<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/NCT01681810</url>
  </required_header>
  <id_info>
    <org_study_id>PRO11030131</org_study_id>
    <nct_id>NCT01681810</nct_id>
  </id_info>
  <brief_title>Oral Nitrite in Adults With Metabolic Syndrome and Hypertension</brief_title>
  <acronym>ONTX</acronym>
  <official_title>An Open-Label Study of Oral Nitrite in Adults With Metabolic Syndrome and Hypertension</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Gladwin, Mark, MD</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Pittsburgh</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This research study is being conducted to examine the effects of daily inorganic nitrite&#xD;
      treatment on the cardiometabolic and hormonal disturbances observed in overweight/obese&#xD;
      adults with the metabolic syndrome and high blood pressure. Ultimately, oral nitrite therapy&#xD;
      may have a major impact on the prevention and treatment of both diabetes and cardiovascular&#xD;
      disease.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Cardiovascular disease remains the leading cause of death in the United States and worldwide.&#xD;
      Several studies have demonstrated that fruit and vegetable rich diets significantly reduced&#xD;
      blood pressure and reduced the risk of ischemic stroke and cardiovascular disease in general,&#xD;
      the exact mechanisms remain poorly understood. Preclinical and clinical research over the&#xD;
      last decade has revealed the important vasoprotective effects of nitrates and nitrites with&#xD;
      regards to reduction in blood pressure, vascular inflammation and endothelial dysfunction.&#xD;
      More recent findings suggest that inorganic nitrate and nitrite therapy may be involved in&#xD;
      the regulation of glucose-insulin homeostasis.&#xD;
&#xD;
      For this reason, development of an oral formulation of nitrite salt represents a rational&#xD;
      avenue of exploration for the treatment of cardiovascular diseases, whereby nitrite would&#xD;
      ensure rapid acting effects upon absorption which can be further oxidized to nitrate via the&#xD;
      enterosalivary circulation pathway. In this pathway, about 25% of circulating nitrate is&#xD;
      concentrated in the saliva and reduced to nitrite by commensal mouth bacteria with nitrate&#xD;
      reductase enzymes. The proposal is the first human study to investigate the inorganic nitrite&#xD;
      effects (in any form) on insulin sensitivity in a patient population. This is the second&#xD;
      human trial using orally delivered nitrite (previously as aqueous solution).&#xD;
&#xD;
      In the initial phase of the study, step up dosing and frequency of oral sodium nitrite to 40&#xD;
      mg three times daily occurred with no serious adverse events. After three subjects completed&#xD;
      the study intervention on sodium nitrite 20 mg three times daily for 2 weeks followed by 40&#xD;
      mg three times daily for the remaining 10 weeks with no serious adverse events, all subjects&#xD;
      in this current phase of the trial (n=20) began the 12-week study intervention with 40 mg&#xD;
      three times daily. At the same time, in person monitoring visits (which included brief&#xD;
      physical exams, directly observed nitrite dosing, secondary outcome measure assessment of&#xD;
      methemoglobin level and blood pressure, interval histories, medication compliance review,&#xD;
      symptom review and dispensing of study drug) were spaced from weekly intervals to subjects&#xD;
      alternating weekly in person visits with phone visits.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>October 2012</start_date>
  <completion_date type="Actual">March 8, 2018</completion_date>
  <primary_completion_date type="Actual">February 8, 2018</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Insulin Stimulated Glucose Disposal Over 12 Week Study Period</measure>
    <time_frame>measured at 0 (baseline) and at 12 weeks</time_frame>
    <description>Change in insulin stimulated glucose disposal was assessed during the 4-hour hyperinsulinemic euglycemic clamp at end of the 12 weeks and was compared to baseline (pre-nitrite). Insulin stimulated glucose disposal (mg/min) was calculated in the final 20 minutes of the 4-hour clamp at steady state and expressed as mg per kg lean body mass (as measured by DEXA) per minute. HumuLIN R regular insulin was infused at a rate of 40 microUnits/m2/min. A non-radioactive glucose isotope dilution (Isotec, Inc) was delivered as a primed, then constant infusion of the 98+% enriched stable isotope of D-glucose [6,6-D2] (0.22 umol x kg-1, 17.6 umol x kg-1 prime). Plasma glucose was clamped between 85-95 mg/dL with a variable infusion of 20% dextrose in water. The rate of dextrose infusion was adjusted based on arterialized plasma glucose measurements obtained every 5 minutes.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Peak Change in Systolic Blood Pressure Over 12 Week Study Period</measure>
    <time_frame>measured at 0 (baseline) and bi-weekly over 12 weeks</time_frame>
    <description>Peak change in systolic blood pressure (SBP) on sodium nitrite compared to baseline. Subjects performed bi-weekly blinded automated blood pressures with a Dinamap DPC200X (GE Medical Systems Information Technology) in triplicate at study visits beginning 30 minutes after directly observed nitrite dosing. Five minute intervals were maintained between measurements while in the supine position with legs uncrossed and sitting upright in a hospital bed in a quiet room. The final 2 of 3 SBP measurements were averaged.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Peak Change in Diastolic Blood Pressure Over 12 Week Study Period</measure>
    <time_frame>measured at 0 (baseline) and bi-weekly over 12 weeks</time_frame>
    <description>Peak change in diastolic blood pressure (DBP) on sodium nitrite compared to baseline. Subjects performed bi-weekly blinded automated blood pressures with a Dinamap DPC200X (GE Medical Systems Information Technology) in triplicate at study visits beginning 30 minutes after directly observed nitrite dosing. Five minute intervals were maintained between measurements while in the supine position with legs uncrossed and sitting upright in a hospital bed in a quiet room. The final 2 of 3 DBP measurements were averaged.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Peak Change in Mean Arterial Pressure Over 12 Week Study Period</measure>
    <time_frame>measured at 0 (baseline) and bi-weekly over 12 weeks</time_frame>
    <description>Peak change in mean arterial pressure (MAP) on sodium nitrite compared to baseline. Subjects performed bi-weekly blinded automated blood pressures with a Dinamap DPC200X (GE Medical Systems Information Technology) in triplicate at study visits beginning 30 minutes after directly observed nitrite dosing. Five minute intervals were maintained between measurements while in the supine position with legs uncrossed and sitting upright in a hospital bed in a quiet room. The final 2 of 3 MAP measurements were averaged.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Peak Change in Methemoglobin Over 12 Week Study Period</measure>
    <time_frame>measured at 0 (baseline) and bi-weekly over 12 weeks</time_frame>
    <description>Peak change in methemoglobin on sodium nitrite compared to baseline. Methemoglobin was assessed bi-weekly at study visits 30 minutes after directly observed nitrite dosing using noninvasive co-oximetry (Masimo Corp, Irvine, CA).</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Metabolic Syndrome</condition>
  <condition>Hypertension</condition>
  <arm_group>
    <arm_group_label>14Nitrogen sodium nitrite</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>sodium nitrite 40 mg three times a day for 12 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>14Nitrogen Sodium Nitrite</intervention_name>
    <description>oral formulation of sodium nitrite 40 mg three times a day for 12 weeks</description>
    <arm_group_label>14Nitrogen sodium nitrite</arm_group_label>
    <other_name>sodium nitrite</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age 18-60 years&#xD;
&#xD;
          -  Body mass index (BMI) greater than or equal to 30 kg/m^2&#xD;
&#xD;
          -  Hypertension: defined as systolic blood pressure (SBP) greater than or equal to 130&#xD;
             and/or diastolic blood pressure (DBP) greater than or equal to 85 mm Hg&#xD;
&#xD;
          -  Waist circumference: greater than 102 cm in men, greater than 88 cm in women&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Positive urine pregnancy test or breastfeeding&#xD;
&#xD;
          -  Concurrent use of medications affecting glucose metabolism (oral hypoglycemics,&#xD;
             insulin, atypical antipsychotics)&#xD;
&#xD;
          -  Recent addition or change in dosing of hormonal contraceptive medications [oral&#xD;
             contraceptive pill (OCP), intrauterine device (IUD), DepoProvera]&#xD;
&#xD;
          -  Current use of greater than or equal to 3 anti-hypertensive agents regardless of blood&#xD;
             pressure control or normotensive on a single or double agent&#xD;
&#xD;
          -  Current use of phosphodiesterase-5 inhibitors or organic nitrates&#xD;
&#xD;
          -  Not stable on treatments for the prior three months or not planning to remain on&#xD;
             current dose of medications for blood pressure, contraception, etc.&#xD;
&#xD;
          -  Known chronic psychiatric or medical conditions including diabetes, liver or kidney&#xD;
             disease or obesity syndromes&#xD;
&#xD;
          -  Thyroid-stimulating hormone (TSH) greater than 8 milli-International unit/mL&#xD;
&#xD;
          -  Smoker&#xD;
&#xD;
          -  Anemia (central lab hemoglobin less than 11g/dL)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Kara S Hughan, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Pittsburgh</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Mark Gladwin, MD</last_name>
    <role>Study Director</role>
    <affiliation>University of Pittsburgh</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Montefiore Hospital of University of Pittsburgh Medical Center (UPMC)</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15213</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2019</verification_date>
  <study_first_submitted>July 3, 2012</study_first_submitted>
  <study_first_submitted_qc>September 7, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 10, 2012</study_first_posted>
  <results_first_submitted>February 1, 2019</results_first_submitted>
  <results_first_submitted_qc>March 24, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">April 16, 2019</results_first_posted>
  <last_update_submitted>March 24, 2019</last_update_submitted>
  <last_update_submitted_qc>March 24, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">April 16, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Pittsburgh</investigator_affiliation>
    <investigator_full_name>Kara S Hughan, MD</investigator_full_name>
    <investigator_title>Assistant Professor of Pediatrics</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hypertension</mesh_term>
    <mesh_term>Metabolic Syndrome</mesh_term>
    <mesh_term>Syndrome</mesh_term>
  </condition_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>May 25, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/10/NCT01681810/Prot_SAP_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>June 5, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/10/NCT01681810/ICF_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Subjects 18-60 years with metabolic syndrome and hypertension were recruited through the University of Pittsburgh Research Participant Registry, University of Pittsburgh Nutrition and Obesity Research Center Registry, university and University of Pittsburgh Medical Center hospital electronic and paper advertising, and radio and bus advertising.</recruitment_details>
      <pre_assignment_details>Twenty four age eligible subjects were consented and eligibility was confirmed. Four were excluded after eligibility confirmed due to poor IV access or not showing to baseline assessment visits, all prior to starting nitrite drug.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>14Nitrogen Sodium Nitrite</title>
          <description>sodium nitrite 40 mg three times a day for 12 weeks&#xD;
14Nitrogen Sodium Nitrite: oral formulation of sodium nitrite 40 mg three times a day for 12 weeks</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="20"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="20"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Participants completing sodium nitrite 40 mg three times a day for 12 weeks</population>
      <group_list>
        <group group_id="B1">
          <title>14Nitrogen Sodium Nitrite</title>
          <description>sodium nitrite 40 mg three times a day for 12 weeks&#xD;
14Nitrogen Sodium Nitrite: oral formulation of sodium nitrite 40 mg three times a day for 12 weeks</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="20"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="52.4" lower_limit="39" upper_limit="59"/>
                  </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>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                  </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>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </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>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Systolic blood pressure (SBP)</title>
          <description>Automated blood pressure was measured with a Dinamap DPC200X (GE Medical Systems Information Technology) after consent, history and physical examination. Subject was in the supine position with legs uncrossed and sitting upright in a chair in a quiet room.</description>
          <units>mmHg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="146" spread="15.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Diastolic blood pressure (DBP)</title>
          <description>Automated blood pressure was measured with a Dinamap DPC200X (GE Medical Systems Information Technology) after consent, history and physical examination. Subject was in the supine position with legs uncrossed and sitting upright in a chair in a quiet room.</description>
          <units>mmHg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="87.8" spread="8.57"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Mean arterial pressure (MAP)</title>
          <description>Automated blood pressure was measured with a Dinamap DPC200X (GE Medical Systems Information Technology) after consent, history and physical examination. Subject was in the supine position with legs uncrossed and sitting upright in a chair in a quiet room.</description>
          <units>mmHg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="109" spread="11.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Body mass index (BMI)</title>
          <description>Height and weight were measured in clothing without shoes. Height measured in centimeters (cm)by stadiometer and body weight measured in kilograms (kg) by Tanita scale. Measured height in cm converted to meters (m). BMI was calculated as weight (kg) divided by height (as m^2).</description>
          <units>kg/m^2</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="40.8" spread="6.63"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Waist circumference-male</title>
          <description>Measurement obtained in triplicate and 3 values averaged.</description>
          <population>displaying sex-specific waist circumference as per eligibility criteria</population>
          <units>cm</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="133.3" spread="11.82"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Waist circumference-female</title>
          <description>Measurement obtained in triplicate and 3 values averaged.</description>
          <population>displaying sex-specific waist circumference as per eligibility criteria</population>
          <units>cm</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="15"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="116.8" spread="13.07"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Thyroid stimulating hormone (TSH)</title>
          <description>TSH obtained by venipuncture.</description>
          <units>mIU/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1.93" spread="1.45"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Hemoglobin</title>
          <description>Hemoglobin obtained by venipuncture.</description>
          <units>g/dL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="14.1" spread="1.25"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change in Insulin Stimulated Glucose Disposal Over 12 Week Study Period</title>
        <description>Change in insulin stimulated glucose disposal was assessed during the 4-hour hyperinsulinemic euglycemic clamp at end of the 12 weeks and was compared to baseline (pre-nitrite). Insulin stimulated glucose disposal (mg/min) was calculated in the final 20 minutes of the 4-hour clamp at steady state and expressed as mg per kg lean body mass (as measured by DEXA) per minute. HumuLIN R regular insulin was infused at a rate of 40 microUnits/m2/min. A non-radioactive glucose isotope dilution (Isotec, Inc) was delivered as a primed, then constant infusion of the 98+% enriched stable isotope of D-glucose [6,6-D2] (0.22 umol x kg-1, 17.6 umol x kg-1 prime). Plasma glucose was clamped between 85-95 mg/dL with a variable infusion of 20% dextrose in water. The rate of dextrose infusion was adjusted based on arterialized plasma glucose measurements obtained every 5 minutes.</description>
        <time_frame>measured at 0 (baseline) and at 12 weeks</time_frame>
        <population>The pre-drug hyperinsulinemic euglycemic clamp isotope data for 1 subject (used to determine insulin stimulated glucose disposal) was not interpretable despite repeat of the mass spectrometry assay. Therefore, the pre- and post- outcome measure for this subject was removed from analysis, giving a n=19 sample size for this analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>14Nitrogen Sodium Nitrite</title>
            <description>sodium nitrite 40 mg three times a day for 12 weeks&#xD;
14Nitrogen Sodium Nitrite: oral formulation of sodium nitrite 40 mg three times a day for 12 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Insulin Stimulated Glucose Disposal Over 12 Week Study Period</title>
          <description>Change in insulin stimulated glucose disposal was assessed during the 4-hour hyperinsulinemic euglycemic clamp at end of the 12 weeks and was compared to baseline (pre-nitrite). Insulin stimulated glucose disposal (mg/min) was calculated in the final 20 minutes of the 4-hour clamp at steady state and expressed as mg per kg lean body mass (as measured by DEXA) per minute. HumuLIN R regular insulin was infused at a rate of 40 microUnits/m2/min. A non-radioactive glucose isotope dilution (Isotec, Inc) was delivered as a primed, then constant infusion of the 98+% enriched stable isotope of D-glucose [6,6-D2] (0.22 umol x kg-1, 17.6 umol x kg-1 prime). Plasma glucose was clamped between 85-95 mg/dL with a variable infusion of 20% dextrose in water. The rate of dextrose infusion was adjusted based on arterialized plasma glucose measurements obtained every 5 minutes.</description>
          <population>The pre-drug hyperinsulinemic euglycemic clamp isotope data for 1 subject (used to determine insulin stimulated glucose disposal) was not interpretable despite repeat of the mass spectrometry assay. Therefore, the pre- and post- outcome measure for this subject was removed from analysis, giving a n=19 sample size for this analysis.</population>
          <units>mg/kg lean body mass/minute</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.76" spread="0.58"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Paired t-test comparing insulin stimulated glucose disposal at end of 12 weeks on nitrite drug to baseline (pre-drug) insulin stimulated glucose disposal.</non_inferiority_desc>
            <p_value>0.2068</p_value>
            <method>t-test, 2 sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Peak Change in Systolic Blood Pressure Over 12 Week Study Period</title>
        <description>Peak change in systolic blood pressure (SBP) on sodium nitrite compared to baseline. Subjects performed bi-weekly blinded automated blood pressures with a Dinamap DPC200X (GE Medical Systems Information Technology) in triplicate at study visits beginning 30 minutes after directly observed nitrite dosing. Five minute intervals were maintained between measurements while in the supine position with legs uncrossed and sitting upright in a hospital bed in a quiet room. The final 2 of 3 SBP measurements were averaged.</description>
        <time_frame>measured at 0 (baseline) and bi-weekly over 12 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>14Nitrogen Sodium Nitrite</title>
            <description>sodium nitrite 40 mg three times a day for 12 weeks&#xD;
14Nitrogen Sodium Nitrite: oral formulation of sodium nitrite 40 mg three times a day for 12 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Peak Change in Systolic Blood Pressure Over 12 Week Study Period</title>
          <description>Peak change in systolic blood pressure (SBP) on sodium nitrite compared to baseline. Subjects performed bi-weekly blinded automated blood pressures with a Dinamap DPC200X (GE Medical Systems Information Technology) in triplicate at study visits beginning 30 minutes after directly observed nitrite dosing. Five minute intervals were maintained between measurements while in the supine position with legs uncrossed and sitting upright in a hospital bed in a quiet room. The final 2 of 3 SBP measurements were averaged.</description>
          <units>mmHg</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-10.45" spread="3.01"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>One-way repeated measures ANOVA comparing blood pressure over time on nitrite drug to baseline (pre-drug) blood pressure.</non_inferiority_desc>
            <p_value>0.0074</p_value>
            <p_value_desc>Bonferroni adjusted p-value for multiple comparisons.</p_value_desc>
            <method>ANOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Peak Change in Diastolic Blood Pressure Over 12 Week Study Period</title>
        <description>Peak change in diastolic blood pressure (DBP) on sodium nitrite compared to baseline. Subjects performed bi-weekly blinded automated blood pressures with a Dinamap DPC200X (GE Medical Systems Information Technology) in triplicate at study visits beginning 30 minutes after directly observed nitrite dosing. Five minute intervals were maintained between measurements while in the supine position with legs uncrossed and sitting upright in a hospital bed in a quiet room. The final 2 of 3 DBP measurements were averaged.</description>
        <time_frame>measured at 0 (baseline) and bi-weekly over 12 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>14Nitrogen Sodium Nitrite</title>
            <description>sodium nitrite 40 mg three times a day for 12 weeks&#xD;
14Nitrogen Sodium Nitrite: oral formulation of sodium nitrite 40 mg three times a day for 12 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Peak Change in Diastolic Blood Pressure Over 12 Week Study Period</title>
          <description>Peak change in diastolic blood pressure (DBP) on sodium nitrite compared to baseline. Subjects performed bi-weekly blinded automated blood pressures with a Dinamap DPC200X (GE Medical Systems Information Technology) in triplicate at study visits beginning 30 minutes after directly observed nitrite dosing. Five minute intervals were maintained between measurements while in the supine position with legs uncrossed and sitting upright in a hospital bed in a quiet room. The final 2 of 3 DBP measurements were averaged.</description>
          <units>mmHg</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-13.05" spread="2.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>One-way repeated measures ANOVA comparing blood pressure over time on nitrite drug to baseline (pre-drug) blood pressure.</non_inferiority_desc>
            <p_value>&lt;0.0001</p_value>
            <p_value_desc>Bonferroni adjusted p-value for multiple comparisons.</p_value_desc>
            <method>ANOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Peak Change in Mean Arterial Pressure Over 12 Week Study Period</title>
        <description>Peak change in mean arterial pressure (MAP) on sodium nitrite compared to baseline. Subjects performed bi-weekly blinded automated blood pressures with a Dinamap DPC200X (GE Medical Systems Information Technology) in triplicate at study visits beginning 30 minutes after directly observed nitrite dosing. Five minute intervals were maintained between measurements while in the supine position with legs uncrossed and sitting upright in a hospital bed in a quiet room. The final 2 of 3 MAP measurements were averaged.</description>
        <time_frame>measured at 0 (baseline) and bi-weekly over 12 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>14Nitrogen Sodium Nitrite</title>
            <description>sodium nitrite 40 mg three times a day for 12 weeks&#xD;
14Nitrogen Sodium Nitrite: oral formulation of sodium nitrite 40 mg three times a day for 12 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Peak Change in Mean Arterial Pressure Over 12 Week Study Period</title>
          <description>Peak change in mean arterial pressure (MAP) on sodium nitrite compared to baseline. Subjects performed bi-weekly blinded automated blood pressures with a Dinamap DPC200X (GE Medical Systems Information Technology) in triplicate at study visits beginning 30 minutes after directly observed nitrite dosing. Five minute intervals were maintained between measurements while in the supine position with legs uncrossed and sitting upright in a hospital bed in a quiet room. The final 2 of 3 MAP measurements were averaged.</description>
          <units>mmHg</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-12.00" spread="2.15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>One-way repeated measures ANOVA comparing blood pressure over time on nitrite drug to baseline (pre-drug) blood pressure.</non_inferiority_desc>
            <p_value>&lt;0.0001</p_value>
            <p_value_desc>Bonferroni adjusted p-value for multiple comparisons.</p_value_desc>
            <method>ANOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Peak Change in Methemoglobin Over 12 Week Study Period</title>
        <description>Peak change in methemoglobin on sodium nitrite compared to baseline. Methemoglobin was assessed bi-weekly at study visits 30 minutes after directly observed nitrite dosing using noninvasive co-oximetry (Masimo Corp, Irvine, CA).</description>
        <time_frame>measured at 0 (baseline) and bi-weekly over 12 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>14Nitrogen Sodium Nitrite</title>
            <description>sodium nitrite 40 mg three times a day for 12 weeks&#xD;
14Nitrogen Sodium Nitrite: oral formulation of sodium nitrite 40 mg three times a day for 12 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Peak Change in Methemoglobin Over 12 Week Study Period</title>
          <description>Peak change in methemoglobin on sodium nitrite compared to baseline. Methemoglobin was assessed bi-weekly at study visits 30 minutes after directly observed nitrite dosing using noninvasive co-oximetry (Masimo Corp, Irvine, CA).</description>
          <units>percentage of total hemoglobin</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.42" spread="0.11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>One-way repeated measures ANOVA comparing methemoglobin percent over time on nitrite drug to baseline (pre-drug) methemoglobin percent.</non_inferiority_desc>
            <p_value>0.0127</p_value>
            <p_value_desc>Bonferroni adjusted p-value for multiple comparisons.</p_value_desc>
            <method>ANOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse event (AE) collection occurred throughout 12 weeks of study drug treatment until 1 month after completing study drug.</time_frame>
      <desc>Adverse event (AE) collection occurred after eligibility was confirmed. AE collection was then queried bi-weekly by standard questionnaire, daily by standard diary card logged by participants, and with regular investigator assessment. First AE assessment began at first baseline assessment study visit prior to first dose of study drug visit.</desc>
      <group_list>
        <group group_id="E1">
          <title>14Nitrogen Sodium Nitrite</title>
          <description>sodium nitrite 40 mg three times a day for 12 weeks&#xD;
14Nitrogen Sodium Nitrite: oral formulation of sodium nitrite 40 mg three times a day for 12 weeks</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="20"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</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="20" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Tachycardia</sub_title>
                <counts group_id="E1" events="5" subjects_affected="2" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="6" subjects_affected="4" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="9" subjects_affected="9" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Sleep disruption</sub_title>
                <counts group_id="E1" events="9" subjects_affected="2" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" events="21" subjects_affected="5" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Joint pain</sub_title>
                <counts group_id="E1" events="7" subjects_affected="4" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Arm/hand pain (non-joint)</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Myalgias</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="62" subjects_affected="15" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="14" subjects_affected="5" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" events="5" subjects_affected="2" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Shortness of breath</sub_title>
                <counts group_id="E1" events="10" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Tachypnea</sub_title>
                <counts group_id="E1" events="6" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Upper respiratory symptoms</sub_title>
                <counts group_id="E1" events="15" subjects_affected="9" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" events="15" subjects_affected="6" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Sore mouth</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Flushing</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="20"/>
              </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>The pre-drug clamp isotope data for 1 subject (used to determine insulin stimulated glucose disposal) was uninterpretable, despite repeating the mass spectrometry assay. Subject's isotope data was removed from analysis (n=19 analysis sample size).</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Dr. Kara Hughan</name_or_title>
      <organization>University of Pittsburgh</organization>
      <phone>4126925173</phone>
      <email>kara.hughan@chp.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/NCT01681810
org study id: PRO11030131
nct id: NCT01681810
lead sponsor: 
has dmc: No
This research study is being conducted to examine the effects of daily inorganic nitrite
      treatment on the cardiometabolic and hormonal disturbances observed in overweight/obese
      adults with the metabolic syndrome and high blood pressure. Ultimately, oral nitrite therapy
      may have a major impact on the prevention and treatment of both diabetes and cardiovascular
      disease.
Cardiovascular disease remains the leading cause of death in the United States and worldwide.
      Several studies have demonstrated that fruit and vegetable rich diets significantly reduced
      blood pressure and reduced the risk of ischemic stroke and cardiovascular disease in general,
      the exact mechanisms remain poorly understood. Preclinical and clinical research over the
      last decade has revealed the important vasoprotective effects of nitrates and nitrites with
      regards to reduction in blood pressure, vascular inflammation and endothelial dysfunction.
      More recent findings suggest that inorganic nitrate and nitrite therapy may be involved in
      the regulation of glucose-insulin homeostasis.

      For this reason, development of an oral formulation of nitrite salt represents a rational
      avenue of exploration for the treatment of cardiovascular diseases, whereby nitrite would
      ensure rapid acting effects upon absorption which can be further oxidized to nitrate via the
      enterosalivary circulation pathway. In this pathway, about 25% of circulating nitrate is
      concentrated in the saliva and reduced to nitrite by commensal mouth bacteria with nitrate
      reductase enzymes. The proposal is the first human study to investigate the inorganic nitrite
      effects (in any form) on insulin sensitivity in a patient population. This is the second
      human trial using orally delivered nitrite (previously as aqueous solution).

      In the initial phase of the study, step up dosing and frequency of oral sodium nitrite to 40
      mg three times daily occurred with no serious adverse events. After three subjects completed
      the study intervention on sodium nitrite 20 mg three times daily for 2 weeks followed by 40
      mg three times daily for the remaining 10 weeks with no serious adverse events, all subjects
      in this current phase of the trial (n=20) began the 12-week study intervention with 40 mg
      three times daily. At the same time, in person monitoring visits (which included brief
      physical exams, directly observed nitrite dosing, secondary outcome measure assessment of
      methemoglobin level and blood pressure, interval histories, medication compliance review,
      symptom review and dispensing of study drug) were spaced from weekly intervals to subjects
      alternating weekly in person visits with phone visits.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Change in Insulin Stimulated Glucose Disposal Over 12 Week Study Period
time frame: measured at 0 (baseline) and at 12 weeks
description: Change in insulin stimulated glucose disposal was assessed during the 4-hour hyperinsulinemic euglycemic clamp at end of the 12 weeks and was compared to baseline (pre-nitrite). Insulin stimulated glucose disposal (mg/min) was calculated in the final 20 minutes of the 4-hour clamp at steady state and expressed as mg per kg lean body mass (as measured by DEXA) per minute. HumuLIN R regular insulin was infused at a rate of 40 microUnits/m2/min. A non-radioactive glucose isotope dilution (Isotec, Inc) was delivered as a primed, then constant infusion of the 98+% enriched stable isotope of D-glucose [6,6-D2] (0.22 umol x kg-1, 17.6 umol x kg-1 prime). Plasma glucose was clamped between 85-95 mg/dL with a variable infusion of 20% dextrose in water. The rate of dextrose infusion was adjusted based on arterialized plasma glucose measurements obtained every 5 minutes.
measure: Peak Change in Systolic Blood Pressure Over 12 Week Study Period
time frame: measured at 0 (baseline) and bi-weekly over 12 weeks
description: Peak change in systolic blood pressure (SBP) on sodium nitrite compared to baseline. Subjects performed bi-weekly blinded automated blood pressures with a Dinamap DPC200X (GE Medical Systems Information Technology) in triplicate at study visits beginning 30 minutes after directly observed nitrite dosing. Five minute intervals were maintained between measurements while in the supine position with legs uncrossed and sitting upright in a hospital bed in a quiet room. The final 2 of 3 SBP measurements were averaged.
measure: Peak Change in Diastolic Blood Pressure Over 12 Week Study Period
time frame: measured at 0 (baseline) and bi-weekly over 12 weeks
description: Peak change in diastolic blood pressure (DBP) on sodium nitrite compared to baseline. Subjects performed bi-weekly blinded automated blood pressures with a Dinamap DPC200X (GE Medical Systems Information Technology) in triplicate at study visits beginning 30 minutes after directly observed nitrite dosing. Five minute intervals were maintained between measurements while in the supine position with legs uncrossed and sitting upright in a hospital bed in a quiet room. The final 2 of 3 DBP measurements were averaged.
measure: Peak Change in Mean Arterial Pressure Over 12 Week Study Period
time frame: measured at 0 (baseline) and bi-weekly over 12 weeks
description: Peak change in mean arterial pressure (MAP) on sodium nitrite compared to baseline. Subjects performed bi-weekly blinded automated blood pressures with a Dinamap DPC200X (GE Medical Systems Information Technology) in triplicate at study visits beginning 30 minutes after directly observed nitrite dosing. Five minute intervals were maintained between measurements while in the supine position with legs uncrossed and sitting upright in a hospital bed in a quiet room. The final 2 of 3 MAP measurements were averaged.
measure: Peak Change in Methemoglobin Over 12 Week Study Period
time frame: measured at 0 (baseline) and bi-weekly over 12 weeks
description: Peak change in methemoglobin on sodium nitrite compared to baseline. Methemoglobin was assessed bi-weekly at study visits 30 minutes after directly observed nitrite dosing using noninvasive co-oximetry (Masimo Corp, Irvine, CA).
arm group label: 14Nitrogen sodium nitrite
arm group type: Experimental
description: sodium nitrite 40 mg three times a day for 12 weeks
intervention type: Drug
intervention name: 14Nitrogen Sodium Nitrite
description: oral formulation of sodium nitrite 40 mg three times a day for 12 weeks
arm group label: 14Nitrogen sodium nitrite
other name: sodium nitrite
criteria: 
gender: All
minimum age: 18 Years
maximum age: 60 Years
healthy volunteers: No
last name: Kara S Hughan, MD
role: Principal Investigator
affiliation: University of Pittsburgh
last name: Mark Gladwin, MD
role: Study Director
affiliation: University of Pittsburgh
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of Pittsburgh
investigator full name: Kara S Hughan, MD
investigator title: Assistant Professor of Pediatrics
mesh term: Hypertension
mesh term: Metabolic Syndrome
mesh term: Syndrome
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: The pre-drug clamp isotope data for 1 subject (used to determine insulin stimulated glucose disposal) was uninterpretable, despite repeating the mass spectrometry assay. Subject's isotope data was removed from analysis (n=19 analysis sample size).
point of contact: 