Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MDCO-2010 in Patients Undergoing Elective Coronary Artery Bypass Graft Surgery

Study Overview
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Brief Summary
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The purpose of this study is to demonstrate that periprocedural infusion of escalating doses of MDCO-2010 is safe and tolerated in patients undergoing elective CABG surgery, to characterize the single dose pharmacokinetics of MDCO-2010, to investigate the effect of MDCO-2010 on pharmacodynamics (biomarkers of fibrinolysis and coagulation parameters), and to investigate the effect on exploratory clinical endpoints of bleeding, transfusion requirements and reexploration.

Detailed Description
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This protocol describes a study of the investigational drug MDCO-2010 as a haemostasis modulator in patients undergoing elective Coronary Artery Bypass Graft (CABG) surgery involving a cardiopulmonary bypass (CPB). Perioperative bleeding is a serious complication that adversely affects the morbidity and mortality of cardiac surgery. To alleviate this complication, prophylactic antifibrinolytic therapies are now widely accepted as a strategy to inhibit excessive fibrinolysis. MDCO-2010, a synthetic small molecule, is a direct inhibitor of plasmin and plasma kallikrein. Both of these have been implicated with impaired haemostasis. In addition, potent inhibition of coagulation factors Xa, XIa and activated Protein C has been demonstrated. Thus, MDCO-2010 has the potential to mitigate excessive fibrinolysis and thrombin generation during cardiac surgery involving a cardiopulmonary bypass. In particular the latter is supposed to provide additional benefits beyond reducing transfusion requirements.

Official Title
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A Double-blind, Placebo-controlled, Randomized, Single Ascending Dose Study of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MDCO-2010 in Patients Undergoing Elective CABG Surgery

Conditions
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Coronary Artery Bypass Graft, Cardiopulmonary Bypass

Intervention / Treatment
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* Drug: MDCO-2010
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Men, aged 18 to 80 years or Post-menopausal women, aged up to 80 years. Postmenopausal status defined as ≥ 1 year since last menstruation in women with no medical history of hysterectomy or women with a medical history of bilateral oophorectomy Planned elective, isolated primary CABG surgery with more than 1 graft, including the use of cardiopulmonary bypass Written informed consent prior to any study-related procedure not part of normal medical care Exclusion Criteria Patients may not meet any of the following exclusion criteria: Planned concomitant surgery including atrial septal defect (ASD) repair, valve replacement, carotid endarterectomy, aortic surgery, any combined procedure or any repeat sternotomy Planned Off-pump CABG Body weight < 55 kg or > 110 kg Planned hypothermia < 28°C Major surgical procedures within 30 days of entry Placement of drug-eluting stent (DES) within 12 months or of bare-metal stent (BMS) within 6 weeks of entry in a vessel which is not intended to be grafted Ejection fraction < 35% Preoperative coagulation abnormalities Platelet count < 100,000/cubic mm, or INR > 1.5 or Quick < 40%, or activated partial thromboplastin time (aPTT) > 1.5 x upper limit of normal (ULN) Preoperative Hb < 11 g/dL for male patients or < 10 g/dL for female patients Patient refusal to receive donor blood products if necessary Administration of thienopyridines within 5 days prior to surgery Administration of warfarin within 5 days prior to surgery Administration of tirofiban or eptifibatide within 24 hours or administration of abciximab within 5 days prior to surgery Administration of fondaparinux within 24 hours prior to surgery Creatinine clearance (calculated using Cockroft-Gault equation) < 60 mL/min Planned intraoperative use of tranexamic acid or of ε-aminocaproic acid History of stroke or transient ischemic attack within 3 months prior to entry Known heparin-induced thrombocytopenia Known history of thrombophilia, eg, deep vein thrombosis (DVT) with pulmonary embolism Active liver disease Any condition requiring chronic immunosuppressive medication Receipt of an investigational drug or device 30 days prior to entry Any other condition which, in the opinion of the investigator, would prevent a patient's participation in the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Single Group Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>3 patients: loading dose 0.005 mg/kg; infusion 0.0125 mg/kg/h; pump prime 0.02 mg | Drug: MDCO-2010<br>* MDCO-2010 solution for infusion. Dosage: Pump priming dose; Loading dose infusion over 6 minutes; Maintenance infusion for duration of surgery<br>* Other names: CU-2010;|
| Experimental: Cohort 2<br>3 pts: loading dose 0.011 mg/kg; infusion 0.0250 mg/kg/h; pump prime 0.04 mg | Drug: MDCO-2010<br>* MDCO-2010 solution for infusion. Dosage: Pump priming dose; Loading dose infusion over 6 minutes; Maintenance infusion for duration of surgery<br>* Other names: CU-2010;|
| Experimental: Cohort 3<br>6 patients: loading dose 0.027 mg/kg; infusion 0.0625 mg/kg/h; pump prime 0.09 mg | Drug: MDCO-2010<br>* MDCO-2010 solution for infusion. Dosage: Pump priming dose; Loading dose infusion over 6 minutes; Maintenance infusion for duration of surgery<br>* Other names: CU-2010;|
| Experimental: Cohort 4<br>6 patients: loading dose 0.054 mg/kg; infusion 0.1250 mg/kg/h; pump prime 0.18mg | Drug: MDCO-2010<br>* MDCO-2010 solution for infusion. Dosage: Pump priming dose; Loading dose infusion over 6 minutes; Maintenance infusion for duration of surgery<br>* Other names: CU-2010;|
| Experimental: Cohort 5<br>6 patients: loading dose 0.108 mg/kg; infusion 0.2500 mg/kg/h; pump prime 0.35 mg | Drug: MDCO-2010<br>* MDCO-2010 solution for infusion. Dosage: Pump priming dose; Loading dose infusion over 6 minutes; Maintenance infusion for duration of surgery<br>* Other names: CU-2010;|
| Placebo Comparator: Placebo<br>8 patients: commercially available NaCl as matching placebo to MDCO-2010 administered as IV infusion | Drug: Placebo<br>* Commercially available NaCl<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events | Number of patients experiencing Adverse Events | 7 days (day of surgery to day 7) | 
| Incidence of Serious Adverse Events | Number of patients experiencing Serious Adverse Events | 7 days (day of surgery to day 7) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cardiac surgery, coronary artery bypass graft, cardiopulmonary bypass, haemostasis modulator, blood loss, direct inhibitor of plasmin and plasma kallikrein, CABG, CPB