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

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

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.

Study Overview

• Status: Completed
• Conditions: Cardiopulmonary Bypass; Coronary Artery Bypass Graft
• Intervention / Treatment: Drug: MDCO-2010; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Quadruple

Number of Arms

6

Arms and Interventions

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

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: The Medicines Company
• Investigators: Principal Investigator: Lars Englberger, PD Dr. Med., University Hospital Inselspital, Bern

Study record dates

Study Major Dates

• Study Start: November 1, 2010
• Primary Completion (Actual): May 1, 2011
• Study Completion (Actual): June 1, 2011

Study Registration Dates

• First Submitted: February 10, 2012
• First Submitted That Met QC Criteria: February 14, 2012
• First Posted (Estimate): February 17, 2012

Study Record Updates

• Last Update Posted (Estimate): July 19, 2012
• Last Update Submitted That Met QC Criteria: June 14, 2012
• Last Verified: June 1, 2012

More Information

Terms related to this study

• Keywords: cardiac surgery; blood loss; CABG; cardiopulmonary bypass; coronary artery bypass graft; CPB; haemostasis modulator; direct inhibitor of plasmin and plasma kallikrein
• Other Study ID Numbers: TMC-CU-10-01