<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/NCT02189889</url>
  </required_header>
  <id_info>
    <org_study_id>APART.V1.2013</org_study_id>
    <nct_id>NCT02189889</nct_id>
  </id_info>
  <brief_title>Active Preoperative Anemia Management in Patients Undergoing Cardiac Surgery</brief_title>
  <acronym>APART</acronym>
  <official_title>Active Preoperative Anemia Management to Reduce Erythrocyte Transfusion in Patients Undergoing Cardiac Surgery (APART): A Pilot, Feasibility Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Texas Southwestern Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>AMAG Pharmaceuticals, Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Texas Southwestern Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Anemia which is a decreased blood count or lower than normal hemoglobin (hgb), is a major&#xD;
      health problem for patients having heart surgery. Hemoglobin is the part of our blood that&#xD;
      carries oxygen from the lungs to the rest of the body. Anemia that is present before surgery,&#xD;
      called preoperative anemia, is a risk factor for an increased chance of morbidity (illness)&#xD;
      and/or mortality (death) after heart surgery. It is also an important indicator of blood&#xD;
      transfusion necessity. Recent clinical research investigations done to study preoperative&#xD;
      anemia suggest a blood transfusion can damage the immune system (the system that protects us&#xD;
      from disease) which can lead to infection, organ dysfunction (especially of the heart,&#xD;
      kidney, brain), prolonged hospital stays, as well as increased supplies, resources and cost&#xD;
      in surgical patients. Comprehensive anemia management can reduce or eliminate the need for&#xD;
      blood transfusions and provide better outcomes after surgery. Therefore, controlling anemia&#xD;
      before surgery is extremely important, and could be a lifesaving measure.&#xD;
&#xD;
      This pilot, feasibility study is being done for several reasons. First of all, it will test&#xD;
      the the safety and effectiveness of using a short-course of two medications, erythropoietin&#xD;
      (EPO) and Feraheme (iron given intravenously [IV]), to increase hemoglobin levels in order to&#xD;
      improve preoperative anemia, reduce transfusions and lower postoperative complications in&#xD;
      anemic patients undergoing heart surgery. Secondly, findings will be used to design a large&#xD;
      randomized controlled trial (RCT). The RCT will establish a protocol to actively manage&#xD;
      anemia before surgery, thus reducing transfusions during surgery and improving recovery&#xD;
      afterwards. It will also help identify valuable information regarding what needs to be done&#xD;
      for timely completion of the planned RCT.&#xD;
&#xD;
      EPO is a medication approved by the Food and Drug Administration (FDA) used to treat anemia&#xD;
      in patients with certain conditions in order to reduce blood transfusions. And although&#xD;
      approved for use during surgery, it has not been FDA approved for use in cardiac (heart) or&#xD;
      vascular (blood vessels, including veins and arteries) surgery. Common side effects include&#xD;
      nausea, vomiting, itching, headache, injection site pain, chills, deep vein thrombosis (blood&#xD;
      clot), cough, and changes in blood pressure (BP). Feraheme is an iron replacement product&#xD;
      approved for the treatment of low iron anemia in adult patients. It may cause serious&#xD;
      allergic reactions, including anaphylaxis (severe, whole body allergic reaction), as well as&#xD;
      low BP and excessive iron storage.&#xD;
&#xD;
      Patients meeting all eligibility requirements that consent to participate will be randomized&#xD;
      into the study. Randomization is being placed by chance (like a flip of a coin) into one of&#xD;
      two study groups, the treatment group or the control group. There is an equal chance of being&#xD;
      placed into either group, which will be done by a computer.&#xD;
&#xD;
        1. The Treatment Group will receive a 300 unit (U) per kilogram (kg) injection of EPO and a&#xD;
           510 milligram (mg) IV infusion of Feraheme 7-28 days before the day of surgery. And&#xD;
           again 1-7 days before the day of surgery, a second dose of both of these medications&#xD;
           will be given. The third dose, of EPO only, will be administered 2 days after surgery.&#xD;
           Before initiating a dose or giving a subsequent dose, laboratory parameters will be&#xD;
           measured to assess the hemoglobin level and response to the medication. If blood values&#xD;
           increase too rapidly or are too high, the meds will not be started or, if already dosed,&#xD;
           they will not be given again.&#xD;
&#xD;
        2. The Control Group will receive no preoperative intervention for anemia unless lab&#xD;
           results show iron deficiency anemia. The control group will be screened for the presence&#xD;
           of iron deficiency anemia by evaluating blood laboratory values drawn during the&#xD;
           baseline or preoperative visit. If lab results indicate iron deficiency anemia,&#xD;
           over-the-counter oral iron will be recommended, to take until the day of surgery. In&#xD;
           doing so, patients may benefit by potentially reducing the need for blood transfusions.&#xD;
&#xD;
      Data will be collected from all participants from the preoperative visits throughout the&#xD;
      admission, including lab results, medications, vital signs, information about the procedure,&#xD;
      transfusions, and any problems or adverse events.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Anemia and transfusion are independent predictors of morbidity and mortality in the cardiac&#xD;
      surgical patient population. Even so, active preoperative anemia management is not currently&#xD;
      the standard of care at our institution. Cost associated with erythrocyte transfusions at&#xD;
      University of Texas Southwestern (UTSW) University Hospitals exceeds twenty million dollars&#xD;
      annually, not including costs associated with treatment of known complications of red cell&#xD;
      transfusions (renal insufficiency, respiratory failure, infection and prolonged length of&#xD;
      stay, etc). Fifty percent of our cardiac surgical population suffer from preoperative anemia&#xD;
      and 79% of these patients will receive one or more red blood cell (RBC) transfusions. In&#xD;
      contrast, the incidence of RBC transfusion was only 35% in those without preoperative anemia&#xD;
      in the calendar year 2011-12.&#xD;
&#xD;
      The mechanism of injury in patients with preoperative anemia is either the duration/intensity&#xD;
      of the anemia exposure and resultant organ ischemia, or the harmful effects of erythrocyte&#xD;
      transfusion(s) itself. Active preoperative anemia management is a strategy that attempts to&#xD;
      minimize both of these events, and in doing so, exert an additive or possibly synergistic&#xD;
      effect on improving clinical outcomes. A randomized controlled trial utilizing a standardized&#xD;
      transfusion strategy is a necessary step in determining if increases in preoperative&#xD;
      hemoglobin lead to improved outcomes. A pilot, feasibility study is the first essential step&#xD;
      in insuring the adequacy of future trials designed to answer this important question.&#xD;
&#xD;
      The APART study is being conducted to test the safety and efficacy of using a short-course&#xD;
      (1-4 weeks) of EPO plus Feraheme to increase erythrocyte mass. The findings will be used to&#xD;
      guide the design of a randomized, controlled trial (RCT) that examines the effects of active&#xD;
      preoperative anemia management on erythrocyte transfusion and clinical outcomes. The RCT will&#xD;
      test the hypothesis that a short-course (1-4 weeks) of EPO plus Feraheme is superior to the&#xD;
      standard of care (SOC) at reducing transfusion and improving outcomes in anemic patients&#xD;
      scheduled for cardiac surgery. Means and standard deviations derived from pilot data on&#xD;
      changes in hemoglobin levels, reticulocyte counts and differences in erythrocyte transfusions&#xD;
      and clinical outcomes will be analyzed for possible use in sample size calculations for the&#xD;
      larger RCT. This pilot will also provide information in determining logistics for timely&#xD;
      completion of the RCT, and will also address data collection, data management, adherence to&#xD;
      the study protocol, transfusion and surveillance strategies and classification of clinical&#xD;
      outcomes and adverse events.&#xD;
&#xD;
      Pilot Study Specific Aims Include:&#xD;
&#xD;
        1. To determine the proportion of patients who fulfill all the eligibility criteria for the&#xD;
           study and agree to be part of a randomized trial of short-course EPO plus supplemental&#xD;
           Feraheme (up to 3 doses given over a 1-4 week interval prior to surgery) vs. standard of&#xD;
           care management in patients scheduled for coronary bypass grafting (CABG), valve&#xD;
           surgery, or CABG/valve surgery.&#xD;
&#xD;
        2. To determine the adherence of patients and health care team to the procedures included&#xD;
           in the study protocol (scheduled appointments, surveillance and transfusion strategies).&#xD;
&#xD;
        3. To determine the increase in hemoglobin levels and reticulocyte counts following a&#xD;
           short-course of EPO plus supplemental Feraheme over a 1-4 week interval prior to the&#xD;
           date of surgery vs. standard of care management in patients scheduled for CABG, valve,&#xD;
           or CABG/valve surgery.&#xD;
&#xD;
        4. To assess differences in the proportion of patients receiving erythrocyte transfusions&#xD;
           and number of blood products utilized (RBC, platelets and plasma) in the peri- and&#xD;
           post-operative periods for those receiving a short-course of EPO plus supplemental&#xD;
           Feraheme vs. standard of care management in patients scheduled for CABG, valve or&#xD;
           CABG/valve surgery.&#xD;
&#xD;
        5. To determine the frequency and intensity of pre-defined clinical outcomes (mortality,&#xD;
           major cardiac, renal, neurological events [associated with anemia] and infection) in the&#xD;
           peri- and post-operative periods for those receiving a short-course of EPO plus Feraheme&#xD;
           vs. standard of care management in patients scheduled for CABG, valve, or CABG/valve&#xD;
           surgery.&#xD;
&#xD;
      Differences in hemoglobin levels and reticulocyte counts from baseline to the day of surgery&#xD;
      and postop day (POD) 5, proportion of patients receiving transfusions and number of blood&#xD;
      products utilized and the pre-defined clinical events will be assessed between the two&#xD;
      groups. Each patient will be enrolled in the study up to 28 days before the day of surgery&#xD;
      and for up to 30 days following the day of surgery. This pilot, feasibility study will enroll&#xD;
      50 subjects (25 per group). Both groups will have detailed clinical data and biological&#xD;
      specimens collected.&#xD;
&#xD;
      Visits and Procedures:&#xD;
&#xD;
        -  Screening: Patients undergoing cardiac surgery (CABG, valve, CABG/valve) with anemia&#xD;
           will be identified in advance of their operations. Basic features of patient medical and&#xD;
           surgical histories (i.e. age, gender, type of surgery) will be screened. If eligible for&#xD;
           the study based on the inclusion/exclusion criteria, they will be consented into the&#xD;
           study.&#xD;
&#xD;
        -  Baseline Visit: Data on demographics, lab results, vital signs, medical history, current&#xD;
           medications, height/weight will be reviewed and recorded. Randomization by computer will&#xD;
           be done and the patient will receive the 1st dose of study drugs, as assigned, then&#xD;
           monitored for any serious reactions (chest pain, dyspnea, seizures, severe headache,&#xD;
           fever, nausea, vomiting, diarrhea, increase in BP). Control group patients with evidence&#xD;
           of iron-deficiency by laboratory criteria will be advised to initiate supplementation&#xD;
           with a non-prescription, over-the-counter oral iron preparation (ferrous sulfate 325 mg,&#xD;
           three times a day is commonly used) to be taken until the planned surgical operation.&#xD;
&#xD;
        -  Pre-op Visit: Patients will receive the 2nd dose of study drugs as assigned. Vital signs&#xD;
           (heart rate, BP, oxygen saturation, temperature) will be recorded before and after drug&#xD;
           administration, then monitored for any serious adverse events; SOC lab results;&#xD;
           reticulocyte count, troponin, creatine kinase-myocardial band (CK-MB) samples will be&#xD;
           collected.&#xD;
&#xD;
        -  Day of Surgery: Patient vital signs (BP, electrocardiogram [EKG], etc) will be monitored&#xD;
           as part of standard of care. Reticulocyte count, iron panel (includes transferrin,&#xD;
           ferritin, total iron binding capacity, iron level) samples will be collected. SOC lab&#xD;
           results, record of transfusions, estimated blood loss, adverse events will be&#xD;
           monitored/recorded.&#xD;
&#xD;
        -  POD 2: Troponin, CK-MB, Rotem (Rotational thromboelastometry) samples will be collected.&#xD;
           Patients will receive study drug, as assigned, then monitored for serious events.&#xD;
&#xD;
        -  POD 1-7: Vital signs (BP, EKG, etc) will be monitored; SOC lab results, record of&#xD;
           transfusions, and adverse events will be monitored/recorded. Estimated blood loss will&#xD;
           be recorded on POD 1 and 2 only.&#xD;
&#xD;
        -  Other lab to be collected: POD 1 - reticulocyte count, iron panel, troponin, CK-MB; POD&#xD;
           2 - troponin, CK-MB, Rotem; POD 5 - reticulocyte count, iron panel, aspartate&#xD;
           transaminase/alanine transaminase (AST/ALT); POD 7 - complete blood count (CBC),&#xD;
           reticulocyte count, creatinine; POD 14 or discharge (whichever comes first) - CBC,&#xD;
           creatinine.&#xD;
&#xD;
      Transfusion Strategy: Erythrocyte transfusion is permitted during cardiopulmonary bypass,&#xD;
      during surgery and afterwards per protocol, when criteria is met. Red cell transfusions&#xD;
      should be given one unit at a time with measurement of the pre- and post-transfusion&#xD;
      hemoglobin levels along with physiologic parameters used to assess adequacy of organ&#xD;
      perfusion. A consensus for transfusion thresholds was established among anesthesiologists,&#xD;
      perfusionists and surgeons in our practice. The transfusion thresholds implemented in this&#xD;
      protocol reflects our current &quot;standard of care;&quot; a threshold at which clinicians generally&#xD;
      believe the benefits of erythrocyte transfusion outweigh the risks. Adherence to the&#xD;
      transfusion strategy will be recorded by the research nurse and protocol deviations will be&#xD;
      discussed with the attending physician of record and a member of the clinical research team.&#xD;
      However, research staff will not order nor prohibit erythrocyte transfusions. This will be&#xD;
      left to the discretion of the treating physician(s) if he/she deems it clinically necessary.&#xD;
      Following randomization, patient's charts will be clearly labeled to indicate participation&#xD;
      in the study protocol.&#xD;
&#xD;
      Surveillance Strategy: The decision to initiate and continue administering doses of EPO is&#xD;
      based on evidence accrued from randomized controlled trials and clinical practice guidelines&#xD;
      provided by multiple sub-specialty and international societies. Substantial heterogeneity&#xD;
      exists in factors that could be included in a surveillance strategy to minimize the risk of a&#xD;
      thrombotic event in this setting; with no one strategy proven to be superior. The&#xD;
      surveillance strategy included in this protocol derives from, what we believe to be, the most&#xD;
      current safety analyses of perioperative EPO use reflected in the literature. Implementing&#xD;
      such surveillance methods are intended to minimize the possibly rare but potentially&#xD;
      life-threatening adverse events. Risk factors considered in our surveillance strategy&#xD;
      include: evidence of unstable angina or myocardial infarction, recent thrombotic event,&#xD;
      hemoglobin levels associated with a higher risk of a myocardial event, excessive&#xD;
      thrombocytosis or laboratory evidence of a hypercoagulable postoperative state. EPO dosing&#xD;
      will be stratified based on patient risk (degree of perioperative anemia), type of procedure&#xD;
      (CABG vs. valve) and laboratory data (hgb, Rotem). All doses will be given per surveillance&#xD;
      guidelines.&#xD;
&#xD;
      Primary End Point: The primary objective is to assess the enrollment rate and adherence to&#xD;
      the dosing protocol and surveillance strategies. We define successful adherence as adherence&#xD;
      to dosing in more than 90% of patients for more than 90% of the doses deemed appropriate by&#xD;
      the surveillance strategy. Secondary outcomes will include changes in hemoglobin levels and&#xD;
      reticulocyte counts within the two groups from baseline to the day of surgery and POD 5,&#xD;
      number of RBC units transfused, frequency of pre-specified clinical outcomes and incidence of&#xD;
      adverse events in each of the study groups. Data from this pilot study will be used for the&#xD;
      power analysis and design of the larger RCT.&#xD;
&#xD;
      Adverse events (AEs) are events that involve physiological, social, or psychological harm to&#xD;
      subjects or risks of harm to additional subjects or others. AEs include expected and&#xD;
      unexpected harmful effects, and unexpected risks of an interaction or an intervention. AEs&#xD;
      may be caused by: the test article or test procedure, other aspects of the interaction or&#xD;
      intervention, the subject's underlying condition, or the subject's concurrent standard&#xD;
      treatment. AEs may be definitely related, probably related, possibly related, unlikely to be&#xD;
      related, or definitely not related to the research. We will report all adverse events and&#xD;
      other reportable incidences to the Institutional Review Board (IRB) per reporting guidelines.&#xD;
      Any adverse event will be documented of that event including a description, subject number,&#xD;
      date, outcome, and follow-up.&#xD;
&#xD;
      The primary safety endpoints of the study are the incidence of adverse events associated with&#xD;
      the use of the study medications. These include: hypersensitivity (e.g. pruritis, rash, and&#xD;
      urticaria), hypertension, hypotension, bleeding, nausea, vomiting, injection site pain, deep&#xD;
      venous thrombosis or other thrombotic complications. Surveillance for these adverse events&#xD;
      will be conducted by direct observation (during drug administration), daily bedside visits by&#xD;
      the research nurse for the first 7 postoperative days, review of the patients medical record&#xD;
      and listing any of these complications in the Society of Thoracic Surgery (STS) database. The&#xD;
      definition of a stroke, myocardial infarction (MI), mesenteric artery occlusion or peripheral&#xD;
      vascular event will be based on STS criteria. Any event resulting in death from time of&#xD;
      initial drug administration to hospital discharge will be recorded.&#xD;
&#xD;
      The Principal Investigator, along with the Secondary Investigators, will be responsible for&#xD;
      the monitoring, reviewing and analyses of study data. This will be done quarterly unless an&#xD;
      issue requires immediate attention or if a recurrent pattern develops into a need for a more&#xD;
      frequent review. An interim analysis will be done at 50% enrollment by the principal and&#xD;
      secondary investigators.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Initial patients were seen at St Paul Hospital. Enrollment changes occurred with the move to&#xD;
    Clements Hospital. We were unable to identify an infusion room at CUH despite an exhaustive&#xD;
    search for alternatives and forced to terminate early.&#xD;
  </why_stopped>
  <start_date type="Actual">April 9, 2013</start_date>
  <completion_date type="Actual">July 26, 2019</completion_date>
  <primary_completion_date type="Actual">July 26, 2019</primary_completion_date>
  <phase>Phase 1/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>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure># of Participants Who Adhered to the Study Protocol</measure>
    <time_frame>Preoperative 1st dose through Postoperative Day (POD) 2.</time_frame>
    <description>Successful adherence is defined as adhering to dosing in ≥90% of patients for ≥90% of the doses deemed appropriate by the surveillance strategy.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline Hemoglobin Level Assessed at Different Time Points Within the 2 Arms.</measure>
    <time_frame>Change from Baseline hemoglobin level to day of surgery (DOS), to POD 5.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline Reticulocyte Count Assessed at Different Time Points Within the 2 Arms.</measure>
    <time_frame>Change from Baseline reticulocyte count to DOS, to POD 5.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Blood Products Utilized Per Patient Receiving Erythrocyte Transfusions.</measure>
    <time_frame>Preoperative 1st dose through 30 days following surgery.</time_frame>
    <description>Number of blood products utilized per patient receiving erythrocyte transfusions, including red blood cells, platelets and plasma.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of Pre-defined Clinical Events in Each of the Study Arms</measure>
    <time_frame>Preoperative 1st dose through 30 days following surgery.</time_frame>
    <description>Incidence of mortality, major cardiac, renal, neurological events (associated with anemia) and infection. These events will include myocardial infarction, prolonged low-output state, encephalopathy, duration of mechanical ventilation, renal insufficiency,mortality and dialysis dependence at 30 days.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">5</enrollment>
  <condition>Anemia</condition>
  <condition>Cardiovascular Disease</condition>
  <arm_group>
    <arm_group_label>EPO and Feraheme</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients in the treatment group will receive a subcutaneous injection of EPO 300U/kg at the Baseline visit, the Preoperative visit and on POD 2; and an infusion of Feraheme 510mg at the Baseline visit and the Preoperative visit.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>The control group will receive no preoperative intervention for anemia. The exception being iron deficiency anemia found during baseline. If laboratory values indicate iron deficiency, oral iron will be recommended to take until surgery.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>EPO</intervention_name>
    <description>The treatment group will receive up to three doses of EPO 300U/kg. The first dose of study medication will be administered up to 28 days before the day of surgery and the second will be administered 1-7 days before the day of surgery. These first two doses will be given at least 7 days apart. A third dose may be administered two days following surgery. All 3 doses will be administered per surveillance strategy guidelines.</description>
    <arm_group_label>EPO and Feraheme</arm_group_label>
    <other_name>erythropoietin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Feraheme</intervention_name>
    <description>Supplementation with Feraheme, 510mg delivered as an IV infusion, will be given following the first two preoperative doses of EPO.</description>
    <arm_group_label>EPO and Feraheme</arm_group_label>
    <other_name>IV iron</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  between the age of 18 and 80 years old&#xD;
&#xD;
          -  diagnosed with preoperative anemia, defined as hemoglobin &lt;13.0 grams per deciliter&#xD;
             (g/dL)&#xD;
&#xD;
          -  scheduled for elective cardiac surgery (CABG, valve, or CABG/valve), including both&#xD;
             first time and repeat procedures&#xD;
&#xD;
          -  documented negative pregnancy test within 7 days prior to the procedure for females of&#xD;
             child-bearing potential&#xD;
&#xD;
          -  a written informed consent prior to any procedure, using a form that is approved by&#xD;
             the UT Southwestern Institutional Review Board&#xD;
&#xD;
          -  agreement to be compliant&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  uncontrolled hypertension (defined as systolic pressure greater than 180 millimeters&#xD;
             of mercury (mmHg), diastolic pressure greater than 100mmHg, not adequately controlled&#xD;
             by anti-hypertensive therapy at the time of procedure)&#xD;
&#xD;
          -  current renal failure on dialysis or serum creatinine &gt;3.0 milligrams per deciliter&#xD;
             (mg/dL)&#xD;
&#xD;
          -  unstable angina (defined by chest pain and EKG changes indicating ischemia at rest)&#xD;
&#xD;
          -  thromboembolism within the past year&#xD;
&#xD;
          -  current active primary or metastatic malignancy or history of myeloid malignancy&#xD;
&#xD;
          -  seizures within the past year&#xD;
&#xD;
          -  history of stroke within the last 6 months&#xD;
&#xD;
          -  patients who have platelet count lower than 50,000 per cubic millimeter (mm3) or&#xD;
             coagulation abnormality&#xD;
&#xD;
          -  sepsis or bacteremia defined by positive blood culture&#xD;
&#xD;
          -  patients who have known hypersensitivity to EPO or any of its components&#xD;
&#xD;
          -  patients who have known hypersensitivity to Feraheme or any of its components&#xD;
&#xD;
          -  patients who refuse blood transfusion, (i.e. Jehovah's Witnesses)&#xD;
&#xD;
          -  pregnant or breast feeding&#xD;
&#xD;
          -  patients who are unable to provide informed consent or who has inability to understand&#xD;
             or corporate with study procedure&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Philip E. Greilich, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Texas Southwestern Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Clements University Hospital</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75390-8894</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clements University Hospital</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75390</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Society of Thoracic Surgeons Blood Conservation Guideline Task Force; Ferraris VA, Ferraris SP, Saha SP, Hessel EA 2nd, Haan CK, Royston BD, Bridges CR, Higgins RS, Despotis G, Brown JR; Society of Cardiovascular Anesthesiologists Special Task Force on Blood Transfusion; Spiess BD, Shore-Lesserson L, Stafford-Smith M, Mazer CD, Bennett-Guerrero E, Hill SE, Body S. Perioperative blood transfusion and blood conservation in cardiac surgery: the Society of Thoracic Surgeons and The Society of Cardiovascular Anesthesiologists clinical practice guideline. Ann Thorac Surg. 2007 May;83(5 Suppl):S27-86. doi: 10.1016/j.athoracsur.2007.02.099.</citation>
    <PMID>17462454</PMID>
  </reference>
  <verification_date>October 2020</verification_date>
  <study_first_submitted>July 11, 2014</study_first_submitted>
  <study_first_submitted_qc>July 11, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 15, 2014</study_first_posted>
  <results_first_submitted>September 24, 2020</results_first_submitted>
  <results_first_submitted_qc>October 21, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">October 23, 2020</results_first_posted>
  <last_update_submitted>October 21, 2020</last_update_submitted>
  <last_update_submitted_qc>October 21, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">October 23, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Texas Southwestern Medical Center</investigator_affiliation>
    <investigator_full_name>Philip Greilich</investigator_full_name>
    <investigator_title>MD, FASE, Professor and Holder S.T. &quot;Buddy&quot; Harris Distinguished Chair in Cardiac Anesthesiology, Quality Officer, University of Texas Healthcare System</investigator_title>
  </responsible_party>
  <keyword>Active preoperative anemia management</keyword>
  <keyword>Erythrocyte transfusion</keyword>
  <keyword>RBC transfusion</keyword>
  <keyword>Red cell transfusion</keyword>
  <keyword>Transfusion in cardiac surgery</keyword>
  <keyword>Anemia treatment with erythropoietin</keyword>
  <keyword>Anemic cardiac surgery patients</keyword>
  <keyword>Erythrocyte stimulating agent (ESA)</keyword>
  <keyword>Iron deficiency anemia</keyword>
  <keyword>EPO</keyword>
  <keyword>Feraheme</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cardiovascular Diseases</mesh_term>
    <mesh_term>Anemia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ferrosoferric Oxide</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
    <ipd_description>All data and information collected during this study will be considered confidential and remains the sole property of UTSW Medical Center. Data may be shared with AMAG Pharmaceuticals, Inc., prior to any publications. All data used in the analysis and summary of this study will be anonymous, and without reference to specific subject names.</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>May 13, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/89/NCT02189889/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>EPO and Feraheme</title>
          <description>Patients in the treatment group will receive a subcutaneous injection of EPO 300U/kg at the Baseline visit, the Preoperative visit and on POD 2; and an infusion of Feraheme 510mg at the Baseline visit and the Preoperative visit.&#xD;
EPO: The treatment group will receive up to three doses of EPO 300U/kg. The first dose of study medication will be administered up to 28 days before the day of surgery and the second will be administered 1-7 days before the day of surgery. These first two doses will be given at least 7 days apart. A third dose may be administered two days following surgery. All 3 doses will be administered per surveillance strategy guidelines.&#xD;
Feraheme: Supplementation with Feraheme, 510mg delivered as an IV infusion, will be given following the first two preoperative doses of EPO.</description>
        </group>
        <group group_id="P2">
          <title>Control</title>
          <description>The control group will receive no preoperative intervention for anemia. The exception being iron deficiency anemia found during baseline. If laboratory values indicate iron deficiency, oral iron will be recommended to take until surgery.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="3"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="3"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>EPO and Feraheme</title>
          <description>Patients in the treatment group will receive a subcutaneous injection of EPO 300U/kg at the Baseline visit, the Preoperative visit and on POD 2; and an infusion of Feraheme 510mg at the Baseline visit and the Preoperative visit.&#xD;
EPO: The treatment group will receive up to three doses of EPO 300U/kg. The first dose of study medication will be administered up to 28 days before the day of surgery and the second will be administered 1-7 days before the day of surgery. These first two doses will be given at least 7 days apart. A third dose may be administered two days following surgery. All 3 doses will be administered per surveillance strategy guidelines.&#xD;
Feraheme: Supplementation with Feraheme, 510mg delivered as an IV infusion, will be given following the first two preoperative doses of EPO.</description>
        </group>
        <group group_id="B2">
          <title>Control</title>
          <description>The control group will receive no preoperative intervention for anemia. The exception being iron deficiency anemia found during baseline. If laboratory values indicate iron deficiency, oral iron will be recommended to take until surgery.</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="2"/>
            <count group_id="B2" value="3"/>
            <count group_id="B3" value="5"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="2"/>
                    <count group_id="B2" value="3"/>
                    <count group_id="B3" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="2"/>
                    <count group_id="B2" value="3"/>
                    <count group_id="B3" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race and Ethnicity Not Collected</title>
          <population>Race and Ethnicity were not collected from any participant.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="0"/>
                    <count group_id="B2" value="0"/>
                    <count group_id="B3" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="2"/>
                    <count group_id="B2" value="3"/>
                    <count group_id="B3" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title># of Participants Who Adhered to the Study Protocol</title>
        <description>Successful adherence is defined as adhering to dosing in ≥90% of patients for ≥90% of the doses deemed appropriate by the surveillance strategy.</description>
        <time_frame>Preoperative 1st dose through Postoperative Day (POD) 2.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>EPO and Feraheme</title>
            <description>Patients in the treatment group will receive a subcutaneous injection of EPO 300U/kg at the Baseline visit, the Preoperative visit and on POD 2; and an infusion of Feraheme 510mg at the Baseline visit and the Preoperative visit.&#xD;
EPO: The treatment group will receive up to three doses of EPO 300U/kg. The first dose of study medication will be administered up to 28 days before the day of surgery and the second will be administered 1-7 days before the day of surgery. These first two doses will be given at least 7 days apart. A third dose may be administered two days following surgery. All 3 doses will be administered per surveillance strategy guidelines.&#xD;
Feraheme: Supplementation with Feraheme, 510mg delivered as an IV infusion, will be given following the first two preoperative doses of EPO.</description>
          </group>
          <group group_id="O2">
            <title>Control</title>
            <description>The control group will receive no preoperative intervention for anemia. The exception being iron deficiency anemia found during baseline. If laboratory values indicate iron deficiency, oral iron will be recommended to take until surgery.</description>
          </group>
        </group_list>
        <measure>
          <title># of Participants Who Adhered to the Study Protocol</title>
          <description>Successful adherence is defined as adhering to dosing in ≥90% of patients for ≥90% of the doses deemed appropriate by the surveillance strategy.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
                <count group_id="O2" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline Hemoglobin Level Assessed at Different Time Points Within the 2 Arms.</title>
        <time_frame>Change from Baseline hemoglobin level to day of surgery (DOS), to POD 5.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>EPO and Feraheme</title>
            <description>Patients in the treatment group will receive a subcutaneous injection of EPO 300U/kg at the Baseline visit, the Preoperative visit and on POD 2; and an infusion of Feraheme 510mg at the Baseline visit and the Preoperative visit.&#xD;
EPO: The treatment group will receive up to three doses of EPO 300U/kg. The first dose of study medication will be administered up to 28 days before the day of surgery and the second will be administered 1-7 days before the day of surgery. These first two doses will be given at least 7 days apart. A third dose may be administered two days following surgery. All 3 doses will be administered per surveillance strategy guidelines.&#xD;
Feraheme: Supplementation with Feraheme, 510mg delivered as an IV infusion, will be given following the first two preoperative doses of EPO.</description>
          </group>
          <group group_id="O2">
            <title>Control</title>
            <description>The control group will receive no preoperative intervention for anemia. The exception being iron deficiency anemia found during baseline. If laboratory values indicate iron deficiency, oral iron will be recommended to take until surgery.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline Hemoglobin Level Assessed at Different Time Points Within the 2 Arms.</title>
          <units>grams per deciliter (g/dl)</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
                <count group_id="O2" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline hemoglobin level to DOS</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.9" spread="1.1"/>
                    <measurement group_id="O2" value="3.33" spread="1.49"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Baseline hemoglobin level to POD5</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.2" spread="0.2"/>
                    <measurement group_id="O2" value="2.2" spread="0.75"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline Reticulocyte Count Assessed at Different Time Points Within the 2 Arms.</title>
        <time_frame>Change from Baseline reticulocyte count to DOS, to POD 5.</time_frame>
        <population>Data were not collected for intervention group</population>
        <group_list>
          <group group_id="O1">
            <title>EPO and Feraheme</title>
            <description>Patients in the treatment group will receive a subcutaneous injection of EPO 300U/kg at the Baseline visit, the Preoperative visit and on POD 2; and an infusion of Feraheme 510mg at the Baseline visit and the Preoperative visit.&#xD;
EPO: The treatment group will receive up to three doses of EPO 300U/kg. The first dose of study medication will be administered up to 28 days before the day of surgery and the second will be administered 1-7 days before the day of surgery. These first two doses will be given at least 7 days apart. A third dose may be administered two days following surgery. All 3 doses will be administered per surveillance strategy guidelines.&#xD;
Feraheme: Supplementation with Feraheme, 510mg delivered as an IV infusion, will be given following the first two preoperative doses of EPO.</description>
          </group>
          <group group_id="O2">
            <title>Control</title>
            <description>The control group will receive no preoperative intervention for anemia. The exception being iron deficiency anemia found during baseline. If laboratory values indicate iron deficiency, oral iron will be recommended to take until surgery.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline Reticulocyte Count Assessed at Different Time Points Within the 2 Arms.</title>
          <population>Data were not collected for intervention group</population>
          <units>cells × 10^9/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline reticulocyte count to DOS</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O2" value="0.43" spread="0.48"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Baseline reticulocyte count to POD5</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O2" value="1.35" spread="0.95"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Blood Products Utilized Per Patient Receiving Erythrocyte Transfusions.</title>
        <description>Number of blood products utilized per patient receiving erythrocyte transfusions, including red blood cells, platelets and plasma.</description>
        <time_frame>Preoperative 1st dose through 30 days following surgery.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>EPO and Feraheme</title>
            <description>Patients in the treatment group will receive a subcutaneous injection of EPO 300U/kg at the Baseline visit, the Preoperative visit and on POD 2; and an infusion of Feraheme 510mg at the Baseline visit and the Preoperative visit.&#xD;
EPO: The treatment group will receive up to three doses of EPO 300U/kg. The first dose of study medication will be administered up to 28 days before the day of surgery and the second will be administered 1-7 days before the day of surgery. These first two doses will be given at least 7 days apart. A third dose may be administered two days following surgery. All 3 doses will be administered per surveillance strategy guidelines.&#xD;
Feraheme: Supplementation with Feraheme, 510mg delivered as an IV infusion, will be given following the first two preoperative doses of EPO.</description>
          </group>
          <group group_id="O2">
            <title>Control</title>
            <description>The control group will receive no preoperative intervention for anemia. The exception being iron deficiency anemia found during baseline. If laboratory values indicate iron deficiency, oral iron will be recommended to take until surgery.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Blood Products Utilized Per Patient Receiving Erythrocyte Transfusions.</title>
          <description>Number of blood products utilized per patient receiving erythrocyte transfusions, including red blood cells, platelets and plasma.</description>
          <units>blood product count</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
                <count group_id="O2" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.5" spread="2.5"/>
                    <measurement group_id="O2" value="12.33" spread="2.36"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Incidence of Pre-defined Clinical Events in Each of the Study Arms</title>
        <description>Incidence of mortality, major cardiac, renal, neurological events (associated with anemia) and infection. These events will include myocardial infarction, prolonged low-output state, encephalopathy, duration of mechanical ventilation, renal insufficiency,mortality and dialysis dependence at 30 days.</description>
        <time_frame>Preoperative 1st dose through 30 days following surgery.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>EPO and Feraheme</title>
            <description>Patients in the treatment group will receive a subcutaneous injection of EPO 300U/kg at the Baseline visit, the Preoperative visit and on POD 2; and an infusion of Feraheme 510mg at the Baseline visit and the Preoperative visit.&#xD;
EPO: The treatment group will receive up to three doses of EPO 300U/kg. The first dose of study medication will be administered up to 28 days before the day of surgery and the second will be administered 1-7 days before the day of surgery. These first two doses will be given at least 7 days apart. A third dose may be administered two days following surgery. All 3 doses will be administered per surveillance strategy guidelines.&#xD;
Feraheme: Supplementation with Feraheme, 510mg delivered as an IV infusion, will be given following the first two preoperative doses of EPO.</description>
          </group>
          <group group_id="O2">
            <title>Control</title>
            <description>The control group will receive no preoperative intervention for anemia. The exception being iron deficiency anemia found during baseline. If laboratory values indicate iron deficiency, oral iron will be recommended to take until surgery.</description>
          </group>
        </group_list>
        <measure>
          <title>Incidence of Pre-defined Clinical Events in Each of the Study Arms</title>
          <description>Incidence of mortality, major cardiac, renal, neurological events (associated with anemia) and infection. These events will include myocardial infarction, prolonged low-output state, encephalopathy, duration of mechanical ventilation, renal insufficiency,mortality and dialysis dependence at 30 days.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
                <count group_id="O2" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse event data were collected from baseline to discharge of the index surgery, including a 30 day follow-up. The average in-patient length of stay was 7.4 days in hospital.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>EPO and Feraheme</title>
          <description>Patients in the treatment group will receive a subcutaneous injection of EPO 300U/kg at the Baseline visit, the Preoperative visit and on POD 2; and an infusion of Feraheme 510mg at the Baseline visit and the Preoperative visit.&#xD;
EPO: The treatment group will receive up to three doses of EPO 300U/kg. The first dose of study medication will be administered up to 28 days before the day of surgery and the second will be administered 1-7 days before the day of surgery. These first two doses will be given at least 7 days apart. A third dose may be administered two days following surgery. All 3 doses will be administered per surveillance strategy guidelines.&#xD;
Feraheme: Supplementation with Feraheme, 510mg delivered as an IV infusion, will be given following the first two preoperative doses of EPO.</description>
        </group>
        <group group_id="E2">
          <title>Control</title>
          <description>The control group will receive no preoperative intervention for anemia. The exception being iron deficiency anemia found during baseline. If laboratory values indicate iron deficiency, oral iron will be recommended to take until surgery.</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Cerebrovascular Accident (CVA)</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>Early termination leading to small numbers of subjects analyzed.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Philip Greilich -PROFESSOR</name_or_title>
      <organization>UT Southwestern Medical Center</organization>
      <phone>214/645-8018</phone>
      <email>PHILIP.GREILICH@UTSouthwestern.edu</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02189889
org study id: APART.V1.2013
nct id: NCT02189889
lead sponsor: 
collaborator: 
has dmc: Yes
Anemia which is a decreased blood count or lower than normal hemoglobin (hgb), is a major
      health problem for patients having heart surgery. Hemoglobin is the part of our blood that
      carries oxygen from the lungs to the rest of the body. Anemia that is present before surgery,
      called preoperative anemia, is a risk factor for an increased chance of morbidity (illness)
      and/or mortality (death) after heart surgery. It is also an important indicator of blood
      transfusion necessity. Recent clinical research investigations done to study preoperative
      anemia suggest a blood transfusion can damage the immune system (the system that protects us
      from disease) which can lead to infection, organ dysfunction (especially of the heart,
      kidney, brain), prolonged hospital stays, as well as increased supplies, resources and cost
      in surgical patients. Comprehensive anemia management can reduce or eliminate the need for
      blood transfusions and provide better outcomes after surgery. Therefore, controlling anemia
      before surgery is extremely important, and could be a lifesaving measure.

      This pilot, feasibility study is being done for several reasons. First of all, it will test
      the the safety and effectiveness of using a short-course of two medications, erythropoietin
      (EPO) and Feraheme (iron given intravenously [IV]), to increase hemoglobin levels in order to
      improve preoperative anemia, reduce transfusions and lower postoperative complications in
      anemic patients undergoing heart surgery. Secondly, findings will be used to design a large
      randomized controlled trial (RCT). The RCT will establish a protocol to actively manage
      anemia before surgery, thus reducing transfusions during surgery and improving recovery
      afterwards. It will also help identify valuable information regarding what needs to be done
      for timely completion of the planned RCT.

      EPO is a medication approved by the Food and Drug Administration (FDA) used to treat anemia
      in patients with certain conditions in order to reduce blood transfusions. And although
      approved for use during surgery, it has not been FDA approved for use in cardiac (heart) or
      vascular (blood vessels, including veins and arteries) surgery. Common side effects include
      nausea, vomiting, itching, headache, injection site pain, chills, deep vein thrombosis (blood
      clot), cough, and changes in blood pressure (BP). Feraheme is an iron replacement product
      approved for the treatment of low iron anemia in adult patients. It may cause serious
      allergic reactions, including anaphylaxis (severe, whole body allergic reaction), as well as
      low BP and excessive iron storage.

      Patients meeting all eligibility requirements that consent to participate will be randomized
      into the study. Randomization is being placed by chance (like a flip of a coin) into one of
      two study groups, the treatment group or the control group. There is an equal chance of being
      placed into either group, which will be done by a computer.

        1. The Treatment Group will receive a 300 unit (U) per kilogram (kg) injection of EPO and a
           510 milligram (mg) IV infusion of Feraheme 7-28 days before the day of surgery. And
           again 1-7 days before the day of surgery, a second dose of both of these medications
           will be given. The third dose, of EPO only, will be administered 2 days after surgery.
           Before initiating a dose or giving a subsequent dose, laboratory parameters will be
           measured to assess the hemoglobin level and response to the medication. If blood values
           increase too rapidly or are too high, the meds will not be started or, if already dosed,
           they will not be given again.

        2. The Control Group will receive no preoperative intervention for anemia unless lab
           results show iron deficiency anemia. The control group will be screened for the presence
           of iron deficiency anemia by evaluating blood laboratory values drawn during the
           baseline or preoperative visit. If lab results indicate iron deficiency anemia,
           over-the-counter oral iron will be recommended, to take until the day of surgery. In
           doing so, patients may benefit by potentially reducing the need for blood transfusions.

      Data will be collected from all participants from the preoperative visits throughout the
      admission, including lab results, medications, vital signs, information about the procedure,
      transfusions, and any problems or adverse events.
Anemia and transfusion are independent predictors of morbidity and mortality in the cardiac
      surgical patient population. Even so, active preoperative anemia management is not currently
      the standard of care at our institution. Cost associated with erythrocyte transfusions at
      University of Texas Southwestern (UTSW) University Hospitals exceeds twenty million dollars
      annually, not including costs associated with treatment of known complications of red cell
      transfusions (renal insufficiency, respiratory failure, infection and prolonged length of
      stay, etc). Fifty percent of our cardiac surgical population suffer from preoperative anemia
      and 79% of these patients will receive one or more red blood cell (RBC) transfusions. In
      contrast, the incidence of RBC transfusion was only 35% in those without preoperative anemia
      in the calendar year 2011-12.

      The mechanism of injury in patients with preoperative anemia is either the duration/intensity
      of the anemia exposure and resultant organ ischemia, or the harmful effects of erythrocyte
      transfusion(s) itself. Active preoperative anemia management is a strategy that attempts to
      minimize both of these events, and in doing so, exert an additive or possibly synergistic
      effect on improving clinical outcomes. A randomized controlled trial utilizing a standardized
      transfusion strategy is a necessary step in determining if increases in preoperative
      hemoglobin lead to improved outcomes. A pilot, feasibility study is the first essential step
      in insuring the adequacy of future trials designed to answer this important question.

      The APART study is being conducted to test the safety and efficacy of using a short-course
      (1-4 weeks) of EPO plus Feraheme to increase erythrocyte mass. The findings will be used to
      guide the design of a randomized, controlled trial (RCT) that examines the effects of active
      preoperative anemia management on erythrocyte transfusion and clinical outcomes. The RCT will
      test the hypothesis that a short-course (1-4 weeks) of EPO plus Feraheme is superior to the
      standard of care (SOC) at reducing transfusion and improving outcomes in anemic patients
      scheduled for cardiac surgery. Means and standard deviations derived from pilot data on
      changes in hemoglobin levels, reticulocyte counts and differences in erythrocyte transfusions
      and clinical outcomes will be analyzed for possible use in sample size calculations for the
      larger RCT. This pilot will also provide information in determining logistics for timely
      completion of the RCT, and will also address data collection, data management, adherence to
      the study protocol, transfusion and surveillance strategies and classification of clinical
      outcomes and adverse events.

      Pilot Study Specific Aims Include:

        1. To determine the proportion of patients who fulfill all the eligibility criteria for the
           study and agree to be part of a randomized trial of short-course EPO plus supplemental
           Feraheme (up to 3 doses given over a 1-4 week interval prior to surgery) vs. standard of
           care management in patients scheduled for coronary bypass grafting (CABG), valve
           surgery, or CABG/valve surgery.

        2. To determine the adherence of patients and health care team to the procedures included
           in the study protocol (scheduled appointments, surveillance and transfusion strategies).

        3. To determine the increase in hemoglobin levels and reticulocyte counts following a
           short-course of EPO plus supplemental Feraheme over a 1-4 week interval prior to the
           date of surgery vs. standard of care management in patients scheduled for CABG, valve,
           or CABG/valve surgery.

        4. To assess differences in the proportion of patients receiving erythrocyte transfusions
           and number of blood products utilized (RBC, platelets and plasma) in the peri- and
           post-operative periods for those receiving a short-course of EPO plus supplemental
           Feraheme vs. standard of care management in patients scheduled for CABG, valve or
           CABG/valve surgery.

        5. To determine the frequency and intensity of pre-defined clinical outcomes (mortality,
           major cardiac, renal, neurological events [associated with anemia] and infection) in the
           peri- and post-operative periods for those receiving a short-course of EPO plus Feraheme
           vs. standard of care management in patients scheduled for CABG, valve, or CABG/valve
           surgery.

      Differences in hemoglobin levels and reticulocyte counts from baseline to the day of surgery
      and postop day (POD) 5, proportion of patients receiving transfusions and number of blood
      products utilized and the pre-defined clinical events will be assessed between the two
      groups. Each patient will be enrolled in the study up to 28 days before the day of surgery
      and for up to 30 days following the day of surgery. This pilot, feasibility study will enroll
      50 subjects (25 per group). Both groups will have detailed clinical data and biological
      specimens collected.

      Visits and Procedures:

        -  Screening: Patients undergoing cardiac surgery (CABG, valve, CABG/valve) with anemia
           will be identified in advance of their operations. Basic features of patient medical and
           surgical histories (i.e. age, gender, type of surgery) will be screened. If eligible for
           the study based on the inclusion/exclusion criteria, they will be consented into the
           study.

        -  Baseline Visit: Data on demographics, lab results, vital signs, medical history, current
           medications, height/weight will be reviewed and recorded. Randomization by computer will
           be done and the patient will receive the 1st dose of study drugs, as assigned, then
           monitored for any serious reactions (chest pain, dyspnea, seizures, severe headache,
           fever, nausea, vomiting, diarrhea, increase in BP). Control group patients with evidence
           of iron-deficiency by laboratory criteria will be advised to initiate supplementation
           with a non-prescription, over-the-counter oral iron preparation (ferrous sulfate 325 mg,
           three times a day is commonly used) to be taken until the planned surgical operation.

        -  Pre-op Visit: Patients will receive the 2nd dose of study drugs as assigned. Vital signs
           (heart rate, BP, oxygen saturation, temperature) will be recorded before and after drug
           administration, then monitored for any serious adverse events; SOC lab results;
           reticulocyte count, troponin, creatine kinase-myocardial band (CK-MB) samples will be
           collected.

        -  Day of Surgery: Patient vital signs (BP, electrocardiogram [EKG], etc) will be monitored
           as part of standard of care. Reticulocyte count, iron panel (includes transferrin,
           ferritin, total iron binding capacity, iron level) samples will be collected. SOC lab
           results, record of transfusions, estimated blood loss, adverse events will be
           monitored/recorded.

        -  POD 2: Troponin, CK-MB, Rotem (Rotational thromboelastometry) samples will be collected.
           Patients will receive study drug, as assigned, then monitored for serious events.

        -  POD 1-7: Vital signs (BP, EKG, etc) will be monitored; SOC lab results, record of
           transfusions, and adverse events will be monitored/recorded. Estimated blood loss will
           be recorded on POD 1 and 2 only.

        -  Other lab to be collected: POD 1 - reticulocyte count, iron panel, troponin, CK-MB; POD
           2 - troponin, CK-MB, Rotem; POD 5 - reticulocyte count, iron panel, aspartate
           transaminase/alanine transaminase (AST/ALT); POD 7 - complete blood count (CBC),
           reticulocyte count, creatinine; POD 14 or discharge (whichever comes first) - CBC,
           creatinine.

      Transfusion Strategy: Erythrocyte transfusion is permitted during cardiopulmonary bypass,
      during surgery and afterwards per protocol, when criteria is met. Red cell transfusions
      should be given one unit at a time with measurement of the pre- and post-transfusion
      hemoglobin levels along with physiologic parameters used to assess adequacy of organ
      perfusion. A consensus for transfusion thresholds was established among anesthesiologists,
      perfusionists and surgeons in our practice. The transfusion thresholds implemented in this
      protocol reflects our current "standard of care;" a threshold at which clinicians generally
      believe the benefits of erythrocyte transfusion outweigh the risks. Adherence to the
      transfusion strategy will be recorded by the research nurse and protocol deviations will be
      discussed with the attending physician of record and a member of the clinical research team.
      However, research staff will not order nor prohibit erythrocyte transfusions. This will be
      left to the discretion of the treating physician(s) if he/she deems it clinically necessary.
      Following randomization, patient's charts will be clearly labeled to indicate participation
      in the study protocol.

      Surveillance Strategy: The decision to initiate and continue administering doses of EPO is
      based on evidence accrued from randomized controlled trials and clinical practice guidelines
      provided by multiple sub-specialty and international societies. Substantial heterogeneity
      exists in factors that could be included in a surveillance strategy to minimize the risk of a
      thrombotic event in this setting; with no one strategy proven to be superior. The
      surveillance strategy included in this protocol derives from, what we believe to be, the most
      current safety analyses of perioperative EPO use reflected in the literature. Implementing
      such surveillance methods are intended to minimize the possibly rare but potentially
      life-threatening adverse events. Risk factors considered in our surveillance strategy
      include: evidence of unstable angina or myocardial infarction, recent thrombotic event,
      hemoglobin levels associated with a higher risk of a myocardial event, excessive
      thrombocytosis or laboratory evidence of a hypercoagulable postoperative state. EPO dosing
      will be stratified based on patient risk (degree of perioperative anemia), type of procedure
      (CABG vs. valve) and laboratory data (hgb, Rotem). All doses will be given per surveillance
      guidelines.

      Primary End Point: The primary objective is to assess the enrollment rate and adherence to
      the dosing protocol and surveillance strategies. We define successful adherence as adherence
      to dosing in more than 90% of patients for more than 90% of the doses deemed appropriate by
      the surveillance strategy. Secondary outcomes will include changes in hemoglobin levels and
      reticulocyte counts within the two groups from baseline to the day of surgery and POD 5,
      number of RBC units transfused, frequency of pre-specified clinical outcomes and incidence of
      adverse events in each of the study groups. Data from this pilot study will be used for the
      power analysis and design of the larger RCT.

      Adverse events (AEs) are events that involve physiological, social, or psychological harm to
      subjects or risks of harm to additional subjects or others. AEs include expected and
      unexpected harmful effects, and unexpected risks of an interaction or an intervention. AEs
      may be caused by: the test article or test procedure, other aspects of the interaction or
      intervention, the subject's underlying condition, or the subject's concurrent standard
      treatment. AEs may be definitely related, probably related, possibly related, unlikely to be
      related, or definitely not related to the research. We will report all adverse events and
      other reportable incidences to the Institutional Review Board (IRB) per reporting guidelines.
      Any adverse event will be documented of that event including a description, subject number,
      date, outcome, and follow-up.

      The primary safety endpoints of the study are the incidence of adverse events associated with
      the use of the study medications. These include: hypersensitivity (e.g. pruritis, rash, and
      urticaria), hypertension, hypotension, bleeding, nausea, vomiting, injection site pain, deep
      venous thrombosis or other thrombotic complications. Surveillance for these adverse events
      will be conducted by direct observation (during drug administration), daily bedside visits by
      the research nurse for the first 7 postoperative days, review of the patients medical record
      and listing any of these complications in the Society of Thoracic Surgery (STS) database. The
      definition of a stroke, myocardial infarction (MI), mesenteric artery occlusion or peripheral
      vascular event will be based on STS criteria. Any event resulting in death from time of
      initial drug administration to hospital discharge will be recorded.

      The Principal Investigator, along with the Secondary Investigators, will be responsible for
      the monitoring, reviewing and analyses of study data. This will be done quarterly unless an
      issue requires immediate attention or if a recurrent pattern develops into a need for a more
      frequent review. An interim analysis will be done at 50% enrollment by the principal and
      secondary investigators.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: # of Participants Who Adhered to the Study Protocol
time frame: Preoperative 1st dose through Postoperative Day (POD) 2.
description: Successful adherence is defined as adhering to dosing in ≥90% of patients for ≥90% of the doses deemed appropriate by the surveillance strategy.
measure: Change From Baseline Hemoglobin Level Assessed at Different Time Points Within the 2 Arms.
time frame: Change from Baseline hemoglobin level to day of surgery (DOS), to POD 5.
measure: Change From Baseline Reticulocyte Count Assessed at Different Time Points Within the 2 Arms.
time frame: Change from Baseline reticulocyte count to DOS, to POD 5.
measure: Number of Blood Products Utilized Per Patient Receiving Erythrocyte Transfusions.
time frame: Preoperative 1st dose through 30 days following surgery.
description: Number of blood products utilized per patient receiving erythrocyte transfusions, including red blood cells, platelets and plasma.
measure: Incidence of Pre-defined Clinical Events in Each of the Study Arms
time frame: Preoperative 1st dose through 30 days following surgery.
description: Incidence of mortality, major cardiac, renal, neurological events (associated with anemia) and infection. These events will include myocardial infarction, prolonged low-output state, encephalopathy, duration of mechanical ventilation, renal insufficiency,mortality and dialysis dependence at 30 days.
arm group label: EPO and Feraheme
arm group type: Active Comparator
description: Patients in the treatment group will receive a subcutaneous injection of EPO 300U/kg at the Baseline visit, the Preoperative visit and on POD 2; and an infusion of Feraheme 510mg at the Baseline visit and the Preoperative visit.
arm group label: Control
arm group type: No Intervention
description: The control group will receive no preoperative intervention for anemia. The exception being iron deficiency anemia found during baseline. If laboratory values indicate iron deficiency, oral iron will be recommended to take until surgery.
intervention type: Drug
intervention name: EPO
description: The treatment group will receive up to three doses of EPO 300U/kg. The first dose of study medication will be administered up to 28 days before the day of surgery and the second will be administered 1-7 days before the day of surgery. These first two doses will be given at least 7 days apart. A third dose may be administered two days following surgery. All 3 doses will be administered per surveillance strategy guidelines.
arm group label: EPO and Feraheme
other name: erythropoietin
intervention type: Drug
intervention name: Feraheme
description: Supplementation with Feraheme, 510mg delivered as an IV infusion, will be given following the first two preoperative doses of EPO.
arm group label: EPO and Feraheme
other name: IV iron
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Philip E. Greilich, MD
role: Principal Investigator
affiliation: University of Texas Southwestern Medical Center
facility: 
facility: 
country: United States
citation: Society of Thoracic Surgeons Blood Conservation Guideline Task Force; Ferraris VA, Ferraris SP, Saha SP, Hessel EA 2nd, Haan CK, Royston BD, Bridges CR, Higgins RS, Despotis G, Brown JR; Society of Cardiovascular Anesthesiologists Special Task Force on Blood Transfusion; Spiess BD, Shore-Lesserson L, Stafford-Smith M, Mazer CD, Bennett-Guerrero E, Hill SE, Body S. Perioperative blood transfusion and blood conservation in cardiac surgery: the Society of Thoracic Surgeons and The Society of Cardiovascular Anesthesiologists clinical practice guideline. Ann Thorac Surg. 2007 May;83(5 Suppl):S27-86. doi: 10.1016/j.athoracsur.2007.02.099.
PMID: 17462454
responsible party type: Principal Investigator
investigator affiliation: University of Texas Southwestern Medical Center
investigator full name: Philip Greilich
investigator title: MD, FASE, Professor and Holder S.T. "Buddy" Harris Distinguished Chair in Cardiac Anesthesiology, Quality Officer, University of Texas Healthcare System
mesh term: Cardiovascular Diseases
mesh term: Anemia
mesh term: Ferrosoferric Oxide
sharing ipd: Undecided
ipd description: All data and information collected during this study will be considered confidential and remains the sole property of UTSW Medical Center. Data may be shared with AMAG Pharmaceuticals, Inc., prior to any publications. All data used in the analysis and summary of this study will be anonymous, and without reference to specific subject names.
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: Early termination leading to small numbers of subjects analyzed.
point of contact: 