<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/NCT03782350</url>
  </required_header>
  <id_info>
    <org_study_id>the OPTIMAL study</org_study_id>
    <nct_id>NCT03782350</nct_id>
  </id_info>
  <brief_title>Outcome Impact of Different Tranexamic Acid Regimen in Cardiac Surgery With Cardiopulmonary Bypass</brief_title>
  <acronym>OPTIMAL</acronym>
  <official_title>Outcome Impact of Different Tranexamic Acid Regimen in Cardiac Surgery With Cardiopulmonary Bypass (the OPTIMAL Study)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Chinese Academy of Medical Sciences, Fuwai Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Chinese Academy of Medical Sciences, Fuwai Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background and Significance A growing amount of evidence linking transfusion of allogeneic&#xD;
      blood products with negative patient outcomes and increased cost continues to drive interest&#xD;
      into strategies and technologies that limit patient exposure to this risk. The single largest&#xD;
      consumer of this resource continues to be cardiac surgery, with 20% of the world wide use of&#xD;
      allogeneic blood products accounted for by this cohort. The lysine analogs tranexamic acid&#xD;
      (TXA) has gained wide spread use in cardiac surgery as a blood-sparing agent. Mounted&#xD;
      evidence has proved its efficacy and safety in cardiac surgery. However, the optimal dose&#xD;
      regimen of TXA and the impact on patients' outcomes remains debated.&#xD;
&#xD;
      Study Objectives The primary objective of the study is to analyze the primary efficacy&#xD;
      (superiority) and primary safety (non-inferiority) of the two dose regimen of tranexamic&#xD;
      acid.. The primary efficacy endpoint includes perioperative allogeneic transfusion rate, and&#xD;
      the primary safety endpoint includes the 30-day rate of the composite of perioperative renal&#xD;
      dysfunction, myocardial infarction, ischaemic stroke, seizure, deep venous thrombosis,&#xD;
      pulmonary embolism and all-cause mortality. The secondary objectives are to demonstrate the&#xD;
      efficacy of the two dose regimens in reducing perioperative allogeneic transfusion volume,&#xD;
      postoperative bleeding (chest tube drainage), reoperation rate, mechanic ventilation&#xD;
      duration, ICU stay, hospital length of stay (LOS), and total hospitalization cost.&#xD;
&#xD;
      Study Endpoints The primary endpoints include efficacy and safety. The primary efficacy&#xD;
      endpoint includes perioperative allogeneic transfusion rate, and the primary safety endpoint&#xD;
      includes the 30-day rate of the composite of perioperative renal dysfunction, myocardial&#xD;
      infarction, ischaemic stroke, seizure, deep venous thrombosis, pulmonary embolism, and&#xD;
      all-cause mortality. The key secondary endpoints of the study are defined as perioperative&#xD;
      allogeneic transfusion volume, postoperative bleeding (chest tube drainage), reoperation&#xD;
      rate, mechanic ventilation duration, ICU stay, hospital length of stay (LOS), and total&#xD;
      hospitalization cost.&#xD;
&#xD;
      Study Population Adult patients aged 18-70 years undergoing elective cardiac surgery with&#xD;
      cardiopulmonary bypass are included. Totally 3008 patients will be required for this study&#xD;
      (1504 in each of the 2 groups).&#xD;
&#xD;
      Study Design The study is a multicenter, randomised, double-blind trial. Cardiac surgery&#xD;
      patients with cardiopulmonary bypass will be randomised to Dosage 1 regimen group or Dosage 2&#xD;
      regimen group of tranexamic acid.&#xD;
&#xD;
      Study Treatment The dosage regimen is implemented with dose of loading (intravenous infusion&#xD;
      in 20 mins), maintenance (throughout the surgery), and pump prime (added into the bypass&#xD;
      machine). The Dosage 2 regimen contains an intravenous bolus of 10 mg/kg after anesthetic&#xD;
      induction followed by an intravenous maintenance of 2 mg/kg/h throughout the surgery, and a&#xD;
      pump prime dose 1 mg/kg. As for the Dosage 1 regimen, the intravenous bolus and the&#xD;
      maintenance are 30 mg/kg and 16 mg/kg/h respectively, and a pump prime dose 2 mg/kg.&#xD;
      Patients, surgeons and research staff interviewing patients postoperatively will be blind to&#xD;
      treatment allocation.&#xD;
&#xD;
      Statistical Considerations The study hypothesis is that the Dosage 1 regimen of tranexamic&#xD;
      acid is superiority to the Dosage 2 regimen in the primary efficacy endpoint, while at the&#xD;
      same time, the Dosage 1 regimen is non-inferiority to the Dosage 2 regimen in the primary&#xD;
      safety endpoint in cardiac surgery with cardiopulmonary bypass. The sample size calculation&#xD;
      is mainly based on the blood transfusion rate, and 30-day rate of the composite of&#xD;
      perioperative renal dysfunction, myocardial infarction, ischaemic stroke, seizure, deep&#xD;
      venous thrombosis, pulmonary embolism and all-cause mortality. For the primary efficacy&#xD;
      endpoint, a sample size estimate of 1,214 randomized subjects (607 for each group) has 90%&#xD;
      power to detect a 12.5% reduction (61.7% vs 70.5% between Dosage 1 regimen and Dosage 2&#xD;
      regimen ), by means of a single-sided α = 0.025 Chi-square test. For the primary safety&#xD;
      endpoint, a sample size estimate of 2,698 randomized subjects (1349 for each group) has 90%&#xD;
      power to detect a noninferiority margin for the difference of 5%, by means of a single-sided&#xD;
      α = 0.025 log rank test. In order to conduct an interim analysis, the sample size in each&#xD;
      group is 1504(10% drop-out rate) for the adjusted significance level (from 0.025 to 0.0245 in&#xD;
      accordance with α spending function by Lan-DeMets Method). Finally, the investigators decided&#xD;
      to enroll 3008 study patients (1:1 ratio) for the OPTIMAL trial.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      A face to face visit (review in hospital, or remote video interview via smart phone and&#xD;
      social media) is required to screen the occurrence of 30-day rate of the composite endpoints&#xD;
      of renal dysfunction, myocardial infarction,stroke, seizure, deep venous thrombosis,&#xD;
      pulmonary embolism and all-cause mortality, specific examinations are needed to confirm the&#xD;
      diagnosis.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 26, 2018</start_date>
  <completion_date type="Actual">November 27, 2021</completion_date>
  <primary_completion_date type="Actual">September 30, 2021</primary_completion_date>
  <phase>Phase 4</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>
    <intervention_model_description>The subject will be assigned to either high dose regimen group or low dose regimen group of tranexamic acid in a blinded fashion</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>Participants, care provider, investigator and outcomes assessor will be blinded to treatment allocation.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Perioperative allogeneic RBC transfusion rate</measure>
    <time_frame>From the operation day to the discharge, an average of 7 days</time_frame>
    <description>The overall transfusion rate of allogeneic package RBC.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Composite rate of renal dysfunction, myocardial infarction,stroke, seizure, deep venous thrombosis, pulmonary embolism and all-cause mortality</measure>
    <time_frame>30-day postoperatively</time_frame>
    <description>A face to face visit (review in hospital, or remote video interview via smart phone and social media) is required to screen the occurrence of 30-day rate of the composite endpoints of renal dysfunction, myocardial infarction,stroke, seizure, deep venous thrombosis, pulmonary embolism and all-cause mortality, specific examinations are needed to confirm the diagnosis.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Perioperative allogeneic RBC transfusion volume</measure>
    <time_frame>From the operation day to the discharge, an average of 7 days</time_frame>
    <description>The overall volume of allogeneic transfused RBC</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Perioperative allogeneic non-RBC transfusion volume</measure>
    <time_frame>From the operation day to the discharge, an average of 7 days</time_frame>
    <description>The overall volume of allogeneic transfused FFP，platelet，and cryoprecipitate</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Perioperative allogeneic non-RBC transfusion rate</measure>
    <time_frame>From the operation day to the discharge, an average of 7 days</time_frame>
    <description>The rate of allogeneic transfused FFP，platelet，and cryoprecipitate</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Postoperative bleeding volume</measure>
    <time_frame>From the operation day to the discharge, an average of 7 days</time_frame>
    <description>The total chest tube drainage postoperatively</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Reoperation rate for bleeding</measure>
    <time_frame>From the operation day to the discharge, an average of 7 days</time_frame>
    <description>Reoperation due to excessive chest tube drainage or pericardial tamponade.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The duration of mechanical ventilation</measure>
    <time_frame>from the end of the operation and the extubation, an average of 24 hours</time_frame>
    <description>The time interval between the end of the operation and the extubation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Length of stay in the intensive care unit</measure>
    <time_frame>From the end of the operation and the discharge from the intensive care unit, an average of 48 hours</time_frame>
    <description>The time interval between the end of the operation and the discharge from the intensive care unit</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Length of stay in hospital</measure>
    <time_frame>From the operation day to the discharge, an average of 7 days</time_frame>
    <description>The days between the operation and the discharge from the hospital</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total hospitalization cost</measure>
    <time_frame>In hospital, an average of 7 days</time_frame>
    <description>The total cost during hospitalization</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Thrombotic test</measure>
    <time_frame>preoperative、4~8 hours postoperative、1st postoperative day、2nd postoperative day、3rd postoperative day</time_frame>
    <description>D-dimer level</description>
  </other_outcome>
  <other_outcome>
    <measure>Correction Dimension of Electroencephalogram</measure>
    <time_frame>12 hours postoperatively</time_frame>
    <description>A reduced correction dimension of EEG indicates seizure</description>
  </other_outcome>
  <other_outcome>
    <measure>Bispectral Index</measure>
    <time_frame>From anesthetic induction until 12 hours postoperatively, an average of 18 hours</time_frame>
    <description>A range of 0~100 (85~100 awake, 65~85 sedation, 40~65 anesthesia, &lt;40 burst suppression)</description>
  </other_outcome>
  <other_outcome>
    <measure>Drug concentration in plasma and cerebrospinal fluid</measure>
    <time_frame>Fourteen timepoints from anesthetic induction until 6 hours postoperatively</time_frame>
    <description>Two mililiter of blood sample will be obtained from the radial artery in 8 participants in the two groups respectively. Two mililiter of cerebrospinal fluid will be obtained in 8 participants receiving aortic surgery with subarachnoid drainage in the two groups respectively.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">3079</enrollment>
  <condition>Homeostasis</condition>
  <condition>Cardiac Surgery</condition>
  <arm_group>
    <arm_group_label>Tranexamic Acid Dosage 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>A bolus of 30 mg/kg Tranexamic Acid for 20 min followed by a maintenance dose of 16 mg/kg/h Tranexamic Acid until the end of surgery, and a pump prime dose 2 mg/kg.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Tranexamic Acid Dosage 2</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>A bolus of 10 mg/kg Tranexamic Acid for 20 min followed by a maintenance dose of 2 mg/kg/h Tranexamic Acid until the end of surgery, and a pump prime dose 1 mg/kg.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tranexamic Acid Dosage 1</intervention_name>
    <description>Tranexamic Acid Dosage 1</description>
    <arm_group_label>Tranexamic Acid Dosage 1</arm_group_label>
    <other_name>Cyklokapron</other_name>
    <other_name>Transamin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tranexamic Acid Dosage 2</intervention_name>
    <description>Tranexamic Acid Dosage 2</description>
    <arm_group_label>Tranexamic Acid Dosage 2</arm_group_label>
    <other_name>Cyklokapron</other_name>
    <other_name>Transamin</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Male or female adult patients aged 18~70 years.&#xD;
&#xD;
          2. Patients receiving cardiac surgery with cardiopulmonary bypass&#xD;
&#xD;
          3. Written Informed consent obtained&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Acquired chromatic disorder&#xD;
&#xD;
          2. Active intravascular coagulation&#xD;
&#xD;
          3. Previous convulsion or seizure&#xD;
&#xD;
          4. Allergy or contraindication to tranexamic acid injection or its components&#xD;
&#xD;
          5. Feeding or pregnancy women&#xD;
&#xD;
          6. Terminal illness with a life expectancy of less than 3 months&#xD;
&#xD;
          7. Patients with mental or legal disability&#xD;
&#xD;
          8. Currently enrolled in another perioperative interventional study&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Zhe Zheng, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Chinese Academy of Medical Sciences, Fuwai Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Chinese Academy of Medical Sciences， Fuwai Hospital</name>
      <address>
        <city>Beijing</city>
        <zip>100037</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <reference>
    <citation>Kalisiak A, Oosterwijk E, Minniti JG, Old LJ, Scheinberg DA. A monoclonal antibody for terminal beta-galactose. Use in analysis of glycosphingolipids. Glycoconj J. 1991 Feb;8(1):55-62. doi: 10.1007/BF00731643.</citation>
    <PMID>1726670</PMID>
  </reference>
  <reference>
    <citation>Murphy GJ, Reeves BC, Rogers CA, Rizvi SI, Culliford L, Angelini GD. Increased mortality, postoperative morbidity, and cost after red blood cell transfusion in patients having cardiac surgery. Circulation. 2007 Nov 27;116(22):2544-52. doi: 10.1161/CIRCULATIONAHA.107.698977. Epub 2007 Nov 12.</citation>
    <PMID>17998460</PMID>
  </reference>
  <reference>
    <citation>Karkouti K, Wijeysundera DN, Yau TM, Beattie WS, Abdelnaem E, McCluskey SA, Ghannam M, Yeo E, Djaiani G, Karski J. The independent association of massive blood loss with mortality in cardiac surgery. Transfusion. 2004 Oct;44(10):1453-62. doi: 10.1111/j.1537-2995.2004.04144.x.</citation>
    <PMID>15383018</PMID>
  </reference>
  <reference>
    <citation>Kurt M, Tanboga IH, Isik T, Kaya A, Ekinci M, Bilen E, Can MM, Karakas MF, Bayram E, Aksakal E, Sevimli S. Comparison of transthoracic and transesophageal 2-dimensional speckle tracking echocardiography. J Cardiothorac Vasc Anesth. 2012 Feb;26(1):26-31. doi: 10.1053/j.jvca.2011.05.014. Epub 2011 Aug 11.</citation>
    <PMID>21835643</PMID>
  </reference>
  <reference>
    <citation>Henry DA, Carless PA, Moxey AJ, O'Connell D, Stokes BJ, Fergusson DA, Ker K. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev. 2011 Mar 16;2011(3):CD001886. doi: 10.1002/14651858.CD001886.pub4.</citation>
    <PMID>21412876</PMID>
  </reference>
  <reference>
    <citation>Levi M, Cromheecke ME, de Jonge E, Prins MH, de Mol BJ, Briet E, Buller HR. Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically relevant endpoints. Lancet. 1999 Dec 4;354(9194):1940-7. doi: 10.1016/S0140-6736(99)01264-7.</citation>
    <PMID>10622296</PMID>
  </reference>
  <reference>
    <citation>Brown JR, Birkmeyer NJ, O'Connor GT. Meta-analysis comparing the effectiveness and adverse outcomes of antifibrinolytic agents in cardiac surgery. Circulation. 2007 Jun 5;115(22):2801-13. doi: 10.1161/CIRCULATIONAHA.106.671222. Epub 2007 May 28.</citation>
    <PMID>17533182</PMID>
  </reference>
  <reference>
    <citation>Butler KD, Smith JR. Mechanisms of Forssman-induced bronchospasm and their inhibition. Br J Pharmacol. 1981 May;73(1):25-32. doi: 10.1111/j.1476-5381.1981.tb16767.x.</citation>
    <PMID>7284697</PMID>
  </reference>
  <reference>
    <citation>Schneeweiss S, Seeger JD, Landon J, Walker AM. Aprotinin during coronary-artery bypass grafting and risk of death. N Engl J Med. 2008 Feb 21;358(8):771-83. doi: 10.1056/NEJMoa0707571.</citation>
    <PMID>18287600</PMID>
  </reference>
  <reference>
    <citation>Fergusson DA, Hebert PC, Mazer CD, Fremes S, MacAdams C, Murkin JM, Teoh K, Duke PC, Arellano R, Blajchman MA, Bussieres JS, Cote D, Karski J, Martineau R, Robblee JA, Rodger M, Wells G, Clinch J, Pretorius R; BART Investigators. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med. 2008 May 29;358(22):2319-31. doi: 10.1056/NEJMoa0802395. Epub 2008 May 14. Erratum In: N Engl J Med. 2010 Sep 23;363(13):1290.</citation>
    <PMID>18480196</PMID>
  </reference>
  <reference>
    <citation>Society of Thoracic Surgeons Blood Conservation Guideline Task Force; Ferraris VA, Brown JR, Despotis GJ, Hammon JW, Reece TB, Saha SP, Song HK, Clough ER; Society of Cardiovascular Anesthesiologists Special Task Force on Blood Transfusion; Shore-Lesserson LJ, Goodnough LT, Mazer CD, Shander A, Stafford-Smith M, Waters J; International Consortium for Evidence Based Perfusion; Baker RA, Dickinson TA, FitzGerald DJ, Likosky DS, Shann KG. 2011 update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines. Ann Thorac Surg. 2011 Mar;91(3):944-82. doi: 10.1016/j.athoracsur.2010.11.078.</citation>
    <PMID>21353044</PMID>
  </reference>
  <reference>
    <citation>Sander M, Spies CD, Martiny V, Rosenthal C, Wernecke KD, von Heymann C. Mortality associated with administration of high-dose tranexamic acid and aprotinin in primary open-heart procedures: a retrospective analysis. Crit Care. 2010;14(4):R148. doi: 10.1186/cc9216. Epub 2010 Aug 3.</citation>
    <PMID>20682059</PMID>
  </reference>
  <reference>
    <citation>Koster A, Borgermann J, Zittermann A, Lueth JU, Gillis-Januszewski T, Schirmer U. Moderate dosage of tranexamic acid during cardiac surgery with cardiopulmonary bypass and convulsive seizures: incidence and clinical outcome. Br J Anaesth. 2013 Jan;110(1):34-40. doi: 10.1093/bja/aes310. Epub 2012 Sep 17.</citation>
    <PMID>22986419</PMID>
  </reference>
  <reference>
    <citation>Murkin JM, Falter F, Granton J, Young B, Burt C, Chu M. High-dose tranexamic Acid is associated with nonischemic clinical seizures in cardiac surgical patients. Anesth Analg. 2010 Feb 1;110(2):350-3. doi: 10.1213/ANE.0b013e3181c92b23. Epub 2009 Dec 8.</citation>
    <PMID>19996135</PMID>
  </reference>
  <reference>
    <citation>Martin K, Knorr J, Breuer T, Gertler R, Macguill M, Lange R, Tassani P, Wiesner G. Seizures after open heart surgery: comparison of epsilon-aminocaproic acid and tranexamic acid. J Cardiothorac Vasc Anesth. 2011 Feb;25(1):20-5. doi: 10.1053/j.jvca.2010.10.007.</citation>
    <PMID>21272777</PMID>
  </reference>
  <reference>
    <citation>Koster A, Schirmer U. Re-evaluation of the role of antifibrinolytic therapy with lysine analogs during cardiac surgery in the post aprotinin era. Curr Opin Anaesthesiol. 2011 Feb;24(1):92-7. doi: 10.1097/ACO.0b013e32833ff3eb.</citation>
    <PMID>20881484</PMID>
  </reference>
  <reference>
    <citation>Schlag MG, Hopf R, Zifko U, Redl H. Epileptic seizures following cortical application of fibrin sealants containing tranexamic acid in rats. Acta Neurochir (Wien). 2002 Jan;144(1):63-9. doi: 10.1007/s701-002-8275-z.</citation>
    <PMID>11807648</PMID>
  </reference>
  <reference>
    <citation>Horrow JC, Van Riper DF, Strong MD, Grunewald KE, Parmet JL. The dose-response relationship of tranexamic acid. Anesthesiology. 1995 Feb;82(2):383-92. doi: 10.1097/00000542-199502000-00009.</citation>
    <PMID>7856897</PMID>
  </reference>
  <reference>
    <citation>Sigaut S, Tremey B, Ouattara A, Couturier R, Taberlet C, Grassin-Delyle S, Dreyfus JF, Schlumberger S, Fischler M. Comparison of two doses of tranexamic acid in adults undergoing cardiac surgery with cardiopulmonary bypass. Anesthesiology. 2014 Mar;120(3):590-600. doi: 10.1097/ALN.0b013e3182a443e8.</citation>
    <PMID>23903022</PMID>
  </reference>
  <reference>
    <citation>Dowd NP, Karski JM, Cheng DC, Carroll JA, Lin Y, James RL, Butterworth J. Pharmacokinetics of tranexamic acid during cardiopulmonary bypass. Anesthesiology. 2002 Aug;97(2):390-9. doi: 10.1097/00000542-200208000-00016.</citation>
    <PMID>12151929</PMID>
  </reference>
  <reference>
    <citation>Grassin-Delyle S, Tremey B, Abe E, Fischler M, Alvarez JC, Devillier P, Urien S. Population pharmacokinetics of tranexamic acid in adults undergoing cardiac surgery with cardiopulmonary bypass. Br J Anaesth. 2013 Dec;111(6):916-24. doi: 10.1093/bja/aet255. Epub 2013 Jul 23.</citation>
    <PMID>23880099</PMID>
  </reference>
  <reference>
    <citation>Fiechtner BK, Nuttall GA, Johnson ME, Dong Y, Sujirattanawimol N, Oliver WC Jr, Sarpal RS, Oyen LJ, Ereth MH. Plasma tranexamic acid concentrations during cardiopulmonary bypass. Anesth Analg. 2001 May;92(5):1131-6. doi: 10.1097/00000539-200105000-00010.</citation>
    <PMID>11323334</PMID>
  </reference>
  <reference>
    <citation>Nuttall GA, Gutierrez MC, Dewey JD, Johnson ME, Oyen LJ, Hanson AC, Oliver WC Jr. A preliminary study of a new tranexamic acid dosing schedule for cardiac surgery. J Cardiothorac Vasc Anesth. 2008 Apr;22(2):230-5. doi: 10.1053/j.jvca.2007.12.016.</citation>
    <PMID>18375325</PMID>
  </reference>
  <reference>
    <citation>Du Y, Xu J, Wang G, Shi J, Yang L, Shi S, Lu H, Wang Y, Ji B, Zheng Z. Comparison of two tranexamic acid dose regimens in patients undergoing cardiac valve surgery. J Cardiothorac Vasc Anesth. 2014 Oct;28(5):1233-7. doi: 10.1053/j.jvca.2013.10.006. Epub 2014 Jan 18.</citation>
    <PMID>24447498</PMID>
  </reference>
  <verification_date>November 2021</verification_date>
  <study_first_submitted>December 17, 2018</study_first_submitted>
  <study_first_submitted_qc>December 18, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 20, 2018</study_first_posted>
  <last_update_submitted>November 27, 2021</last_update_submitted>
  <last_update_submitted_qc>November 27, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">November 30, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Chinese Academy of Medical Sciences, Fuwai Hospital</investigator_affiliation>
    <investigator_full_name>SHI Jia</investigator_full_name>
    <investigator_title>Director, the department of Anesthesiology</investigator_title>
  </responsible_party>
  <keyword>Tranexamic Acid</keyword>
  <keyword>Antifibrinolytics</keyword>
  <keyword>Mortality and Morbidity</keyword>
  <keyword>Cardiac Surgery</keyword>
  <keyword>Cardiopulmonary Bypass</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tranexamic Acid</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03782350
org study id: the OPTIMAL study
nct id: NCT03782350
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
Background and Significance A growing amount of evidence linking transfusion of allogeneic
      blood products with negative patient outcomes and increased cost continues to drive interest
      into strategies and technologies that limit patient exposure to this risk. The single largest
      consumer of this resource continues to be cardiac surgery, with 20% of the world wide use of
      allogeneic blood products accounted for by this cohort. The lysine analogs tranexamic acid
      (TXA) has gained wide spread use in cardiac surgery as a blood-sparing agent. Mounted
      evidence has proved its efficacy and safety in cardiac surgery. However, the optimal dose
      regimen of TXA and the impact on patients' outcomes remains debated.

      Study Objectives The primary objective of the study is to analyze the primary efficacy
      (superiority) and primary safety (non-inferiority) of the two dose regimen of tranexamic
      acid.. The primary efficacy endpoint includes perioperative allogeneic transfusion rate, and
      the primary safety endpoint includes the 30-day rate of the composite of perioperative renal
      dysfunction, myocardial infarction, ischaemic stroke, seizure, deep venous thrombosis,
      pulmonary embolism and all-cause mortality. The secondary objectives are to demonstrate the
      efficacy of the two dose regimens in reducing perioperative allogeneic transfusion volume,
      postoperative bleeding (chest tube drainage), reoperation rate, mechanic ventilation
      duration, ICU stay, hospital length of stay (LOS), and total hospitalization cost.

      Study Endpoints The primary endpoints include efficacy and safety. The primary efficacy
      endpoint includes perioperative allogeneic transfusion rate, and the primary safety endpoint
      includes the 30-day rate of the composite of perioperative renal dysfunction, myocardial
      infarction, ischaemic stroke, seizure, deep venous thrombosis, pulmonary embolism, and
      all-cause mortality. The key secondary endpoints of the study are defined as perioperative
      allogeneic transfusion volume, postoperative bleeding (chest tube drainage), reoperation
      rate, mechanic ventilation duration, ICU stay, hospital length of stay (LOS), and total
      hospitalization cost.

      Study Population Adult patients aged 18-70 years undergoing elective cardiac surgery with
      cardiopulmonary bypass are included. Totally 3008 patients will be required for this study
      (1504 in each of the 2 groups).

      Study Design The study is a multicenter, randomised, double-blind trial. Cardiac surgery
      patients with cardiopulmonary bypass will be randomised to Dosage 1 regimen group or Dosage 2
      regimen group of tranexamic acid.

      Study Treatment The dosage regimen is implemented with dose of loading (intravenous infusion
      in 20 mins), maintenance (throughout the surgery), and pump prime (added into the bypass
      machine). The Dosage 2 regimen contains an intravenous bolus of 10 mg/kg after anesthetic
      induction followed by an intravenous maintenance of 2 mg/kg/h throughout the surgery, and a
      pump prime dose 1 mg/kg. As for the Dosage 1 regimen, the intravenous bolus and the
      maintenance are 30 mg/kg and 16 mg/kg/h respectively, and a pump prime dose 2 mg/kg.
      Patients, surgeons and research staff interviewing patients postoperatively will be blind to
      treatment allocation.

      Statistical Considerations The study hypothesis is that the Dosage 1 regimen of tranexamic
      acid is superiority to the Dosage 2 regimen in the primary efficacy endpoint, while at the
      same time, the Dosage 1 regimen is non-inferiority to the Dosage 2 regimen in the primary
      safety endpoint in cardiac surgery with cardiopulmonary bypass. The sample size calculation
      is mainly based on the blood transfusion rate, and 30-day rate of the composite of
      perioperative renal dysfunction, myocardial infarction, ischaemic stroke, seizure, deep
      venous thrombosis, pulmonary embolism and all-cause mortality. For the primary efficacy
      endpoint, a sample size estimate of 1,214 randomized subjects (607 for each group) has 90%
      power to detect a 12.5% reduction (61.7% vs 70.5% between Dosage 1 regimen and Dosage 2
      regimen ), by means of a single-sided α = 0.025 Chi-square test. For the primary safety
      endpoint, a sample size estimate of 2,698 randomized subjects (1349 for each group) has 90%
      power to detect a noninferiority margin for the difference of 5%, by means of a single-sided
      α = 0.025 log rank test. In order to conduct an interim analysis, the sample size in each
      group is 1504(10% drop-out rate) for the adjusted significance level (from 0.025 to 0.0245 in
      accordance with α spending function by Lan-DeMets Method). Finally, the investigators decided
      to enroll 3008 study patients (1:1 ratio) for the OPTIMAL trial.
A face to face visit (review in hospital, or remote video interview via smart phone and
      social media) is required to screen the occurrence of 30-day rate of the composite endpoints
      of renal dysfunction, myocardial infarction,stroke, seizure, deep venous thrombosis,
      pulmonary embolism and all-cause mortality, specific examinations are needed to confirm the
      diagnosis.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: The subject will be assigned to either high dose regimen group or low dose regimen group of tranexamic acid in a blinded fashion
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: Participants, care provider, investigator and outcomes assessor will be blinded to treatment allocation.
measure: Perioperative allogeneic RBC transfusion rate
time frame: From the operation day to the discharge, an average of 7 days
description: The overall transfusion rate of allogeneic package RBC.
measure: Composite rate of renal dysfunction, myocardial infarction,stroke, seizure, deep venous thrombosis, pulmonary embolism and all-cause mortality
time frame: 30-day postoperatively
description: A face to face visit (review in hospital, or remote video interview via smart phone and social media) is required to screen the occurrence of 30-day rate of the composite endpoints of renal dysfunction, myocardial infarction,stroke, seizure, deep venous thrombosis, pulmonary embolism and all-cause mortality, specific examinations are needed to confirm the diagnosis.
measure: Perioperative allogeneic RBC transfusion volume
time frame: From the operation day to the discharge, an average of 7 days
description: The overall volume of allogeneic transfused RBC
measure: Perioperative allogeneic non-RBC transfusion volume
time frame: From the operation day to the discharge, an average of 7 days
description: The overall volume of allogeneic transfused FFP，platelet，and cryoprecipitate
measure: Perioperative allogeneic non-RBC transfusion rate
time frame: From the operation day to the discharge, an average of 7 days
description: The rate of allogeneic transfused FFP，platelet，and cryoprecipitate
measure: Postoperative bleeding volume
time frame: From the operation day to the discharge, an average of 7 days
description: The total chest tube drainage postoperatively
measure: Reoperation rate for bleeding
time frame: From the operation day to the discharge, an average of 7 days
description: Reoperation due to excessive chest tube drainage or pericardial tamponade.
measure: The duration of mechanical ventilation
time frame: from the end of the operation and the extubation, an average of 24 hours
description: The time interval between the end of the operation and the extubation
measure: Length of stay in the intensive care unit
time frame: From the end of the operation and the discharge from the intensive care unit, an average of 48 hours
description: The time interval between the end of the operation and the discharge from the intensive care unit
measure: Length of stay in hospital
time frame: From the operation day to the discharge, an average of 7 days
description: The days between the operation and the discharge from the hospital
measure: Total hospitalization cost
time frame: In hospital, an average of 7 days
description: The total cost during hospitalization
measure: Thrombotic test
time frame: preoperative、4~8 hours postoperative、1st postoperative day、2nd postoperative day、3rd postoperative day
description: D-dimer level
measure: Correction Dimension of Electroencephalogram
time frame: 12 hours postoperatively
description: A reduced correction dimension of EEG indicates seizure
measure: Bispectral Index
time frame: From anesthetic induction until 12 hours postoperatively, an average of 18 hours
description: A range of 0~100 (85~100 awake, 65~85 sedation, 40~65 anesthesia, <40 burst suppression)
measure: Drug concentration in plasma and cerebrospinal fluid
time frame: Fourteen timepoints from anesthetic induction until 6 hours postoperatively
description: Two mililiter of blood sample will be obtained from the radial artery in 8 participants in the two groups respectively. Two mililiter of cerebrospinal fluid will be obtained in 8 participants receiving aortic surgery with subarachnoid drainage in the two groups respectively.
arm group label: Tranexamic Acid Dosage 1
arm group type: Experimental
description: A bolus of 30 mg/kg Tranexamic Acid for 20 min followed by a maintenance dose of 16 mg/kg/h Tranexamic Acid until the end of surgery, and a pump prime dose 2 mg/kg.
arm group label: Tranexamic Acid Dosage 2
arm group type: Active Comparator
description: A bolus of 10 mg/kg Tranexamic Acid for 20 min followed by a maintenance dose of 2 mg/kg/h Tranexamic Acid until the end of surgery, and a pump prime dose 1 mg/kg.
intervention type: Drug
intervention name: Tranexamic Acid Dosage 1
description: Tranexamic Acid Dosage 1
arm group label: Tranexamic Acid Dosage 1
other name: Cyklokapron
other name: Transamin
intervention type: Drug
intervention name: Tranexamic Acid Dosage 2
description: Tranexamic Acid Dosage 2
arm group label: Tranexamic Acid Dosage 2
other name: Cyklokapron
other name: Transamin
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Zhe Zheng, MD
role: Principal Investigator
affiliation: Chinese Academy of Medical Sciences, Fuwai Hospital
facility: 
country: China
citation: Kalisiak A, Oosterwijk E, Minniti JG, Old LJ, Scheinberg DA. A monoclonal antibody for terminal beta-galactose. Use in analysis of glycosphingolipids. Glycoconj J. 1991 Feb;8(1):55-62. doi: 10.1007/BF00731643.
PMID: 1726670
citation: Murphy GJ, Reeves BC, Rogers CA, Rizvi SI, Culliford L, Angelini GD. Increased mortality, postoperative morbidity, and cost after red blood cell transfusion in patients having cardiac surgery. Circulation. 2007 Nov 27;116(22):2544-52. doi: 10.1161/CIRCULATIONAHA.107.698977. Epub 2007 Nov 12.
PMID: 17998460
citation: Karkouti K, Wijeysundera DN, Yau TM, Beattie WS, Abdelnaem E, McCluskey SA, Ghannam M, Yeo E, Djaiani G, Karski J. The independent association of massive blood loss with mortality in cardiac surgery. Transfusion. 2004 Oct;44(10):1453-62. doi: 10.1111/j.1537-2995.2004.04144.x.
PMID: 15383018
citation: Kurt M, Tanboga IH, Isik T, Kaya A, Ekinci M, Bilen E, Can MM, Karakas MF, Bayram E, Aksakal E, Sevimli S. Comparison of transthoracic and transesophageal 2-dimensional speckle tracking echocardiography. J Cardiothorac Vasc Anesth. 2012 Feb;26(1):26-31. doi: 10.1053/j.jvca.2011.05.014. Epub 2011 Aug 11.
PMID: 21835643
citation: Henry DA, Carless PA, Moxey AJ, O'Connell D, Stokes BJ, Fergusson DA, Ker K. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev. 2011 Mar 16;2011(3):CD001886. doi: 10.1002/14651858.CD001886.pub4.
PMID: 21412876
citation: Levi M, Cromheecke ME, de Jonge E, Prins MH, de Mol BJ, Briet E, Buller HR. Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically relevant endpoints. Lancet. 1999 Dec 4;354(9194):1940-7. doi: 10.1016/S0140-6736(99)01264-7.
PMID: 10622296
citation: Brown JR, Birkmeyer NJ, O'Connor GT. Meta-analysis comparing the effectiveness and adverse outcomes of antifibrinolytic agents in cardiac surgery. Circulation. 2007 Jun 5;115(22):2801-13. doi: 10.1161/CIRCULATIONAHA.106.671222. Epub 2007 May 28.
PMID: 17533182
citation: Butler KD, Smith JR. Mechanisms of Forssman-induced bronchospasm and their inhibition. Br J Pharmacol. 1981 May;73(1):25-32. doi: 10.1111/j.1476-5381.1981.tb16767.x.
PMID: 7284697
citation: Schneeweiss S, Seeger JD, Landon J, Walker AM. Aprotinin during coronary-artery bypass grafting and risk of death. N Engl J Med. 2008 Feb 21;358(8):771-83. doi: 10.1056/NEJMoa0707571.
PMID: 18287600
citation: Fergusson DA, Hebert PC, Mazer CD, Fremes S, MacAdams C, Murkin JM, Teoh K, Duke PC, Arellano R, Blajchman MA, Bussieres JS, Cote D, Karski J, Martineau R, Robblee JA, Rodger M, Wells G, Clinch J, Pretorius R; BART Investigators. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med. 2008 May 29;358(22):2319-31. doi: 10.1056/NEJMoa0802395. Epub 2008 May 14. Erratum In: N Engl J Med. 2010 Sep 23;363(13):1290.
PMID: 18480196
citation: Society of Thoracic Surgeons Blood Conservation Guideline Task Force; Ferraris VA, Brown JR, Despotis GJ, Hammon JW, Reece TB, Saha SP, Song HK, Clough ER; Society of Cardiovascular Anesthesiologists Special Task Force on Blood Transfusion; Shore-Lesserson LJ, Goodnough LT, Mazer CD, Shander A, Stafford-Smith M, Waters J; International Consortium for Evidence Based Perfusion; Baker RA, Dickinson TA, FitzGerald DJ, Likosky DS, Shann KG. 2011 update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines. Ann Thorac Surg. 2011 Mar;91(3):944-82. doi: 10.1016/j.athoracsur.2010.11.078.
PMID: 21353044
citation: Sander M, Spies CD, Martiny V, Rosenthal C, Wernecke KD, von Heymann C. Mortality associated with administration of high-dose tranexamic acid and aprotinin in primary open-heart procedures: a retrospective analysis. Crit Care. 2010;14(4):R148. doi: 10.1186/cc9216. Epub 2010 Aug 3.
PMID: 20682059
citation: Koster A, Borgermann J, Zittermann A, Lueth JU, Gillis-Januszewski T, Schirmer U. Moderate dosage of tranexamic acid during cardiac surgery with cardiopulmonary bypass and convulsive seizures: incidence and clinical outcome. Br J Anaesth. 2013 Jan;110(1):34-40. doi: 10.1093/bja/aes310. Epub 2012 Sep 17.
PMID: 22986419
citation: Murkin JM, Falter F, Granton J, Young B, Burt C, Chu M. High-dose tranexamic Acid is associated with nonischemic clinical seizures in cardiac surgical patients. Anesth Analg. 2010 Feb 1;110(2):350-3. doi: 10.1213/ANE.0b013e3181c92b23. Epub 2009 Dec 8.
PMID: 19996135
citation: Martin K, Knorr J, Breuer T, Gertler R, Macguill M, Lange R, Tassani P, Wiesner G. Seizures after open heart surgery: comparison of epsilon-aminocaproic acid and tranexamic acid. J Cardiothorac Vasc Anesth. 2011 Feb;25(1):20-5. doi: 10.1053/j.jvca.2010.10.007.
PMID: 21272777
citation: Koster A, Schirmer U. Re-evaluation of the role of antifibrinolytic therapy with lysine analogs during cardiac surgery in the post aprotinin era. Curr Opin Anaesthesiol. 2011 Feb;24(1):92-7. doi: 10.1097/ACO.0b013e32833ff3eb.
PMID: 20881484
citation: Schlag MG, Hopf R, Zifko U, Redl H. Epileptic seizures following cortical application of fibrin sealants containing tranexamic acid in rats. Acta Neurochir (Wien). 2002 Jan;144(1):63-9. doi: 10.1007/s701-002-8275-z.
PMID: 11807648
citation: Horrow JC, Van Riper DF, Strong MD, Grunewald KE, Parmet JL. The dose-response relationship of tranexamic acid. Anesthesiology. 1995 Feb;82(2):383-92. doi: 10.1097/00000542-199502000-00009.
PMID: 7856897
citation: Sigaut S, Tremey B, Ouattara A, Couturier R, Taberlet C, Grassin-Delyle S, Dreyfus JF, Schlumberger S, Fischler M. Comparison of two doses of tranexamic acid in adults undergoing cardiac surgery with cardiopulmonary bypass. Anesthesiology. 2014 Mar;120(3):590-600. doi: 10.1097/ALN.0b013e3182a443e8.
PMID: 23903022
citation: Dowd NP, Karski JM, Cheng DC, Carroll JA, Lin Y, James RL, Butterworth J. Pharmacokinetics of tranexamic acid during cardiopulmonary bypass. Anesthesiology. 2002 Aug;97(2):390-9. doi: 10.1097/00000542-200208000-00016.
PMID: 12151929
citation: Grassin-Delyle S, Tremey B, Abe E, Fischler M, Alvarez JC, Devillier P, Urien S. Population pharmacokinetics of tranexamic acid in adults undergoing cardiac surgery with cardiopulmonary bypass. Br J Anaesth. 2013 Dec;111(6):916-24. doi: 10.1093/bja/aet255. Epub 2013 Jul 23.
PMID: 23880099
citation: Fiechtner BK, Nuttall GA, Johnson ME, Dong Y, Sujirattanawimol N, Oliver WC Jr, Sarpal RS, Oyen LJ, Ereth MH. Plasma tranexamic acid concentrations during cardiopulmonary bypass. Anesth Analg. 2001 May;92(5):1131-6. doi: 10.1097/00000539-200105000-00010.
PMID: 11323334
citation: Nuttall GA, Gutierrez MC, Dewey JD, Johnson ME, Oyen LJ, Hanson AC, Oliver WC Jr. A preliminary study of a new tranexamic acid dosing schedule for cardiac surgery. J Cardiothorac Vasc Anesth. 2008 Apr;22(2):230-5. doi: 10.1053/j.jvca.2007.12.016.
PMID: 18375325
citation: Du Y, Xu J, Wang G, Shi J, Yang L, Shi S, Lu H, Wang Y, Ji B, Zheng Z. Comparison of two tranexamic acid dose regimens in patients undergoing cardiac valve surgery. J Cardiothorac Vasc Anesth. 2014 Oct;28(5):1233-7. doi: 10.1053/j.jvca.2013.10.006. Epub 2014 Jan 18.
PMID: 24447498
responsible party type: Principal Investigator
investigator affiliation: Chinese Academy of Medical Sciences, Fuwai Hospital
investigator full name: SHI Jia
investigator title: Director, the department of Anesthesiology
mesh term: Tranexamic Acid
sharing ipd: No