<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/NCT04434001</url>
  </required_header>
  <id_info>
    <org_study_id>ZEPLAST-PED</org_study_id>
    <nct_id>NCT04434001</nct_id>
  </id_info>
  <brief_title>ZEPLAST- PED: ZEro_PLASma Trial in Small Infants Undergoing Cardiac Surgery</brief_title>
  <acronym>ZEPLAST-PED</acronym>
  <official_title>ZEPLAST- PED: ZEro_PLASma Trial in Small Infants Undergoing Cardiac Surgery Randomized Controlled Pilot Phase II Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>IRCCS Policlinico S. Donato</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>IRCCS Policlinico S. Donato</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      In pediatric patients (newborns and infants weighing less than 10 kg) undergoing cardiac&#xD;
      surgery with extracorporeal circulation postoperative bleeding represents a known&#xD;
      complication with a significant impact on outcome. Fresh frozen plasma (FFP) for bleeding&#xD;
      management is associated, particularly in this kind of patients, to volume overload and a&#xD;
      significative increase of Transfusion Related Acute Lung Injury (TRALI), further worsening&#xD;
      the postoperative outcome. In the adult patient FFP employment could be almost completely&#xD;
      canceled by administration of concentrated hemostatic components - the fibrinogen concentrate&#xD;
      and prothrombin complex concentrate (PCC). We designed this phase II pilot study to establish&#xD;
      whether an analogous strategy, modified accordingly to pediatric physiology, could be safely&#xD;
      and successfully applied in newborns and infants.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The study population will be randomized to two groups: ZEPLAST and control, respectively.&#xD;
&#xD;
      The two groups will receive the same priming solution (containing Red Blood Cells and albumin&#xD;
      5%) and heparin/protamine management. In both groups coagulation will be assessed with&#xD;
      rotational thromboelastometry (ROTEM - EXTEM, INTEM, HEPTEM and FIBTEM tests) after heparin&#xD;
      antagonization. In case of bleeding, coagulopathies will be treated differently:&#xD;
&#xD;
        -  in the ZEPLAST group, fibrinogen deficiency (FIBTEM Maximum Clot Firmness MCF &lt; 8 mm)&#xD;
           will be treated with 30 mg/kg of concentrated fibrinogen; low thrombin generation (EXTEM&#xD;
           Clotting Time CT &gt; 100 s) will be treated with 20 mg/kg of prothrombin complex&#xD;
           concentrate;&#xD;
&#xD;
        -  in the control group, coagulopathies will be treated with 10-20 ml/kg of FFP. In case of&#xD;
           refractory bleeding, PCC and fibrinogen can be administered as a rescue treatment.&#xD;
&#xD;
      Further ROTEM tests will be performed at 24 and 48 hours post surgery. Outcome parameters&#xD;
      will be collected at the same timepoints.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    The study encountered unexpected difficulties in enrolling patients due to requirements for the&#xD;
    Informed Consent. 60% of our patients comes from abroad with only one accompanying parent. The&#xD;
    rules of our EC require both parents to sign the consent.&#xD;
  </why_stopped>
  <start_date type="Actual">February 27, 2020</start_date>
  <completion_date type="Actual">June 30, 2021</completion_date>
  <primary_completion_date type="Actual">May 31, 2021</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>Treatment</primary_purpose>
    <masking>Single (Participant)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Transfusion of Fresh Frozen Plasma (FFP)</measure>
    <time_frame>First 48 hours after surgery</time_frame>
    <description>Number of patients transfused with FFP</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Postoperative bleeding</measure>
    <time_frame>First 12, 24 and 48 hours after surgery</time_frame>
    <description>Amount of blood collected by chest drainages</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Severe bleeding</measure>
    <time_frame>First 12 hours after surgery</time_frame>
    <description>Number of patients who experienced severe bleeding (higher than 30 ml/kg in the first 12 hours after surgery)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Surgical re-exploration for bleeding</measure>
    <time_frame>First 12, 24 and 48 hours after surgery</time_frame>
    <description>Number of patients requiring surgical re-exploration due to bleeding (bleeding with no coagulopathies detected or refractory to pharmacological treatment)</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">40</enrollment>
  <condition>Bleeding</condition>
  <condition>Cardiac Defect</condition>
  <condition>Surgery--Complications</condition>
  <condition>Fibrinogenopenia; Acquired</condition>
  <condition>Transfusion-Related Acute Lung Injury</condition>
  <condition>Transfusion-Associated Circulatory Overload</condition>
  <condition>Congenital Heart Disease</condition>
  <arm_group>
    <arm_group_label>ZEPLAST</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>In case of bleeding and:&#xD;
CT INTEM &gt; CT HEPTEM by 25% : give protamine 0.25 mg/kg;&#xD;
MCF FIBTEM &lt; 8 mm : give Fibrinogen Concentrate 30 mg/kg;&#xD;
CT EXTEM &gt; 100 s : give Prothrombin Complex Concentrate 20 mg/kg.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>In case of bleeding and:&#xD;
CT INTEM &gt; CT HEPTEM by 25% : give protamine 0.25 mg/kg;&#xD;
fibrinogen and/or thrombin generation deficiency : give FFP 10-20 ml/kg.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fibrinogen Concentrate Human</intervention_name>
    <description>Treatment of acquired postoperatively fibrinogen deficiency as assessed by ROTEM FIBTEM test.</description>
    <arm_group_label>ZEPLAST</arm_group_label>
    <other_name>Haemocomplettan</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Prothrombin Complex Concentrate</intervention_name>
    <description>Treatment of acquired postoperatively thrombin generation deficiency as assessed by ROTEM EXTEM test.</description>
    <arm_group_label>ZEPLAST</arm_group_label>
    <other_name>Confidex</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Fresh Frozen Plasma</intervention_name>
    <description>Treatment of acquired postoperative coagulopathy as assessed by ROTEM FIBTEM and INTEM tests.</description>
    <arm_group_label>Control</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  newborns and infants with weight lower than 10 kg undergoing cardiac surgery with&#xD;
             extracorporeal circulation:&#xD;
&#xD;
          -  informed consent signed by both parents or legal guardian.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  emergency surgery;&#xD;
&#xD;
          -  known congenital coagulopathy or suspected based on anamnesis;&#xD;
&#xD;
          -  participation to other clinical trials;&#xD;
&#xD;
          -  known hypersensitivity to components and excipients of FFP , prothrombin complex&#xD;
             concentrate or fibrinogen concentrate.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Day</minimum_age>
    <maximum_age>2 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Marco Ranucci, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>IRCCS Policlinico S. Donato</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>IRCCS Policlinico San Donato</name>
      <address>
        <city>San Donato Milanese</city>
        <state>MI</state>
        <zip>20097</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <reference>
    <citation>Moore SB. Transfusion-related acute lung injury (TRALI): clinical presentation, treatment, and prognosis. Crit Care Med. 2006 May;34(5 Suppl):S114-7. doi: 10.1097/01.CCM.0000214312.20718.3E.</citation>
    <PMID>16617254</PMID>
  </reference>
  <reference>
    <citation>Ranucci M, Baryshnikova E. Fibrinogen supplementation after cardiac surgery: insights from the Zero-Plasma trial (ZEPLAST). Br J Anaesth. 2016 May;116(5):618-23. doi: 10.1093/bja/aev539. Epub 2016 Feb 17.</citation>
    <PMID>26893405</PMID>
  </reference>
  <reference>
    <citation>Bianchi P, Cotza M, Beccaris C, Silvetti S, Isgro G, Pome G, Giamberti A, Ranucci M; Surgical and Clinical Outcome REsearch (SCORE) group. Early or late fresh frozen plasma administration in newborns and small infants undergoing cardiac surgery: the APPEAR randomized trial. Br J Anaesth. 2017 May 1;118(5):788-796. doi: 10.1093/bja/aex069.</citation>
    <PMID>28510741</PMID>
  </reference>
  <reference>
    <citation>Ranucci M, Bianchi P, Cotza M, Beccaris C, Silvetti S, Isgro G, Giamberti A, Baryshnikova E. Fibrinogen levels and postoperative chest drain blood loss in low-weight (&lt;10 kg) children undergoing cardiac surgery. Perfusion. 2019 Nov;34(8):629-636. doi: 10.1177/0267659119854246. Epub 2019 Jun 28.</citation>
    <PMID>31250738</PMID>
  </reference>
  <verification_date>October 2021</verification_date>
  <study_first_submitted>June 12, 2020</study_first_submitted>
  <study_first_submitted_qc>June 12, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 16, 2020</study_first_posted>
  <last_update_submitted>October 28, 2021</last_update_submitted>
  <last_update_submitted_qc>October 28, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">November 3, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>IRCCS Policlinico S. Donato</investigator_affiliation>
    <investigator_full_name>Marco Ranucci</investigator_full_name>
    <investigator_title>Head of Cardiothoracic and Vascular Anesthesia and Intensive Care</investigator_title>
  </responsible_party>
  <keyword>bleeding</keyword>
  <keyword>pediatric cardiac surgery</keyword>
  <keyword>fresh frozen plasma</keyword>
  <keyword>fibrinogen concentrate</keyword>
  <keyword>prothrombin complex concentrate</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lung Injury</mesh_term>
    <mesh_term>Acute Lung Injury</mesh_term>
    <mesh_term>Transfusion-Related Acute Lung Injury</mesh_term>
    <mesh_term>Heart Diseases</mesh_term>
    <mesh_term>Heart Defects, Congenital</mesh_term>
    <mesh_term>Transfusion Reaction</mesh_term>
    <mesh_term>Hemorrhage</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Thrombin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT04434001
org study id: ZEPLAST-PED
nct id: NCT04434001
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
In pediatric patients (newborns and infants weighing less than 10 kg) undergoing cardiac
      surgery with extracorporeal circulation postoperative bleeding represents a known
      complication with a significant impact on outcome. Fresh frozen plasma (FFP) for bleeding
      management is associated, particularly in this kind of patients, to volume overload and a
      significative increase of Transfusion Related Acute Lung Injury (TRALI), further worsening
      the postoperative outcome. In the adult patient FFP employment could be almost completely
      canceled by administration of concentrated hemostatic components - the fibrinogen concentrate
      and prothrombin complex concentrate (PCC). We designed this phase II pilot study to establish
      whether an analogous strategy, modified accordingly to pediatric physiology, could be safely
      and successfully applied in newborns and infants.
The study population will be randomized to two groups: ZEPLAST and control, respectively.

      The two groups will receive the same priming solution (containing Red Blood Cells and albumin
      5%) and heparin/protamine management. In both groups coagulation will be assessed with
      rotational thromboelastometry (ROTEM - EXTEM, INTEM, HEPTEM and FIBTEM tests) after heparin
      antagonization. In case of bleeding, coagulopathies will be treated differently:

        -  in the ZEPLAST group, fibrinogen deficiency (FIBTEM Maximum Clot Firmness MCF < 8 mm)
           will be treated with 30 mg/kg of concentrated fibrinogen; low thrombin generation (EXTEM
           Clotting Time CT > 100 s) will be treated with 20 mg/kg of prothrombin complex
           concentrate;

        -  in the control group, coagulopathies will be treated with 10-20 ml/kg of FFP. In case of
           refractory bleeding, PCC and fibrinogen can be administered as a rescue treatment.

      Further ROTEM tests will be performed at 24 and 48 hours post surgery. Outcome parameters
      will be collected at the same timepoints.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Participant)
measure: Transfusion of Fresh Frozen Plasma (FFP)
time frame: First 48 hours after surgery
description: Number of patients transfused with FFP
measure: Postoperative bleeding
time frame: First 12, 24 and 48 hours after surgery
description: Amount of blood collected by chest drainages
measure: Severe bleeding
time frame: First 12 hours after surgery
description: Number of patients who experienced severe bleeding (higher than 30 ml/kg in the first 12 hours after surgery)
measure: Surgical re-exploration for bleeding
time frame: First 12, 24 and 48 hours after surgery
description: Number of patients requiring surgical re-exploration due to bleeding (bleeding with no coagulopathies detected or refractory to pharmacological treatment)
arm group label: ZEPLAST
arm group type: Experimental
description: In case of bleeding and:
CT INTEM > CT HEPTEM by 25% : give protamine 0.25 mg/kg;
MCF FIBTEM < 8 mm : give Fibrinogen Concentrate 30 mg/kg;
CT EXTEM > 100 s : give Prothrombin Complex Concentrate 20 mg/kg.
arm group label: Control
arm group type: Active Comparator
description: In case of bleeding and:
CT INTEM > CT HEPTEM by 25% : give protamine 0.25 mg/kg;
fibrinogen and/or thrombin generation deficiency : give FFP 10-20 ml/kg.
intervention type: Drug
intervention name: Fibrinogen Concentrate Human
description: Treatment of acquired postoperatively fibrinogen deficiency as assessed by ROTEM FIBTEM test.
arm group label: ZEPLAST
other name: Haemocomplettan
intervention type: Drug
intervention name: Prothrombin Complex Concentrate
description: Treatment of acquired postoperatively thrombin generation deficiency as assessed by ROTEM EXTEM test.
arm group label: ZEPLAST
other name: Confidex
intervention type: Biological
intervention name: Fresh Frozen Plasma
description: Treatment of acquired postoperative coagulopathy as assessed by ROTEM FIBTEM and INTEM tests.
arm group label: Control
criteria: 
gender: All
minimum age: 1 Day
maximum age: 2 Years
healthy volunteers: No
last name: Marco Ranucci, MD
role: Principal Investigator
affiliation: IRCCS Policlinico S. Donato
facility: 
country: Italy
citation: Moore SB. Transfusion-related acute lung injury (TRALI): clinical presentation, treatment, and prognosis. Crit Care Med. 2006 May;34(5 Suppl):S114-7. doi: 10.1097/01.CCM.0000214312.20718.3E.
PMID: 16617254
citation: Ranucci M, Baryshnikova E. Fibrinogen supplementation after cardiac surgery: insights from the Zero-Plasma trial (ZEPLAST). Br J Anaesth. 2016 May;116(5):618-23. doi: 10.1093/bja/aev539. Epub 2016 Feb 17.
PMID: 26893405
citation: Bianchi P, Cotza M, Beccaris C, Silvetti S, Isgro G, Pome G, Giamberti A, Ranucci M; Surgical and Clinical Outcome REsearch (SCORE) group. Early or late fresh frozen plasma administration in newborns and small infants undergoing cardiac surgery: the APPEAR randomized trial. Br J Anaesth. 2017 May 1;118(5):788-796. doi: 10.1093/bja/aex069.
PMID: 28510741
citation: Ranucci M, Bianchi P, Cotza M, Beccaris C, Silvetti S, Isgro G, Giamberti A, Baryshnikova E. Fibrinogen levels and postoperative chest drain blood loss in low-weight (<10 kg) children undergoing cardiac surgery. Perfusion. 2019 Nov;34(8):629-636. doi: 10.1177/0267659119854246. Epub 2019 Jun 28.
PMID: 31250738
responsible party type: Principal Investigator
investigator affiliation: IRCCS Policlinico S. Donato
investigator full name: Marco Ranucci
investigator title: Head of Cardiothoracic and Vascular Anesthesia and Intensive Care
mesh term: Lung Injury
mesh term: Acute Lung Injury
mesh term: Transfusion-Related Acute Lung Injury
mesh term: Heart Diseases
mesh term: Heart Defects, Congenital
mesh term: Transfusion Reaction
mesh term: Hemorrhage
mesh term: Thrombin
sharing ipd: No