<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/NCT03289481</url>
  </required_header>
  <id_info>
    <org_study_id>Neo40 Study</org_study_id>
    <nct_id>NCT03289481</nct_id>
  </id_info>
  <brief_title>Treatment of HFpEF With Nitrate Supplement</brief_title>
  <official_title>Treatment of HFpEF With Nitrate Supplement: A Double-blind, Placebo Controlled Trial Including Patients With Atrial Fibrillation</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>MaineHealth</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>HumanN</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>MaineHealth</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>
      The objective of this project is to determine if Neo40, a nitric oxide generating lozenge,&#xD;
      when consumed twice daily by subjects with HFpEF, will increase exercise tolerance, decrease&#xD;
      symptoms and improve quality of life for patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Heart failure (HF) is the most common principal diagnosis for hospital admission in patients&#xD;
      over 65 years old. There are two types of HF, those with reduced ejection fraction (HFrEF)&#xD;
      and those with preserved ejection fraction (HFpEF). Approximately half of patients with the&#xD;
      clinical syndrome of HF have preserved systolic function. HEpEF is becoming more prevalent&#xD;
      with aging of the population and obesity. There are only two class I recommendations for the&#xD;
      treatment of HFpEF, which are controlling blood pressure and the use of diuretics to relieve&#xD;
      symptoms. Exercise training is another approach to improving symptoms, however it may be&#xD;
      poorly tolerated.&#xD;
&#xD;
      Nitrate supplement in the form of concentrated beetroot juice was recently shown to improve&#xD;
      exercise tolerance in patients with HFpEF. (1) Beetroot juice contains high concentration of&#xD;
      nitrate (NO3). This is metabolized to nitrite (NO2). It enters the blood stream, where it is&#xD;
      further reduced to nitric oxide (NO) resulting in intense vasodilation.&#xD;
&#xD;
      Patients with diastolic dysfunction are often asymptomatic at rest but complain of dyspnea&#xD;
      with exertion. Increase in heart rate with exercise causes reduced diastolic filling time and&#xD;
      increases left sided filling pressure. Borloug, et al demonstrated this with right heart&#xD;
      catheterization and supine exercise in patients with diastolic dysfunction. Infusion of NO2&#xD;
      resulted in decreased filling pressures and increased cardiac output. (2)&#xD;
&#xD;
      Neo40 is a new product made from concentrated beetroot juice in the form of a lozenge&#xD;
      designed to dissolve on the tongue. NO3 supplement causes vasodilatation only in the setting&#xD;
      of hypoxia and acidosis resulting in targeted vasodilatation.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 29, 2017</start_date>
  <completion_date type="Actual">August 22, 2018</completion_date>
  <primary_completion_date type="Actual">August 22, 2018</primary_completion_date>
  <phase>Early Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <intervention_model_description>Double-blind, placebo controlled crossover study</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>Masking will be done by the pharmacy. Active and placebo lozenges will look identical.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Time on Treadmill</measure>
    <time_frame>after one week of active lozenges compared to one week of placebo lozenges</time_frame>
    <description>change in total time traveled on treadmill</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Metabolic Equivalents</measure>
    <time_frame>after one week of active lozenges compared to one week of placebo lozenges</time_frame>
    <description>change in metabolic equivalents on treadmill</description>
  </primary_outcome>
  <primary_outcome>
    <measure>E/E Prime</measure>
    <time_frame>after one week of active lozenges compared to one week of placebo lozenges</time_frame>
    <description>change in E/E prime on exercise echo (E/E prime is a ratio between early mitral inflow velocity and mitral annular early diastolic velocity in order to measure diastolic dysfunction)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Estimated Right Ventricular Systolic Pressure</measure>
    <time_frame>after one week of active lozenges compared to one week of placebo lozenges</time_frame>
    <description>change in estimated right ventricular systolic pressure on echo</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">13</enrollment>
  <condition>Heart Failure With Normal Ejection Fraction</condition>
  <arm_group>
    <arm_group_label>Active lozenge first</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Subject will take active lozenge (Vitamin C, Vitamin B12, Nitric Oxide Blend, L-citrulline, Sodium Nitrite) for one week, perform cardiac testing then take placebo lozenge for one week and perform cardiac testing.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo lozenge first</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Subject will take placebo lozenge for one week, perform cardiac testing then take active lozenge (Vitamin C, Vitamin B12, Nitric Oxide Blend, L-citrulline, Sodium Nitrite) for one week and perform cardiac testing.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Active lozenge</intervention_name>
    <description>nitric oxide generating lozenge</description>
    <arm_group_label>Active lozenge first</arm_group_label>
    <arm_group_label>Placebo lozenge first</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>placebo tablet</description>
    <arm_group_label>Active lozenge first</arm_group_label>
    <arm_group_label>Placebo lozenge first</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Diagnosis of HFpEF, defined as:&#xD;
&#xD;
               -  symptomatic with one of more of the following: orthopnea, paroxysmal nocturnal&#xD;
                  dyspnea, lower-extremity edema, dyspnea on exertion; AND&#xD;
&#xD;
               -  ejection fraction &gt;50%&#xD;
&#xD;
               -  ratio of early mitral inflow velocity to septal tissue dopler velocity &gt;8; AND&#xD;
&#xD;
               -  one or more of the following: left atrium measurement &gt;34 mL/m2, elevated&#xD;
                  N-terminal pro-brain natriuretic peptide level within the past 12 months, long&#xD;
                  term loop diuretic use for control of symptoms or elevated filling pressures on&#xD;
                  prior cardiac catheterization&#xD;
&#xD;
          2. Stable medical therapy, defined as: no change in cardiac medications within 30 days&#xD;
&#xD;
          3. Willing to comply with the protocol and provide written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Non-cardiac condition causing limitation of exercise tolerance&#xD;
&#xD;
          2. Acute coronary syndrome, myocardial infarction or cardiac revascularization within 60&#xD;
             days&#xD;
&#xD;
          3. Clinically significant valvular disease, defined as moderate-severe or severe stenosis&#xD;
             or insufficiency&#xD;
&#xD;
          4. Significant ischemia seen on stress testing within the past 12 months that was not&#xD;
             revascularized&#xD;
&#xD;
          5. Subject has taken and investigational medication within the past 30 days&#xD;
&#xD;
          6. History of allergy to beets&#xD;
&#xD;
          7. Systolic blood pressure of &lt;100 at screening&#xD;
&#xD;
          8. Significant medical condition that would interfere with treatment, safety or&#xD;
             compliance with the protocol&#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>Ralph Hamill, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>MaineHealth</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Penobscot Bay Medical Center</name>
      <address>
        <city>Rockport</city>
        <state>Maine</state>
        <zip>04856</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Eggebeen J, Kim-Shapiro DB, Haykowsky M, Morgan TM, Basu S, Brubaker P, Rejeski J, Kitzman DW. One Week of Daily Dosing With Beetroot Juice Improves Submaximal Endurance and Blood Pressure in Older Patients With Heart Failure and Preserved Ejection Fraction. JACC Heart Fail. 2016 Jun;4(6):428-37. doi: 10.1016/j.jchf.2015.12.013. Epub 2016 Feb 10.</citation>
    <PMID>26874390</PMID>
  </reference>
  <reference>
    <citation>Borlaug BA, Koepp KE, Melenovsky V. Sodium Nitrite Improves Exercise Hemodynamics and Ventricular Performance in Heart Failure With Preserved Ejection Fraction. J Am Coll Cardiol. 2015 Oct 13;66(15):1672-82. doi: 10.1016/j.jacc.2015.07.067.</citation>
    <PMID>26449137</PMID>
  </reference>
  <verification_date>September 2021</verification_date>
  <study_first_submitted>September 18, 2017</study_first_submitted>
  <study_first_submitted_qc>September 18, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 21, 2017</study_first_posted>
  <results_first_submitted>February 14, 2019</results_first_submitted>
  <results_first_submitted_qc>August 22, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">August 26, 2019</results_first_posted>
  <last_update_submitted>September 16, 2021</last_update_submitted>
  <last_update_submitted_qc>September 16, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">October 6, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>MaineHealth</investigator_affiliation>
    <investigator_full_name>Ralph Hamill</investigator_full_name>
    <investigator_title>Cardiologist</investigator_title>
  </responsible_party>
  <keyword>Heart failure</keyword>
  <keyword>HFpEF</keyword>
  <keyword>Nitrate supplement</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heart Failure</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>March 20, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/81/NCT03289481/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>March 20, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/81/NCT03289481/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>This study was a cross over case-control study (each subject was a control for themselves).</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>Active Lozenge First</title>
          <description>Subject will take active lozenge for one week, perform cardiac testing then take placebo lozenge for one week and perform cardiac testing.&#xD;
Active lozenge: nitric oxide generating lozenge</description>
        </group>
        <group group_id="P2">
          <title>Placebo Lozenge First</title>
          <description>Subject will take placebo lozenge for one week, perform cardiac testing then take active lozenge for one week and perform cardiac testing.&#xD;
Active lozenge: nitric oxide generating lozenge</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
                <participants group_id="P2" count="7"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="5"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Active Lozenge First</title>
          <description>Subject will take active lozenge for one week, perform cardiac testing then take placebo lozenge for one week and perform cardiac testing.&#xD;
Active lozenge: nitric oxide generating lozenge</description>
        </group>
        <group group_id="B2">
          <title>Placebo Lozenge First</title>
          <description>Subject will take placebo lozenge for one week, perform cardiac testing then take active lozenge for one week and perform cardiac testing.&#xD;
Active lozenge: nitric oxide generating lozenge</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="4"/>
            <count group_id="B2" value="5"/>
            <count group_id="B3" value="9"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="7"/>
                  </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="2"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Diagnosis of HFpEF</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Time on Treadmill</title>
        <description>change in total time traveled on treadmill</description>
        <time_frame>after one week of active lozenges compared to one week of placebo lozenges</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Active Lozenge</title>
            <description>Participants who received Neo40 (active lozenge) in either the first week or the last week of the study.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Participants who received the placebo (matching Neo40) in either the first week or the last week of the study.</description>
          </group>
        </group_list>
        <measure>
          <title>Time on Treadmill</title>
          <description>change in total time traveled on treadmill</description>
          <units>seconds</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="9"/>
                <count group_id="O2" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="402.8" lower_limit="156" upper_limit="729"/>
                    <measurement group_id="O2" value="181.2" lower_limit="180" upper_limit="660"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Metabolic Equivalents</title>
        <description>change in metabolic equivalents on treadmill</description>
        <time_frame>after one week of active lozenges compared to one week of placebo lozenges</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Active Lozenge</title>
            <description>Participants who received Neo40 (active lozenge) in either the first week or the last week of the study.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Participants who received the placebo (matching Neo40) in either the first week or the last week of the study.</description>
          </group>
        </group_list>
        <measure>
          <title>Metabolic Equivalents</title>
          <description>change in metabolic equivalents on treadmill</description>
          <units>cal/min</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="9"/>
                <count group_id="O2" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.99" lower_limit="4.2" upper_limit="12.8"/>
                    <measurement group_id="O2" value="8.46" lower_limit="4.2" upper_limit="12.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>E/E Prime</title>
        <description>change in E/E prime on exercise echo (E/E prime is a ratio between early mitral inflow velocity and mitral annular early diastolic velocity in order to measure diastolic dysfunction)</description>
        <time_frame>after one week of active lozenges compared to one week of placebo lozenges</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Active Lozenge</title>
            <description>Participants who received Neo40 (active lozenge) in either the first week or the last week of the study.</description>
          </group>
          <group group_id="O2">
            <title>Placebo Lozenge</title>
            <description>Participants who received the placebo (matching Neo40) in either the first week or the last week of the study.</description>
          </group>
        </group_list>
        <measure>
          <title>E/E Prime</title>
          <description>change in E/E prime on exercise echo (E/E prime is a ratio between early mitral inflow velocity and mitral annular early diastolic velocity in order to measure diastolic dysfunction)</description>
          <units>ratio</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="9"/>
                <count group_id="O2" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.93" lower_limit="-6.2" upper_limit="8"/>
                    <measurement group_id="O2" value="-.05" lower_limit="-6.8" upper_limit="2.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Estimated Right Ventricular Systolic Pressure</title>
        <description>change in estimated right ventricular systolic pressure on echo</description>
        <time_frame>after one week of active lozenges compared to one week of placebo lozenges</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Active Lozenge</title>
            <description>Participants who received Neo40 (active lozenge) in either the first week or the last week of the study.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Participants who received the placebo (matching Neo40) in either the first week or the last week of the study.</description>
          </group>
        </group_list>
        <measure>
          <title>Estimated Right Ventricular Systolic Pressure</title>
          <description>change in estimated right ventricular systolic pressure on echo</description>
          <units>mmHg</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="9"/>
                <count group_id="O2" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11.79" lower_limit="5" upper_limit="27"/>
                    <measurement group_id="O2" value="8.6" lower_limit="-1.2" upper_limit="28"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>1 year</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Active Lozenge</title>
          <description>Participants who received Neo40 (active lozenge) in either the first week or the last week of the study.</description>
        </group>
        <group group_id="E2">
          <title>Placebo Lozenge</title>
          <description>Participants who received the placebo (matching Neo40) in either the first week or the last week of the study.</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="9"/>
              </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="9"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other 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="9"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT 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>Low enrollment number</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Caroline Knight</name_or_title>
      <organization>Clinical Research</organization>
      <phone>2079218959</phone>
      <email>CKnight@pbmc.org</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/NCT03289481
org study id: Neo40 Study
nct id: NCT03289481
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
The objective of this project is to determine if Neo40, a nitric oxide generating lozenge,
      when consumed twice daily by subjects with HFpEF, will increase exercise tolerance, decrease
      symptoms and improve quality of life for patients.
Heart failure (HF) is the most common principal diagnosis for hospital admission in patients
      over 65 years old. There are two types of HF, those with reduced ejection fraction (HFrEF)
      and those with preserved ejection fraction (HFpEF). Approximately half of patients with the
      clinical syndrome of HF have preserved systolic function. HEpEF is becoming more prevalent
      with aging of the population and obesity. There are only two class I recommendations for the
      treatment of HFpEF, which are controlling blood pressure and the use of diuretics to relieve
      symptoms. Exercise training is another approach to improving symptoms, however it may be
      poorly tolerated.

      Nitrate supplement in the form of concentrated beetroot juice was recently shown to improve
      exercise tolerance in patients with HFpEF. (1) Beetroot juice contains high concentration of
      nitrate (NO3). This is metabolized to nitrite (NO2). It enters the blood stream, where it is
      further reduced to nitric oxide (NO) resulting in intense vasodilation.

      Patients with diastolic dysfunction are often asymptomatic at rest but complain of dyspnea
      with exertion. Increase in heart rate with exercise causes reduced diastolic filling time and
      increases left sided filling pressure. Borloug, et al demonstrated this with right heart
      catheterization and supine exercise in patients with diastolic dysfunction. Infusion of NO2
      resulted in decreased filling pressures and increased cardiac output. (2)

      Neo40 is a new product made from concentrated beetroot juice in the form of a lozenge
      designed to dissolve on the tongue. NO3 supplement causes vasodilatation only in the setting
      of hypoxia and acidosis resulting in targeted vasodilatation.
allocation: Randomized
intervention model: Crossover Assignment
intervention model description: Double-blind, placebo controlled crossover study
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: Masking will be done by the pharmacy. Active and placebo lozenges will look identical.
measure: Time on Treadmill
time frame: after one week of active lozenges compared to one week of placebo lozenges
description: change in total time traveled on treadmill
measure: Metabolic Equivalents
time frame: after one week of active lozenges compared to one week of placebo lozenges
description: change in metabolic equivalents on treadmill
measure: E/E Prime
time frame: after one week of active lozenges compared to one week of placebo lozenges
description: change in E/E prime on exercise echo (E/E prime is a ratio between early mitral inflow velocity and mitral annular early diastolic velocity in order to measure diastolic dysfunction)
measure: Estimated Right Ventricular Systolic Pressure
time frame: after one week of active lozenges compared to one week of placebo lozenges
description: change in estimated right ventricular systolic pressure on echo
arm group label: Active lozenge first
arm group type: Active Comparator
description: Subject will take active lozenge (Vitamin C, Vitamin B12, Nitric Oxide Blend, L-citrulline, Sodium Nitrite) for one week, perform cardiac testing then take placebo lozenge for one week and perform cardiac testing.
arm group label: Placebo lozenge first
arm group type: Active Comparator
description: Subject will take placebo lozenge for one week, perform cardiac testing then take active lozenge (Vitamin C, Vitamin B12, Nitric Oxide Blend, L-citrulline, Sodium Nitrite) for one week and perform cardiac testing.
intervention type: Dietary Supplement
intervention name: Active lozenge
description: nitric oxide generating lozenge
arm group label: Active lozenge first
arm group label: Placebo lozenge first
intervention type: Drug
intervention name: Placebo
description: placebo tablet
arm group label: Active lozenge first
arm group label: Placebo lozenge first
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Ralph Hamill, MD
role: Principal Investigator
affiliation: MaineHealth
facility: 
country: United States
citation: Eggebeen J, Kim-Shapiro DB, Haykowsky M, Morgan TM, Basu S, Brubaker P, Rejeski J, Kitzman DW. One Week of Daily Dosing With Beetroot Juice Improves Submaximal Endurance and Blood Pressure in Older Patients With Heart Failure and Preserved Ejection Fraction. JACC Heart Fail. 2016 Jun;4(6):428-37. doi: 10.1016/j.jchf.2015.12.013. Epub 2016 Feb 10.
PMID: 26874390
citation: Borlaug BA, Koepp KE, Melenovsky V. Sodium Nitrite Improves Exercise Hemodynamics and Ventricular Performance in Heart Failure With Preserved Ejection Fraction. J Am Coll Cardiol. 2015 Oct 13;66(15):1672-82. doi: 10.1016/j.jacc.2015.07.067.
PMID: 26449137
responsible party type: Principal Investigator
investigator affiliation: MaineHealth
investigator full name: Ralph Hamill
investigator title: Cardiologist
mesh term: Heart Failure
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: Low enrollment number
point of contact: 