<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/NCT02232399</url>
  </required_header>
  <id_info>
    <org_study_id>MiLe-1</org_study_id>
    <secondary_id>2013-003105-25</secondary_id>
    <nct_id>NCT02232399</nct_id>
  </id_info>
  <brief_title>Is Levosimendan Superior to Milrinone Regarding Acute Kidney Injury After Cardiac Surgery for Congenital Heart Disease?</brief_title>
  <acronym>MiLe-1</acronym>
  <official_title>The Prophylactic Effect of Levosimendan in Reducting Acute Kidney Injury Postoperatively in Pediatric Patients Undergoing Corrective Heart Surgery</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Göteborg University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Helsinki University Central Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Göteborg University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The aim of the study is to assess the ability of Levosimendan to reduce the postoperative&#xD;
      acute kidney injury in pediatric patients undergoing surgery for congenital heart disease&#xD;
      (CHDs). Young children, between the age of 1 to 12 months, with congenital heart disease in&#xD;
      need of elective heart surgery will be included in this study.&#xD;
&#xD;
      The trial will contain two study groups, 35 patients in each. One group will receive&#xD;
      Levosimendan and the second group will receive Milrinone as a heart muscle-strengthening&#xD;
      agent during and after the operation. Milrinone is currently used as the drug of choice in&#xD;
      many pediatric cardiac surgery centers. It remains to see if Levosimendan can exert a kidney&#xD;
      protecting function in addition to its heart muscle-strengthening properties.&#xD;
&#xD;
      The primary objective of this study is to investigate the preventive effect of Levosimendan&#xD;
      on postoperative acute kidney injury in pediatric patients undergoing surgery for their CHDs.&#xD;
      Creatinine levels postoperatively will be the primary endpoint. Creatinine, the common marker&#xD;
      of kidney injury, will be measured daily.&#xD;
&#xD;
      The treatment with Levosimendan or Milrinone will be started during the operation (after&#xD;
      initiation of cardiopulmonary bypass) and will last 24 hours. Blood samples will be obtained&#xD;
      at six occasions perioperatively. Patients will be followed 4 days after termination of&#xD;
      treatment (totally 5 days).&#xD;
&#xD;
      The duration of study will be 30 days (24 hours treatment + 4 days follow up +&#xD;
      30-days-mortality registration).&#xD;
&#xD;
      Creatinine is the primary outcome in this study. Inflammatory biomarkers and other relevant&#xD;
      biomarkers will comprise the secondary outcome variables.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>October 2014</start_date>
  <completion_date type="Actual">April 25, 2017</completion_date>
  <primary_completion_date type="Actual">April 25, 2017</primary_completion_date>
  <phase>Phase 2</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>Double (Participant, Care Provider)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Serum creatinine</measure>
    <time_frame>Second postoperative day</time_frame>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">72</enrollment>
  <condition>Congenital Heart Defects</condition>
  <arm_group>
    <arm_group_label>Milrinone</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>In this arm the patients will receive Milrinone as an inotrope agent. Concentration: 0.2 mg/mL Infusion rate: 0.12 mL / kg / hr = Dose delivered 0.4 μg / kg / min --- Bolus dose: 1.44 ml / kg / hr in ten minutes (a maximum volume 0.24 ml / kg) = 48 μg / kg</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Levosimendan</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>In this arm the patients will receive Levosimendan as an inotrope agent. Concentration: 0.05 mg/mL Infusion rate: 0.12 mL / kg / hr = Dose delivered 0.1 μg / kg / min --- Bolus dose: 1.44 ml / kg / hr in ten minutes (a maximum volume 0.24 ml / kg) = 12 μg/kg</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Levosimendan</intervention_name>
    <description>The drug infusion will be started after initiation of cardiopulmonary bypass and will continue for 24 hours.</description>
    <arm_group_label>Levosimendan</arm_group_label>
    <other_name>Simdax</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Milrinone</intervention_name>
    <description>The drug infusion will be started after initiation of cardiopulmonary bypass and will continue for 24 hours.</description>
    <arm_group_label>Milrinone</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Provision of informed consent prior to any study specific procedures&#xD;
&#xD;
          2. Female and male children between 1 and 12 months of age&#xD;
&#xD;
          3. Non-restrictive VSD (corrective surgery)&#xD;
&#xD;
          4. Complete AVSD (biventricular repair)&#xD;
&#xD;
          5. Tetralogy of Fallot&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Unbalanced AtrioVentricular Septal Defect or AVSD with cyanosis&#xD;
&#xD;
          2. Age less than one month and more than one year&#xD;
&#xD;
          3. Acute operation that is unscheduled operation during the first 24 hours after&#xD;
             presentation to the department for thoracic surgery&#xD;
&#xD;
          4. Mild, moderate, or severe kidney dysfunction and known anatomical anomalies of kidneys&#xD;
&#xD;
          5. Liver impairment or disease&#xD;
&#xD;
          6. Ongoing infection&#xD;
&#xD;
          7. Use of nephrotoxic drugs (like ibuprofen, angiotensin-converting-enzyme inhibitors,&#xD;
             gentamicin, vancomycin) preoperative or postoperative until first post operative day.&#xD;
             Contrast agents whithin 24 hours before operation.&#xD;
&#xD;
          8. Use of inhibitors of membrane transport proteins (cimetidine, cetirizine,&#xD;
             trimethoprim, probenecid, rifampin and gemfibrosil).&#xD;
&#xD;
          9. Allergy to Levosimendan or substance included in the preparation or previous use of&#xD;
             Levosimendan.&#xD;
&#xD;
         10. Severe arrhythmias needing pace-maker treatment prior to the operation&#xD;
&#xD;
         11. Severe cardiac dysfunction needing for treatment with extracorporeal membrane&#xD;
             oxygenation (ECMO) prior to the operation.&#xD;
&#xD;
         12. Preoperative need for mechanical ventilation and/or inotropic agents.&#xD;
&#xD;
         13. Re-operation (open heart surgery). Earlier surgical closure of the arterial duct does&#xD;
             not count as an exclusion criteria.&#xD;
&#xD;
         14. Prematurity: Gestational age &lt; 30 weeks, irrespective of postpartum age. Gestational&#xD;
             age 30-34 weeks if patient is included at postpartum age under 3 months.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Month</minimum_age>
    <maximum_age>12 Months</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Albert Castellheim, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Queen Silvia Children´s Hospital, Department of anesthesia and intensive care</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Håkan Wåhlander, MD, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Queen Silvia Children´s Hospital, Department of pediatric cardiology</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Birgitta Romlin, MD, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Queen Silvia Children´s Hospital, Department of anesthesiology and intensive care</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Elin Thorlacius, MD</last_name>
    <role>Study Chair</role>
    <affiliation>Queen Silvia Children´s Hospital, Department of anesthesiology and intensive care</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Sven-Erik Ricksten, MD, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Sahlgrenska University Hospital, Department of anesthesiology and intensive care</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Children´s Hospital, Helsinki University Central Hospital</name>
      <address>
        <city>Helsinki</city>
        <zip>FIN-00029 HYKS</zip>
        <country>Finland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Queen Silvia Children´s Hospital</name>
      <address>
        <city>Göteborg</city>
        <state>Västra Götaland</state>
        <zip>416 85</zip>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Finland</country>
    <country>Sweden</country>
  </location_countries>
  <verification_date>April 2017</verification_date>
  <study_first_submitted>September 2, 2014</study_first_submitted>
  <study_first_submitted_qc>September 4, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 5, 2014</study_first_posted>
  <last_update_submitted>April 25, 2017</last_update_submitted>
  <last_update_submitted_qc>April 25, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">April 26, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Göteborg University</investigator_affiliation>
    <investigator_full_name>Albert Castellheim</investigator_full_name>
    <investigator_title>Associate professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Acute Kidney Injury</mesh_term>
    <mesh_term>Heart Defects, Congenital</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Simendan</mesh_term>
    <mesh_term>Milrinone</mesh_term>
  </intervention_browse>
  <pending_results>
    <submitted>May 9, 2022</submitted>
    <returned>February 7, 2023</returned>
  </pending_results>
  <!-- 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/NCT02232399
org study id: MiLe-1
secondary id: 2013-003105-25
nct id: NCT02232399
lead sponsor: 
collaborator: 
has dmc: Yes
The aim of the study is to assess the ability of Levosimendan to reduce the postoperative
      acute kidney injury in pediatric patients undergoing surgery for congenital heart disease
      (CHDs). Young children, between the age of 1 to 12 months, with congenital heart disease in
      need of elective heart surgery will be included in this study.

      The trial will contain two study groups, 35 patients in each. One group will receive
      Levosimendan and the second group will receive Milrinone as a heart muscle-strengthening
      agent during and after the operation. Milrinone is currently used as the drug of choice in
      many pediatric cardiac surgery centers. It remains to see if Levosimendan can exert a kidney
      protecting function in addition to its heart muscle-strengthening properties.

      The primary objective of this study is to investigate the preventive effect of Levosimendan
      on postoperative acute kidney injury in pediatric patients undergoing surgery for their CHDs.
      Creatinine levels postoperatively will be the primary endpoint. Creatinine, the common marker
      of kidney injury, will be measured daily.

      The treatment with Levosimendan or Milrinone will be started during the operation (after
      initiation of cardiopulmonary bypass) and will last 24 hours. Blood samples will be obtained
      at six occasions perioperatively. Patients will be followed 4 days after termination of
      treatment (totally 5 days).

      The duration of study will be 30 days (24 hours treatment + 4 days follow up +
      30-days-mortality registration).

      Creatinine is the primary outcome in this study. Inflammatory biomarkers and other relevant
      biomarkers will comprise the secondary outcome variables.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Double (Participant, Care Provider)
measure: Serum creatinine
time frame: Second postoperative day
arm group label: Milrinone
arm group type: Active Comparator
description: In this arm the patients will receive Milrinone as an inotrope agent. Concentration: 0.2 mg/mL Infusion rate: 0.12 mL / kg / hr = Dose delivered 0.4 μg / kg / min --- Bolus dose: 1.44 ml / kg / hr in ten minutes (a maximum volume 0.24 ml / kg) = 48 μg / kg
arm group label: Levosimendan
arm group type: Experimental
description: In this arm the patients will receive Levosimendan as an inotrope agent. Concentration: 0.05 mg/mL Infusion rate: 0.12 mL / kg / hr = Dose delivered 0.1 μg / kg / min --- Bolus dose: 1.44 ml / kg / hr in ten minutes (a maximum volume 0.24 ml / kg) = 12 μg/kg
intervention type: Drug
intervention name: Levosimendan
description: The drug infusion will be started after initiation of cardiopulmonary bypass and will continue for 24 hours.
arm group label: Levosimendan
other name: Simdax
intervention type: Drug
intervention name: Milrinone
description: The drug infusion will be started after initiation of cardiopulmonary bypass and will continue for 24 hours.
arm group label: Milrinone
criteria: 
gender: All
minimum age: 1 Month
maximum age: 12 Months
healthy volunteers: No
last name: Albert Castellheim, MD, PhD
role: Principal Investigator
affiliation: Queen Silvia Children´s Hospital, Department of anesthesia and intensive care
last name: Håkan Wåhlander, MD, PhD
role: Study Chair
affiliation: Queen Silvia Children´s Hospital, Department of pediatric cardiology
last name: Birgitta Romlin, MD, PhD
role: Study Chair
affiliation: Queen Silvia Children´s Hospital, Department of anesthesiology and intensive care
last name: Elin Thorlacius, MD
role: Study Chair
affiliation: Queen Silvia Children´s Hospital, Department of anesthesiology and intensive care
last name: Sven-Erik Ricksten, MD, PhD
role: Study Chair
affiliation: Sahlgrenska University Hospital, Department of anesthesiology and intensive care
facility: 
facility: 
country: Finland
country: Sweden
responsible party type: Principal Investigator
investigator affiliation: Göteborg University
investigator full name: Albert Castellheim
investigator title: Associate professor
mesh term: Acute Kidney Injury
mesh term: Heart Defects, Congenital
mesh term: Simendan
mesh term: Milrinone
submitted: May 9, 2022
returned: February 7, 2023