper_limit="78.8"/>
                    <measurement group_id="O2" value="106.5" lower_limit="59.2" upper_limit="153.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>End of week 1 visit</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="59.2" lower_limit="42.1" upper_limit="76.2"/>
                    <measurement group_id="O2" value="110.4" lower_limit="63.2" upper_limit="157.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>End of Week 2 visit</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="62.2" lower_limit="46.6" upper_limit="77.7"/>
                    <measurement group_id="O2" value="45.4" lower_limit="5.0" upper_limit="85.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Aortic Augmentation Index</title>
        <description>Percent change in augmentation index, whereas augmentation index at each time point (visit) is defined as the amplitude of the second peak to the first peak of the aortic pulse wave form multiplied by 100: augmentation index = (P2/P1)×100.</description>
        <time_frame>Baseline, end of week 1, end of week 2</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Randomized to KNO3</title>
            <description>KNO3 will be given at a dose of 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if well tolerated&#xD;
Active Comparator: Potassium Nitrate</description>
          </group>
          <group group_id="O2">
            <title>Randomized to KCl</title>
            <description>KCl will be used as a placebo and will be given as 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if tolerating well.&#xD;
Placebo Comparator: Potassium Chloride</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Aortic Augmentation Index</title>
          <description>Percent change in augmentation index, whereas augmentation index at each time point (visit) is defined as the amplitude of the second peak to the first peak of the aortic pulse wave form multiplied by 100: augmentation index = (P2/P1)×100.</description>
          <units>Percent change in augumentation index</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="9"/>
                <count group_id="O2" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline visit</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.0" lower_limit="-5.4" upper_limit="11.4"/>
                    <measurement group_id="O2" value="-2.3" lower_limit="-11.5" upper_limit="6.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>End of week 1 visit</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-5.4" lower_limit="-13.1" upper_limit="2.4"/>
                    <measurement group_id="O2" value="-11.9" lower_limit="-23.5" upper_limit="-0.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>End of week 2 visit</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-7.1" lower_limit="-14.9" upper_limit="0.6"/>
                    <measurement group_id="O2" value="-0.2" lower_limit="-9.4" upper_limit="9.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse events were collected at every visit. There are a total of three visits that are 1 week apart.</time_frame>
      <desc>All adverse events were non serious so they are reported under Other Adverse Events</desc>
      <group_list>
        <group group_id="E1">
          <title>Randomized to KNO3</title>
          <description>KNO3 will be given at a dose of 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if well tolerated&#xD;
Active Comparator: Potassium Nitrate</description>
        </group>
        <group group_id="E2">
          <title>Randomized to KCl</title>
          <description>KCl will be used as a placebo and will be given as 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if tolerating well.&#xD;
Placebo Comparator: Potassium Chloride</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Palpitations</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Mild lower extremity edema</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>GI symptoms</sub_title>
                <description>Includes GI upset, nausea, vomiting, flatulence</description>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Any side effect</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="9"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Tooth infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>Small sample size&#xD;
Serial blood draws, which caused a decrease in hemoglobin concentration, which may have constrained the increase in VO2,peak and reduced the magnitude of the improvement in exercise capacity and quality of life.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Julio Chirinos</name_or_title>
      <organization>UPenn</organization>
      <phone>2158235800</phone>
      <email>julio.chirinos@uphs.upenn.edu</email>
    </point_of_contact>
  </clinical_results>
</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/NCT02256345
org study id: 01340
nct id: NCT02256345
lead sponsor: 
has dmc: No
This study will be performed to determine the safety, tolerability, and dose-response to
      inorganic nitrate on exercise capacity in HFpEF. There are two primary goals for this study:

        1. Determine the population-specific pharmacokinetics and dose of KNO3 that can be safely
           given to subjects with HFpEF.

        2. Determine if there is a dose-response effect of nitrate supplementation on exercise
           capacity, evidenced by peak oxygen consumption (peak VO2), and physiologic adaptations
           to exercise.
This study randomized subjects to either placebo (n=3) or KNO3 (n=9) given a sequential
      dosing regimen: 6 mmol twice daily for 1 week followed by dose escalation to 6 mmol thrice
      daily for 1 week). Although a primary goal of the study was to assess the safety of KNO3 and
      within-group changes in various end points in KNO3-treated subjects, a small number of
      placebo-treated (PB, n=3) subjects were included only to assess for any potential training
      effect on repeated exercise and Kansas City Cardiomyopathy Questionnaire (KCCQ) measurements.
      Potassium chloride, given in equivalent doses, was used as the PB to account for differences
      in blood pressure or flow that could be attributed to potassium.

      The study was initially designed to be single-blinded to allow the principal investigator to
      be aware of arm allocation because of potential concerns for methemoglobinemia with drug
      administration. One investigator, who was the primary investigator responsible for
      supervising all visits and measurements during the study, remained blinded to treatment
      allocation throughout the entirety of the study. All physiological and imaging data were
      analyzed in a double-blind manner.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Participant)
measure: Change in Peak Oxygen Uptake (VO2) From Baseline Upto 1 Week of Administration for Each Dose
time frame: Baseline, end of week 1, end of week 2
description: Peak oxygen uptake (VO2) defined as the average value obtained during the last 30 seconds of exercise.
measure: Change in Vasodilatory Reserve for Each Dose
time frame: Baseline, end of week 1, end of week 2
description: Percent change in peak vascular resistance from rest to peak exercise
measure: Change in Mitochondrial Oxidative Capacity for Each Dose
time frame: Baseline, end of week 1, end of week 2
description: Percent change in oxidative capacity (oxyhemoglobin levels) before and after occlusion
measure: Change in Aortic Augmentation Index
time frame: Baseline, end of week 1, end of week 2
description: Percent change in augmentation index, whereas augmentation index at each time point (visit) is defined as the amplitude of the second peak to the first peak of the aortic pulse wave form multiplied by 100: augmentation index = (P2/P1)×100.
arm group label: KNO3 active comparator
arm group type: Active Comparator
description: KNO3 will be given at a dose of 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if well tolerated
arm group label: KCl placebo comparator
arm group type: Placebo Comparator
description: KCl will be used as a placebo and will be given as 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if well tolerated
intervention type: Drug
intervention name: KNO3
description: Active Comparator
arm group label: KNO3 active comparator
other name: Potassium Nitrate
intervention type: Drug
intervention name: KCl
description: Placebo Comparator
arm group label: KCl placebo comparator
other name: Potassium Chloride
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Julio A Chirinos, MD
role: Principal Investigator
affiliation: University of Pennsylvania
facility: 
country: United States
responsible party type: Sponsor
mesh term: Heart Failure
mesh term: Heart Failure, Diastolic
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: Small sample size
Serial blood draws, which caused a decrease in hemoglobin concentration, which may have constrained the increase in VO2,peak and reduced the magnitude of the improvement in exercise capacity and quality of life.
point of contact: 