Bloodloss, Surgical Procedures, Operative
Conditions
Brief summary
A Phase 2 Randomized Double-Blind Active-Controlled Study in Subjects Exposed to Cardio-pulmonary Bypass During Cardiac Surgery at High Risk of Bleeding
Interventions
DRUGEcallantide
2.25 mg/L pump prime, 0.13 mg/kg loading dose, 2.25 mg/L constant infusion
DRUGCyklokapron(R)
1000-mg loading dose followed by a continuous infusion of 400 mg/hr with an additional 500 mg added to the pump prime
Sponsors
Cubist Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Written informed consent (by study subject) prior to any study-related procedure not part of normal medical care; * Male or female between the ages of 18 and 85 years old, inclusive; and * Planned cardiac surgery using cardio-pulmonary bypass, for one of the following procedures: any repeat sternotomy; surgery to repair or replace more than one valve; combined CABG plus repair or replacement of at least one valve * If female, subject is non-lactating, and is either:Not of childbearing potential, defined as postmenopausal for at least one year or surgically sterile due to bilateral tubal ligation, bilateral oophorectomy, or hysterectomy;Of childbearing potential but is not pregnant as confirmed by negative pregnancy test at time of screening (based on the β-subunit of HCG), and is practicing the barrier method of birth control along with one of the following methods: oral or parenteral contraceptives for three months prior to study drug administration, a vasectomized partner, or abstinence from sexual intercourse.
Exclusion criteria
* Planned primary CABG, single valve repair or replacement surgery, or any off pump procedure; * Body weight \<55 kg; * Planned hypothermia (\<28ºC); * Planned transfusion in the peri-operative or post-operative periods; * Planned transfusion of pre-operatively donated autologous blood; * Female subjects who are pregnant or lactating; * Planned use of desmopressin, lysine analogs (other than study medication), atrial natriuretic hormone or recombinant activated Factor VII; * Planned use of corticosteroids in the pump prime solution; * Ejection fraction \<30% within 90 days prior to surgery; * Evidence of a myocardial infarction within 5 days prior to surgery; * History of stroke or transient ischemic attack within 3 months prior to surgery; * Hypotension or heart failure requiring the use of inotropes or mechanical devices within 24 hours prior to surgery; * Serum creatinine \>2.0 mg/dL within 48 hours prior to surgery; * Serum hepatic enzymes (aspartate aminotransferase or alanine aminotransferase) above 2.5 times the upper limit of normal for the applicable laboratory; * Hematocrit \<32% within 48 hours prior to surgery; * Platelet count below the normal range for the applicable laboratory within 14 days prior to surgery; * History of, or family history of, bleeding or clotting disorder (e.g. von Willebrand's Disease, idiopathic thrombocytopenia purpura) or thrombophilia such as anti-thrombin III deficiency or Factor V Leiden mutation; * History of heparin-induced thrombocytopenia; * Prothrombin time (PT) and/or activated partial thromboplastin time (aPTT) \>1.5 X normal range unless subject received heparin within 24 hours of test; * Serious intercurrent illness or active infection (e.g. endocarditis, sepsis, active malignancy requiring treatment); * Any previous exposure to ecallantide; * Receipt of an investigational drug or device 30 days prior to participation in the current study; * Any other condition that, in the opinion of the investigator, may compromise the safety or compliance of the subject or would preclude the subject from successful completion of the study; * Inability to comply with the protocol for the duration of the study; * Known allergy to any agent expected to be used in the intra-operative or post-operative periods; and * Administration of: Eptifibatide within 6 hours prior to surgery, Tirofiban hydrochloride within 6 hours prior to surgery, (Enoxaparin sodium or other low-molecular-weight heparin \<24 hours prior to surgery), Prasugrel within 10 days prior to surgery, Clopidogrel within 3 days prior to surgery, Ticlopidine within 7 days prior to surgery, Abciximab within 5 days prior to surgery, (Bivalirudin, argatroban or lepirudin within 6 hours prior to surgery), (Fondaparinux within 72 hours prior to surgery), Chlorpromazine within 7 days prior to surgery (Prophylactic use permitted for the prevention of deep vein thrombosis.) * Planned use of heparin bonded bypass circuits; * Known allergy or hypersensitivity to tranexamic acid or any of the other ingredients; * Disturbance of color sense; * Evidence of hematuria or any acute thromboses or thromboembolic diseases such as deep vein thrombosis, pulmonary embolism, or vertebral vein thrombosis.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Cumulative Volume of Packed Red Blood Cells Transfused | 12 hours after the end of surgery |
Secondary
| Measure | Time frame |
|---|---|
| Treatment-emergent Adverse Events. | Over the duration of the study. |
Countries
Germany, Poland, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ecallantide 2.25 mg/L pump prime, 0.13 mg/kg loading dose, 2.25 mg/L constant infusion | 120 |
| Cyklokapron(R) 1000-mg loading dose followed by a continuous infusion of 400 mg/hr with an additional 500 mg added to the pump prime | 122 |
| Total | 242 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 12 | 3 |
| Overall Study | Lost to Follow-up | 5 | 5 |
| Overall Study | Randomized Not Treated | 11 | 13 |
Baseline characteristics
| Characteristic | Cyklokapron(R) | Total | Ecallantide |
|---|---|---|---|
| Age, Continuous | 66.9 years STANDARD_DEVIATION 10.88 | 68.2 years STANDARD_DEVIATION 9.65 | 69.6 years STANDARD_DEVIATION 8.02 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 122 Participants | 242 Participants | 120 Participants |
| Sex: Female, Male Female | 50 Participants | 95 Participants | 45 Participants |
| Sex: Female, Male Male | 72 Participants | 147 Participants | 75 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 93 / 109 | 91 / 109 |
| serious Total, serious adverse events | 45 / 109 | 28 / 109 |
Outcome results
Primary
Cumulative Volume of Packed Red Blood Cells Transfused
Time frame: 12 hours after the end of surgery
Population: Modified Intent to Treat = all subjects received at least one dose and analyzed according to planned treatment assignment. 3 subjects in ecallantide group not included due to no value being present
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ecallantide | Cumulative Volume of Packed Red Blood Cells Transfused | 1223.2 mL | Standard Deviation 1334.57 |
| Cyklokapron(R) | Cumulative Volume of Packed Red Blood Cells Transfused | 623.5 mL | Standard Deviation 974.64 |
p-value: 0.001Wilcoxon (Mann-Whitney)
Secondary
Treatment-emergent Adverse Events.
Time frame: Over the duration of the study.
Population: Safety population analyzed
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ecallantide | Treatment-emergent Adverse Events. | At Least 1 Related & Serious TEAE | 4 events |
| Ecallantide | Treatment-emergent Adverse Events. | At Least 1 Severe TEAE | 38 events |
| Ecallantide | Treatment-emergent Adverse Events. | Premature Study Drug Discontinuations Due to TEAE | 2 events |
| Ecallantide | Treatment-emergent Adverse Events. | At Least 1 Related TEAE | 5 events |
| Ecallantide | Treatment-emergent Adverse Events. | Related TEAE Resulting in Discontinuation of Drug | 0 events |
| Ecallantide | Treatment-emergent Adverse Events. | TEAE Resulting in Death | 13 events |
| Ecallantide | Treatment-emergent Adverse Events. | At Least 1 Serious TEAE | 45 events |
| Ecallantide | Treatment-emergent Adverse Events. | Related TEAE Resulting in Death | 0 events |
| Ecallantide | Treatment-emergent Adverse Events. | At Least 1 TEAE | 100 events |
| Cyklokapron(R) | Treatment-emergent Adverse Events. | Related TEAE Resulting in Death | 0 events |
| Cyklokapron(R) | Treatment-emergent Adverse Events. | At Least 1 TEAE | 94 events |
| Cyklokapron(R) | Treatment-emergent Adverse Events. | At Least 1 Related TEAE | 5 events |
| Cyklokapron(R) | Treatment-emergent Adverse Events. | At Least 1 Severe TEAE | 17 events |
| Cyklokapron(R) | Treatment-emergent Adverse Events. | At Least 1 Serious TEAE | 28 events |
| Cyklokapron(R) | Treatment-emergent Adverse Events. | At Least 1 Related & Serious TEAE | 1 events |
| Cyklokapron(R) | Treatment-emergent Adverse Events. | Premature Study Drug Discontinuations Due to TEAE | 2 events |
| Cyklokapron(R) | Treatment-emergent Adverse Events. | TEAE Resulting in Death | 4 events |
| Cyklokapron(R) | Treatment-emergent Adverse Events. | Related TEAE Resulting in Discontinuation of Drug | 0 events |