<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/NCT02228408</url>
  </required_header>
  <id_info>
    <org_study_id>DK100772-01</org_study_id>
    <nct_id>NCT02228408</nct_id>
  </id_info>
  <brief_title>Safety and Cardiovascular Efficacy of Hydralazine and Isosorbide Dinitrate in Dialysis-Dependent ESRD</brief_title>
  <acronym>HIDE</acronym>
  <official_title>A Phase IV Randomized, Double-blind, Active-controlled, Single-center Study of the Safety and Effects on Cardiac Structure and Function of Hydralazine and Isosorbide Dinitrate in Patients With Hemodialysis Dependent ESRD</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Brigham and Women's Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Brigham and Women's Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study is a pilot study designed to compare the safety and cardiovascular effects of 26&#xD;
      weeks of combination hydralazine/isorsorbide dinitrate therapy with placebo therapy in&#xD;
      patients receiving chronic hemodialysis.&#xD;
&#xD;
      The investigators hypothesize that treatment of chronic hemodialysis (ESRD) patients with a&#xD;
      combination of hydralazine/isosorbide dinitrate compared with placebo is safe and that it&#xD;
      will improve heart function as well blood flow/blood vessel supply.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Sixteen patients receiving maintenance hemodialysis will be randomized to 26 weeks of therapy&#xD;
      with combination hydralazine/isosorbide dinitrate or placebo. Study medications will be&#xD;
      titrated to goal dose during the first 4 weeks and maintained at goal dose (as tolerated)&#xD;
      between weeks 4-26. A final study visit to assess symptoms after drug discontinuation will&#xD;
      occur 4 weeks after drug discontinuation.&#xD;
&#xD;
      Study duration-Maximum of 32 weeks with 26 weeks of active therapy.&#xD;
&#xD;
      Efficacy Measures -Tissue Doppler echocardiography and myocardial perfusion scanning using&#xD;
      radioactive NH3 PET will be assessed at weeks 0 and 26.&#xD;
&#xD;
      Safety Measures-Adverse events rates including inter- and intra-dialytic hypotension,&#xD;
      ,cardiovascular death and gastrointestinal symptoms will be assessed throughout the duration&#xD;
      of the study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 28, 2017</start_date>
  <completion_date type="Actual">May 7, 2019</completion_date>
  <primary_completion_date type="Actual">May 7, 2019</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Rate of Hypotension, Serious Adverse Events, GI Events and Cardiovascular Death</measure>
    <time_frame>6 months</time_frame>
    <description>Rate of primary Safety Outcomes(hypotension, serious adverse events, GI events and CV death)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Efficacy-Change in Coronary Flow Reserve (CFR) From 0-6 Months</measure>
    <time_frame>0 to 6 months</time_frame>
    <description>Primary Efficacy Measure-CFR measured on rest and stress Positron Emission Tomography</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in E' on TDI Echo From 0-6 Months</measure>
    <time_frame>0 to 6 months</time_frame>
    <description>Co-primary efficacy measure measured on Tissue Doppler Echocardiography</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Reduction in Drug Dose or Discontinuation of Study Drug</measure>
    <time_frame>0 to 6 months</time_frame>
    <description>Primary Tolerability measure</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Patients Completing Study From 0 to 6 Months</measure>
    <time_frame>0 to 6 months</time_frame>
    <description>Primary Feasibility Measure</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Circulating Fibrosis Markers and Angiogenesis Markers</measure>
    <time_frame>0 to 6 months</time_frame>
    <description>Circulating concentrations of markers such as the carboxy terminal of pro-collagen type 1 or ADMA will be measured</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in LVMI</measure>
    <time_frame>0 to 6 months</time_frame>
    <description>Change in left ventricular mass index between baseline and 6 months.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">17</enrollment>
  <condition>Chronic Hemodialysis (ESRD)</condition>
  <arm_group>
    <arm_group_label>Hydralazine/Isorsorbide Dinitrate</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Hydralazine/Isorsorbide Dinitrate (ISD/HY) will be administered with a target dose of 40 mg of ISD and 75 mg of Hydralazine 3x/daily. Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.&#xD;
Allowable Dosage Forms:&#xD;
ISD/HY 10 mg/10-3x/day ISD/HY 20 mg/35mg-3x/day ISD/HY 40 mg/75 mg-3x/day</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Placebo will be administered Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Hydralazine/Isorsorbide Dinitrate</intervention_name>
    <description>Hydralazine/Isorsorbide Dinitrate (ISD/HY) will be administered with a target dose of 40 mg of ISD and 75 mg of Hydralazine 3x/daily. Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.&#xD;
Target Dose:&#xD;
Hydralazine 75 mg 3x day Isorsorbide Dintrate 40 mg 3x/day&#xD;
Allowable Dosage Forms:&#xD;
ISD/HY 10 mg/10-3x/day ISD/HY 20 mg/35 mg-3x/day ISD/HY 40 mg/75 mg-3x/day&#xD;
Dose Titration:&#xD;
ISD/HY will be administered at a starting dose ISD/HY 10 mg/10-3x/day and titrated to ISD/HY 20 mg/35 mg-3x/day after 4 days and to ISD/HY 40 mg/75 mg-3x/day at 4 weeks. Dose will be decreased as necessary for dose-limiting side effects.</description>
    <arm_group_label>Hydralazine/Isorsorbide Dinitrate</arm_group_label>
    <other_name>Apresoline</other_name>
    <other_name>Isordil</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo titration will mimic titration of active study arm</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria&#xD;
&#xD;
          1. Maintenance hemodialysis therapy for end-stage renal disease&#xD;
&#xD;
          2. Age 18-85 years&#xD;
&#xD;
          3. ≥ 90 days since dialysis initiation&#xD;
&#xD;
          4. Ability to provide informed consent&#xD;
&#xD;
          5. Pre-dialysis seated systolic blood pressure measurements must be ≥ 120 mm Hg in the 2&#xD;
             weeks before enrollment and on the day of randomization.&#xD;
&#xD;
        Exclusion Criteria&#xD;
&#xD;
          1. Serum potassium ≥6.5 mEq/L within 2 months prior to screening&#xD;
&#xD;
          2. Unscheduled dialysis for hyperkalemia within the 3 months prior to screening&#xD;
&#xD;
          3. Hypotension defined as pre-dialysis SBP &lt;100 mm Hg (seated measurement) within 4 weeks&#xD;
             prior to enrollment&#xD;
&#xD;
          4. Recurrent intra-dialytic hypotension, defined as systolic blood pressure &lt;80 mm Hg&#xD;
             during ≥3 dialysis sessions per 30-day rolling period or treatment for either&#xD;
             hypotension or symptoms of hypotension if systolic blood pressure is &lt; 100 mm Hg&#xD;
             during ≥3 dialysis sessions per 30-day rolling period.&#xD;
&#xD;
          5. Mitral valve repair or replacement&#xD;
&#xD;
          6. Severe mitral valve disease by echocardiography, coronary angiography or cardiac&#xD;
             magnetic resonance imaging&#xD;
&#xD;
          7. Prior coronary artery bypass graft&#xD;
&#xD;
          8. Anticipated kidney transplant, change to peritoneal dialysis, or transfer to another&#xD;
             dialysis unit within 6 months&#xD;
&#xD;
          9. Expected survival &lt; 6 months&#xD;
&#xD;
         10. Allergy to study medications (ISD, HY, adenosine/diprimidole)&#xD;
&#xD;
         11. Active use of sildenafil, vardenafil or tadalafil&#xD;
&#xD;
         12. History of severe aortic stenosis or other cause of LV outflow obstruction&#xD;
&#xD;
         13. Pregnancy, anticipated pregnancy, or breastfeeding, confirmed by serum pregnancy test&#xD;
             on the day of PET scan&#xD;
&#xD;
         14. Incarceration&#xD;
&#xD;
         15. Participation in another intervention study&#xD;
&#xD;
         16. Use of monoamine oxidase inhibitors&#xD;
&#xD;
         17. Contraindication to adenosine including&#xD;
&#xD;
               -  2nd or 3rd degree heart block, sick sinus syndrome or symptomatic bradycardia&#xD;
                  (without a functioning pacemaker)&#xD;
&#xD;
               -  moderate or severe asthma&#xD;
&#xD;
               -  chronic obstructive pulmonary disease&#xD;
&#xD;
         18. Active use of any of the study medications unless participant and physician willing to&#xD;
             discontinue prior to enrollment.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>David Charytan, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Brigham and Women's Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Brigham &amp; Women's Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02115</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2021</verification_date>
  <study_first_submitted>August 26, 2014</study_first_submitted>
  <study_first_submitted_qc>August 27, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 29, 2014</study_first_posted>
  <results_first_submitted>March 3, 2021</results_first_submitted>
  <results_first_submitted_qc>March 31, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">April 27, 2021</results_first_posted>
  <last_update_submitted>March 31, 2021</last_update_submitted>
  <last_update_submitted_qc>March 31, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">April 27, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Brigham and Women's Hospital</investigator_affiliation>
    <investigator_full_name>David Charytan M.D.</investigator_full_name>
    <investigator_title>Assistant Professor of Medicine</investigator_title>
  </responsible_party>
  <keyword>hemodialysis</keyword>
  <keyword>ESRD</keyword>
  <keyword>Cardiovascular Disease</keyword>
  <keyword>Isosorbide Dinitrate</keyword>
  <keyword>Hydralazine</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Kidney Failure, Chronic</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hydralazine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>deidentified may be shared upon request to the PI</ipd_description>
  </patient_data>
  <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>April 13, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/08/NCT02228408/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Hydralazine/Isorsorbide Dinitrate</title>
          <description>Hydralazine/Isorsorbide Dinitrate (ISD/HY) will be administered with a target dose of 40 mg of ISD and 75 mg of Hydralazine 3x/daily. Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.&#xD;
Allowable Dosage Forms:&#xD;
ISD/HY 10 mg/10-3x/day ISD/HY 20 mg/35mg-3x/day ISD/HY 40 mg/75 mg-3x/day&#xD;
Hydralazine/Isorsorbide Dinitrate: Hydralazine/Isorsorbide Dinitrate (ISD/HY) will be administered with a target dose of 40 mg of ISD and 75 mg of Hydralazine 3x/daily. Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.&#xD;
Target Dose:&#xD;
Hydralazine 75 mg 3x day Isorsorbide Dintrate 40 mg 3x/day&#xD;
Allowable Dosage Forms:&#xD;
ISD/HY 10 mg/10-3x/day ISD/HY 20 mg/35 mg-3x/day ISD/HY 40 mg/75 mg-3x/day&#xD;
Dose Titration:&#xD;
ISD/HY will be administered at a starting dose ISD/HY 10 mg/10-3x/day and titrated to ISD/HY 20 mg/35 mg-3x/day after 4 days and to ISD/HY 40 mg/75 mg-3x/day at 4 weeks. Dose will be decreased as necessary for dose-limiting side effects.</description>
        </group>
        <group group_id="P2">
          <title>Placebo</title>
          <description>Placebo will be administered Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.&#xD;
Placebo: Placebo titration will mimic titration of active study arm</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
                <participants group_id="P2" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
                <participants group_id="P2" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Hydralazine/Isorsorbide Dinitrate</title>
          <description>Hydralazine/Isorsorbide Dinitrate (ISD/HY) will be administered with a target dose of 40 mg of ISD and 75 mg of Hydralazine 3x/daily. Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.&#xD;
Allowable Dosage Forms:&#xD;
ISD/HY 10 mg/10-3x/day ISD/HY 20 mg/35mg-3x/day ISD/HY 40 mg/75 mg-3x/day&#xD;
Hydralazine/Isorsorbide Dinitrate: Hydralazine/Isorsorbide Dinitrate (ISD/HY) will be administered with a target dose of 40 mg of ISD and 75 mg of Hydralazine 3x/daily. Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.&#xD;
Target Dose:&#xD;
Hydralazine 75 mg 3x day Isorsorbide Dintrate 40 mg 3x/day&#xD;
Allowable Dosage Forms:&#xD;
ISD/HY 10 mg/10-3x/day ISD/HY 20 mg/35 mg-3x/day ISD/HY 40 mg/75 mg-3x/day&#xD;
Dose Titration:&#xD;
ISD/HY will be administered at a starting dose ISD/HY 10 mg/10-3x/day and titrated to ISD/HY 20 mg/35 mg-3x/day after 4 days and to ISD/HY 40 mg/75 mg-3x/day at 4 weeks. Dose will be decreased as necessary for dose-limiting side effects.</description>
        </group>
        <group group_id="B2">
          <title>Placebo</title>
          <description>Placebo will be administered Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.&#xD;
Placebo: Placebo titration will mimic titration of active study arm</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="7"/>
            <count group_id="B2" value="10"/>
            <count group_id="B3" value="17"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="62" lower_limit="54" upper_limit="65"/>
                    <measurement group_id="B2" value="63" lower_limit="55" upper_limit="68"/>
                    <measurement group_id="B3" value="62" lower_limit="53" upper_limit="66"/>
                  </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="3"/>
                    <measurement group_id="B3" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="12"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</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_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="5"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="13"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <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="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                  </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="7"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Rate of Hypotension, Serious Adverse Events, GI Events and Cardiovascular Death</title>
        <description>Rate of primary Safety Outcomes(hypotension, serious adverse events, GI events and CV death)</description>
        <time_frame>6 months</time_frame>
        <population>intent to treat</population>
        <group_list>
          <group group_id="O1">
            <title>Hydralazine/Isorsorbide Dinitrate</title>
            <description>Hydralazine/Isorsorbide Dinitrate (ISD/HY) will be administered with a target dose of 40 mg of ISD and 75 mg of Hydralazine 3x/daily. Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.&#xD;
Allowable Dosage Forms:&#xD;
ISD/HY 10 mg/10-3x/day ISD/HY 20 mg/35mg-3x/day ISD/HY 40 mg/75 mg-3x/day&#xD;
Hydralazine/Isorsorbide Dinitrate: Hydralazine/Isorsorbide Dinitrate (ISD/HY) will be administered with a target dose of 40 mg of ISD and 75 mg of Hydralazine 3x/daily. Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.&#xD;
Target Dose:&#xD;
Hydralazine 75 mg 3x day Isorsorbide Dintrate 40 mg 3x/day&#xD;
Allowable Dosage Forms:&#xD;
ISD/HY 10 mg/10-3x/day ISD/HY 20 mg/35 mg-3x/day ISD/HY 40 mg/75 mg-3x/day&#xD;
Dose Titration:&#xD;
ISD/HY will be administered at a starting dose ISD/HY 10 mg/10-3x/day and titrated to ISD/HY 20 mg/35 mg-3x/day after 4 days and to ISD/HY 40 mg/75 mg-3x/day at 4 weeks. Dose will be decreased as necessary for dose-limiting side effects.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo will be administered Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.&#xD;
Placebo: Placebo titration will mimic titration of active study arm</description>
          </group>
        </group_list>
        <measure>
          <title>Rate of Hypotension, Serious Adverse Events, GI Events and Cardiovascular Death</title>
          <description>Rate of primary Safety Outcomes(hypotension, serious adverse events, GI events and CV death)</description>
          <population>intent to treat</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
                <count group_id="O2" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>intradialytic hpypotension</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>SAE</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                    <measurement group_id="O2" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Nausea</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                    <measurement group_id="O2" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CV death rate per patient year</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.04</p_value>
            <method>poisson</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Efficacy-Change in Coronary Flow Reserve (CFR) From 0-6 Months</title>
        <description>Primary Efficacy Measure-CFR measured on rest and stress Positron Emission Tomography</description>
        <time_frame>0 to 6 months</time_frame>
        <population>intent to treat</population>
        <group_list>
          <group group_id="O1">
            <title>Hydralazine/Isorsorbide Dinitrate</title>
            <description>Hydralazine/Isorsorbide Dinitrate (ISD/HY) will be administered with a target dose of 40 mg of ISD and 75 mg of Hydralazine 3x/daily. Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.&#xD;
Allowable Dosage Forms:&#xD;
ISD/HY 10 mg/10-3x/day ISD/HY 20 mg/35mg-3x/day ISD/HY 40 mg/75 mg-3x/day&#xD;
Hydralazine/Isorsorbide Dinitrate: Hydralazine/Isorsorbide Dinitrate (ISD/HY) will be administered with a target dose of 40 mg of ISD and 75 mg of Hydralazine 3x/daily. Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.&#xD;
Target Dose:&#xD;
Hydralazine 75 mg 3x day Isorsorbide Dintrate 40 mg 3x/day&#xD;
Allowable Dosage Forms:&#xD;
ISD/HY 10 mg/10-3x/day ISD/HY 20 mg/35 mg-3x/day ISD/HY 40 mg/75 mg-3x/day&#xD;
Dose Titration:&#xD;
ISD/HY will be administered at a starting dose ISD/HY 10 mg/10-3x/day and titrated to ISD/HY 20 mg/35 mg-3x/day after 4 days and to ISD/HY 40 mg/75 mg-3x/day at 4 weeks. Dose will be decreased as necessary for dose-limiting side effects.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo will be administered Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.&#xD;
Placebo: Placebo titration will mimic titration of active study arm</description>
          </group>
        </group_list>
        <measure>
          <title>Efficacy-Change in Coronary Flow Reserve (CFR) From 0-6 Months</title>
          <description>Primary Efficacy Measure-CFR measured on rest and stress Positron Emission Tomography</description>
          <population>intent to treat</population>
          <units>ratio</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.27" spread="0.23"/>
                    <measurement group_id="O2" value="-0.03" spread="0.46"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.19</p_value>
            <method>t-test, 2 sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Change in E' on TDI Echo From 0-6 Months</title>
        <description>Co-primary efficacy measure measured on Tissue Doppler Echocardiography</description>
        <time_frame>0 to 6 months</time_frame>
        <population>intent to treat</population>
        <group_list>
          <group group_id="O1">
            <title>Hydralazine/Isorsorbide Dinitrate</title>
            <description>Hydralazine/Isorsorbide Dinitrate (ISD/HY) will be administered with a target dose of 40 mg of ISD and 75 mg of Hydralazine 3x/daily. Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.&#xD;
Allowable Dosage Forms:&#xD;
ISD/HY 10 mg/10-3x/day ISD/HY 20 mg/35mg-3x/day ISD/HY 40 mg/75 mg-3x/day&#xD;
Hydralazine/Isorsorbide Dinitrate: Hydralazine/Isorsorbide Dinitrate (ISD/HY) will be administered with a target dose of 40 mg of ISD and 75 mg of Hydralazine 3x/daily. Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.&#xD;
Target Dose:&#xD;
Hydralazine 75 mg 3x day Isorsorbide Dintrate 40 mg 3x/day&#xD;
Allowable Dosage Forms:&#xD;
ISD/HY 10 mg/10-3x/day ISD/HY 20 mg/35 mg-3x/day ISD/HY 40 mg/75 mg-3x/day&#xD;
Dose Titration:&#xD;
ISD/HY will be administered at a starting dose ISD/HY 10 mg/10-3x/day and titrated to ISD/HY 20 mg/35 mg-3x/day after 4 days and to ISD/HY 40 mg/75 mg-3x/day at 4 weeks. Dose will be decreased as necessary for dose-limiting side effects.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo will be administered Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.&#xD;
Placebo: Placebo titration will mimic titration of active study arm</description>
          </group>
        </group_list>
        <measure>
          <title>Change in E' on TDI Echo From 0-6 Months</title>
          <description>Co-primary efficacy measure measured on Tissue Doppler Echocardiography</description>
          <population>intent to treat</population>
          <units>cm/s</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.56" spread="1.1"/>
                    <measurement group_id="O2" value="-0.04" spread="0.92"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.34</p_value>
            <method>t-test, 2 sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Reduction in Drug Dose or Discontinuation of Study Drug</title>
        <description>Primary Tolerability measure</description>
        <time_frame>0 to 6 months</time_frame>
        <population>intent to treat</population>
        <group_list>
          <group group_id="O1">
            <title>Hydralazine/Isorsorbide Dinitrate</title>
            <description>Hydralazine/Isorsorbide Dinitrate (ISD/HY) will be administered with a target dose of 40 mg of ISD and 75 mg of Hydralazine 3x/daily. Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.&#xD;
Allowable Dosage Forms:&#xD;
ISD/HY 10 mg/10-3x/day ISD/HY 20 mg/35mg-3x/day ISD/HY 40 mg/75 mg-3x/day&#xD;
Hydralazine/Isorsorbide Dinitrate: Hydralazine/Isorsorbide Dinitrate (ISD/HY) will be administered with a target dose of 40 mg of ISD and 75 mg of Hydralazine 3x/daily. Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.&#xD;
Target Dose:&#xD;
Hydralazine 75 mg 3x day Isorsorbide Dintrate 40 mg 3x/day&#xD;
Allowable Dosage Forms:&#xD;
ISD/HY 10 mg/10-3x/day ISD/HY 20 mg/35 mg-3x/day ISD/HY 40 mg/75 mg-3x/day&#xD;
Dose Titration:&#xD;
ISD/HY will be administered at a starting dose ISD/HY 10 mg/10-3x/day and titrated to ISD/HY 20 mg/35 mg-3x/day after 4 days and to ISD/HY 40 mg/75 mg-3x/day at 4 weeks. Dose will be decreased as necessary for dose-limiting side effects.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo will be administered Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.&#xD;
Placebo: Placebo titration will mimic titration of active study arm</description>
          </group>
        </group_list>
        <measure>
          <title>Reduction in Drug Dose or Discontinuation of Study Drug</title>
          <description>Primary Tolerability measure</description>
          <population>intent to treat</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
                <count group_id="O2" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>discontinuation</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>reduction</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Number of Patients Completing Study From 0 to 6 Months</title>
        <description>Primary Feasibility Measure</description>
        <time_frame>0 to 6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Hydralazine/Isorsorbide Dinitrate</title>
            <description>Hydralazine/Isorsorbide Dinitrate (ISD/HY) will be administered with a target dose of 40 mg of ISD and 75 mg of Hydralazine 3x/daily. Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.&#xD;
Allowable Dosage Forms:&#xD;
ISD/HY 10 mg/10-3x/day ISD/HY 20 mg/35mg-3x/day ISD/HY 40 mg/75 mg-3x/day&#xD;
Hydralazine/Isorsorbide Dinitrate: Hydralazine/Isorsorbide Dinitrate (ISD/HY) will be administered with a target dose of 40 mg of ISD and 75 mg of Hydralazine 3x/daily. Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.&#xD;
Target Dose:&#xD;
Hydralazine 75 mg 3x day Isorsorbide Dintrate 40 mg 3x/day&#xD;
Allowable Dosage Forms:&#xD;
ISD/HY 10 mg/10-3x/day ISD/HY 20 mg/35 mg-3x/day ISD/HY 40 mg/75 mg-3x/day&#xD;
Dose Titration:&#xD;
ISD/HY will be administered at a starting dose ISD/HY 10 mg/10-3x/day and titrated to ISD/HY 20 mg/35 mg-3x/day after 4 days and to ISD/HY 40 mg/75 mg-3x/day at 4 weeks. Dose will be decreased as necessary for dose-limiting side effects.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo will be administered Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.&#xD;
Placebo: Placebo titration will mimic titration of active study arm</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Patients Completing Study From 0 to 6 Months</title>
          <description>Primary Feasibility Measure</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
                <count group_id="O2" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                    <measurement group_id="O2" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Circulating Fibrosis Markers and Angiogenesis Markers</title>
        <description>Circulating concentrations of markers such as the carboxy terminal of pro-collagen type 1 or ADMA will be measured</description>
        <time_frame>0 to 6 months</time_frame>
        <population>Not done-data. samples not analyzed due to lack of additional funding.</population>
        <group_list>
          <group group_id="O1">
            <title>Hydralazine/Isorsorbide Dinitrate</title>
            <description>Hydralazine/Isorsorbide Dinitrate (ISD/HY) will be administered with a target dose of 40 mg of ISD and 75 mg of Hydralazine 3x/daily. Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.&#xD;
Allowable Dosage Forms:&#xD;
ISD/HY 10 mg/10-3x/day ISD/HY 20 mg/35mg-3x/day ISD/HY 40 mg/75 mg-3x/day&#xD;
Hydralazine/Isorsorbide Dinitrate: Hydralazine/Isorsorbide Dinitrate (ISD/HY) will be administered with a target dose of 40 mg of ISD and 75 mg of Hydralazine 3x/daily. Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.&#xD;
Target Dose:&#xD;
Hydralazine 75 mg 3x day Isorsorbide Dintrate 40 mg 3x/day&#xD;
Allowable Dosage Forms:&#xD;
ISD/HY 10 mg/10-3x/day ISD/HY 20 mg/35 mg-3x/day ISD/HY 40 mg/75 mg-3x/day&#xD;
Dose Titration:&#xD;
ISD/HY will be administered at a starting dose ISD/HY 10 mg/10-3x/day and titrated to ISD/HY 20 mg/35 mg-3x/day after 4 days and to ISD/HY 40 mg/75 mg-3x/day at 4 weeks. Dose will be decreased as necessary for dose-limiting side effects.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo will be administered Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.&#xD;
Placebo: Placebo titration will mimic titration of active study arm</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Circulating Fibrosis Markers and Angiogenesis Markers</title>
          <description>Circulating concentrations of markers such as the carboxy terminal of pro-collagen type 1 or ADMA will be measured</description>
          <population>Not done-data. samples not analyzed due to lack of additional funding.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in LVMI</title>
        <description>Change in left ventricular mass index between baseline and 6 months.</description>
        <time_frame>0 to 6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Hydralazine/Isorsorbide Dinitrate</title>
            <description>Hydralazine/Isorsorbide Dinitrate (ISD/HY) will be administered with a target dose of 40 mg of ISD and 75 mg of Hydralazine 3x/daily. Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.&#xD;
Allowable Dosage Forms:&#xD;
ISD/HY 10 mg/10-3x/day ISD/HY 20 mg/35mg-3x/day ISD/HY 40 mg/75 mg-3x/day&#xD;
Hydralazine/Isorsorbide Dinitrate: Hydralazine/Isorsorbide Dinitrate (ISD/HY) will be administered with a target dose of 40 mg of ISD and 75 mg of Hydralazine 3x/daily. Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.&#xD;
Target Dose:&#xD;
Hydralazine 75 mg 3x day Isorsorbide Dintrate 40 mg 3x/day&#xD;
Allowable Dosage Forms:&#xD;
ISD/HY 10 mg/10-3x/day ISD/HY 20 mg/35 mg-3x/day ISD/HY 40 mg/75 mg-3x/day&#xD;
Dose Titration:&#xD;
ISD/HY will be administered at a starting dose ISD/HY 10 mg/10-3x/day and titrated to ISD/HY 20 mg/35 mg-3x/day after 4 days and to ISD/HY 40 mg/75 mg-3x/day at 4 weeks. Dose will be decreased as necessary for dose-limiting side effects.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo will be administered Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.&#xD;
Placebo: Placebo titration will mimic titration of active study arm</description>
          </group>
        </group_list>
        <measure>
          <title>Change in LVMI</title>
          <description>Change in left ventricular mass index between baseline and 6 months.</description>
          <units>g/m2</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-10.6" spread="8.5"/>
                    <measurement group_id="O2" value="-8" spread="11.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.62</p_value>
            <method>t-test, 2 sided</method>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>6 months</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Hydralazine/Isorsorbide Dinitrate</title>
          <description>Hydralazine/Isorsorbide Dinitrate (ISD/HY) will be administered with a target dose of 40 mg of ISD and 75 mg of Hydralazine 3x/daily. Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.&#xD;
Allowable Dosage Forms:&#xD;
ISD/HY 10 mg/10-3x/day ISD/HY 20 mg/35mg-3x/day ISD/HY 40 mg/75 mg-3x/day&#xD;
Hydralazine/Isorsorbide Dinitrate: Hydralazine/Isorsorbide Dinitrate (ISD/HY) will be administered with a target dose of 40 mg of ISD and 75 mg of Hydralazine 3x/daily. Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.&#xD;
Target Dose:&#xD;
Hydralazine 75 mg 3x day Isorsorbide Dintrate 40 mg 3x/day&#xD;
Allowable Dosage Forms:&#xD;
ISD/HY 10 mg/10-3x/day ISD/HY 20 mg/35 mg-3x/day ISD/HY 40 mg/75 mg-3x/day&#xD;
Dose Titration:&#xD;
ISD/HY will be administered at a starting dose ISD/HY 10 mg/10-3x/day and titrated to ISD/HY 20 mg/35 mg-3x/day after 4 days and to ISD/HY 40 mg/75 mg-3x/day at 4 weeks. Dose will be decreased as necessary for dose-limiting side effects.</description>
        </group>
        <group group_id="E2">
          <title>Placebo</title>
          <description>Placebo will be administered Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.&#xD;
Placebo: Placebo titration will mimic titration of active study arm</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Systematic Assessment</default_assessment>
        <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="7"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>av fisula thrombosis</sub_title>
                <assessment>Non-systematic Assessment</assessment>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>cv hospitalization</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>nausea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>vomitting</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>gi bleeding</sub_title>
                <assessment>Non-systematic Assessment</assessment>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>fall</sub_title>
                <assessment>Non-systematic Assessment</assessment>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="10" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>diarrhea</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>headache</sub_title>
                <counts group_id="E1" events="8" subjects_affected="5" subjects_at_risk="7"/>
                <counts group_id="E2" events="7" subjects_affected="7" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>vomitting</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </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>small study. unbalanced randomization</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>David Charytan</name_or_title>
      <organization>New York University Medical Center</organization>
      <phone>(646) 501-9086</phone>
      <email>david.charytan@nyulangone.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/NCT02228408
org study id: DK100772-01
nct id: NCT02228408
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
This study is a pilot study designed to compare the safety and cardiovascular effects of 26
      weeks of combination hydralazine/isorsorbide dinitrate therapy with placebo therapy in
      patients receiving chronic hemodialysis.

      The investigators hypothesize that treatment of chronic hemodialysis (ESRD) patients with a
      combination of hydralazine/isosorbide dinitrate compared with placebo is safe and that it
      will improve heart function as well blood flow/blood vessel supply.
Sixteen patients receiving maintenance hemodialysis will be randomized to 26 weeks of therapy
      with combination hydralazine/isosorbide dinitrate or placebo. Study medications will be
      titrated to goal dose during the first 4 weeks and maintained at goal dose (as tolerated)
      between weeks 4-26. A final study visit to assess symptoms after drug discontinuation will
      occur 4 weeks after drug discontinuation.

      Study duration-Maximum of 32 weeks with 26 weeks of active therapy.

      Efficacy Measures -Tissue Doppler echocardiography and myocardial perfusion scanning using
      radioactive NH3 PET will be assessed at weeks 0 and 26.

      Safety Measures-Adverse events rates including inter- and intra-dialytic hypotension,
      ,cardiovascular death and gastrointestinal symptoms will be assessed throughout the duration
      of the study.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Rate of Hypotension, Serious Adverse Events, GI Events and Cardiovascular Death
time frame: 6 months
description: Rate of primary Safety Outcomes(hypotension, serious adverse events, GI events and CV death)
measure: Efficacy-Change in Coronary Flow Reserve (CFR) From 0-6 Months
time frame: 0 to 6 months
description: Primary Efficacy Measure-CFR measured on rest and stress Positron Emission Tomography
measure: Change in E' on TDI Echo From 0-6 Months
time frame: 0 to 6 months
description: Co-primary efficacy measure measured on Tissue Doppler Echocardiography
measure: Reduction in Drug Dose or Discontinuation of Study Drug
time frame: 0 to 6 months
description: Primary Tolerability measure
measure: Number of Patients Completing Study From 0 to 6 Months
time frame: 0 to 6 months
description: Primary Feasibility Measure
measure: Change in Circulating Fibrosis Markers and Angiogenesis Markers
time frame: 0 to 6 months
description: Circulating concentrations of markers such as the carboxy terminal of pro-collagen type 1 or ADMA will be measured
measure: Change in LVMI
time frame: 0 to 6 months
description: Change in left ventricular mass index between baseline and 6 months.
arm group label: Hydralazine/Isorsorbide Dinitrate
arm group type: Experimental
description: Hydralazine/Isorsorbide Dinitrate (ISD/HY) will be administered with a target dose of 40 mg of ISD and 75 mg of Hydralazine 3x/daily. Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.
Allowable Dosage Forms:
ISD/HY 10 mg/10-3x/day ISD/HY 20 mg/35mg-3x/day ISD/HY 40 mg/75 mg-3x/day
arm group label: Placebo
arm group type: Active Comparator
description: Placebo will be administered Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.
intervention type: Drug
intervention name: Hydralazine/Isorsorbide Dinitrate
description: Hydralazine/Isorsorbide Dinitrate (ISD/HY) will be administered with a target dose of 40 mg of ISD and 75 mg of Hydralazine 3x/daily. Doses will be titrated between weeks 0-4 and may be decreased as necessary for treatment of adverse events.
Target Dose:
Hydralazine 75 mg 3x day Isorsorbide Dintrate 40 mg 3x/day
Allowable Dosage Forms:
ISD/HY 10 mg/10-3x/day ISD/HY 20 mg/35 mg-3x/day ISD/HY 40 mg/75 mg-3x/day
Dose Titration:
ISD/HY will be administered at a starting dose ISD/HY 10 mg/10-3x/day and titrated to ISD/HY 20 mg/35 mg-3x/day after 4 days and to ISD/HY 40 mg/75 mg-3x/day at 4 weeks. Dose will be decreased as necessary for dose-limiting side effects.
arm group label: Hydralazine/Isorsorbide Dinitrate
other name: Apresoline
other name: Isordil
intervention type: Drug
intervention name: Placebo
description: Placebo titration will mimic titration of active study arm
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 85 Years
healthy volunteers: No
last name: David Charytan, MD
role: Principal Investigator
affiliation: Brigham and Women's Hospital
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Brigham and Women's Hospital
investigator full name: David Charytan M.D.
investigator title: Assistant Professor of Medicine
mesh term: Kidney Failure, Chronic
mesh term: Hydralazine
sharing ipd: Yes
ipd description: deidentified may be shared upon request to the PI
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: small study. unbalanced randomization
point of contact: 