Clinical trial NCT01535222: Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MDCO-2010 in Patients Undergoing Elective Coronary Artery Bypass Graft Surgery
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Coronary Artery Bypass Graft
Cardiopulmonary Bypass
Keywords: cardiac surgery
coronary artery bypass graft
cardiopulmonary bypass
haemostasis modulator
blood loss
direct inhibitor of plasmin and plasma kallikrein
CABG
CPB
Lead sponsor: The Medicines Company
Sponsor class: INDUSTRY
First posted: 2012-02-17
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

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 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

Primary outcomes:
measure: Incidence of Adverse Events
timeFrame: 7 days (day of surgery to day 7)
measure: Incidence of Serious Adverse Events
timeFrame: 7 days (day of surgery to day 7)
Secondary outcomes:
Other outcomes:
Locations:
Study officials:
affiliation: Insel Gruppe AG, University Hospital Bern
name: Lars Englberger, PD Dr. Med.
role: PRINCIPAL_INVESTIGATOR
References: