Phase II Study to Compare MDCO-2010 vs Placebo and Tranexamic Acid in Patients Undergoing Cardiac Surgery
Condition: Bleeding
Intervention: MDCO 1; MDCO 2; MDCO 3; MDCO 4; Tranexamic Acid; Saline
Intervention description: MDCO-2010 will be administered as a loading dose followed by a continuous infusion until sternal closure. In addition, the CPB reservoir will be primed with MDCO-2010. MDCO 1: load 15 μg/kg; infusion 30 μg/kg/h; CPB prime 0.11 μg/mL priming volume; MDCO-2010 will be administered as a loading dose followed by a continuous infusion until sternal closure. In addition, the CPB reservoir will be primed with MDCO-2010. MDCO 2: load 30 μg/kg; infusion 60 μg/kg/h; CPB prime 0.22 μg/mL priming volume; MDCO-2010 will be administered as a loading dose followed by a continuous infusion until sternal closure. In addition, the CPB reservoir will be primed with MDCO-2010. MDCO 3: load 60 μg/kg ; infusion 120 μg/kg/h; CPB prime 0.44 μg/mL priming volume; MDCO-2010 will be administered as a loading dose followed by a continuous infusion until sternal closure. In addition, the CPB reservoir will be primed with MDCO-2010. MDCO 4: load 90 μg/kg; infusion 180 μg/kg/h; CPB prime 0.65 μg/mL priming volume; Tranexamic acid will be administered as a loading dose followed by a continuous infusion until sternal closure. In addition, the CPB reservoir will be primed with tranexamic acid. The flow rates will be the same as for MDCO-2010.; A loading dose of saline will be followed by a continuous infusion of saline until sternal closure. In addition, the CPB reservoir will be primed with saline. The flow rates will be the same as for MDCO-2010.
Intervention MeSH terms: Tranexamic Acid
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 44.0
Sex: All
Minimum age: 18 Years
Maximum age: 85 Years
Healthy volunteers: No

Summary:

      The objective of this study is to determine the dose response relationship regarding blood
      loss, PK, PD and clinical outcomes of MDCO-2010 in comparison to placebo and tranexamic acid
      in patients undergoing primary cardiac surgery with cardiopulmonary bypass. The aim of the
      study is to define minimally effective dose of MDCO-2010.
    

Eligibility criteria:

        Inclusion Criteria:

          -  For Stage 1: Planned primary isolated CABG surgery

          -  For Stage 2: Planned primary isolated CABG surgery, OR Planned primary combined CABG
             and aortic valve replacement surgery

          -  Men, aged 18 to 85 years, or Women, aged 18 to 85 years, either of postmenopausal
             status, defined as ≥1 year since last menstrual period AND if less than 65 years old
             with a negative pre-operative pregnancy test within 24 hours of surgery OR with
             medical history of hysterectomy or bilateral oophorectomy

          -  Written informed consent

        Exclusion Criteria:

          -  Off-pump surgery or hybrid procedures

          -  Patients undergoing repeat sternotomy

          -  Planned deep hypothermic circulatory arrest (<28°C)

          -  Known allergy, sensitivity, or contraindications to tranexamic acid

          -  Epileptiform disorders, history of seizure activity, or anticonvulsive medication

          -  Administration of clopidogrel, ticagrelor or ticlopidine within 5 days prior to
             surgery or prasugrel within 7 days prior to surgery.

          -  Administration of low molecular weight heparin, glycoprotein IIb/IIIa inhibitors, or
             fondaparinux within 12 hours prior to surgery

          -  Known history of coronary stent thrombosis within the last three months

          -  History of stroke or transient ischemic attack within 3 months prior to surgery

          -  History of deep venous thrombosis or pulmonary embolism

          -  LVEF ≤35% or Grade III or IV

          -  Body mass index <20 or >35

          -  Known active gastrointestinal (GI) or other non-catheterization bleeding within 7 days
             prior to surgery

          -  Preoperative coagulation abnormalities defined as:

          -  Platelet count <100,000/L or >350,000/L, or

          -  International normalized ration (INR) >1.5, or

          -  Hematocrit <36%, or

          -  aPTT >1.5 x ULN

          -  Major surgical procedures within 30 days prior to surgery

          -  Patient inability or refusal to receive donor blood products if necessary

          -  Creatinine >2 mg/dL or estimated glomerular filtration rate (eGFR) (calculated using
             Modification of Diet in Renal Disease [MDRD] equation <30 mL/min)

          -  Known heparin-induced thrombocytopenia type II

          -  Known history of thrombophilia, such as AT-III, Protein C or Protein S deficiency,
             Factor V Leiden, anti-phospholipid syndrome

          -  Active liver disease defined as any known current infectious, neoplastic or metabolic
             pathology of the liver OR ALT or AST elevation >2x ULN or total bilirubin elevation
             >1.5x ULN at Screening

          -  Any condition requiring ongoing chronic immunosuppressive medication

          -  Malignancy within 5 years prior to surgery

          -  Receipt of an investigational drug or device within 60 days prior to surgery Any other
             condition which, in the opinion of the Principal Investigator, would put the subject
             at increased risk from participating in the study or otherwise prevent a patient"s
             participation in the study