<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/NCT01726049</url>
  </required_header>
  <id_info>
    <org_study_id>Sildenafil Groningen Study</org_study_id>
    <nct_id>NCT01726049</nct_id>
  </id_info>
  <brief_title>Sildenafil in HFpEF (Heart Failure With Preserved Ejection Fraction) and PH</brief_title>
  <official_title>Effects of Sildenafil on Pulmonary Arterial Pressure in Patients With Heart Failure With Preserved Ejection Fraction ( HFpEF) and Pulmonary Hypertension</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Medical Center Groningen</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Pfizer</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University Medical Center Groningen</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Aim of the study is to investigate whether Sildenafil treatment results in a reduction of&#xD;
      pulmonary artery pressure without decrease of cardiac output (CO) and in improvement of&#xD;
      exercise capacity in patients with heart failure with preserved ejection fraction (HFpEF)&#xD;
      with pulmonary hypertension ( PH).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Rationale: Treatment of diastolic left heart failure is a challenging task. Compared to&#xD;
      systolic left heart failure the level of evidence for known medical treatment regiments is&#xD;
      low. Sildenafil, a phosphodiesterase 5 (PDE 5) inhibitor and effective therapy for pulmonary&#xD;
      arterial hypertension acts as a selective pulmonary vasodilator by inhibiting the impaired&#xD;
      nitric oxide (NO) pathway. Reducing the pulmonary vascular resistance would be the primary&#xD;
      target by treatment of diastolic left heart failure with PH. But clinical and hemodynamical&#xD;
      studies to evaluate the role of Sildenafil in diastolic heart failure, also called heart&#xD;
      failure with preserved ejection fraction (HFpEF) with secondary pulmonary hypertension are&#xD;
      lacking. Our hypothesis is that Sildenafil decreases pulmonary artery pressure in patients&#xD;
      with HFpEF and pulmonary hypertension.&#xD;
&#xD;
      Objective: To investigate whether Sildenafil treatment results in a hemodynamic improvement&#xD;
      and in an improvement of exercise capacity in these patients.&#xD;
&#xD;
      Study design: single-center, prospective, randomized, placebo controlled study. Study&#xD;
      population: 52 patients with HFpEF and PH Intervention : One group receives three times daily&#xD;
      20 mg Sildenafil for 2 weeks followed by three times daily 60 mg Sildenafil for 10 weeks. The&#xD;
      other group receives three times daily 20 mg of Placebo, followed by 3 times daily 60 mg&#xD;
      placebo.&#xD;
&#xD;
      Main study parameters/endpoints:&#xD;
&#xD;
      Primary objectives&#xD;
&#xD;
      1. To investigate whether Sildenafil treatment results in a reduction of pulmonary artery&#xD;
      pressure (PAP) in HFpEF patients with PH (investigated invasively by right heart&#xD;
      catheterization) .&#xD;
&#xD;
      Secondary objectives&#xD;
&#xD;
        1. To investigate whether Sildenafil treatment results in an reduction of wedge pressure in&#xD;
           HFpEF patients.&#xD;
&#xD;
        2. To investigate whether Sildenafil treatment results in an improvenemt of cardiac output&#xD;
           (CO) in HFpEF patients.&#xD;
&#xD;
        3. To investigate whether Sildenafil treatment results in improvement of exercise capacity&#xD;
           in these patients ( defined as change in VO2max)&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>October 2011</start_date>
  <completion_date type="Actual">December 2014</completion_date>
  <primary_completion_date type="Actual">September 2014</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Mean Pulmonary Artery Pressure Measured by Right Heart Catheterization</measure>
    <time_frame>baseline and 12 weeks</time_frame>
    <description>change of mean pulmonary artery pressure between baseline and 12 weeks measured by heart catheterisation</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>VO2max</measure>
    <time_frame>baseline and 12 weeks</time_frame>
    <description>difference in change of VO2 max between baseline and 12 weeks between Sildenafil and placebo group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cardiac Output Measured Invasively by Right Heart Catheterization</measure>
    <time_frame>baseline and 12 weeks</time_frame>
    <description>difference in change of cardiac output between baseline and 12 weeks between Sildenafil and Placebo group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Wedge Pressure Measured Invasively by Right Heart Catheterization</measure>
    <time_frame>baseline and 12 weeks</time_frame>
    <description>Difference in change of wedge pressure between baseline and 12 weeks between Sildenafil group and Placebo group</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Echocardiographic Parameters of Diastolic LV Dysfunction</measure>
    <time_frame>12 weeks</time_frame>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">52</enrollment>
  <condition>Heart Failure, Diastolic</condition>
  <condition>Pulmonary Hypertension</condition>
  <arm_group>
    <arm_group_label>Sildenafil</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Sildenafil orally 3 times 20mg for 2 weeks , followed by 3 times 60 mg for 10 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>placebo orally 3 times 20mg tablets, followed by 3 times 60 mg for 10 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sildenafil</intervention_name>
    <description>Sildenafil administered orally 3 times per day 20 mg for the first 2 weeks, followed by 3 times 60 mg for 10 weeks</description>
    <arm_group_label>Sildenafil</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo tablets 3 times per day 20 mg foor de first 2 weeks, followed by 3 times 60 mg for 10 weeks</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  &gt;18 years&#xD;
&#xD;
          -  Written inform consent&#xD;
&#xD;
          -  PH secondary to diastolic left heart failure defined as&#xD;
&#xD;
          -  PAP mean &gt;25 mmHg&#xD;
&#xD;
          -  Wedge mean &gt;15 mmHg&#xD;
&#xD;
          -  Normal systolic left ventricular (LV) function on echo/nuclear imaging (left&#xD;
             ventricular ejection fraction (LVEF) &gt; or =45%)&#xD;
&#xD;
          -  New York Heart Association class (NYHA) II-IV despite heart failure therapy&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Severe noncardiac limitation to exercise (as severe chronic obstructive pulmonary&#xD;
             disease)&#xD;
&#xD;
          -  Other cause of PH besides diastolic heart failure&#xD;
&#xD;
          -  Coronary ischemia or recent myocardial infarction (&lt;6 months)&#xD;
&#xD;
          -  Hypotension ( &lt;90/50 mmHg)&#xD;
&#xD;
          -  Ongoing nitrate therapy&#xD;
&#xD;
          -  Ongoing therapy with citochrome P450 3A4 ( CYP3A4) inhibitors (ketoconazole,&#xD;
             erythromycin, cimetidine, clarithromycin, itraconazole, voriconazole and protease&#xD;
             inhibitors) or CYP3A4 inductors(carbamacepine, phenytoin, phenobarbital, rifampicin,&#xD;
             Sint Janskruid ). Furthermore patients will be informed not to drink grapefruit juice&#xD;
             while on study medication because of the known impact of grape fruit on&#xD;
             pharmacokinetics of Sildenafil.&#xD;
&#xD;
          -  Ongoing therapy with alpha -inhibitors&#xD;
&#xD;
          -  Significant mitral or aortic valve dysfunction&#xD;
&#xD;
          -  Severe liver dysfunction&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Unable to read and comprehend Dutch language&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>E S Hoendermis, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University Medical Center Groningen</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University Medical Center Groningen</name>
      <address>
        <city>Groningen</city>
        <zip>9700 RB</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <verification_date>February 2016</verification_date>
  <study_first_submitted>September 21, 2012</study_first_submitted>
  <study_first_submitted_qc>November 8, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 14, 2012</study_first_posted>
  <results_first_submitted>October 16, 2015</results_first_submitted>
  <results_first_submitted_qc>February 20, 2016</results_first_submitted_qc>
  <results_first_posted type="Estimate">March 21, 2016</results_first_posted>
  <last_update_submitted>February 20, 2016</last_update_submitted>
  <last_update_submitted_qc>February 20, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">March 21, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University Medical Center Groningen</investigator_affiliation>
    <investigator_full_name>E.S. Hoendermis</investigator_full_name>
    <investigator_title>MD, PhD</investigator_title>
  </responsible_party>
  <keyword>HFpEF</keyword>
  <keyword>PH</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hypertension, Pulmonary</mesh_term>
    <mesh_term>Hypertension</mesh_term>
    <mesh_term>Heart Failure</mesh_term>
    <mesh_term>Heart Failure, Diastolic</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Sildenafil Citrate</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Stabile outpatients with heart failure with preserved ejection fraction (HFpEF) and signs of pulmonary hypertension (PH) on echocardiogram were referred for right heart cath as part of clinical care. After heart catheter measurements , eligible patients were asked for participation. Recruitment from october 2011 until september 2014</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>Sildenafil</title>
          <description>Sildenafil: Sildenafil administered orally 3 times per day 20 mg for the first 2 weeks, followed by 3 times 60 mg for 10 weeks</description>
        </group>
        <group group_id="P2">
          <title>Placebo</title>
          <description>Placebo: Placebo tablets 3 times per day 20 mg foor de first 2 weeks, followed by 3 times 60 mg for 10 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="26"/>
                <participants group_id="P2" count="26"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="21"/>
                <participants group_id="P2" count="22"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
                <participants group_id="P2" count="4"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>refused second HC</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Sildenafil</title>
          <description>Sildenafil: Sildenafil administered orally 3 times per day 20 mg for the first 2 weeks, followed by 3 times 60 mg for 10 weeks</description>
        </group>
        <group group_id="B2">
          <title>Placebo</title>
          <description>Placebo: Placebo tablets 3 times per day 20 mg foor de first 2 weeks, followed by 3 times 60 mg for 10 weeks</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="26"/>
            <count group_id="B2" value="26"/>
            <count group_id="B3" value="52"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="72" spread="12"/>
                    <measurement group_id="B2" value="76" spread="7"/>
                    <measurement group_id="B3" value="74" spread="10"/>
                  </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="20"/>
                    <measurement group_id="B2" value="17"/>
                    <measurement group_id="B3" value="37"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="15"/>
                  </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>Netherlands</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="26"/>
                    <measurement group_id="B2" value="26"/>
                    <measurement group_id="B3" value="52"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Mean Pulmonary Artery Pressure Measured by Right Heart Catheterization</title>
        <description>change of mean pulmonary artery pressure between baseline and 12 weeks measured by heart catheterisation</description>
        <time_frame>baseline and 12 weeks</time_frame>
        <population>52 patients randomized. 26 Sildenafil arm: 26 placebo arm: change in mean pulmonary artery pressure could be evaluated in the intention to treat (ITT) analyses in 21 and 22 subjects of the Sildenafil and placebo treatment group</population>
        <group_list>
          <group group_id="O1">
            <title>Sildenafil</title>
            <description>Sildenafil: Sildenafil administered orally 3 times per day 20 mg for the first 2 weeks, followed by 3 times 60 mg for 10 weeks</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo: Placebo tablets 3 times per day 20 mg foor de first 2 weeks, followed by 3 times 60 mg for 10 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Mean Pulmonary Artery Pressure Measured by Right Heart Catheterization</title>
          <description>change of mean pulmonary artery pressure between baseline and 12 weeks measured by heart catheterisation</description>
          <population>52 patients randomized. 26 Sildenafil arm: 26 placebo arm: change in mean pulmonary artery pressure could be evaluated in the intention to treat (ITT) analyses in 21 and 22 subjects of the Sildenafil and placebo treatment group</population>
          <units>mmHG</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
                <count group_id="O2" value="22"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-2.4" lower_limit="-4.5" upper_limit="-0.3"/>
                    <measurement group_id="O2" value="-4.7" lower_limit="-7.1" upper_limit="-2.3"/>
                  </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>Superiority or Other</non_inferiority_type>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>-2.4</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-4.5</ci_lower_limit>
            <ci_upper_limit>-0.3</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>-4.7</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-7.1</ci_lower_limit>
            <ci_upper_limit>-2.3</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>VO2max</title>
        <description>difference in change of VO2 max between baseline and 12 weeks between Sildenafil and placebo group</description>
        <time_frame>baseline and 12 weeks</time_frame>
        <population>52 patients randomized. 26 Sildenafil arm: 26 placebo arm: change in VO2max could be evaluated in the ITT analyses in 18 and 22 subjects of the Sildenafil and placebo treatment group</population>
        <group_list>
          <group group_id="O1">
            <title>Sildenafil</title>
            <description>Sildenafil: Sildenafil administered orally 3 times per day 20 mg for the first 2 weeks, followed by 3 times 60 mg for 10 weeks</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo: Placebo tablets 3 times per day 20 mg foor de first 2 weeks, followed by 3 times 60 mg for 10 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>VO2max</title>
          <description>difference in change of VO2 max between baseline and 12 weeks between Sildenafil and placebo group</description>
          <population>52 patients randomized. 26 Sildenafil arm: 26 placebo arm: change in VO2max could be evaluated in the ITT analyses in 18 and 22 subjects of the Sildenafil and placebo treatment group</population>
          <units>ml/kg/min</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="18"/>
                <count group_id="O2" value="22"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.2" lower_limit="-0.9" upper_limit="1.4"/>
                    <measurement group_id="O2" value="0.7" lower_limit="-0.3" upper_limit="1.6"/>
                  </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>Superiority or Other</non_inferiority_type>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>0.2</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.9</ci_lower_limit>
            <ci_upper_limit>1.4</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>0.7</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.3</ci_lower_limit>
            <ci_upper_limit>1.6</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Cardiac Output Measured Invasively by Right Heart Catheterization</title>
        <description>difference in change of cardiac output between baseline and 12 weeks between Sildenafil and Placebo group</description>
        <time_frame>baseline and 12 weeks</time_frame>
        <population>52 patients randomized. 26 Sildenafil arm: 26 placebo arm: change in cardiac output could be evaluated in the ITT analyses in 20 and 22 subjects of the Sildenafil and placebo treatment group</population>
        <group_list>
          <group group_id="O1">
            <title>Sildenafil</title>
            <description>Sildenafil: Sildenafil administered orally 3 times per day 20 mg for the first 2 weeks, followed by 3 times 60 mg for 10 weeks</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo: Placebo tablets 3 times per day 20 mg foor de first 2 weeks, followed by 3 times 60 mg for 10 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Cardiac Output Measured Invasively by Right Heart Catheterization</title>
          <description>difference in change of cardiac output between baseline and 12 weeks between Sildenafil and Placebo group</description>
          <population>52 patients randomized. 26 Sildenafil arm: 26 placebo arm: change in cardiac output could be evaluated in the ITT analyses in 20 and 22 subjects of the Sildenafil and placebo treatment group</population>
          <units>mililiter/min</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="22"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.4" lower_limit="-0.9" upper_limit="0.1"/>
                    <measurement group_id="O2" value="-0.2" lower_limit="-0.5" upper_limit="0.1"/>
                  </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>Superiority or Other</non_inferiority_type>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>-0.4</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.9</ci_lower_limit>
            <ci_upper_limit>0.1</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>-0.2</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.5</ci_lower_limit>
            <ci_upper_limit>0.1</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Wedge Pressure Measured Invasively by Right Heart Catheterization</title>
        <description>Difference in change of wedge pressure between baseline and 12 weeks between Sildenafil group and Placebo group</description>
        <time_frame>baseline and 12 weeks</time_frame>
        <population>52 patients randomized. 26 Sildenafil arm: 26 placebo arm: change in wedge pressure could be evaluated in the ITT analyses in 21 and 22 subjects of the Sildenafil and placebo treatment group</population>
        <group_list>
          <group group_id="O1">
            <title>Sildenafil</title>
            <description>Sildenafil: Sildenafil administered orally 3 times per day 20 mg for the first 2 weeks, followed by 3 times 60 mg for 10 weeks</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo: Placebo tablets 3 times per day 20 mg foor de first 2 weeks, followed by 3 times 60 mg for 10 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Wedge Pressure Measured Invasively by Right Heart Catheterization</title>
          <description>Difference in change of wedge pressure between baseline and 12 weeks between Sildenafil group and Placebo group</description>
          <population>52 patients randomized. 26 Sildenafil arm: 26 placebo arm: change in wedge pressure could be evaluated in the ITT analyses in 21 and 22 subjects of the Sildenafil and placebo treatment group</population>
          <units>mmHg</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
                <count group_id="O2" value="22"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.5" lower_limit="-1.9" upper_limit="1.0"/>
                    <measurement group_id="O2" value="-3.5" lower_limit="-5.2" upper_limit="-1.8"/>
                  </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>Superiority or Other</non_inferiority_type>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>-0.5</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-1.9</ci_lower_limit>
            <ci_upper_limit>1.0</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>-3.5</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-5.2</ci_lower_limit>
            <ci_upper_limit>-1.8</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Echocardiographic Parameters of Diastolic LV Dysfunction</title>
        <time_frame>12 weeks</time_frame>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>3 months</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Sildenafil</title>
          <description>Sildenafil: Sildenafil administered orally 3 times per day 20 mg for the first 2 weeks, followed by 3 times 60 mg for 10 weeks</description>
        </group>
        <group group_id="E2">
          <title>Placebo</title>
          <description>Placebo: Placebo tablets 3 times per day 20 mg foor de first 2 weeks, followed by 3 times 60 mg for 10 weeks</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="26"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="26"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>cardiac failure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="26"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="26"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>intestinal infarction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="26"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="26"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>pneumonia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="26"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="26"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>pseudoaneurysma</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="26"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="26"/>
              </event>
              <event>
                <sub_title>medical device complication</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="26"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="26"/>
              </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="22" subjects_at_risk="26"/>
                <counts group_id="E2" subjects_affected="21" subjects_at_risk="26"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>visual impairment</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="26"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="26"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>nausea</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="26"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="26"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>headache</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="26"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="26"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>respiratory tract infection</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="26"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="26"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>myalgia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="26"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="26"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>dizziness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="26"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="26"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>chest pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="26"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="26"/>
              </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>
    <point_of_contact>
      <name_or_title>E.S. Hoendermis, MD, PHD</name_or_title>
      <organization>University Hospital Groningen, NL</organization>
      <phone>0031503616161</phone>
      <email>e.s.hoendermis@umcg.nl</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/NCT01726049
org study id: Sildenafil Groningen Study
nct id: NCT01726049
lead sponsor: 
collaborator: 
has dmc: Yes
Aim of the study is to investigate whether Sildenafil treatment results in a reduction of
      pulmonary artery pressure without decrease of cardiac output (CO) and in improvement of
      exercise capacity in patients with heart failure with preserved ejection fraction (HFpEF)
      with pulmonary hypertension ( PH).
Rationale: Treatment of diastolic left heart failure is a challenging task. Compared to
      systolic left heart failure the level of evidence for known medical treatment regiments is
      low. Sildenafil, a phosphodiesterase 5 (PDE 5) inhibitor and effective therapy for pulmonary
      arterial hypertension acts as a selective pulmonary vasodilator by inhibiting the impaired
      nitric oxide (NO) pathway. Reducing the pulmonary vascular resistance would be the primary
      target by treatment of diastolic left heart failure with PH. But clinical and hemodynamical
      studies to evaluate the role of Sildenafil in diastolic heart failure, also called heart
      failure with preserved ejection fraction (HFpEF) with secondary pulmonary hypertension are
      lacking. Our hypothesis is that Sildenafil decreases pulmonary artery pressure in patients
      with HFpEF and pulmonary hypertension.

      Objective: To investigate whether Sildenafil treatment results in a hemodynamic improvement
      and in an improvement of exercise capacity in these patients.

      Study design: single-center, prospective, randomized, placebo controlled study. Study
      population: 52 patients with HFpEF and PH Intervention : One group receives three times daily
      20 mg Sildenafil for 2 weeks followed by three times daily 60 mg Sildenafil for 10 weeks. The
      other group receives three times daily 20 mg of Placebo, followed by 3 times daily 60 mg
      placebo.

      Main study parameters/endpoints:

      Primary objectives

      1. To investigate whether Sildenafil treatment results in a reduction of pulmonary artery
      pressure (PAP) in HFpEF patients with PH (investigated invasively by right heart
      catheterization) .

      Secondary objectives

        1. To investigate whether Sildenafil treatment results in an reduction of wedge pressure in
           HFpEF patients.

        2. To investigate whether Sildenafil treatment results in an improvenemt of cardiac output
           (CO) in HFpEF patients.

        3. To investigate whether Sildenafil treatment results in improvement of exercise capacity
           in these patients ( defined as change in VO2max)
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Mean Pulmonary Artery Pressure Measured by Right Heart Catheterization
time frame: baseline and 12 weeks
description: change of mean pulmonary artery pressure between baseline and 12 weeks measured by heart catheterisation
measure: VO2max
time frame: baseline and 12 weeks
description: difference in change of VO2 max between baseline and 12 weeks between Sildenafil and placebo group
measure: Cardiac Output Measured Invasively by Right Heart Catheterization
time frame: baseline and 12 weeks
description: difference in change of cardiac output between baseline and 12 weeks between Sildenafil and Placebo group
measure: Wedge Pressure Measured Invasively by Right Heart Catheterization
time frame: baseline and 12 weeks
description: Difference in change of wedge pressure between baseline and 12 weeks between Sildenafil group and Placebo group
measure: Echocardiographic Parameters of Diastolic LV Dysfunction
time frame: 12 weeks
arm group label: Sildenafil
arm group type: Active Comparator
description: Sildenafil orally 3 times 20mg for 2 weeks , followed by 3 times 60 mg for 10 weeks
arm group label: Placebo
arm group type: Placebo Comparator
description: placebo orally 3 times 20mg tablets, followed by 3 times 60 mg for 10 weeks
intervention type: Drug
intervention name: Sildenafil
description: Sildenafil administered orally 3 times per day 20 mg for the first 2 weeks, followed by 3 times 60 mg for 10 weeks
arm group label: Sildenafil
intervention type: Drug
intervention name: Placebo
description: Placebo tablets 3 times per day 20 mg foor de first 2 weeks, followed by 3 times 60 mg for 10 weeks
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: E S Hoendermis, MD PhD
role: Principal Investigator
affiliation: University Medical Center Groningen
facility: 
country: Netherlands
responsible party type: Principal Investigator
investigator affiliation: University Medical Center Groningen
investigator full name: E.S. Hoendermis
investigator title: MD, PhD
mesh term: Hypertension, Pulmonary
mesh term: Hypertension
mesh term: Heart Failure
mesh term: Heart Failure, Diastolic
mesh term: Sildenafil Citrate
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 