<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/NCT03815773</url>
  </required_header>
  <id_info>
    <org_study_id>IRRB/15/17</org_study_id>
    <nct_id>NCT03815773</nct_id>
  </id_info>
  <brief_title>PRospective Multicenter Observational Study on Transfusion Practice in Vv-ECMO Patients: The PROTECMO Study</brief_title>
  <acronym>PROTECMO</acronym>
  <official_title>PRospective Multicenter Observational Study on Transfusion Practice in Vv-ECMO Patients: The PROTECMO Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The Mediterranean Institute for Transplantation and Advanced Specialized Therapies</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Medical University of Vienna</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Maryland, College Park</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Milan</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Milano Bicocca</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Pitié-Salpêtrière Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Hospital Vall d'Hebron</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>St Vincent's Hospital, Sydney</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Columbia University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Guy's and St Thomas' NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Hospital Sao Joao</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Azienda Policlinico Umberto I</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Bari</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Turin, Italy</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Fondazione Policlinico Universitario Agostino Gemelli IRCCS</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>The Mediterranean Institute for Transplantation and Advanced Specialized Therapies</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background: Over the past decade, the use of extracorporeal membrane oxygenation (ECMO) for&#xD;
      respiratory support in adults has increased. Several trials have highlighted how red blood&#xD;
      cells transfusion can cause several negative effects and, currently, a restrictive&#xD;
      transfusion trigger in critically ill patients is widely accepted.&#xD;
&#xD;
      The optimal management of anticoagulation targets and transfusion practice in&#xD;
      veno-venous-ECMO (VV-ECMO) patients is still under debate. Traditionally, the threshold for&#xD;
      transfusions of packed red blood cells (PRBC) in ECMO is aimed at keeping hemoglobin (Hb)&#xD;
      values in the normal range (12-14 g/dL), but some case series have shown how the Hb target&#xD;
      can be lower, and with comparable clinical outcomes.&#xD;
&#xD;
      While there are extensive reviews on predicted ECMO survival, and management (even with many&#xD;
      debated issues), there is a significant knowledge gap in understanding the benefits and risks&#xD;
      of transfusions during VV-ECMO Methods/Design: Prospective observational multicenter study.&#xD;
      The principal aim is to describe current effective blood product usage, during VV-ECMO. The&#xD;
      secondary aim is to describe in a large cohort of ECMO patients the current anticoagulation&#xD;
      strategy and bleeding episodes occurrence.&#xD;
&#xD;
      The study will be conducted at a multicenter level including in each center all consecutive&#xD;
      adult vv-ECMO patients during one year up. The data collection will include pre-ECMO&#xD;
      characteristics, transfusion strategies and blood test results during the first twenty-eight&#xD;
      days after ECMO cannulation or until the end of ECMO support if the length is shorter, and&#xD;
      clinical outcomes up to the end of ICU stay.&#xD;
&#xD;
      The descriptive variable end points for the primary aim will be the daily and the total&#xD;
      amount of PRBC and other blood products (Plasma, Platelets, Fibrinogen, Antithrombin III).&#xD;
&#xD;
      The descriptive variable end points for the secondary aim will be the type and dose of&#xD;
      anticoagulation, and episodes of bleeding according to site and severity.&#xD;
&#xD;
      Expected Results: A collaborative combination of ECMO centers will evaluate prospective data&#xD;
      of transfusion practices during ECMO. The investigators would be able to describe the&#xD;
      currently strategy for administration of blood products, anticoagulation and the effective&#xD;
      incidence of bleeding episodes worldwide.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background Over the past decade, the use of extracorporeal Membrane Oxygnation (ECMO) for&#xD;
      respiratory support in adults has vastly increased. Veno-venous ECMO (VV-ECMO) can be&#xD;
      initiated in case of Acute Respiratory Distress Syndrome (ARDS) as salvage therapy for&#xD;
      patients with profound gas exchange abnormalities despite protective lung ventilation and&#xD;
      other rescue therapies. Many aspects of ECMO management are still under debate despite the&#xD;
      increasing number of cases. Among these debated topics there is certainly the optimal&#xD;
      management of transfusion practice.&#xD;
&#xD;
      Several trials have recognized how red blood cells transfusion can cause several negative&#xD;
      effects, including transfusion related immune reactions, the potential transmission of&#xD;
      diseases, the development of transfusion-related complications (such as transfusion-related&#xD;
      acute lung injury - TRALI - or transfusion-associated circulatory overload - TACO) and&#xD;
      immunosuppression. On the other hand, anemia can also cause a potential increase in morbidity&#xD;
      and mortality in critically ill patients, and in ECMO is an even greater critical issue in&#xD;
      reducing delivery of oxygen (DO2).&#xD;
&#xD;
      Moreover, despite improvement in technology and care, complications related to ECMO are still&#xD;
      high, and frequently involve an imbalance in the coagulation status due to anticoagulant use&#xD;
      in the presence of coagulopathy. Consequently, the risk of thrombosis (presumably&#xD;
      microthrombosis) and hemorrhage remain to be high. In the case of ongoing bleeding,&#xD;
      transfusion of Packed Red Blood Cell (PRBC) is required to support desired haemoglobin&#xD;
      levels.&#xD;
&#xD;
      Traditionally, the threshold for PRBC transfusions in ECMO is aimed to maintain hemoglobin&#xD;
      (Hb) values in the normal range (12-14 g/dL). Despite this, there is considerable uncertainty&#xD;
      regarding the optimal haemoglobin threshold for the use of PRBC transfusions in anemic&#xD;
      patients during ECMO support.&#xD;
&#xD;
      Prompted by the general reappraisal of PRBC transfusion use, some case series using lower&#xD;
      target for Hb during vv-ECMO support have been published. However, such protocols do not&#xD;
      use/suggest a definitive trigger/target of Hb.&#xD;
&#xD;
      There is also some evidence that a higher number of transfusions in ECMO patients is&#xD;
      associated with worse outcomes. However, such a relationship is difficult to assess given the&#xD;
      large number of factors influencing transfusion practice in this setting: target of&#xD;
      anticoagulation, frequent bleeding episodes, the peculiar characteristics of the circuits&#xD;
      that can cause mechanical damage, activation of inflammation, and consumption of platelet and&#xD;
      coagulation factors, to name but a few.&#xD;
&#xD;
      Moreover, most of the available data on transfusions during ECMO are heterogeneous, usually&#xD;
      including VV-ECMO and veno-arterial-ECMO (VA-ECMO) configuration, and mixing adults with&#xD;
      neonatal and pediatric cohorts, which are historically more represented.&#xD;
&#xD;
      In this context, the decision of giving a transfusion during ECMO support is still a real&#xD;
      challenge since several parameters have to be taken into account at the same time. A strict&#xD;
      trigger has not yet been defined in this population, and the literature on critically ill&#xD;
      patients suggests a relevant reduction in the amount of transfusion.&#xD;
&#xD;
      Rationale for the study Providing adequate DO2 can be approached in several ways during&#xD;
      vv-ECMO support, but the hemoglobin target is always a critical point, and a relevant piece&#xD;
      of the puzzle of assuring the best oxygenation in patients affected with acute respiratory&#xD;
      failure (ARF). There may be important variations between hospitals and countries in the use&#xD;
      of PRBC transfusions, which may impact patient outcome. Large scale, national, and&#xD;
      international studies are currently lacking.&#xD;
&#xD;
      There is a significant knowledge gap in understanding the benefits and risks of transfusion&#xD;
      during VV-ECMO.&#xD;
&#xD;
      An international multicenter study will evaluate prospective observational data of&#xD;
      transfusion practices during VV-ECMO, analyzing it in light of anticoagulation and bleeding&#xD;
      episodes.&#xD;
&#xD;
      Aim of the study The PROTECMO study is aimed at being a collaborative study including a large&#xD;
      number of ECMO centers worldwide, describing, in real practice,&#xD;
&#xD;
        1. Incidence of major bleeding events and amount of blood product transfused&#xD;
&#xD;
        2. Type, trigger and level of anticoagulation adopted&#xD;
&#xD;
      Study Design: international multicenter prospective observational cohort study. For the&#xD;
      primary outcome PRBC will be evaluated as total amount during the ECMO run and in the first&#xD;
      28 days also as daily amount. The total amount of PRBC, adjusted for the ECMO length of stay,&#xD;
      will be evaluated in light of pre-ECMO parameters (age, comorbidities, postoperative state&#xD;
      and severity scores) and of daily data (bleeding episodes, ECMO blood flow, dieresis, CRRT,&#xD;
      Hb, major events). Daily occurrence of PRBC transfusion will be described according to&#xD;
      pre-ECMO characteristics and daily parameters (Hb, bleeding, hemodynamics, renal function,&#xD;
      circuit change).&#xD;
&#xD;
      Plasma, platelets, Fibrinogen, Antithrombin III administration will be evaluated according to&#xD;
      pre-ECMO data and according to daily APTT level (or other coagulation monitoring adopted),&#xD;
      bleeding episodes, sepsis occurred For the secondary outcomes type of anticoagulant will be&#xD;
      described as well as daily dose and daily target for the parameter targeted (APTT, ACT,&#xD;
      r-TEG, anti-Xa according to local protocol). Anticoagulation will be described in relation to&#xD;
      pre-ECMO parameters and daily episodes of bleeding and occurrence of sepsis.&#xD;
&#xD;
      Bleeding episodes will be described according to site (airway - including tracheotomy -&#xD;
      oro-nasal, gastric, intrathoracic, abdominal, intestinal, retroperitoneal, urinary tract,&#xD;
      other) and classified according to severity following 5 adjusted categories of the Bleeding&#xD;
      Academic Research Consortium (BARC) score: Type 0, no bleeding; Type 1, Any overt bleeding&#xD;
      that requires heparin infusion rate reduction or PRBC transfusion (provided Hb drop was&#xD;
      related to bleeding); Type 2, any overt bleeding that requires heparin infusion rate&#xD;
      reduction and packed red blood cells transfusion or non-surgical procedure to stop bleeding&#xD;
      (provided Hb drop was related to bleeding); Type 3, Any life-threatening bleeding that&#xD;
      required PRBC transfusion and surgical intervention for control of bleeding or ECMO&#xD;
      discontinuation; Type 4: any fatal bleeding.&#xD;
&#xD;
      Every patient included will be registered for baseline values, and will then be followed for&#xD;
      ECMO management and transfusion management daily for the first 28 days or until ECMO weaning&#xD;
      if the ECMO run will be shorter than the observation time. Daily parameters will be recorded.&#xD;
      Moreover, data will be recorded for every PRBC, Plasma, Platelets transfusion event. The&#xD;
      patients will be observed for the clinical outcomes until they are discharged from the ICU&#xD;
      and 6-months mortality will be recorded. Considering that according the Extracorporeal Life&#xD;
      Support Organization summary, the average length of respiratory ECMO run is about 12 days we&#xD;
      believe that the majority of ECMO run will be fully covered by the observation period and, at&#xD;
      least, it will be paradigmatic of a center's actual practice and, at the same time, will&#xD;
      assure a considerable sample size of transfusion events.&#xD;
&#xD;
      Data will be reported according to the STROBE (Strengthening the reporting of observational&#xD;
      studies in epidemiology) statement checklist.&#xD;
&#xD;
      Study conduction Given the explorative nature of this study, the required number of patients&#xD;
      was not calculated, but considering at least 10 patients/year for each center (considered the&#xD;
      worst prediction) we imagine that the included patients will be at least 100 in Italy and we&#xD;
      presume to enroll at least a double number worldwide.&#xD;
&#xD;
      Study duration&#xD;
&#xD;
        -  Transfusions decisions for each patient will be recorded daily for 28 days after ECMO&#xD;
           cannulation or until the end of ECMO support if the length is &lt; 28 days.&#xD;
&#xD;
        -  Patients will be observed until ICU discharge with a follow up to sixth months for&#xD;
           mortality&#xD;
&#xD;
        -  The inclusion period will be 12 months for each center.&#xD;
&#xD;
      Data collection methods Data will be recorded using pre-printed CRF by the principal&#xD;
      investigator (PI) in each center or directly they will be recorded online. All data will be&#xD;
      reported in a centralized online and Web-based fully encrypted database (REDCAP)&#xD;
&#xD;
      Data will include clinical characteristics: baseline demographics, basic biological values&#xD;
      (e.g., blood gas, hemoglobin), primary diagnosis, comorbidities, underlying etiology of acute&#xD;
      respiratory failure, severity of illness (e.g., SOFA, SAPS 2), type of ECMO, and the size of&#xD;
      the cannulas.&#xD;
&#xD;
      ECMO management data will be collected daily for 28 days. Additionally, fluid balance,&#xD;
      adverse events, Hb and all hematological data, anticoagulation management and monitoring will&#xD;
      be collected every 24 hours.&#xD;
&#xD;
      For 28 days, transfusion amounts and values of Hb, HTC, Platelets, will be recorded.&#xD;
&#xD;
      Bleeding will be evaluated according to site and severity according to 5 adjusted categories&#xD;
      of the Bleeding Academic Research Consortium (BARC) score.&#xD;
&#xD;
      Data will also be collected for the duration of mechanical ventilation, duration of ECMO, and&#xD;
      ICU length of stay. Clinical outcome assessment will be made, with date of death, ICU&#xD;
      discharge, hospital discharge, sixth month mortality.&#xD;
&#xD;
      Statistical Analysis Descriptive statistics including frequency (percentage), median and&#xD;
      interquartile range (IQR) will describe overall population and groups of survivors and&#xD;
      non-survivors.&#xD;
&#xD;
      In order to describe current transfusion practice the amount of PRBC, Plasma and Platelets,&#xD;
      will be described as units and ml and as a number of transfusions adjusted for ECMO length of&#xD;
      stay and considering the concomitant bleeding episodes.&#xD;
&#xD;
      Fibrinogen and Antithrombin III will be described as mg or units respectively and as a number&#xD;
      of administration.&#xD;
&#xD;
      Anticoagulation will be reported as type, mean dosage and the confidence interval (CI 95%).&#xD;
&#xD;
      Hb average level and the confidence interval (CI 95%) will be reported. Baseline categorical&#xD;
      and continuous variables will be compared for transfusion and ECMO weaning groups. In&#xD;
      particular categorical variables will be compared with chi-square tests and continuous&#xD;
      variables will be compared with Student's T-test, or Wilcoxon rank-sum tests, otherwise.&#xD;
&#xD;
      Multiple COX regression analysis will be used in order to explore the impact of confounding&#xD;
      factors such as baseline patient severity, ECMO length of stay, bleeding episodes and&#xD;
      possible others covariates and factors that will be observed and raised relevance during the&#xD;
      first exploratory or univariate analysis. The impact of relevant confounding factors such as&#xD;
      length of ECMO run, pre-ECMO severity scores, pre-ECMO administration of transfusions will be&#xD;
      analyzed separately and together in multiple analyses.&#xD;
&#xD;
      In particular daily RBC transfusion will be studied according to the association to renal&#xD;
      function, fluid balance, worst Hb level, episodes of bleeding, use of vasopressors, ECMO&#xD;
      blood flow.&#xD;
&#xD;
      A p-value less of than 0.05 will be considered significant. Data handling and analyses will&#xD;
      be done with SAS 9.4 software (SAS Institute Inc, Cary, NC, USA) and R 3.3 software (R&#xD;
      Foundation for Statistical Computing).&#xD;
&#xD;
      Ethics: Informed Consent and Treatment of personal data The study will be conducted in&#xD;
      compliance with the current Helsinki Declaration and the standards of good clinical practice.&#xD;
&#xD;
      The study involves the enrollment of patients undergoing extracorporeal membrane oxygenation&#xD;
      support and therefore unable to express a consent.&#xD;
&#xD;
      Every participating center will have to ask the permission to their Ethic Committee or other&#xD;
      relevant and competent authorities according to the local rules.&#xD;
&#xD;
      At ISMETT, according the Italian rules (and we strongly suggest to follow the same at the&#xD;
      other centers), the investigators will apply the following practice about informed consent as&#xD;
      it was approved by the Ethic Committee. The participating centers will be supperted with&#xD;
      approval by ISMETT Ethic Committee and providing materials and translated informed consent&#xD;
      either for the participation in the study and for the data protection policy.&#xD;
&#xD;
      According to the art. 82 of the Codice Privacy the investigators will ask for a consent for&#xD;
      the treatment of personal data of the patients that for the particular support of the ECMO&#xD;
      are almost always sedated at least at the beginning of the ECMO run - so they have to be&#xD;
      considered temporarily unable to express a consent - to those that have legal authority over&#xD;
      them or to the immediate relatives or to a person cohabiting with them or - failing these -&#xD;
      to the person in charge of the facility where the data subject is hosted. In case the patient&#xD;
      is able to an informed consent it will be asked to himself.&#xD;
&#xD;
      In the case of following improvement of neurological condition of the patient we will ask for&#xD;
      a consent directly to the patient as soon as we will consider him again able to express a&#xD;
      valid consent.&#xD;
&#xD;
      The results of the research will be diffused as aggregate data and in ways that will not&#xD;
      allow in any case the identification of the enrolled patients.&#xD;
&#xD;
      Safety The present study, giving its observational design, has a complete safety profile.&#xD;
&#xD;
      There will be no additional interventions or measurements other than those that are standard&#xD;
      of care at the participating center. All clinical activity will follow the well established&#xD;
      protocols for ECMO support at each participating center and consequently the patients are at&#xD;
      no risk by in participating in the study.&#xD;
&#xD;
      Predefined subgroup analyses If the sample size will be adequate, as explorative analyses,&#xD;
      some subgroup analyses will be performed according to the following predefined plan.&#xD;
&#xD;
      Exploratory analyses will stratify data for center workload (&lt;10, 10-20, &gt;20 ECMO run per&#xD;
      year), according to geographical areas (we imagine a stratification among continents but we&#xD;
      will verify if, giving the amount of data, will be reasonable a country stratification), and&#xD;
      for pre-ECMO severity scores (Preserve score and Respscore) divided in quartiles.&#xD;
&#xD;
      Moreover, by the repeated measurements of hemoglobin and eventual transfusion event, for each&#xD;
      center we will profile the actual and effective hemoglobin accepted as a trigger. The outcome&#xD;
      weaning from ECMO and effective ICU discharge will be stratified also according to different&#xD;
      hemoglobin values (&lt;7, 7-10, &gt;10, &gt;12).&#xD;
&#xD;
      Another subgroups analysis will involve age, considered a major impacting factor in survival&#xD;
      during ECMO. Patients will be divided in quartiles and patients &gt; 60 years old will moreover&#xD;
      evaluated.&#xD;
&#xD;
      Jehovah's witnesses and all patients refusing transfusions for personal reasons, as well as&#xD;
      patients affected with hematological malignances will be analyzed separately.&#xD;
&#xD;
      Expected results, potential benefit of the study and publication program A collaborative&#xD;
      combination of ECMO centers will evaluate prospective data of transfusion practices during&#xD;
      ECMO. The investigators would be able to describe the currently strategy for administration&#xD;
      of blood products, anticoagulation and the effective incidence of bleeding episodes&#xD;
      worldwide.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 1, 2018</start_date>
  <completion_date type="Actual">December 31, 2020</completion_date>
  <primary_completion_date type="Actual">December 31, 2020</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Descriptive data of PRBC transfusion in patients receiving VV-ECMO</measure>
    <time_frame>Day 28 after ECMO start</time_frame>
    <description>Packed Red Blood Cells Transfused, amount</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Descriptive data of Platelets transfusion in patients receiving VV-ECMO</measure>
    <time_frame>Day 28 after ECMO start</time_frame>
    <description>Platelets, amount</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Descriptive data of Plasma transfusion in patients receiving VV-ECMO</measure>
    <time_frame>Day 28 after ECMO start</time_frame>
    <description>Plasma, amount</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Descriptive data of Fibrinogen administration in patients receiving VV-ECMO</measure>
    <time_frame>Day 28 after ECMO start</time_frame>
    <description>Fibrinogen, amount</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Descriptive data of Antithrombin III administration in patients receiving VV-ECMO</measure>
    <time_frame>Day 28 after ECMO start</time_frame>
    <description>Antithrombin III, amount</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Descriptive data of anticoagulation practices in patients receiving VV-ECMO</measure>
    <time_frame>daily for 28 days</time_frame>
    <description>Type of anticoagulant adopted during ECMO</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Descriptive data of anticoagulation practices in patients receiving VV-ECMO</measure>
    <time_frame>daily for 28 days</time_frame>
    <description>Dose of anticoagulant adopted during ECMO</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Descriptive data of bleeding episodes in patients receiving VV-ECMO</measure>
    <time_frame>daily for 28 days</time_frame>
    <description>Episodes of bleeding according to site and severity</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlate the amount of transfusions to clinical outcomes</measure>
    <time_frame>Day 28 after ECMO start</time_frame>
    <description>ECMO weaning, Yes/Not</description>
  </secondary_outcome>
  <enrollment type="Actual">656</enrollment>
  <condition>Extracorporeal Membrane Oxygenation Complication</condition>
  <condition>Transfusion Related Complication</condition>
  <condition>Hemorrhage</condition>
  <condition>Anticoagulant-induced Bleeding</condition>
  <eligibility>
    <study_pop>
      <textblock>
        The study is prospective and, consequently, in each center all consecutive VV-ECMO adult&#xD;
        patients who are eligible according to inclusion and exclusion criteria should be included&#xD;
        in the study.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion criteria:&#xD;
&#xD;
        - All consecutive patients who receive veno-venous ECMO for respiratory causes. Of note,&#xD;
        considering the observational design of our study, patients can be included in other&#xD;
        studies concurrently (this will be noted on the CRF).&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
        - Refusal to include expressed by the relatives when tha patient is unconscious or by the&#xD;
        patient when he is recovered.&#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>Antonio Arcadipane, MD</last_name>
    <role>Study Director</role>
    <affiliation>The Mediterranean Institute for Transplantation and Advanced Specialized Therapies</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Gennaro Martucci, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>The Mediterranean Institute for Transplantation and Advanced Specialized Therapies</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Ismett</name>
      <address>
        <city>Palermo</city>
        <zip>90133</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <verification_date>September 2021</verification_date>
  <study_first_submitted>December 17, 2018</study_first_submitted>
  <study_first_submitted_qc>January 22, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 24, 2019</study_first_posted>
  <last_update_submitted>September 10, 2021</last_update_submitted>
  <last_update_submitted_qc>September 10, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">September 13, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>ECMO</keyword>
  <keyword>PRBC</keyword>
  <keyword>Fresh frozen Plasma</keyword>
  <keyword>Fibrinogen</keyword>
  <keyword>Antithrombin III</keyword>
  <keyword>Bleeding</keyword>
  <keyword>Anticoagulation</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hemorrhage</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>Aggregate data will be shared</ipd_description>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>November 30, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/73/NCT03815773/Prot_SAP_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>October 1, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/73/NCT03815773/ICF_001.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- 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/NCT03815773
org study id: IRRB/15/17
nct id: NCT03815773
lead sponsor: 
collaborator: 
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has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Background: Over the past decade, the use of extracorporeal membrane oxygenation (ECMO) for
      respiratory support in adults has increased. Several trials have highlighted how red blood
      cells transfusion can cause several negative effects and, currently, a restrictive
      transfusion trigger in critically ill patients is widely accepted.

      The optimal management of anticoagulation targets and transfusion practice in
      veno-venous-ECMO (VV-ECMO) patients is still under debate. Traditionally, the threshold for
      transfusions of packed red blood cells (PRBC) in ECMO is aimed at keeping hemoglobin (Hb)
      values in the normal range (12-14 g/dL), but some case series have shown how the Hb target
      can be lower, and with comparable clinical outcomes.

      While there are extensive reviews on predicted ECMO survival, and management (even with many
      debated issues), there is a significant knowledge gap in understanding the benefits and risks
      of transfusions during VV-ECMO Methods/Design: Prospective observational multicenter study.
      The principal aim is to describe current effective blood product usage, during VV-ECMO. The
      secondary aim is to describe in a large cohort of ECMO patients the current anticoagulation
      strategy and bleeding episodes occurrence.

      The study will be conducted at a multicenter level including in each center all consecutive
      adult vv-ECMO patients during one year up. The data collection will include pre-ECMO
      characteristics, transfusion strategies and blood test results during the first twenty-eight
      days after ECMO cannulation or until the end of ECMO support if the length is shorter, and
      clinical outcomes up to the end of ICU stay.

      The descriptive variable end points for the primary aim will be the daily and the total
      amount of PRBC and other blood products (Plasma, Platelets, Fibrinogen, Antithrombin III).

      The descriptive variable end points for the secondary aim will be the type and dose of
      anticoagulation, and episodes of bleeding according to site and severity.

      Expected Results: A collaborative combination of ECMO centers will evaluate prospective data
      of transfusion practices during ECMO. The investigators would be able to describe the
      currently strategy for administration of blood products, anticoagulation and the effective
      incidence of bleeding episodes worldwide.
Background Over the past decade, the use of extracorporeal Membrane Oxygnation (ECMO) for
      respiratory support in adults has vastly increased. Veno-venous ECMO (VV-ECMO) can be
      initiated in case of Acute Respiratory Distress Syndrome (ARDS) as salvage therapy for
      patients with profound gas exchange abnormalities despite protective lung ventilation and
      other rescue therapies. Many aspects of ECMO management are still under debate despite the
      increasing number of cases. Among these debated topics there is certainly the optimal
      management of transfusion practice.

      Several trials have recognized how red blood cells transfusion can cause several negative
      effects, including transfusion related immune reactions, the potential transmission of
      diseases, the development of transfusion-related complications (such as transfusion-related
      acute lung injury - TRALI - or transfusion-associated circulatory overload - TACO) and
      immunosuppression. On the other hand, anemia can also cause a potential increase in morbidity
      and mortality in critically ill patients, and in ECMO is an even greater critical issue in
      reducing delivery of oxygen (DO2).

      Moreover, despite improvement in technology and care, complications related to ECMO are still
      high, and frequently involve an imbalance in the coagulation status due to anticoagulant use
      in the presence of coagulopathy. Consequently, the risk of thrombosis (presumably
      microthrombosis) and hemorrhage remain to be high. In the case of ongoing bleeding,
      transfusion of Packed Red Blood Cell (PRBC) is required to support desired haemoglobin
      levels.

      Traditionally, the threshold for PRBC transfusions in ECMO is aimed to maintain hemoglobin
      (Hb) values in the normal range (12-14 g/dL). Despite this, there is considerable uncertainty
      regarding the optimal haemoglobin threshold for the use of PRBC transfusions in anemic
      patients during ECMO support.

      Prompted by the general reappraisal of PRBC transfusion use, some case series using lower
      target for Hb during vv-ECMO support have been published. However, such protocols do not
      use/suggest a definitive trigger/target of Hb.

      There is also some evidence that a higher number of transfusions in ECMO patients is
      associated with worse outcomes. However, such a relationship is difficult to assess given the
      large number of factors influencing transfusion practice in this setting: target of
      anticoagulation, frequent bleeding episodes, the peculiar characteristics of the circuits
      that can cause mechanical damage, activation of inflammation, and consumption of platelet and
      coagulation factors, to name but a few.

      Moreover, most of the available data on transfusions during ECMO are heterogeneous, usually
      including VV-ECMO and veno-arterial-ECMO (VA-ECMO) configuration, and mixing adults with
      neonatal and pediatric cohorts, which are historically more represented.

      In this context, the decision of giving a transfusion during ECMO support is still a real
      challenge since several parameters have to be taken into account at the same time. A strict
      trigger has not yet been defined in this population, and the literature on critically ill
      patients suggests a relevant reduction in the amount of transfusion.

      Rationale for the study Providing adequate DO2 can be approached in several ways during
      vv-ECMO support, but the hemoglobin target is always a critical point, and a relevant piece
      of the puzzle of assuring the best oxygenation in patients affected with acute respiratory
      failure (ARF). There may be important variations between hospitals and countries in the use
      of PRBC transfusions, which may impact patient outcome. Large scale, national, and
      international studies are currently lacking.

      There is a significant knowledge gap in understanding the benefits and risks of transfusion
      during VV-ECMO.

      An international multicenter study will evaluate prospective observational data of
      transfusion practices during VV-ECMO, analyzing it in light of anticoagulation and bleeding
      episodes.

      Aim of the study The PROTECMO study is aimed at being a collaborative study including a large
      number of ECMO centers worldwide, describing, in real practice,

        1. Incidence of major bleeding events and amount of blood product transfused

        2. Type, trigger and level of anticoagulation adopted

      Study Design: international multicenter prospective observational cohort study. For the
      primary outcome PRBC will be evaluated as total amount during the ECMO run and in the first
      28 days also as daily amount. The total amount of PRBC, adjusted for the ECMO length of stay,
      will be evaluated in light of pre-ECMO parameters (age, comorbidities, postoperative state
      and severity scores) and of daily data (bleeding episodes, ECMO blood flow, dieresis, CRRT,
      Hb, major events). Daily occurrence of PRBC transfusion will be described according to
      pre-ECMO characteristics and daily parameters (Hb, bleeding, hemodynamics, renal function,
      circuit change).

      Plasma, platelets, Fibrinogen, Antithrombin III administration will be evaluated according to
      pre-ECMO data and according to daily APTT level (or other coagulation monitoring adopted),
      bleeding episodes, sepsis occurred For the secondary outcomes type of anticoagulant will be
      described as well as daily dose and daily target for the parameter targeted (APTT, ACT,
      r-TEG, anti-Xa according to local protocol). Anticoagulation will be described in relation to
      pre-ECMO parameters and daily episodes of bleeding and occurrence of sepsis.

      Bleeding episodes will be described according to site (airway - including tracheotomy -
      oro-nasal, gastric, intrathoracic, abdominal, intestinal, retroperitoneal, urinary tract,
      other) and classified according to severity following 5 adjusted categories of the Bleeding
      Academic Research Consortium (BARC) score: Type 0, no bleeding; Type 1, Any overt bleeding
      that requires heparin infusion rate reduction or PRBC transfusion (provided Hb drop was
      related to bleeding); Type 2, any overt bleeding that requires heparin infusion rate
      reduction and packed red blood cells transfusion or non-surgical procedure to stop bleeding
      (provided Hb drop was related to bleeding); Type 3, Any life-threatening bleeding that
      required PRBC transfusion and surgical intervention for control of bleeding or ECMO
      discontinuation; Type 4: any fatal bleeding.

      Every patient included will be registered for baseline values, and will then be followed for
      ECMO management and transfusion management daily for the first 28 days or until ECMO weaning
      if the ECMO run will be shorter than the observation time. Daily parameters will be recorded.
      Moreover, data will be recorded for every PRBC, Plasma, Platelets transfusion event. The
      patients will be observed for the clinical outcomes until they are discharged from the ICU
      and 6-months mortality will be recorded. Considering that according the Extracorporeal Life
      Support Organization summary, the average length of respiratory ECMO run is about 12 days we
      believe that the majority of ECMO run will be fully covered by the observation period and, at
      least, it will be paradigmatic of a center's actual practice and, at the same time, will
      assure a considerable sample size of transfusion events.

      Data will be reported according to the STROBE (Strengthening the reporting of observational
      studies in epidemiology) statement checklist.

      Study conduction Given the explorative nature of this study, the required number of patients
      was not calculated, but considering at least 10 patients/year for each center (considered the
      worst prediction) we imagine that the included patients will be at least 100 in Italy and we
      presume to enroll at least a double number worldwide.

      Study duration

        -  Transfusions decisions for each patient will be recorded daily for 28 days after ECMO
           cannulation or until the end of ECMO support if the length is < 28 days.

        -  Patients will be observed until ICU discharge with a follow up to sixth months for
           mortality

        -  The inclusion period will be 12 months for each center.

      Data collection methods Data will be recorded using pre-printed CRF by the principal
      investigator (PI) in each center or directly they will be recorded online. All data will be
      reported in a centralized online and Web-based fully encrypted database (REDCAP)

      Data will include clinical characteristics: baseline demographics, basic biological values
      (e.g., blood gas, hemoglobin), primary diagnosis, comorbidities, underlying etiology of acute
      respiratory failure, severity of illness (e.g., SOFA, SAPS 2), type of ECMO, and the size of
      the cannulas.

      ECMO management data will be collected daily for 28 days. Additionally, fluid balance,
      adverse events, Hb and all hematological data, anticoagulation management and monitoring will
      be collected every 24 hours.

      For 28 days, transfusion amounts and values of Hb, HTC, Platelets, will be recorded.

      Bleeding will be evaluated according to site and severity according to 5 adjusted categories
      of the Bleeding Academic Research Consortium (BARC) score.

      Data will also be collected for the duration of mechanical ventilation, duration of ECMO, and
      ICU length of stay. Clinical outcome assessment will be made, with date of death, ICU
      discharge, hospital discharge, sixth month mortality.

      Statistical Analysis Descriptive statistics including frequency (percentage), median and
      interquartile range (IQR) will describe overall population and groups of survivors and
      non-survivors.

      In order to describe current transfusion practice the amount of PRBC, Plasma and Platelets,
      will be described as units and ml and as a number of transfusions adjusted for ECMO length of
      stay and considering the concomitant bleeding episodes.

      Fibrinogen and Antithrombin III will be described as mg or units respectively and as a number
      of administration.

      Anticoagulation will be reported as type, mean dosage and the confidence interval (CI 95%).

      Hb average level and the confidence interval (CI 95%) will be reported. Baseline categorical
      and continuous variables will be compared for transfusion and ECMO weaning groups. In
      particular categorical variables will be compared with chi-square tests and continuous
      variables will be compared with Student's T-test, or Wilcoxon rank-sum tests, otherwise.

      Multiple COX regression analysis will be used in order to explore the impact of confounding
      factors such as baseline patient severity, ECMO length of stay, bleeding episodes and
      possible others covariates and factors that will be observed and raised relevance during the
      first exploratory or univariate analysis. The impact of relevant confounding factors such as
      length of ECMO run, pre-ECMO severity scores, pre-ECMO administration of transfusions will be
      analyzed separately and together in multiple analyses.

      In particular daily RBC transfusion will be studied according to the association to renal
      function, fluid balance, worst Hb level, episodes of bleeding, use of vasopressors, ECMO
      blood flow.

      A p-value less of than 0.05 will be considered significant. Data handling and analyses will
      be done with SAS 9.4 software (SAS Institute Inc, Cary, NC, USA) and R 3.3 software (R
      Foundation for Statistical Computing).

      Ethics: Informed Consent and Treatment of personal data The study will be conducted in
      compliance with the current Helsinki Declaration and the standards of good clinical practice.

      The study involves the enrollment of patients undergoing extracorporeal membrane oxygenation
      support and therefore unable to express a consent.

      Every participating center will have to ask the permission to their Ethic Committee or other
      relevant and competent authorities according to the local rules.

      At ISMETT, according the Italian rules (and we strongly suggest to follow the same at the
      other centers), the investigators will apply the following practice about informed consent as
      it was approved by the Ethic Committee. The participating centers will be supperted with
      approval by ISMETT Ethic Committee and providing materials and translated informed consent
      either for the participation in the study and for the data protection policy.

      According to the art. 82 of the Codice Privacy the investigators will ask for a consent for
      the treatment of personal data of the patients that for the particular support of the ECMO
      are almost always sedated at least at the beginning of the ECMO run - so they have to be
      considered temporarily unable to express a consent - to those that have legal authority over
      them or to the immediate relatives or to a person cohabiting with them or - failing these -
      to the person in charge of the facility where the data subject is hosted. In case the patient
      is able to an informed consent it will be asked to himself.

      In the case of following improvement of neurological condition of the patient we will ask for
      a consent directly to the patient as soon as we will consider him again able to express a
      valid consent.

      The results of the research will be diffused as aggregate data and in ways that will not
      allow in any case the identification of the enrolled patients.

      Safety The present study, giving its observational design, has a complete safety profile.

      There will be no additional interventions or measurements other than those that are standard
      of care at the participating center. All clinical activity will follow the well established
      protocols for ECMO support at each participating center and consequently the patients are at
      no risk by in participating in the study.

      Predefined subgroup analyses If the sample size will be adequate, as explorative analyses,
      some subgroup analyses will be performed according to the following predefined plan.

      Exploratory analyses will stratify data for center workload (<10, 10-20, >20 ECMO run per
      year), according to geographical areas (we imagine a stratification among continents but we
      will verify if, giving the amount of data, will be reasonable a country stratification), and
      for pre-ECMO severity scores (Preserve score and Respscore) divided in quartiles.

      Moreover, by the repeated measurements of hemoglobin and eventual transfusion event, for each
      center we will profile the actual and effective hemoglobin accepted as a trigger. The outcome
      weaning from ECMO and effective ICU discharge will be stratified also according to different
      hemoglobin values (<7, 7-10, >10, >12).

      Another subgroups analysis will involve age, considered a major impacting factor in survival
      during ECMO. Patients will be divided in quartiles and patients > 60 years old will moreover
      evaluated.

      Jehovah's witnesses and all patients refusing transfusions for personal reasons, as well as
      patients affected with hematological malignances will be analyzed separately.

      Expected results, potential benefit of the study and publication program A collaborative
      combination of ECMO centers will evaluate prospective data of transfusion practices during
      ECMO. The investigators would be able to describe the currently strategy for administration
      of blood products, anticoagulation and the effective incidence of bleeding episodes
      worldwide.
observational model: Cohort
time perspective: Prospective
measure: Descriptive data of PRBC transfusion in patients receiving VV-ECMO
time frame: Day 28 after ECMO start
description: Packed Red Blood Cells Transfused, amount
measure: Descriptive data of Platelets transfusion in patients receiving VV-ECMO
time frame: Day 28 after ECMO start
description: Platelets, amount
measure: Descriptive data of Plasma transfusion in patients receiving VV-ECMO
time frame: Day 28 after ECMO start
description: Plasma, amount
measure: Descriptive data of Fibrinogen administration in patients receiving VV-ECMO
time frame: Day 28 after ECMO start
description: Fibrinogen, amount
measure: Descriptive data of Antithrombin III administration in patients receiving VV-ECMO
time frame: Day 28 after ECMO start
description: Antithrombin III, amount
measure: Descriptive data of anticoagulation practices in patients receiving VV-ECMO
time frame: daily for 28 days
description: Type of anticoagulant adopted during ECMO
measure: Descriptive data of anticoagulation practices in patients receiving VV-ECMO
time frame: daily for 28 days
description: Dose of anticoagulant adopted during ECMO
measure: Descriptive data of bleeding episodes in patients receiving VV-ECMO
time frame: daily for 28 days
description: Episodes of bleeding according to site and severity
measure: Correlate the amount of transfusions to clinical outcomes
time frame: Day 28 after ECMO start
description: ECMO weaning, Yes/Not
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Antonio Arcadipane, MD
role: Study Director
affiliation: The Mediterranean Institute for Transplantation and Advanced Specialized Therapies
last name: Gennaro Martucci, MD
role: Principal Investigator
affiliation: The Mediterranean Institute for Transplantation and Advanced Specialized Therapies
facility: 
country: Italy
responsible party type: Sponsor
mesh term: Hemorrhage
sharing ipd: No
ipd description: Aggregate data will be shared
provided document: 
provided document: 