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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
The Medicines Company
ClinicalTrials.gov Identifier:
NCT01535222
First received: February 10, 2012
Last updated: June 14, 2012
Last verified: June 2012
History of Changes
  Purpose

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.


Condition Intervention Phase
Coronary Artery Bypass Graft
Cardiopulmonary Bypass
 Drug: MDCO-2010
Drug: Placebo
 Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:

U.S. FDA Resources

Further study details as provided by The Medicines Company:

Primary Outcome Measures:
  • Incidence of Adverse Events [ Time Frame: 7 days (day of surgery to day 7) ] [ Designated as safety issue: Yes ]
    Number of patients experiencing Adverse Events

  • Incidence of Serious Adverse Events [ Time Frame: 7 days (day of surgery to day 7) ] [ Designated as safety issue: Yes ]
    Number of patients experiencing Serious Adverse Events


Enrollment: 32
Study Start Date: November 2010
Study Completion Date: June 2011
Primary Completion Date: May 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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

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.

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01535222

Sponsors and Collaborators
The Medicines Company
Investigators
Principal Investigator: Lars Englberger, PD Dr. Med. University Hospital/ Inselspital Bern
  More Information

No publications provided

Responsible Party: The Medicines Company
ClinicalTrials.gov Identifier: NCT01535222     History of Changes
Other Study ID Numbers: TMC-CU-10-01
Study First Received: February 10, 2012
Results First Received: June 14, 2012
Last Updated: June 14, 2012
Health Authority: Switzerland: Swissmedic

Keywords provided by The Medicines Company:
cardiac surgery
coronary artery bypass graft
cardiopulmonary bypass
haemostasis modulator
 blood loss
direct inhibitor of plasmin and plasma kallikrein
CABG
CPB

ClinicalTrials.gov processed this record on May 22, 2013