<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/NCT02184819</url>
  </required_header>
  <id_info>
    <org_study_id>P110138</org_study_id>
    <nct_id>NCT02184819</nct_id>
  </id_info>
  <brief_title>Preoperative Levosimendan in CABG Patients With Poor LV Function</brief_title>
  <acronym>LICORN</acronym>
  <official_title>Effects of Levosimendan Pretreatment in Patients With Low Ejection Fraction (40 % or Less) Undergoing CABG: a Randomised, Double Blind, Multicenter Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Assistance Publique - Hôpitaux de Paris</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Ministry of Health, France</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Assistance Publique - Hôpitaux de Paris</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The investigators want to test the hypothesis that an infusion of levosimendan started prior&#xD;
      to CABG surgery can reduce incidence and severity of low cardiac output syndrome in patients&#xD;
      with poor LV function (EF 40% or less).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background: Patients with an ejection fraction of less than 40% are at high risk of&#xD;
      developing postoperative low cardiac output syndrome (LCOS). Despite the use of potent&#xD;
      inotropic agents or even ventricular mechanical assist devices, the mortality rate of such&#xD;
      patients remains very high (from 17 to 38%). Their hospital stay is also prolonged and the&#xD;
      cost of care for this population is increased. Two studies have suggested that post-operative&#xD;
      administration of levosimendan could reduce hospital length of stay and long term (Day180)&#xD;
      mortality in patients with LCOS. In addition a few studies have also suggested that&#xD;
      pre-operative infusion of levosimendan (pre-conditioning) could reduce the use of other&#xD;
      inotropes and mechanical assist devices in patients at high risk of developing LCOS.&#xD;
      Unfortunately, the data supporting the beneficial effects of levosimendan in high risk&#xD;
      cardiac surgery patients is very limited. Main goal: To evaluate the efficacy of a&#xD;
      pre-operative infusion of levosimendan in high risk patients (EF less than 40%) undergoing&#xD;
      cardiac surgery (CABG or combined surgery: CABG and valve replacement) to improve outcome.&#xD;
      Secondary goals: To evaluate: 1) the clinical safety of a pre-operative infusion of&#xD;
      levosimendan, 2) the costs of care in the levosimendan and control groups. Experimental&#xD;
      setup: Prospective, multicenter, randomized versus placebo, double-blind trial. Treatment&#xD;
      modalities: levosimendan will be administered by the intravenous route, according to a&#xD;
      continuous infusion of 0.1mcg/kg/min over 24 hours. Levosimendan infusion (0.1mcg/kg/min)&#xD;
      will be started immediately after induction of anaesthesia. The delay between infusion start&#xD;
      and skin incision can be estimated between 30 to 60 min. The investigators decided to skip&#xD;
      the bolus infusion that is frequently associated with systemic hypotension, which may result&#xD;
      in serious adverse events and protocol exclusion. Study duration and patient follow-up:&#xD;
      Patients will be recruited over 23 months. Individual follow-up will last 6 months. Overall&#xD;
      duration of study will be 29 months.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>June 2013</start_date>
  <completion_date type="Actual">November 2015</completion_date>
  <primary_completion_date type="Actual">June 2015</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>Prevention</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Confirmed low cardiac output syndrome</measure>
    <time_frame>within the 28 days after ICU admission</time_frame>
    <description>Composite of the three following items:the need for inotropic agents beyond 24 hours following the end of levosimendan/placebo infusion; the need for post-operative mechanical assist devices (intra-aortic balloon pump: IABP, extra-corporeal life support: ECLS) or failure to wean from these techniques if they were inserted pre-operatively; the need for renal replacement therapy during ICU stay</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>mortality at Day 28 and Day 180</measure>
    <time_frame>180 postoperative days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The need for inotropic agents beyond 24 hours following the end of levosimendan/placebo infusion</measure>
    <time_frame>1 time during 24h beyond operative</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The description of renal replacement therapy during ICU stay</measure>
    <time_frame>within the 28 days after ICU admission</time_frame>
    <description>renal failure requiring renal replacement therapy may occur anytime within 12 hours following surgery and may last 1-2 weeks on average.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>number of ventilator-free days and out-of-ICU days at Day 28.</measure>
    <time_frame>28 postoperative days</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">335</enrollment>
  <condition>Coronary Artery Bypass Grafting</condition>
  <condition>Left Ventricular Dysfonction</condition>
  <arm_group>
    <arm_group_label>levosimendan</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>study drug</description>
  </arm_group>
  <arm_group>
    <arm_group_label>placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>placebo group</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>levosimendan</intervention_name>
    <description>24 hour continuous infusion at the rate of 0,1 µg/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>24 hour infusion at a rate of 0,1 µg/kg/min assuming that it contains study drug</description>
    <arm_group_label>placebo</arm_group_label>
    <other_name>riboflavine</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  18 Years and older&#xD;
&#xD;
          -  scheduled for CABG with CPB&#xD;
&#xD;
          -  with or without asociated cardiac repair&#xD;
&#xD;
          -  ejection fraction less than 40%&#xD;
&#xD;
          -  signed informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  preoperative renal failure (creatinine clearance less than 30 ml/min)&#xD;
&#xD;
          -  liver failure (prothrombine time less than 50% in the absence of vitamin K antagonist)&#xD;
&#xD;
          -  cardiac surgery without CABG&#xD;
&#xD;
          -  pregnancy&#xD;
&#xD;
          -  emergency surgery&#xD;
&#xD;
          -  known allergy to levosimendan&#xD;
&#xD;
          -  severe hypotension prior to surgery&#xD;
&#xD;
          -  severe tachycardia&#xD;
&#xD;
          -  prior history of torsade de pointe&#xD;
&#xD;
          -  dynamic obstruction od left ventricular outflow tract&#xD;
&#xD;
          -  lack of signed informed consent.&#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>Bernard Cholley, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Anesthesiology and Intensive Care, Hopital Européen Georges Pompidou, Paris, France</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Thibaut Caruba, PharmD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Pharmacy department, Hopital Européen Georges Pompidou, Paris, France</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, France</name>
      <address>
        <city>Paris</city>
        <zip>75015</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <reference>
    <citation>Levin R, Degrange M, Del Mazo C, Tanus E, Porcile R. Preoperative levosimendan decreases mortality and the development of low cardiac output in high-risk patients with severe left ventricular dysfunction undergoing coronary artery bypass grafting with cardiopulmonary bypass. Exp Clin Cardiol. 2012 Sep;17(3):125-30.</citation>
    <PMID>23620700</PMID>
  </reference>
  <reference>
    <citation>De Hert SG, Lorsomradee S, Cromheecke S, Van der Linden PJ. The effects of levosimendan in cardiac surgery patients with poor left ventricular function. Anesth Analg. 2007 Apr;104(4):766-73. doi: 10.1213/01.ane.0000256863.92050.d3. Erratum In: Anesth Analg. 2007 Jun;104(6):1544. Dosage error in article text.</citation>
    <PMID>17377079</PMID>
  </reference>
  <reference>
    <citation>Tritapepe L, De Santis V, Vitale D, Santulli M, Morelli A, Nofroni I, Puddu PE, Singer M, Pietropaoli P. Preconditioning effects of levosimendan in coronary artery bypass grafting--a pilot study. Br J Anaesth. 2006 Jun;96(6):694-700. doi: 10.1093/bja/ael082. Epub 2006 Apr 4.</citation>
    <PMID>16595616</PMID>
  </reference>
  <verification_date>November 2015</verification_date>
  <study_first_submitted>October 23, 2013</study_first_submitted>
  <study_first_submitted_qc>July 3, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 9, 2014</study_first_posted>
  <last_update_submitted>February 24, 2016</last_update_submitted>
  <last_update_submitted_qc>February 24, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">February 25, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>coronary artery bypass graft</keyword>
  <keyword>left ventricular dysfunction</keyword>
  <keyword>low cardiac output syndrome</keyword>
  <keyword>levosimendan</keyword>
  <keyword>mortality</keyword>
  <keyword>inotropic agents</keyword>
  <keyword>cardiac mechanical assist devices</keyword>
  <keyword>renal replacement therapy</keyword>
  <keyword>mechanical ventilation duration</keyword>
  <keyword>ICU stay</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Riboflavin</mesh_term>
    <mesh_term>Simendan</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</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/NCT02184819
org study id: P110138
nct id: NCT02184819
lead sponsor: 
collaborator: 
has dmc: Yes
The investigators want to test the hypothesis that an infusion of levosimendan started prior
      to CABG surgery can reduce incidence and severity of low cardiac output syndrome in patients
      with poor LV function (EF 40% or less).
Background: Patients with an ejection fraction of less than 40% are at high risk of
      developing postoperative low cardiac output syndrome (LCOS). Despite the use of potent
      inotropic agents or even ventricular mechanical assist devices, the mortality rate of such
      patients remains very high (from 17 to 38%). Their hospital stay is also prolonged and the
      cost of care for this population is increased. Two studies have suggested that post-operative
      administration of levosimendan could reduce hospital length of stay and long term (Day180)
      mortality in patients with LCOS. In addition a few studies have also suggested that
      pre-operative infusion of levosimendan (pre-conditioning) could reduce the use of other
      inotropes and mechanical assist devices in patients at high risk of developing LCOS.
      Unfortunately, the data supporting the beneficial effects of levosimendan in high risk
      cardiac surgery patients is very limited. Main goal: To evaluate the efficacy of a
      pre-operative infusion of levosimendan in high risk patients (EF less than 40%) undergoing
      cardiac surgery (CABG or combined surgery: CABG and valve replacement) to improve outcome.
      Secondary goals: To evaluate: 1) the clinical safety of a pre-operative infusion of
      levosimendan, 2) the costs of care in the levosimendan and control groups. Experimental
      setup: Prospective, multicenter, randomized versus placebo, double-blind trial. Treatment
      modalities: levosimendan will be administered by the intravenous route, according to a
      continuous infusion of 0.1mcg/kg/min over 24 hours. Levosimendan infusion (0.1mcg/kg/min)
      will be started immediately after induction of anaesthesia. The delay between infusion start
      and skin incision can be estimated between 30 to 60 min. The investigators decided to skip
      the bolus infusion that is frequently associated with systemic hypotension, which may result
      in serious adverse events and protocol exclusion. Study duration and patient follow-up:
      Patients will be recruited over 23 months. Individual follow-up will last 6 months. Overall
      duration of study will be 29 months.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Confirmed low cardiac output syndrome
time frame: within the 28 days after ICU admission
description: Composite of the three following items:the need for inotropic agents beyond 24 hours following the end of levosimendan/placebo infusion; the need for post-operative mechanical assist devices (intra-aortic balloon pump: IABP, extra-corporeal life support: ECLS) or failure to wean from these techniques if they were inserted pre-operatively; the need for renal replacement therapy during ICU stay
measure: mortality at Day 28 and Day 180
time frame: 180 postoperative days
measure: The need for inotropic agents beyond 24 hours following the end of levosimendan/placebo infusion
time frame: 1 time during 24h beyond operative
measure: The description of renal replacement therapy during ICU stay
time frame: within the 28 days after ICU admission
description: renal failure requiring renal replacement therapy may occur anytime within 12 hours following surgery and may last 1-2 weeks on average.
measure: number of ventilator-free days and out-of-ICU days at Day 28.
time frame: 28 postoperative days
arm group label: levosimendan
arm group type: Active Comparator
description: study drug
arm group label: placebo
arm group type: Placebo Comparator
description: placebo group
intervention type: Drug
intervention name: levosimendan
description: 24 hour continuous infusion at the rate of 0,1 µg/kg/min
arm group label: levosimendan
other name: Simdax
intervention type: Drug
intervention name: Placebo
description: 24 hour infusion at a rate of 0,1 µg/kg/min assuming that it contains study drug
arm group label: placebo
other name: riboflavine
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Bernard Cholley, MD, PhD
role: Principal Investigator
affiliation: Anesthesiology and Intensive Care, Hopital Européen Georges Pompidou, Paris, France
last name: Thibaut Caruba, PharmD
role: Principal Investigator
affiliation: Pharmacy department, Hopital Européen Georges Pompidou, Paris, France
facility: 
country: France
citation: Levin R, Degrange M, Del Mazo C, Tanus E, Porcile R. Preoperative levosimendan decreases mortality and the development of low cardiac output in high-risk patients with severe left ventricular dysfunction undergoing coronary artery bypass grafting with cardiopulmonary bypass. Exp Clin Cardiol. 2012 Sep;17(3):125-30.
PMID: 23620700
citation: De Hert SG, Lorsomradee S, Cromheecke S, Van der Linden PJ. The effects of levosimendan in cardiac surgery patients with poor left ventricular function. Anesth Analg. 2007 Apr;104(4):766-73. doi: 10.1213/01.ane.0000256863.92050.d3. Erratum In: Anesth Analg. 2007 Jun;104(6):1544. Dosage error in article text.
PMID: 17377079
citation: Tritapepe L, De Santis V, Vitale D, Santulli M, Morelli A, Nofroni I, Puddu PE, Singer M, Pietropaoli P. Preconditioning effects of levosimendan in coronary artery bypass grafting--a pilot study. Br J Anaesth. 2006 Jun;96(6):694-700. doi: 10.1093/bja/ael082. Epub 2006 Apr 4.
PMID: 16595616
responsible party type: Sponsor
mesh term: Riboflavin
mesh term: Simendan