Phase II Study to Compare MDCO-2010 vs Placebo and Tranexamic Acid in Patients Undergoing Cardiac Surgery

Study Overview
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Brief Summary
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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.

Detailed Description
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This was a two-stage, double-blind, randomized, parallel-group, multicenter Phase II dose-selection study to compare antifibrinolytic MDCO-2010 vs tranexamic acid and placebo in reducing blood loss. This study was designed to examine a broad range of doses to fully characterize the dose-response relationship between MDCO-2010 dose, plasma PK, PD, and clinical effects. In Stage 1, 90 patients were to be enrolled into one of six treatment groups with 15 patients per group: four groups were to receive MDCO-2010, one group was to receive tranexamic acid, and one group was to receive placebo. Stage 2 was to be an expansion of Stage 1. The study was terminated after 49 patients were enrolled into Stage 1.

Official Title
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A Phase II, Double-blind, Parallel Group, Dose-selection Study to Compare Antifibrinolytic MDCO-2010 vs. Placebo and Tranexamic Acid in Reducing Blood Loss in Patients Undergoing Primary Cardiac Surgery

Conditions
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Bleeding

Intervention / Treatment
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* Drug: MDCO 1
* Drug: MDCO 2
* Drug: MDCO 3
* Drug: MDCO 4
* Drug: Tranexamic Acid
* Drug: Saline


Participation Criteria
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Eligibility Criteria
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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 patients participation in the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MDCO 1<br>MDCO-2010: load 15 μg/kg; infusion 30 μg/kg/h; CPB prime 0.11 μg/mL priming volume | Drug: MDCO 1<br>* 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<br>* Other names: MDCO-2010;|
| Experimental: MDCO 2<br>MDCO-2010: load 30 μg/kg; infusion 60 μg/kg/h; CPB prime 0.22 μg/mL priming volume | Drug: MDCO 2<br>* 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<br>* Other names: MDCO-2010;|
| Experimental: MDCO 3<br>MDCO-2010: load 60 μg/kg ; infusion 120 μg/kg/h; CPB prime 0.44 μg/mL priming volume | Drug: MDCO 3<br>* 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<br>* Other names: MDCO-2010;|
| Experimental: MDCO 4<br>MDCO-2010: load 90 μg/kg; infusion 180 μg/kg/h; CPB prime 0.65 μg/mL priming volume | Drug: MDCO 4<br>* 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<br>* Other names: MDCO-2010;|
| Placebo Comparator: Saline<br>Commercially available saline (0.9% NaCl solution) | Drug: Tranexamic Acid<br>* 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.<br>* Other names: TXA;|
| Active Comparator: Tranexamic acid<br>Tranexamic acid: 12 mg/kg loading dose; 5 mg/kg/h infusion; 0.556 mg/mL CPB priming | Drug: Saline<br>* 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.<br>* Other names: NaCl 0.9%;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Chest Tube Drainage at 12 Hours After Surgery |  | 12 hours post CABG |