Cardiopulmonary Bypass, Coronary Artery Bypass Graft
Conditions
Keywords
cardiac surgery, coronary artery bypass graft, cardiopulmonary bypass, haemostasis modulator, blood loss, direct inhibitor of plasmin and plasma kallikrein, CABG, CPB
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.
Interventions
DRUGMDCO-2010
MDCO-2010 solution for infusion. Dosage: Pump priming dose; Loading dose infusion over 6 minutes; Maintenance infusion for duration of surgery
DRUGPlacebo
Commercially available NaCl
Sponsors
The Medicines Company
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Adverse Events | 7 days (day of surgery to day 7) | Number of patients experiencing Adverse Events |
| Incidence of Serious Adverse Events | 7 days (day of surgery to day 7) | Number of patients experiencing Serious Adverse Events |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 loading dose 0.005 mg/kg; infusion 0.0125 mg/kg/h; pump prime 0.02 mg | 3 |
| Cohort 2 loading dose 0.011 mg/kg; infusion 0.0250 mg/kg/h; pump prime 0.04 mg | 3 |
| Cohort 3 loading dose 0.027 mg/kg; infusion 0.0625 mg/kg/h; pump prime 0.09 mg | 7 |
| Cohort 4 loading dose 0.054 mg/kg; infusion 0.1250 mg/kg/h; pump prime 0.18mg | 6 |
| Cohort 5 loading dose 0.108 mg/kg; infusion 0.2500 mg/kg/h; pump prime 0.35 mg | 6 |
| Placebo commercially available NaCl as matching placebo to MDCO-2010 administered as IV infusion | 8 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Inclusion/exclusion | 0 | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Cohort 2 | Cohort 3 | Cohort 4 | Cohort 1 | Cohort 5 | Placebo | Total |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 3 Participants | 3 Participants | 1 Participants | 3 Participants | 5 Participants | 17 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 4 Participants | 3 Participants | 2 Participants | 3 Participants | 3 Participants | 16 Participants |
| Age Continuous | 62 years STANDARD_DEVIATION 10.8 | 59 years STANDARD_DEVIATION 8.3 | 68 years STANDARD_DEVIATION 9.6 | 63.3 years STANDARD_DEVIATION 12.1 | 63.2 years STANDARD_DEVIATION 12.4 | 65.9 years STANDARD_DEVIATION 5.6 | 63.9 years STANDARD_DEVIATION 9.2 |
| Region of Enrollment Switzerland | 3 participants | 7 participants | 6 participants | 3 participants | 6 participants | 8 participants | 33 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 3 Participants | 0 Participants | 5 Participants |
| Sex: Female, Male Male | 3 Participants | 7 Participants | 4 Participants | 3 Participants | 3 Participants | 8 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 5 / 6 | 4 / 6 | 6 / 6 | 7 / 8 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 | 1 / 6 | 0 / 6 | 2 / 6 | 0 / 8 |
Outcome results
Primary
Incidence of Adverse Events
Number of patients experiencing Adverse Events
Time frame: 7 days (day of surgery to day 7)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | Incidence of Adverse Events | 3 participants |
| Cohort 2 | Incidence of Adverse Events | 3 participants |
| Cohort 3 | Incidence of Adverse Events | 5 participants |
| Cohort 4 | Incidence of Adverse Events | 4 participants |
| Cohort 5 | Incidence of Adverse Events | 6 participants |
| Placebo | Incidence of Adverse Events | 7 participants |
Primary
Incidence of Serious Adverse Events
Number of patients experiencing Serious Adverse Events
Time frame: 7 days (day of surgery to day 7)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | Incidence of Serious Adverse Events | 0 participants |
| Cohort 2 | Incidence of Serious Adverse Events | 0 participants |
| Cohort 3 | Incidence of Serious Adverse Events | 1 participants |
| Cohort 4 | Incidence of Serious Adverse Events | 0 participants |
| Cohort 5 | Incidence of Serious Adverse Events | 2 participants |
| Placebo | Incidence of Serious Adverse Events | 0 participants |