<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/NCT02261948</url>
  </required_header>
  <id_info>
    <org_study_id>CCFM 199/312</org_study_id>
    <nct_id>NCT02261948</nct_id>
  </id_info>
  <brief_title>Levosimendan Efficacy Assessment by Cardiopulmonary Exercise Test (CPET)</brief_title>
  <official_title>Levosimendan Efficacy Assessment by Cardiopulmonary Exercise Test (CPET)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Centro Cardiologico Monzino</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Orion Corporation, Orion Pharma</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Centro Cardiologico Monzino</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The present study was conceived to evaluate the effects of levosimendan on cardiopulmonary&#xD;
      exercise test (CPET) and DLCO ( Diffusion capacity of Lung for carbon monoxide) in patients&#xD;
      with severe heart failure in stable clinical conditions (NYHA - New York Heart Association -&#xD;
      class III, with a peak VO2 (Oxygen consumption ) &lt; 12 ml/min/kg) on top of optimized standard&#xD;
      therapy.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Eligible patients should have chronic HF (Heart Failure -class NYHA III or IV) in stable&#xD;
      clinical conditions. Inclusion criteria were: left ejection fraction (EF) at echocardiography&#xD;
      ≤35%, age ≥18 years old, peak VO2 &lt;12 ml/min/kg measured by a CPET, a standard optimized&#xD;
      therapy for HF that include ACE-inhibitors, ARBs (angiotensin II Receptor Blocker),&#xD;
      aldosterone blocking agents (spironolactone), diuretics, and beta-blockers.&#xD;
&#xD;
      The exclusion criteria are: ongoing mechanical ventilation; recent or acute coronary&#xD;
      syndromes; sustained ventricular tachycardia or ventricular fibrillation; severe aortic or&#xD;
      mitral regurgitation, or known malfunctioning artificial heart valve; uncorrected obstructive&#xD;
      valvular disease; hypertrophic obstructive cardiomyopathy; uncorrected thyroid disease.&#xD;
&#xD;
      Patients will be randomly assigned by means of prepared letters to the levosimendan or&#xD;
      placebo group stratified by clinical centre in a 1:1 allocation using block randomization.&#xD;
      The placebo infusion will be coloured identically to its respective active counterpart.&#xD;
      Patients and investigators will be kept blinded to the treatment allocation for the entire&#xD;
      duration of the trial. Study drug will be infused with an injection speed between 6 and 20&#xD;
      ml/min based on blood pressure, without a bolus, for 24 hours.&#xD;
&#xD;
      Medical history, physical examination and a blood sample examination will be recorded: NYHA&#xD;
      class, BNP (Brain Natriuretic Peptide), haemoglobin, creatinine, blood urea nitrogen (BUN)&#xD;
      will be recorded before and 24 hours after the drug infusion.&#xD;
&#xD;
      A two-dimensional standard echocardiography evaluation will be performed at the admission in&#xD;
      the hospital.&#xD;
&#xD;
      A maximal CPET performed on a cycle ergometer (Sensor Medics Ergo 800S and V-max,&#xD;
      Yorba-Linda, CA) with a personalized ramp aimed at achieving peak exercise in 10 minutes will&#xD;
      be performed before and 24 hours after the drug infusion. Expiratory O2, CO2 (Carbon dioxide)&#xD;
      and ventilation (VE) will be measured breath by breath. Peak VO2 (Carbon dioxide production)&#xD;
      was considered to be the highest VO2 achieved during the exercise. A 12-lead&#xD;
      electrocardiogram will be also recorded. Spirometry and DLCO measurements will be performed&#xD;
      before ad 24-hours after the drug infusion. . DLCO will be measured by the single&#xD;
      breath-constant expiratory flow technique&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>September 2012</start_date>
  <completion_date type="Actual">December 2014</completion_date>
  <primary_completion_date type="Actual">September 2014</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>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Peak VO2 (Oxygen Consumption )</measure>
    <time_frame>48 hours</time_frame>
    <description>Primary endpoints: Levosimendan induced changes in peak VO2 (Oxygen consumption )</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Changes in VE/VCO2</measure>
    <time_frame>48 hours</time_frame>
    <description>Levosimendan induced changes on VE/VCO2 (VE: Expired Volume - VCO2: carbon dioxide production) relationship</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in DLCO (Diffusion Lung CO)</measure>
    <time_frame>48 hours</time_frame>
    <description>Levosimendan induced changes on DLCO ( Diffusion Lung CO). DLCO is measured by the single breath-constant expiratory flow technique (Sensor Medics 2200, Yorba Linda, CA) and we calculate also the DLCO adjusted for hemoglobin. Dilution of CH4 is used to measure alveolar volume.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">42</enrollment>
  <condition>Heart Failure</condition>
  <arm_group>
    <arm_group_label>Levosimendan</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Levosimendan must be diluted before the administration (500 ml of glucose). The intravenous infusion may be administered either by the peripheral or central. The dose and duration of therapy should be decided according to the patient's clinical condition and response to the drug. Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min. A low infusion bolus (6 mcg / kg) is recommended for patients who have a concomitant intravenous treatment with vasodilators or inotropic. The patient's response should be evaluated during the infusion bolus or within 30 to 60 minutes and a dose adjustment based on clinical response.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo must be diluted before the administration (500 ml of glucose). The intravenous infusion may' be administered either by the peripheral or central. The dose and duration of therapy should be decided according to the patient's clinical condition and response to the drug. Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min. A low infusion bolus (6 mcg / kg) is recommended for patients who have a concomitant intravenous treatment with vasodilators or inotropic. The patient's response should be evaluated during the infusion bolus or within 30 to 60 minutes and a dose adjustment based on clinical response.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Levosimendan</intervention_name>
    <description>Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min.</description>
    <arm_group_label>Levosimendan</arm_group_label>
    <other_name>SIMDAX</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min.</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  informed consent of the study signed&#xD;
&#xD;
          -  severe heart failure in stable clinical condition (NYHA class III, peak VO2 &lt;12 ml /&#xD;
             kg / min) in optimized medical therapy. The clinical stability is defined by the&#xD;
             stability of the therapy, the weight and urine output for 3 days&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  unstable patients from a clinical point of view, not in optimized therapy&#xD;
&#xD;
          -  patients unable to perform a CPET (Cardiopulmonary Exercise Test) .&#xD;
&#xD;
          -  are excluded from the protocol also patients with absolute contraindications to CPET&#xD;
             (acute myocardial infarction, severe aortic stenosis, myocarditis or pericarditis,&#xD;
             active, acute thromboembolism, sepsis,unstable angina, uncontrolled arrhythmia.&#xD;
&#xD;
          -  age &lt; 18 years.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Piergiuseppe Agostoni, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Centro Cardiologico Monzino,IRCCS</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Centro Cardiologico Monzino</name>
      <address>
        <city>Milano</city>
        <state>MI</state>
        <zip>20138</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <verification_date>October 2015</verification_date>
  <study_first_submitted>July 22, 2014</study_first_submitted>
  <study_first_submitted_qc>October 7, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 10, 2014</study_first_posted>
  <results_first_submitted>August 4, 2015</results_first_submitted>
  <results_first_submitted_qc>October 7, 2015</results_first_submitted_qc>
  <results_first_posted type="Estimate">November 6, 2015</results_first_posted>
  <last_update_submitted>October 7, 2015</last_update_submitted>
  <last_update_submitted_qc>October 7, 2015</last_update_submitted_qc>
  <last_update_posted type="Estimate">November 6, 2015</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Centro Cardiologico Monzino</investigator_affiliation>
    <investigator_full_name>Piergiuseppe Agostoni</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>Cardiac Failure</keyword>
  <keyword>Severe Heart Failure</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heart Failure</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Simendan</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <recruitment_details>From September 2012 to December 2014 we enrolled forty-two patients who fulfilled the study inclusion/ exclusion criteria:19 patients received placebo and 23 received levosimendan. All patients was enrolled at Centro Cardiologico Monzino.</recruitment_details>
      <pre_assignment_details>Eligible patients had advanced chronic heart failure and were admitted because of worsening HF (Heart Failure),although the patients included in the study had been returned to a stable clinical condition and were free from both inotrope support and other i.v. therapies for at least 48h prior to study inclusion, except for diuretics where needed.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Levosimendan</title>
          <description>Levosimendan must be diluted before the administration (500 ml of glucose). The intravenous infusion may be administered either by the peripheral or central. The dose and duration of therapy should be decided according to the patient's clinical condition and response to the drug. Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min. A low infusion bolus (6 mcg / kg) is recommended for patients who have a concomitant intravenous treatment with vasodilators or inotropic. The patient's response should be evaluated during the infusion bolus or within 30 to 60 minutes and a dose adjustment based on clinical response.&#xD;
Levosimendan: Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min.</description>
        </group>
        <group group_id="P2">
          <title>Placebo</title>
          <description>Placebo must be diluted before the administration (500 ml of glucose). The intravenous infusion may' be administered either by the peripheral or central. The dose and duration of therapy should be decided according to the patient's clinical condition and response to the drug. Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min. A low infusion bolus (6 mcg / kg) is recommended for patients who have a concomitant intravenous treatment with vasodilators or inotropic. The patient's response should be evaluated during the infusion bolus or within 30 to 60 minutes and a dose adjustment based on clinical response.&#xD;
Placebo: Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="23"/>
                <participants group_id="P2" count="19"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="23"/>
                <participants group_id="P2" count="19"/>
              </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>Levosimendan</title>
          <description>Levosimendan must be diluted before the administration (500 ml of glucose). The intravenous infusion may be administered either by the peripheral or central. The dose and duration of therapy should be decided according to the patient's clinical condition and response to the drug. Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min. A low infusion bolus (6 mcg / kg) is recommended for patients who have a concomitant intravenous treatment with vasodilators or inotropic. The patient's response should be evaluated during the infusion bolus or within 30 to 60 minutes and a dose adjustment based on clinical response.&#xD;
Levosimendan: Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min.</description>
        </group>
        <group group_id="B2">
          <title>Placebo</title>
          <description>Placebo must be diluted before the administration (500 ml of glucose). The intravenous infusion may' be administered either by the peripheral or central. The dose and duration of therapy should be decided according to the patient's clinical condition and response to the drug. Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min. A low infusion bolus (6 mcg / kg) is recommended for patients who have a concomitant intravenous treatment with vasodilators or inotropic. The patient's response should be evaluated during the infusion bolus or within 30 to 60 minutes and a dose adjustment based on clinical response.&#xD;
Placebo: Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min.</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="23"/>
            <count group_id="B2" value="19"/>
            <count group_id="B3" value="42"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                    <measurement group_id="B2" value="15"/>
                    <measurement group_id="B3" value="32"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <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="70.39" spread="9.4"/>
                    <measurement group_id="B2" value="68.2" spread="8.3"/>
                    <measurement group_id="B3" value="69" spread="8.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="7"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="19"/>
                    <measurement group_id="B2" value="16"/>
                    <measurement group_id="B3" value="35"/>
                  </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>Italy</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="23"/>
                    <measurement group_id="B2" value="19"/>
                    <measurement group_id="B3" value="42"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>NYHA class</title>
          <description>New York Heart Association Class is the index used to classify the severity of symptoms referred by patients with heart failure. Lower index (1-2) is considered to have better outcome.</description>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3.3" spread="0.4"/>
                    <measurement group_id="B2" value="3.2" spread="0.4"/>
                    <measurement group_id="B3" value="3.3" spread="0.47"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change in Peak VO2 (Oxygen Consumption )</title>
        <description>Primary endpoints: Levosimendan induced changes in peak VO2 (Oxygen consumption )</description>
        <time_frame>48 hours</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Levosimendan</title>
            <description>Levosimendan must be diluted before the administration (500 ml of glucose). The intravenous infusion may be administered either by the peripheral or central. The dose and duration of therapy should be decided according to the patient's clinical condition and response to the drug. Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min. A low infusion bolus (6 mcg / kg) is recommended for patients who have a concomitant intravenous treatment with vasodilators or inotropic. The patient's response should be evaluated during the infusion bolus or within 30 to 60 minutes and a dose adjustment based on clinical response.&#xD;
Levosimendan: Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo must be diluted before the administration (500 ml of glucose). The intravenous infusion may' be administered either by the peripheral or central. The dose and duration of therapy should be decided according to the patient's clinical condition and response to the drug. Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min. A low infusion bolus (6 mcg / kg) is recommended for patients who have a concomitant intravenous treatment with vasodilators or inotropic. The patient's response should be evaluated during the infusion bolus or within 30 to 60 minutes and a dose adjustment based on clinical response.&#xD;
Placebo: Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Peak VO2 (Oxygen Consumption )</title>
          <description>Primary endpoints: Levosimendan induced changes in peak VO2 (Oxygen consumption )</description>
          <units>ml/kg/min</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="23"/>
                <count group_id="O2" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.21" spread="1.9"/>
                    <measurement group_id="O2" value="0.48" spread="1.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Changes in VE/VCO2</title>
        <description>Levosimendan induced changes on VE/VCO2 (VE: Expired Volume - VCO2: carbon dioxide production) relationship</description>
        <time_frame>48 hours</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Levosimendan</title>
            <description>Levosimendan must be diluted before the administration (500 ml of glucose). The intravenous infusion may be administered either by the peripheral or central. The dose and duration of therapy should be decided according to the patient's clinical condition and response to the drug. Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min. A low infusion bolus (6 mcg / kg) is recommended for patients who have a concomitant intravenous treatment with vasodilators or inotropic. The patient's response should be evaluated during the infusion bolus or within 30 to 60 minutes and a dose adjustment based on clinical response.&#xD;
Levosimendan: Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo must be diluted before the administration (500 ml of glucose). The intravenous infusion may' be administered either by the peripheral or central. The dose and duration of therapy should be decided according to the patient's clinical condition and response to the drug. Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min. A low infusion bolus (6 mcg / kg) is recommended for patients who have a concomitant intravenous treatment with vasodilators or inotropic. The patient's response should be evaluated during the infusion bolus or within 30 to 60 minutes and a dose adjustment based on clinical response.&#xD;
Placebo: Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min.</description>
          </group>
        </group_list>
        <measure>
          <title>Changes in VE/VCO2</title>
          <description>Levosimendan induced changes on VE/VCO2 (VE: Expired Volume - VCO2: carbon dioxide production) relationship</description>
          <units>VE/VCO2 Slope</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="23"/>
                <count group_id="O2" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-5.34" spread="7"/>
                    <measurement group_id="O2" value="-0.91" spread="4.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in DLCO (Diffusion Lung CO)</title>
        <description>Levosimendan induced changes on DLCO ( Diffusion Lung CO). DLCO is measured by the single breath-constant expiratory flow technique (Sensor Medics 2200, Yorba Linda, CA) and we calculate also the DLCO adjusted for hemoglobin. Dilution of CH4 is used to measure alveolar volume.</description>
        <time_frame>48 hours</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Levosimendan</title>
            <description>Levosimendan must be diluted before the administration (500 ml of glucose). The intravenous infusion may be administered either by the peripheral or central. The dose and duration of therapy should be decided according to the patient's clinical condition and response to the drug. Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min. A low infusion bolus (6 mcg / kg) is recommended for patients who have a concomitant intravenous treatment with vasodilators or inotropic. The patient's response should be evaluated during the infusion bolus or within 30 to 60 minutes and a dose adjustment based on clinical response.&#xD;
Levosimendan: Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo must be diluted before the administration (500 ml of glucose). The intravenous infusion may' be administered either by the peripheral or central. The dose and duration of therapy should be decided according to the patient's clinical condition and response to the drug. Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min. A low infusion bolus (6 mcg / kg) is recommended for patients who have a concomitant intravenous treatment with vasodilators or inotropic. The patient's response should be evaluated during the infusion bolus or within 30 to 60 minutes and a dose adjustment based on clinical response.&#xD;
Placebo: Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in DLCO (Diffusion Lung CO)</title>
          <description>Levosimendan induced changes on DLCO ( Diffusion Lung CO). DLCO is measured by the single breath-constant expiratory flow technique (Sensor Medics 2200, Yorba Linda, CA) and we calculate also the DLCO adjusted for hemoglobin. Dilution of CH4 is used to measure alveolar volume.</description>
          <units>ml/mmHg/min</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="23"/>
                <count group_id="O2" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.96" spread="2"/>
                    <measurement group_id="O2" value="0.88" spread="3.14"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <group_list>
        <group group_id="E1">
          <title>Levosimendan</title>
          <description>Levosimendan must be diluted before the administration (500 ml of glucose). The intravenous infusion may be administered either by the peripheral or central. The dose and duration of therapy should be decided according to the patient's clinical condition and response to the drug. Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min. A low infusion bolus (6 mcg / kg) is recommended for patients who have a concomitant intravenous treatment with vasodilators or inotropic. The patient's response should be evaluated during the infusion bolus or within 30 to 60 minutes and a dose adjustment based on clinical response.&#xD;
Levosimendan: Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min.</description>
        </group>
        <group group_id="E2">
          <title>Placebo</title>
          <description>Placebo must be diluted before the administration (500 ml of glucose). The intravenous infusion may' be administered either by the peripheral or central. The dose and duration of therapy should be decided according to the patient's clinical condition and response to the drug. Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min. A low infusion bolus (6 mcg / kg) is recommended for patients who have a concomitant intravenous treatment with vasodilators or inotropic. The patient's response should be evaluated during the infusion bolus or within 30 to 60 minutes and a dose adjustment based on clinical response.&#xD;
Placebo: Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="23"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="23"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </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>Piergiuseppe Agostoni</name_or_title>
      <organization>Centro Cardiologoco Monzino</organization>
      <phone>02 5800 ext 2772</phone>
      <email>piergiuseppe.agostoni@ccfm.it</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/NCT02261948
org study id: CCFM 199/312
nct id: NCT02261948
lead sponsor: 
collaborator: 
has dmc: No
The present study was conceived to evaluate the effects of levosimendan on cardiopulmonary
      exercise test (CPET) and DLCO ( Diffusion capacity of Lung for carbon monoxide) in patients
      with severe heart failure in stable clinical conditions (NYHA - New York Heart Association -
      class III, with a peak VO2 (Oxygen consumption ) < 12 ml/min/kg) on top of optimized standard
      therapy.
Eligible patients should have chronic HF (Heart Failure -class NYHA III or IV) in stable
      clinical conditions. Inclusion criteria were: left ejection fraction (EF) at echocardiography
      ≤35%, age ≥18 years old, peak VO2 <12 ml/min/kg measured by a CPET, a standard optimized
      therapy for HF that include ACE-inhibitors, ARBs (angiotensin II Receptor Blocker),
      aldosterone blocking agents (spironolactone), diuretics, and beta-blockers.

      The exclusion criteria are: ongoing mechanical ventilation; recent or acute coronary
      syndromes; sustained ventricular tachycardia or ventricular fibrillation; severe aortic or
      mitral regurgitation, or known malfunctioning artificial heart valve; uncorrected obstructive
      valvular disease; hypertrophic obstructive cardiomyopathy; uncorrected thyroid disease.

      Patients will be randomly assigned by means of prepared letters to the levosimendan or
      placebo group stratified by clinical centre in a 1:1 allocation using block randomization.
      The placebo infusion will be coloured identically to its respective active counterpart.
      Patients and investigators will be kept blinded to the treatment allocation for the entire
      duration of the trial. Study drug will be infused with an injection speed between 6 and 20
      ml/min based on blood pressure, without a bolus, for 24 hours.

      Medical history, physical examination and a blood sample examination will be recorded: NYHA
      class, BNP (Brain Natriuretic Peptide), haemoglobin, creatinine, blood urea nitrogen (BUN)
      will be recorded before and 24 hours after the drug infusion.

      A two-dimensional standard echocardiography evaluation will be performed at the admission in
      the hospital.

      A maximal CPET performed on a cycle ergometer (Sensor Medics Ergo 800S and V-max,
      Yorba-Linda, CA) with a personalized ramp aimed at achieving peak exercise in 10 minutes will
      be performed before and 24 hours after the drug infusion. Expiratory O2, CO2 (Carbon dioxide)
      and ventilation (VE) will be measured breath by breath. Peak VO2 (Carbon dioxide production)
      was considered to be the highest VO2 achieved during the exercise. A 12-lead
      electrocardiogram will be also recorded. Spirometry and DLCO measurements will be performed
      before ad 24-hours after the drug infusion. . DLCO will be measured by the single
      breath-constant expiratory flow technique
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: Change in Peak VO2 (Oxygen Consumption )
time frame: 48 hours
description: Primary endpoints: Levosimendan induced changes in peak VO2 (Oxygen consumption )
measure: Changes in VE/VCO2
time frame: 48 hours
description: Levosimendan induced changes on VE/VCO2 (VE: Expired Volume - VCO2: carbon dioxide production) relationship
measure: Change in DLCO (Diffusion Lung CO)
time frame: 48 hours
description: Levosimendan induced changes on DLCO ( Diffusion Lung CO). DLCO is measured by the single breath-constant expiratory flow technique (Sensor Medics 2200, Yorba Linda, CA) and we calculate also the DLCO adjusted for hemoglobin. Dilution of CH4 is used to measure alveolar volume.
arm group label: Levosimendan
arm group type: Active Comparator
description: Levosimendan must be diluted before the administration (500 ml of glucose). The intravenous infusion may be administered either by the peripheral or central. The dose and duration of therapy should be decided according to the patient's clinical condition and response to the drug. Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min. A low infusion bolus (6 mcg / kg) is recommended for patients who have a concomitant intravenous treatment with vasodilators or inotropic. The patient's response should be evaluated during the infusion bolus or within 30 to 60 minutes and a dose adjustment based on clinical response.
arm group label: Placebo
arm group type: Placebo Comparator
description: Placebo must be diluted before the administration (500 ml of glucose). The intravenous infusion may' be administered either by the peripheral or central. The dose and duration of therapy should be decided according to the patient's clinical condition and response to the drug. Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min. A low infusion bolus (6 mcg / kg) is recommended for patients who have a concomitant intravenous treatment with vasodilators or inotropic. The patient's response should be evaluated during the infusion bolus or within 30 to 60 minutes and a dose adjustment based on clinical response.
intervention type: Drug
intervention name: Levosimendan
description: Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min.
arm group label: Levosimendan
other name: SIMDAX
intervention type: Drug
intervention name: Placebo
description: Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min.
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 90 Years
healthy volunteers: No
last name: Piergiuseppe Agostoni, MD, PhD
role: Principal Investigator
affiliation: Centro Cardiologico Monzino,IRCCS
facility: 
country: Italy
responsible party type: Principal Investigator
investigator affiliation: Centro Cardiologico Monzino
investigator full name: Piergiuseppe Agostoni
investigator title: Professor
mesh term: Heart Failure
mesh term: Simendan
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 