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

Cardiopulmonary Bypass Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01535222
• Other study ID #: TMC-CU-10-01
• Status: Completed
• Phase: Phase 2
• First received: February 10, 2012
• Last updated: June 14, 2012
• Start date: November 2010
• Est. completion date: June 2011

Study information

• Verified date: June 2012
• Source: The Medicines Company
• Contact: n/a
• Is FDA regulated: No
• Health authority: Switzerland: Swissmedic
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 32
• Est. completion date: June 2011
• Est. primary completion date: May 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

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 e-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 Design

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

Related Conditions & MeSH terms

• Cardiopulmonary Bypass
• Coronary Artery Bypass Graft

Intervention

Drug:
• MDCO-2010
MDCO-2010 solution for infusion. Dosage: Pump priming dose; Loading dose infusion over 6 minutes; Maintenance infusion for duration of surgery
• Placebo
Commercially available NaCl

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
The Medicines Company

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of Adverse Events	Number of patients experiencing Adverse Events	7 days (day of surgery to day 7)	Yes
Primary	Incidence of Serious Adverse Events	Number of patients experiencing Serious Adverse Events	7 days (day of surgery to day 7)	Yes