<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/NCT02191839</url>
  </required_header>
  <id_info>
    <org_study_id>SOR 133-13 ctil</org_study_id>
    <nct_id>NCT02191839</nct_id>
  </id_info>
  <brief_title>Single Dose Administration of Alpha-1 Anti-Trypsin for the Amelioration of Organ Injury in Patients Undergoing Cardiac Surgery</brief_title>
  <official_title>Single Dose Administration of Alpha-1 Anti-Trypsin for the Amelioration of Organ Injury and Post Operative Bleeding in Patients Undergoing Cardiac Surgery With Cardiopulmonary Bypass: Double-blind, Placebo-controlled Pilot Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Soroka University Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Soroka University Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Protocol Summary STUDY DESIGN A pilot, prospective, double blind, randomized, placebo&#xD;
      controlled study.&#xD;
&#xD;
      STUDY POPULATION Patients assigned to elective CABG with cardiopulmonary bypass (CPB) at the&#xD;
      Department of Cardiothoracic Surgery, Soroka University Medical Center.&#xD;
&#xD;
      OBJECTIVE To evaluate anti-inflammatory effects, effects on organ function preservation, and&#xD;
      postoperative blood loss reduction following AAT-1 administration in patients undergoing CABG&#xD;
      with CPB.&#xD;
&#xD;
      PRIMARY ENDPOINT Postoperative organ function preservation and blood loss following&#xD;
      preoperative single-dose AAT-1 administration.&#xD;
&#xD;
      SAMPLE SIZE CONSIDERATIONS A cohort of 20 patients will be recruited. Patients will be&#xD;
      randomized to receive either AAT-1 or placebo prior to surgery. Whereas this is a proof of&#xD;
      concept pilot study, statistical significance is not the primary objective.&#xD;
&#xD;
      INCLUSION CRITERIA 1. The study population will comprise patients between 40 and 70 years of&#xD;
      age, irrespective of gender, at low or intermediate operative risk (calculated Logistic&#xD;
      Euroscore stratification of 5% or less), assigned to elective CABG with CPB. Recruitment&#xD;
      depending on patients informed consent.&#xD;
&#xD;
      EXCLUSION CRITERIA Co-existing conditions including:&#xD;
&#xD;
        1. Coagulation abnormalities&#xD;
&#xD;
        2. Severe pulmonary disease defined by blood oxygen saturation of 90% or less or FEV1 of&#xD;
           less than 60% of predicted.&#xD;
&#xD;
        3. Renal dysfunction defined be serum creatinine levels higher or equal to 1.8 mg%,&#xD;
&#xD;
        4. Abnormal liver function tests&#xD;
&#xD;
        5. Uncontrolled diabetes mellitus,&#xD;
&#xD;
        6. Severe peripheral vascular disease&#xD;
&#xD;
        7. Prior cerebrovascular neurological event.&#xD;
&#xD;
        8. Abnormal left or right ventricular function.&#xD;
&#xD;
        9. Treatment with warfarin or thienopyridine class of anti platelet agents.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      3 Background The use of cardiopulmonary bypass (CPB) during cardiac surgery elicits&#xD;
      generalized non-specific systemic inflammatory response syndrome (SIRS) and subsequent&#xD;
      activation of the cytokine, complement, and coagulation-fibrinolytic cascades (1). In&#xD;
      approximately 11% of the patients SIRS may deteriorate to severe multi-organ failure (MOF)&#xD;
      resulting in mortality rate of 40-98%.&#xD;
&#xD;
      Inflammatory modulation by intraoperative administration of anti-inflammatory substances has&#xD;
      been advocated to attenuate the effects of SIRS. Attempts have subsequently focused on&#xD;
      aprotinin which inhibits proteases that are key mediators in the complement, coagulation, and&#xD;
      fibrinolytic system. Related anti-inflammatory properties of aprotinin include the inhibition&#xD;
      of platelets, neutrophils and kallikrein activation. Reduction in blood loss and reduced need&#xD;
      for allogenic blood transfusions have been proposed as additional mechanisms by which&#xD;
      aprotinin limits the inflammatory response (2). The use of aprotinin during cardiac surgery,&#xD;
      however, was discontinued following alarming results in terms of higher rate of bypass graft&#xD;
      occlusion and overall inferior postoperative outcome.&#xD;
&#xD;
      AAT-1 mechanism of action:&#xD;
&#xD;
      Similar to aprotinin, α1-Antitrypsin (AAT) is a 52-kDa circulating serine protease inhibitor&#xD;
      classified as a SERPIN protein. Besides its ability to inhibit serine proteases, accumulating&#xD;
      data suggest that AAT-1 possesses independent anti-inflammatory and tissue-protective effects&#xD;
      (3). AAT-1 modifies dendritic cell maturation and promotes regulatory T-cell differentiation,&#xD;
      induces interleukin (IL)-1 receptor antagonist and IL-10 release, protects various cell types&#xD;
      from cell death, inhibits caspases-1 and -3 activities and inhibits IL-1 production and&#xD;
      activity (4). Contradictory to classic immunosuppressants, AAT-1 allows undeterred isolated&#xD;
      T-lymphocyte responses (5).These effects have been repeatedly corroborated.&#xD;
&#xD;
      Unlike aprotinin, AAT-1 is produced from human plasma, and does not have strong pro coagulant&#xD;
      characteristics.&#xD;
&#xD;
      AAT-1 in different clinical settings:&#xD;
&#xD;
      Circulating AAT-1 levels increase by 4-fold during acute-phase response (3). Patients with&#xD;
      low circulating levels of AAT-1 are at increase risk for lung, liver and pancreatic&#xD;
      destructive diseases, particularly emphysema (3). Preclinical and clinical studies have shown&#xD;
      that AAT-1 therapy for non-deficient individuals is safe, and may modify disease progression&#xD;
      in type 1 and type 2 diabetes, acute myocardial infarction, rheumatoid arthritis,&#xD;
      inflammatory bowel disease, cystic fibrosis, transplant rejection, graft versus host disease&#xD;
      and multiple sclerosis (6-17, 32,33,37,38) . AAT-1 treatment has subsequently advanced from&#xD;
      replacement therapy to potential treatment for a broad spectrum of inflammatory and&#xD;
      immune-mediated diseases. AAT-1 also appears to be antibacterial and an inhibitor of viral&#xD;
      infections, such as influenza and human immunodeficiency virus (HIV) (18).&#xD;
&#xD;
      Human pharmacokinetic data:&#xD;
&#xD;
      In patients with AAT-1 deficiency, intravenous administration of AAT-1 in a dose of 60 mg per&#xD;
      kg body weight maintain plasma levels resembling acute phase response immediately after&#xD;
      administration, and retain an appropriate level of serum AAT above the protective threshold&#xD;
      (50 mg/dl) a week afterwards (39).&#xD;
&#xD;
      Rational of AAT-1 dosage:&#xD;
&#xD;
      Based on previous studies and clinical practice, the administration of multiple intravenous&#xD;
      dosage of 60 mg per kg body weight of AAT-1 is safe and is associated with low incidence of&#xD;
      benign side-effects.&#xD;
&#xD;
      Derived from pharmacokinetic studies (39), AAT-1 plasma levels immediately following the&#xD;
      administration of this external dosage resembles acute phase response. A 30% reduction in&#xD;
      AAT-1 plasma levels is anticipated with gradual return to preoperative levels after&#xD;
      termination of CPB (40).&#xD;
&#xD;
      Risk/ benefit of the study:&#xD;
&#xD;
      The role of AAT-1 in mitigating inflammatory response has been established. CPB is a potent&#xD;
      stimulator of inflammatory cascades and associated with bleeding diatheses, coagulation&#xD;
      abnormalities, potentially leading to organ dysfunction. To date, the administration of AAT-1&#xD;
      in patients undergoing cardiac surgery with CPB has not been explored. It may be postulated&#xD;
      that inherent AAT-1 effects may offset deleterious CPB effects. This may clinically result in&#xD;
      improved preservation of organ function, reduced postoperative bleeding and reduced hospital&#xD;
      stay. The benefits of other protease inhibitors in corresponding settings have been recently&#xD;
      demonstrated (41-43).&#xD;
&#xD;
      As mentioned above, administration of AAT-1 in various clinical settings is considered safe&#xD;
      with low rate of side effects (see section 6.1 - potential risks).&#xD;
&#xD;
      4 Methods 4.1 Primary Objective&#xD;
&#xD;
        1. To evaluate the efficacy and safety of preoperative AAT-1 administration in patients&#xD;
           undergoing CABG with CPB.&#xD;
&#xD;
        2. Postoperative blood loss and organ function will be assessed.&#xD;
&#xD;
      To date, no data exists with regard to AAT-1 effects in the settings of CPB. The primary&#xD;
      goals of this study are to evaluate anti-inflammatory effects, organ function preservation&#xD;
      (1-2) and postoperative blood loss reduction following AAT-1 administration in patients&#xD;
      undergoing cardiac surgery with CPB.&#xD;
&#xD;
      4.2 Determination of Study Eligibility 4.2.1 Inclusion Criteria&#xD;
&#xD;
        1. Male/female patients 40-70 years of age.&#xD;
&#xD;
        2. Candidates for isolated CABG with CPB.&#xD;
&#xD;
        3. Calculated logistic Euroscore risk stratification of 5% or less.&#xD;
&#xD;
        4. Signed patient's written informed consent.&#xD;
&#xD;
      4.2.2 Exclusion Criteria&#xD;
&#xD;
      Co-existing conditions including:&#xD;
&#xD;
      10. Coagulation abnormalities 11. Severe pulmonary disease defined by blood oxygen saturation&#xD;
      of 90% or less or FEV1 of less than 60% of predicted.&#xD;
&#xD;
      12. Renal dysfunction defined be serum creatinine levels higher or equal to 1.8 mg%, 13.&#xD;
      Abnormal liver function tests 14. Uncontrolled diabetes mellitus, 15. Severe peripheral&#xD;
      vascular disease 16. Prior cerebrovascular neurological event. 17. Abnormal left or right&#xD;
      ventricular function. 18. Treatment with warfarin or thienopyridine class of anti-platelet&#xD;
      agents. 4.2.3 Withdrawal Criteria Patients will preserve the right to withdraw from the study&#xD;
      at any time during treatment without prejudice.&#xD;
&#xD;
      If medically indicated, the principal investigator or the surgeon poses the right to&#xD;
      discontinue patient enrollment at any stage of the study.&#xD;
&#xD;
      Discontinuation (failure to complete the study) will be documented. The reason for&#xD;
      discontinuation will be recorded.&#xD;
&#xD;
      Potential causes that may lead to discontinuation include:&#xD;
&#xD;
        -  Adverse event(s)&#xD;
&#xD;
        -  Protocol violation&#xD;
&#xD;
        -  Patient withdrew consent&#xD;
&#xD;
        -  Administrative problems 4.3 Enrollment Prior to participation in this study, the&#xD;
           Investigator will obtain written appropriate approval for the protocol and the informed&#xD;
           consent form the Ethics Committee (EC) and other local regulatory organizations. The&#xD;
           approved consent form will clearly reflect the EC approval date.&#xD;
&#xD;
      Failure to obtain a signed and hand dated informed consent prior to the procedure constitutes&#xD;
      a protocol violation, and subsequently reportable to the EC.&#xD;
&#xD;
      4.4 Subject Screening Patients that have been already scheduled for isolated CABG operation&#xD;
      will be addressed by a member of the research team during the preoperative waiting period&#xD;
      (either in the Department of Cardiothoracic Surgery, the Department of Cardiology or the&#xD;
      Department of Internal Medicine). The goal of the study, procedure and incentive will be&#xD;
      explained by a research staff member to each potential participant. Consenting subjects will&#xD;
      be asked to provide written consent.&#xD;
&#xD;
      4.4.1 Randomization The study participants will be randomized to receive either single dose&#xD;
      AAT-1 60 mg per kg or placebo.&#xD;
&#xD;
      4.4.2 Trial medication administration: Preparation and dosing of AAT-1 will be performed by&#xD;
      an unblinded pharmacist. The medication will be diluted just prior to administration. The&#xD;
      placebo solution will comprise human albumin that resembles the color and consistency of&#xD;
      AAT-1 solution. The medication will be given 3-5 hours prior to surgery (skin incision).&#xD;
      Administration rate of the drug will not exceed 0.04 ml per kg per minute (approximately&#xD;
      60-80 minutes). Vital signs including blood pressure, pulse rate and body temperature will be&#xD;
      correspondingly monitored.&#xD;
&#xD;
      The patients, research staff, laboratory personnel and data analysts will remain blinded to&#xD;
      the identity of the treatment from the time of randomization and until database lock. Data&#xD;
      unblinding will commence in the case of patient's emergency.&#xD;
&#xD;
      A randomization list will be produced by the pharmacist, however, will be secured and&#xD;
      confidential until time of unblinding.&#xD;
&#xD;
      4.4.3 Surgical technique Consistent with our routine policy, fentanyl citrate (20-50mcg/kg),&#xD;
      midazolam (2-3mg) and isoflurane (0.5-2%) will be used for induction and maintenance of&#xD;
      anesthesia.&#xD;
&#xD;
      Standard median sternotomy will be followed by procurement of the conduits. Heparin loading&#xD;
      dose will be administered to achieve a kaolin activated coagulation time (ACT). Ascending&#xD;
      aorta - right atrial cannulation will be performed to institute CPB and ACT will be monitored&#xD;
      at 480 seconds or more. Standard centrifugal pump and a membrane oxygenator will be used for&#xD;
      extracorporeal circulation (cardiopulmonary bypass). Compatible with the standard technique,&#xD;
      systemic active cooling will be avoided and patients core temperature will remain range&#xD;
      between 32 and 37˚C. Distal anastomoses will be performed during single aortic cross-clamp&#xD;
      and blood cardioplegic arrest. Proximal anastomoses will be performed during aortic&#xD;
      cross-clamp. Cold (10˚C) blood cardioplegic solution will be delivered in a 4:1 ratio.&#xD;
      Cardioplegia will be delivered antegrade via the aortic root with or without additional&#xD;
      retrograde administration via the coronary sinus. After cardioplegic induction (10 ml / Kg),&#xD;
      intermittent doses (300 - 500 ml) will be administered following completion of each distal&#xD;
      anastomosis. Heparin will be reversed using protamine sulphate in a ratio of 1:1 after&#xD;
      weaning from CPB.&#xD;
&#xD;
      4.4.4 Data collection Preoperative data: Demographic, morphological and clinical descriptors&#xD;
      including age, gender, body mass index (BMI), body surface area (BSA) co-morbidity, Euroscore&#xD;
      risk-stratification, medication, etc. will be recorded. Preoperative laboratory analysis will&#xD;
      include complete blood count, coagulation profile, serum creatinine levels and creatinine&#xD;
      clearance, liver function test and arterial blood gases test and serology for HIV,HCV,HBC.&#xD;
      Compatible with our routine policy, all patients will undergo preoperative echocardiography,&#xD;
      coronary angiography, chest x-ray, lung function tests (spirometry) and carotid artery duplex&#xD;
      study.&#xD;
&#xD;
      Study participants will be assigned to undergo preoperative brain MRI; subjected to the&#xD;
      protocol described below.&#xD;
&#xD;
      Intraoperative: The type of surgery will be classified. The following data will be recorded:&#xD;
      heparin dose given prior to bypass initiation; activated clotting time (ACT) counts during&#xD;
      the operation (prior, during and after CPB); operative time, cross-clamp time and CPB time;&#xD;
      number of trials to wean from CPB, type of inotropes and dosage used during weaning from CPB;&#xD;
      blood products utilization during surgery. Allergic reactions or adverse events observed by&#xD;
      the surgeon or anesthesiologist will be documented. The individual surgeon's impression&#xD;
      regarding bleeding tendency will be recorded.&#xD;
&#xD;
      Postoperative organ function and blood loss evaluation:&#xD;
&#xD;
      The occurrence and magnitude of systemic inflammatory response and organ dysfunction will be&#xD;
      recorded and quantified by laboratory markers. Related laboratory markers will be monitored&#xD;
      on a daily basis during the recovery period (in the intensive care unit and at the ward). The&#xD;
      following organs and corresponding markers will be monitored:&#xD;
&#xD;
      Pulmonary function: Pulmonary function will be evaluated by measured overall mechanical&#xD;
      ventilation time, peak inspiratory pressures (PIP), plateau pressures, physiologic dead space&#xD;
      and static and dynamic lung compliance. Bronchoalveolar lavage (BAL) will be performed 3&#xD;
      hours after operation (while the patient is anesthesized and intubated) and extracted fluid&#xD;
      will be analyzed for inflammatory markers. A-a DO2 calculation [AaDO2 = (713 x FiO2) - (pCO2&#xD;
      / 0.8) - (paO2)] will be measured daily.&#xD;
&#xD;
      Complete pulmonary function test will be performed before and 4 days after the operation.&#xD;
      Chest radiographs will be evaluated and quantified by an independent radiologist for the&#xD;
      occurrence of atelectasis, pulmonary edema, or pleural changes.&#xD;
&#xD;
      Renal function: Daily measurements of urine output, serum creatinine levels, creatinine&#xD;
      clearance and urinary albumin levels. Acute kidney injury (AKI) markers will be sampled in&#xD;
      the ICU.&#xD;
&#xD;
      Brain injury assessment: The degree of insult to the brain will be measured by plasma S-100&#xD;
      proteinlevels. Assessment of damage to the blood-brain barrier (BBB) will be performed by&#xD;
      magnetical resonance imaging (MRI) modality (see technique protocol below).&#xD;
&#xD;
      Hepatic function: Daily measurements of serum hepatic enzymes levels. Cardiac function:&#xD;
      Monitoring of cardiac enzymes levels; need and magnitude of required inotrope treatment;&#xD;
      occurrence of low cardiac output syndrome (defined as systolic blood pressure of 90 mmHg or&#xD;
      less coupled with central venous pressure (CVP) of 15 mmHg or more) and incidence of cardiac&#xD;
      arrhythmias. Transthoracic echocardiography examination will be performed on postoperative&#xD;
      day 5 and assessed by an independent cardiologist.&#xD;
&#xD;
      Blood loss: Operative and postoperative blood loss will be monitored as well as daily&#xD;
      hemoglobin levels. Daily platelet counts and thromboelastograms will be performed. The&#xD;
      distribution of blood products and total administered will be recorded daily. Postoperative&#xD;
      CRP levels will be evaluated daily.&#xD;
&#xD;
      Blood sampling and laboratory analysis methods for cytokine levels:&#xD;
&#xD;
      Ten mL whole blood venous EDTA samples will be collected from radial artery catheter at five&#xD;
      specified occasions: before induction of anaesthesia, 30 minutes after aortic cross-clamp&#xD;
      positioning and 3, 6, and 9 hours after aortic cross clamp positioning. The blood samples&#xD;
      will be subsequently centrifuged at 4 °C for 15 min and the serum stored at -70 °C. Samples&#xD;
      will be analyzed for the following markers: Polimorphonuclear Neutrophil Elastase (PMNE),&#xD;
      Interleukin-1α (IL-1α), Interleukin-1ß (IL-1ß), Interleukin-2 (IL-2), Interleukin-4 (IL-4),&#xD;
      Interleukin-6 (IL-6), Interleukin-8 (IL-8), Interleukin-10 (IL-10), Interferon-γ (IFN-γ),&#xD;
      Tumor Necrosis Factor-α (TNF-α), Vascular Endothelial Growth Factor (VEGF), Monocyte&#xD;
      Chemoattractant Protein-1 (MCP-1), and Endothelial Growth Factor (EGF).&#xD;
&#xD;
      Daily blood samples will be collected postoperatively for platelet count, renal function,&#xD;
      liver function, CRP levels S-100 protein and troponin.&#xD;
&#xD;
      Early postoperative adverse events will be documented. These include 30-day mortality, new&#xD;
      neurological events, myocardial infarction, renal dysfunction, need for re-exploration for&#xD;
      bleeding and deep sternal wound infection.&#xD;
&#xD;
      Blood-Brain Barrier (BBB) assessment by MRI The imaging modality used for BBB assessment will&#xD;
      be MRI scanner (Philips 3T or General Electric 1.5T). The examination format will include 24&#xD;
      cm FOV, 35 contiguous interleaved slices, 3.5-4 mm thick and co-localized across series.&#xD;
      Trace-weighted DWI images will be obtained at b=1000 from a 13-15 direction DTI sequence with&#xD;
      an in-plane resolution of 2.5×2.5mm and TR/TE=10s/58ms at 3T or TR/TE=10s/72ms at 1.5T.&#xD;
      T2-FLAIR images will be obtained with an in-plane resolution of 0.94×0.94 mm, TR/TE=9000/120&#xD;
      ms and TI=2600 ms at 3T or TR/TE=9000/140 ms and TI=2200 ms at 1.5T. (25)&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date>July 2014</start_date>
  <completion_date type="Anticipated">July 2015</completion_date>
  <primary_completion_date type="Anticipated">July 2015</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>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>post operative inflammatory response</measure>
    <time_frame>post operative day 1-5</time_frame>
    <description>1. The occurrence and magnitude of systemic inflammatory response and organ dysfunction will be recorded and quantified by laboratory markers. Related laboratory markers will be monitored on a daily basis during the recovery period (in the intensive care unit and at the ward).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Pulmonary function:</measure>
    <time_frame>post op day 1-5</time_frame>
    <description>Pulmonary function will be evaluated by measured overall mechanical ventilation time, peak inspiratory pressures (PIP), plateau pressures, physiologic dead space and static and dynamic lung compliance. Bronchoalveolar lavage (BAL) will be performed 3 hours after operation (while the patient is anesthetised and intubated) and extracted fluid will be analyzed for inflammatory markers. A-a DO2 calculation [AaDO2 = (713 x FiO2) - (pCO2 / 0.8) - (paO2)] will be measured daily.&#xD;
Complete pulmonary function test will be performed before and 4 days after the operation. Chest radiographs will be evaluated and quantified by an independent radiologist for the occurrence of atelectasis, pulmonary edema, or pleural changes.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Renal function:</measure>
    <time_frame>post op day 1-5</time_frame>
    <description>Daily measurements of urine output, serum creatinine levels, creatinine clearance and urinary albumin levels. Acute kidney injury (AKI) markers will be sampled in the ICU.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Brain injury assessment:</measure>
    <time_frame>post op day 1-5</time_frame>
    <description>The degree of insult to the brain will be measured by plasma S-100 proteinlevels. Assessment of damage to the blood-brain barrier (BBB) will be performed by magnetical resonance imaging (MRI) modality</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Hepatic function:</measure>
    <time_frame>post op day 1-5</time_frame>
    <description>Daily measurements of serum hepatic enzymes levels.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Cardiac function:</measure>
    <time_frame>post op day 1-5</time_frame>
    <description>Monitoring of cardiac enzymes levels; need and magnitude of required inotrope treatment; occurrence of low cardiac output syndrome (defined as systolic blood pressure of 90 mmHg or less coupled with central venous pressure (CVP) of 15 mmHg or more) and incidence of cardiac arrhythmias. Transthoracic echocardiography examination will be performed on postoperative day 5 and assessed by an independent cardiologist.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Blood loss:</measure>
    <time_frame>post op day 1-2</time_frame>
    <description>Operative and postoperative blood loss will be monitored as well as daily hemoglobin levels. Daily platelet counts and thromboelastograms will be performed. The distribution of blood products and total administered will be recorded daily. Postoperative CRP levels will be evaluated daily.</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">20</enrollment>
  <condition>Post Cardiac Surgery Systemic Inflammatory Response</condition>
  <arm_group>
    <arm_group_label>alpha 1 antitrypsin</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>patients receive 4 grams of IV alpha 1 antitrypsin preoperatively</description>
  </arm_group>
  <arm_group>
    <arm_group_label>placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>10 patients will randomely receive placebo</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Alpha 1-Antitrypsin</intervention_name>
    <arm_group_label>alpha 1 antitrypsin</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        1. The study population will comprise patients between 40 and 70 years of age, irrespective&#xD;
        of gender, at low or intermediate operative risk (calculated Logistic Euroscore&#xD;
        stratification of 5% or less), assigned to elective CABG with CPB. Recruitment depending on&#xD;
        patients informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Co-existing conditions including:&#xD;
&#xD;
          1. Coagulation abnormalities&#xD;
&#xD;
          2. Severe pulmonary disease defined by blood oxygen saturation of 90% or less or FEV1 of&#xD;
             less than 60% of predicted.&#xD;
&#xD;
          3. Renal dysfunction defined be serum creatinine levels higher or equal to 1.8 mg%,&#xD;
&#xD;
          4. Abnormal liver function tests&#xD;
&#xD;
          5. Uncontrolled diabetes mellitus,&#xD;
&#xD;
          6. Severe peripheral vascular disease&#xD;
&#xD;
          7. Prior cerebrovascular neurological event.&#xD;
&#xD;
          8. Abnormal left or right ventricular function.&#xD;
&#xD;
          9. Treatment with warfarin or thienopyridine class of anti platelet agents -&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>DAN ABRAHAMOV, DR</last_name>
    <role>Principal Investigator</role>
    <affiliation>Soroka University Medical Center</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>DAN ABRAHAMOV, DR</last_name>
    <phone>972504506205</phone>
    <email>danab3@clalit.org.il</email>
  </overall_contact>
  <verification_date>July 2014</verification_date>
  <study_first_submitted>July 7, 2014</study_first_submitted>
  <study_first_submitted_qc>July 15, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 16, 2014</study_first_posted>
  <last_update_submitted>July 15, 2014</last_update_submitted>
  <last_update_submitted_qc>July 15, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">July 16, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Soroka University Medical Center</investigator_affiliation>
    <investigator_full_name>Dan Abramov</investigator_full_name>
    <investigator_title>Dr</investigator_title>
  </responsible_party>
  <keyword>cardiac surgery</keyword>
  <keyword>alpha 1 antitrypsin</keyword>
  <keyword>inflammation</keyword>
  <keyword>post operative bleeding</keyword>
  <keyword>organ function</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Alpha 1-Antitrypsin Deficiency</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Alpha 1-Antitrypsin</mesh_term>
    <mesh_term>Protein C Inhibitor</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02191839
org study id: SOR 133-13 ctil
nct id: NCT02191839
lead sponsor: 
has dmc: Yes
Protocol Summary STUDY DESIGN A pilot, prospective, double blind, randomized, placebo
      controlled study.

      STUDY POPULATION Patients assigned to elective CABG with cardiopulmonary bypass (CPB) at the
      Department of Cardiothoracic Surgery, Soroka University Medical Center.

      OBJECTIVE To evaluate anti-inflammatory effects, effects on organ function preservation, and
      postoperative blood loss reduction following AAT-1 administration in patients undergoing CABG
      with CPB.

      PRIMARY ENDPOINT Postoperative organ function preservation and blood loss following
      preoperative single-dose AAT-1 administration.

      SAMPLE SIZE CONSIDERATIONS A cohort of 20 patients will be recruited. Patients will be
      randomized to receive either AAT-1 or placebo prior to surgery. Whereas this is a proof of
      concept pilot study, statistical significance is not the primary objective.

      INCLUSION CRITERIA 1. The study population will comprise patients between 40 and 70 years of
      age, irrespective of gender, at low or intermediate operative risk (calculated Logistic
      Euroscore stratification of 5% or less), assigned to elective CABG with CPB. Recruitment
      depending on patients informed consent.

      EXCLUSION CRITERIA Co-existing conditions including:

        1. Coagulation abnormalities

        2. Severe pulmonary disease defined by blood oxygen saturation of 90% or less or FEV1 of
           less than 60% of predicted.

        3. Renal dysfunction defined be serum creatinine levels higher or equal to 1.8 mg%,

        4. Abnormal liver function tests

        5. Uncontrolled diabetes mellitus,

        6. Severe peripheral vascular disease

        7. Prior cerebrovascular neurological event.

        8. Abnormal left or right ventricular function.

        9. Treatment with warfarin or thienopyridine class of anti platelet agents.
3 Background The use of cardiopulmonary bypass (CPB) during cardiac surgery elicits
      generalized non-specific systemic inflammatory response syndrome (SIRS) and subsequent
      activation of the cytokine, complement, and coagulation-fibrinolytic cascades (1). In
      approximately 11% of the patients SIRS may deteriorate to severe multi-organ failure (MOF)
      resulting in mortality rate of 40-98%.

      Inflammatory modulation by intraoperative administration of anti-inflammatory substances has
      been advocated to attenuate the effects of SIRS. Attempts have subsequently focused on
      aprotinin which inhibits proteases that are key mediators in the complement, coagulation, and
      fibrinolytic system. Related anti-inflammatory properties of aprotinin include the inhibition
      of platelets, neutrophils and kallikrein activation. Reduction in blood loss and reduced need
      for allogenic blood transfusions have been proposed as additional mechanisms by which
      aprotinin limits the inflammatory response (2). The use of aprotinin during cardiac surgery,
      however, was discontinued following alarming results in terms of higher rate of bypass graft
      occlusion and overall inferior postoperative outcome.

      AAT-1 mechanism of action:

      Similar to aprotinin, α1-Antitrypsin (AAT) is a 52-kDa circulating serine protease inhibitor
      classified as a SERPIN protein. Besides its ability to inhibit serine proteases, accumulating
      data suggest that AAT-1 possesses independent anti-inflammatory and tissue-protective effects
      (3). AAT-1 modifies dendritic cell maturation and promotes regulatory T-cell differentiation,
      induces interleukin (IL)-1 receptor antagonist and IL-10 release, protects various cell types
      from cell death, inhibits caspases-1 and -3 activities and inhibits IL-1 production and
      activity (4). Contradictory to classic immunosuppressants, AAT-1 allows undeterred isolated
      T-lymphocyte responses (5).These effects have been repeatedly corroborated.

      Unlike aprotinin, AAT-1 is produced from human plasma, and does not have strong pro coagulant
      characteristics.

      AAT-1 in different clinical settings:

      Circulating AAT-1 levels increase by 4-fold during acute-phase response (3). Patients with
      low circulating levels of AAT-1 are at increase risk for lung, liver and pancreatic
      destructive diseases, particularly emphysema (3). Preclinical and clinical studies have shown
      that AAT-1 therapy for non-deficient individuals is safe, and may modify disease progression
      in type 1 and type 2 diabetes, acute myocardial infarction, rheumatoid arthritis,
      inflammatory bowel disease, cystic fibrosis, transplant rejection, graft versus host disease
      and multiple sclerosis (6-17, 32,33,37,38) . AAT-1 treatment has subsequently advanced from
      replacement therapy to potential treatment for a broad spectrum of inflammatory and
      immune-mediated diseases. AAT-1 also appears to be antibacterial and an inhibitor of viral
      infections, such as influenza and human immunodeficiency virus (HIV) (18).

      Human pharmacokinetic data:

      In patients with AAT-1 deficiency, intravenous administration of AAT-1 in a dose of 60 mg per
      kg body weight maintain plasma levels resembling acute phase response immediately after
      administration, and retain an appropriate level of serum AAT above the protective threshold
      (50 mg/dl) a week afterwards (39).

      Rational of AAT-1 dosage:

      Based on previous studies and clinical practice, the administration of multiple intravenous
      dosage of 60 mg per kg body weight of AAT-1 is safe and is associated with low incidence of
      benign side-effects.

      Derived from pharmacokinetic studies (39), AAT-1 plasma levels immediately following the
      administration of this external dosage resembles acute phase response. A 30% reduction in
      AAT-1 plasma levels is anticipated with gradual return to preoperative levels after
      termination of CPB (40).

      Risk/ benefit of the study:

      The role of AAT-1 in mitigating inflammatory response has been established. CPB is a potent
      stimulator of inflammatory cascades and associated with bleeding diatheses, coagulation
      abnormalities, potentially leading to organ dysfunction. To date, the administration of AAT-1
      in patients undergoing cardiac surgery with CPB has not been explored. It may be postulated
      that inherent AAT-1 effects may offset deleterious CPB effects. This may clinically result in
      improved preservation of organ function, reduced postoperative bleeding and reduced hospital
      stay. The benefits of other protease inhibitors in corresponding settings have been recently
      demonstrated (41-43).

      As mentioned above, administration of AAT-1 in various clinical settings is considered safe
      with low rate of side effects (see section 6.1 - potential risks).

      4 Methods 4.1 Primary Objective

        1. To evaluate the efficacy and safety of preoperative AAT-1 administration in patients
           undergoing CABG with CPB.

        2. Postoperative blood loss and organ function will be assessed.

      To date, no data exists with regard to AAT-1 effects in the settings of CPB. The primary
      goals of this study are to evaluate anti-inflammatory effects, organ function preservation
      (1-2) and postoperative blood loss reduction following AAT-1 administration in patients
      undergoing cardiac surgery with CPB.

      4.2 Determination of Study Eligibility 4.2.1 Inclusion Criteria

        1. Male/female patients 40-70 years of age.

        2. Candidates for isolated CABG with CPB.

        3. Calculated logistic Euroscore risk stratification of 5% or less.

        4. Signed patient's written informed consent.

      4.2.2 Exclusion Criteria

      Co-existing conditions including:

      10. Coagulation abnormalities 11. Severe pulmonary disease defined by blood oxygen saturation
      of 90% or less or FEV1 of less than 60% of predicted.

      12. Renal dysfunction defined be serum creatinine levels higher or equal to 1.8 mg%, 13.
      Abnormal liver function tests 14. Uncontrolled diabetes mellitus, 15. Severe peripheral
      vascular disease 16. Prior cerebrovascular neurological event. 17. Abnormal left or right
      ventricular function. 18. Treatment with warfarin or thienopyridine class of anti-platelet
      agents. 4.2.3 Withdrawal Criteria Patients will preserve the right to withdraw from the study
      at any time during treatment without prejudice.

      If medically indicated, the principal investigator or the surgeon poses the right to
      discontinue patient enrollment at any stage of the study.

      Discontinuation (failure to complete the study) will be documented. The reason for
      discontinuation will be recorded.

      Potential causes that may lead to discontinuation include:

        -  Adverse event(s)

        -  Protocol violation

        -  Patient withdrew consent

        -  Administrative problems 4.3 Enrollment Prior to participation in this study, the
           Investigator will obtain written appropriate approval for the protocol and the informed
           consent form the Ethics Committee (EC) and other local regulatory organizations. The
           approved consent form will clearly reflect the EC approval date.

      Failure to obtain a signed and hand dated informed consent prior to the procedure constitutes
      a protocol violation, and subsequently reportable to the EC.

      4.4 Subject Screening Patients that have been already scheduled for isolated CABG operation
      will be addressed by a member of the research team during the preoperative waiting period
      (either in the Department of Cardiothoracic Surgery, the Department of Cardiology or the
      Department of Internal Medicine). The goal of the study, procedure and incentive will be
      explained by a research staff member to each potential participant. Consenting subjects will
      be asked to provide written consent.

      4.4.1 Randomization The study participants will be randomized to receive either single dose
      AAT-1 60 mg per kg or placebo.

      4.4.2 Trial medication administration: Preparation and dosing of AAT-1 will be performed by
      an unblinded pharmacist. The medication will be diluted just prior to administration. The
      placebo solution will comprise human albumin that resembles the color and consistency of
      AAT-1 solution. The medication will be given 3-5 hours prior to surgery (skin incision).
      Administration rate of the drug will not exceed 0.04 ml per kg per minute (approximately
      60-80 minutes). Vital signs including blood pressure, pulse rate and body temperature will be
      correspondingly monitored.

      The patients, research staff, laboratory personnel and data analysts will remain blinded to
      the identity of the treatment from the time of randomization and until database lock. Data
      unblinding will commence in the case of patient's emergency.

      A randomization list will be produced by the pharmacist, however, will be secured and
      confidential until time of unblinding.

      4.4.3 Surgical technique Consistent with our routine policy, fentanyl citrate (20-50mcg/kg),
      midazolam (2-3mg) and isoflurane (0.5-2%) will be used for induction and maintenance of
      anesthesia.

      Standard median sternotomy will be followed by procurement of the conduits. Heparin loading
      dose will be administered to achieve a kaolin activated coagulation time (ACT). Ascending
      aorta - right atrial cannulation will be performed to institute CPB and ACT will be monitored
      at 480 seconds or more. Standard centrifugal pump and a membrane oxygenator will be used for
      extracorporeal circulation (cardiopulmonary bypass). Compatible with the standard technique,
      systemic active cooling will be avoided and patients core temperature will remain range
      between 32 and 37˚C. Distal anastomoses will be performed during single aortic cross-clamp
      and blood cardioplegic arrest. Proximal anastomoses will be performed during aortic
      cross-clamp. Cold (10˚C) blood cardioplegic solution will be delivered in a 4:1 ratio.
      Cardioplegia will be delivered antegrade via the aortic root with or without additional
      retrograde administration via the coronary sinus. After cardioplegic induction (10 ml / Kg),
      intermittent doses (300 - 500 ml) will be administered following completion of each distal
      anastomosis. Heparin will be reversed using protamine sulphate in a ratio of 1:1 after
      weaning from CPB.

      4.4.4 Data collection Preoperative data: Demographic, morphological and clinical descriptors
      including age, gender, body mass index (BMI), body surface area (BSA) co-morbidity, Euroscore
      risk-stratification, medication, etc. will be recorded. Preoperative laboratory analysis will
      include complete blood count, coagulation profile, serum creatinine levels and creatinine
      clearance, liver function test and arterial blood gases test and serology for HIV,HCV,HBC.
      Compatible with our routine policy, all patients will undergo preoperative echocardiography,
      coronary angiography, chest x-ray, lung function tests (spirometry) and carotid artery duplex
      study.

      Study participants will be assigned to undergo preoperative brain MRI; subjected to the
      protocol described below.

      Intraoperative: The type of surgery will be classified. The following data will be recorded:
      heparin dose given prior to bypass initiation; activated clotting time (ACT) counts during
      the operation (prior, during and after CPB); operative time, cross-clamp time and CPB time;
      number of trials to wean from CPB, type of inotropes and dosage used during weaning from CPB;
      blood products utilization during surgery. Allergic reactions or adverse events observed by
      the surgeon or anesthesiologist will be documented. The individual surgeon's impression
      regarding bleeding tendency will be recorded.

      Postoperative organ function and blood loss evaluation:

      The occurrence and magnitude of systemic inflammatory response and organ dysfunction will be
      recorded and quantified by laboratory markers. Related laboratory markers will be monitored
      on a daily basis during the recovery period (in the intensive care unit and at the ward). The
      following organs and corresponding markers will be monitored:

      Pulmonary function: Pulmonary function will be evaluated by measured overall mechanical
      ventilation time, peak inspiratory pressures (PIP), plateau pressures, physiologic dead space
      and static and dynamic lung compliance. Bronchoalveolar lavage (BAL) will be performed 3
      hours after operation (while the patient is anesthesized and intubated) and extracted fluid
      will be analyzed for inflammatory markers. A-a DO2 calculation [AaDO2 = (713 x FiO2) - (pCO2
      / 0.8) - (paO2)] will be measured daily.

      Complete pulmonary function test will be performed before and 4 days after the operation.
      Chest radiographs will be evaluated and quantified by an independent radiologist for the
      occurrence of atelectasis, pulmonary edema, or pleural changes.

      Renal function: Daily measurements of urine output, serum creatinine levels, creatinine
      clearance and urinary albumin levels. Acute kidney injury (AKI) markers will be sampled in
      the ICU.

      Brain injury assessment: The degree of insult to the brain will be measured by plasma S-100
      proteinlevels. Assessment of damage to the blood-brain barrier (BBB) will be performed by
      magnetical resonance imaging (MRI) modality (see technique protocol below).

      Hepatic function: Daily measurements of serum hepatic enzymes levels. Cardiac function:
      Monitoring of cardiac enzymes levels; need and magnitude of required inotrope treatment;
      occurrence of low cardiac output syndrome (defined as systolic blood pressure of 90 mmHg or
      less coupled with central venous pressure (CVP) of 15 mmHg or more) and incidence of cardiac
      arrhythmias. Transthoracic echocardiography examination will be performed on postoperative
      day 5 and assessed by an independent cardiologist.

      Blood loss: Operative and postoperative blood loss will be monitored as well as daily
      hemoglobin levels. Daily platelet counts and thromboelastograms will be performed. The
      distribution of blood products and total administered will be recorded daily. Postoperative
      CRP levels will be evaluated daily.

      Blood sampling and laboratory analysis methods for cytokine levels:

      Ten mL whole blood venous EDTA samples will be collected from radial artery catheter at five
      specified occasions: before induction of anaesthesia, 30 minutes after aortic cross-clamp
      positioning and 3, 6, and 9 hours after aortic cross clamp positioning. The blood samples
      will be subsequently centrifuged at 4 °C for 15 min and the serum stored at -70 °C. Samples
      will be analyzed for the following markers: Polimorphonuclear Neutrophil Elastase (PMNE),
      Interleukin-1α (IL-1α), Interleukin-1ß (IL-1ß), Interleukin-2 (IL-2), Interleukin-4 (IL-4),
      Interleukin-6 (IL-6), Interleukin-8 (IL-8), Interleukin-10 (IL-10), Interferon-γ (IFN-γ),
      Tumor Necrosis Factor-α (TNF-α), Vascular Endothelial Growth Factor (VEGF), Monocyte
      Chemoattractant Protein-1 (MCP-1), and Endothelial Growth Factor (EGF).

      Daily blood samples will be collected postoperatively for platelet count, renal function,
      liver function, CRP levels S-100 protein and troponin.

      Early postoperative adverse events will be documented. These include 30-day mortality, new
      neurological events, myocardial infarction, renal dysfunction, need for re-exploration for
      bleeding and deep sternal wound infection.

      Blood-Brain Barrier (BBB) assessment by MRI The imaging modality used for BBB assessment will
      be MRI scanner (Philips 3T or General Electric 1.5T). The examination format will include 24
      cm FOV, 35 contiguous interleaved slices, 3.5-4 mm thick and co-localized across series.
      Trace-weighted DWI images will be obtained at b=1000 from a 13-15 direction DTI sequence with
      an in-plane resolution of 2.5×2.5mm and TR/TE=10s/58ms at 3T or TR/TE=10s/72ms at 1.5T.
      T2-FLAIR images will be obtained with an in-plane resolution of 0.94×0.94 mm, TR/TE=9000/120
      ms and TI=2600 ms at 3T or TR/TE=9000/140 ms and TI=2200 ms at 1.5T. (25)
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: post operative inflammatory response
time frame: post operative day 1-5
description: 1. The occurrence and magnitude of systemic inflammatory response and organ dysfunction will be recorded and quantified by laboratory markers. Related laboratory markers will be monitored on a daily basis during the recovery period (in the intensive care unit and at the ward).
measure: Pulmonary function:
time frame: post op day 1-5
description: Pulmonary function will be evaluated by measured overall mechanical ventilation time, peak inspiratory pressures (PIP), plateau pressures, physiologic dead space and static and dynamic lung compliance. Bronchoalveolar lavage (BAL) will be performed 3 hours after operation (while the patient is anesthetised and intubated) and extracted fluid will be analyzed for inflammatory markers. A-a DO2 calculation [AaDO2 = (713 x FiO2) - (pCO2 / 0.8) - (paO2)] will be measured daily.
Complete pulmonary function test will be performed before and 4 days after the operation. Chest radiographs will be evaluated and quantified by an independent radiologist for the occurrence of atelectasis, pulmonary edema, or pleural changes.
measure: Renal function:
time frame: post op day 1-5
description: Daily measurements of urine output, serum creatinine levels, creatinine clearance and urinary albumin levels. Acute kidney injury (AKI) markers will be sampled in the ICU.
measure: Brain injury assessment:
time frame: post op day 1-5
description: The degree of insult to the brain will be measured by plasma S-100 proteinlevels. Assessment of damage to the blood-brain barrier (BBB) will be performed by magnetical resonance imaging (MRI) modality
measure: Hepatic function:
time frame: post op day 1-5
description: Daily measurements of serum hepatic enzymes levels.
measure: Cardiac function:
time frame: post op day 1-5
description: Monitoring of cardiac enzymes levels; need and magnitude of required inotrope treatment; occurrence of low cardiac output syndrome (defined as systolic blood pressure of 90 mmHg or less coupled with central venous pressure (CVP) of 15 mmHg or more) and incidence of cardiac arrhythmias. Transthoracic echocardiography examination will be performed on postoperative day 5 and assessed by an independent cardiologist.
measure: Blood loss:
time frame: post op day 1-2
description: Operative and postoperative blood loss will be monitored as well as daily hemoglobin levels. Daily platelet counts and thromboelastograms will be performed. The distribution of blood products and total administered will be recorded daily. Postoperative CRP levels will be evaluated daily.
arm group label: alpha 1 antitrypsin
arm group type: Active Comparator
description: patients receive 4 grams of IV alpha 1 antitrypsin preoperatively
arm group label: placebo
arm group type: Placebo Comparator
description: 10 patients will randomely receive placebo
intervention type: Drug
intervention name: Alpha 1-Antitrypsin
arm group label: alpha 1 antitrypsin
criteria: 
gender: All
minimum age: 40 Years
maximum age: 70 Years
healthy volunteers: No
last name: DAN ABRAHAMOV, DR
role: Principal Investigator
affiliation: Soroka University Medical Center
last name: DAN ABRAHAMOV, DR
phone: 972504506205
email: danab3@clalit.org.il
responsible party type: Principal Investigator
investigator affiliation: Soroka University Medical Center
investigator full name: Dan Abramov
investigator title: Dr
mesh term: Alpha 1-Antitrypsin Deficiency
mesh term: Alpha 1-Antitrypsin
mesh term: Protein C Inhibitor