Bloodloss, Surgical Procedures, Operative
Conditions
Brief summary
The purpose of this study is to assess the efficacy and identify the optimal dose(s) of ecallantide in reducing blood loss in subjects undergoing coronary artery bypass surgery including the use of cardio pulmonary bypass.
Interventions
DRUGecallantide
infusion administered IV over the duration of the surgical procedure
DRUGplacebo
solution for IV infusion over the duration of the surgical\>\> procedure
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 or appropriate legal representative) prior to any study-related procedure not part of normal medical care * Planned primary CABG surgery including the use of cardio-pulmonary bypass.
Exclusion criteria
* Planned concomitant surgery including ASD repair, valve replacement, carotid endarterectomy, CABG combined procedures or any repeat sternotomy; * 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, 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 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 or thrombophilia; * History of heparin-induced thrombocytopenia; * Prothrombin time and/or activated partial thromboplastin time \>1.5 X normal range; * Serious intercurrent illness or active infection; * Any previous exposure to ecallantide; * Receipt of an investigational drug or device 30 days prior to participation in the current 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 HCl within 6 hours prior to surgery, \*Enoxaparin sodium or other low-molecular-weight heparin \<24 hours prior to surgery, Clopidogrel within 5 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, Prasugrel within 10 days prior to surgery \[\*Prophylactic use permitted for the prevention of deep vein thrombosis.\]
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Cumulative Volume of Packed Red Blood Cells Transfused at 12 Hours Post Surgery | Start of surgery up to 12 hours after the end of surgery |
Secondary
| Measure | Time frame |
|---|---|
| Treatment-emergent Adverse Events | Over the duration of the study. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ecallantide Low Dose target steady state concentration of 0.15 mg/L | 71 |
| Ecallantide Medium Dose target steady state concentration of 0.75 mg/L | 62 |
| Ecallantide High Dose target steady state concentration of 2.25 mg/L | 69 |
| Placebo | 74 |
| Total | 276 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | assessments complete prior to window | 1 | 1 | 2 | 1 |
| Overall Study | Lost to Follow-up | 1 | 1 | 0 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 1 | 0 |
| Overall Study | Randomized Not Treated | 6 | 4 | 6 | 11 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Ecallantide Low Dose | Total | Placebo | Ecallantide High Dose | Ecallantide Medium Dose |
|---|---|---|---|---|---|
| Age, Continuous | 63.1 years STANDARD_DEVIATION 9.96 | 63.4 years STANDARD_DEVIATION 10.15 | 63.6 years STANDARD_DEVIATION 10.9 | 63.2 years STANDARD_DEVIATION 10.73 | 63.9 years STANDARD_DEVIATION 9.4 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 4 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 18 Participants | 3 Participants | 5 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 66 Participants | 252 Participants | 71 Participants | 61 Participants | 54 Participants |
| Sex: Female, Male Female | 13 Participants | 54 Participants | 11 Participants | 15 Participants | 15 Participants |
| Sex: Female, Male Male | 58 Participants | 222 Participants | 63 Participants | 54 Participants | 47 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 62 / 62 | 59 / 59 | 65 / 65 | 63 / 63 |
| serious Total, serious adverse events | 19 / 62 | 19 / 59 | 15 / 65 | 15 / 63 |
Outcome results
Primary
Cumulative Volume of Packed Red Blood Cells Transfused at 12 Hours Post Surgery
Time frame: Start of surgery up to 12 hours after the end of surgery
Population: The Modified Intent to Treat population was the basis of this analysis, defined as all randomized subjects who received any amount of study drug and analyzed according to the planned treatment assignment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ecallantide Low Dose | Cumulative Volume of Packed Red Blood Cells Transfused at 12 Hours Post Surgery | 401.9 mL | Standard Deviation 624.87 |
| Ecallantide Medium Dose | Cumulative Volume of Packed Red Blood Cells Transfused at 12 Hours Post Surgery | 383.1 mL | Standard Deviation 620.62 |
| Ecallantide High Dose | Cumulative Volume of Packed Red Blood Cells Transfused at 12 Hours Post Surgery | 410.3 mL | Standard Deviation 639.47 |
| Placebo | Cumulative Volume of Packed Red Blood Cells Transfused at 12 Hours Post Surgery | 377.6 mL | Standard Deviation 608.54 |
p-value: 0.474Jonckheere-Terpstra
Secondary
Treatment-emergent Adverse Events
Time frame: Over the duration of the study.
Population: Analysis conducted on Safety population, defined as all subjects randomized and received any study drug. Treatment groups are based on actual treatment received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ecallantide Low Dose | Treatment-emergent Adverse Events | At least 1 TEAE | 65 participants |
| Ecallantide Low Dose | Treatment-emergent Adverse Events | At least 1 Treatment-related SAE | 1 participants |
| Ecallantide Low Dose | Treatment-emergent Adverse Events | Treatment-related TEAE Resulting in Death | 0 participants |
| Ecallantide Low Dose | Treatment-emergent Adverse Events | At least 1 Treatment-related AE | 7 participants |
| Ecallantide Low Dose | Treatment-emergent Adverse Events | TEAE Resulting on Discontinuation of Study Drug | 0 participants |
| Ecallantide Low Dose | Treatment-emergent Adverse Events | At least 1 AE of Severe Intensity | 11 participants |
| Ecallantide Low Dose | Treatment-emergent Adverse Events | At least 1 Treatment-emergent SAE | 15 participants |
| Ecallantide Low Dose | Treatment-emergent Adverse Events | TEAE Resulting in Death | 0 participants |
| Ecallantide Medium Dose | Treatment-emergent Adverse Events | At least 1 TEAE | 59 participants |
| Ecallantide Medium Dose | Treatment-emergent Adverse Events | At least 1 Treatment-emergent SAE | 19 participants |
| Ecallantide Medium Dose | Treatment-emergent Adverse Events | At least 1 Treatment-related SAE | 3 participants |
| Ecallantide Medium Dose | Treatment-emergent Adverse Events | At least 1 AE of Severe Intensity | 13 participants |
| Ecallantide Medium Dose | Treatment-emergent Adverse Events | TEAE Resulting in Death | 1 participants |
| Ecallantide Medium Dose | Treatment-emergent Adverse Events | Treatment-related TEAE Resulting in Death | 0 participants |
| Ecallantide Medium Dose | Treatment-emergent Adverse Events | TEAE Resulting on Discontinuation of Study Drug | 0 participants |
| Ecallantide Medium Dose | Treatment-emergent Adverse Events | At least 1 Treatment-related AE | 9 participants |
| Ecallantide High Dose | Treatment-emergent Adverse Events | TEAE Resulting on Discontinuation of Study Drug | 1 participants |
| Ecallantide High Dose | Treatment-emergent Adverse Events | TEAE Resulting in Death | 0 participants |
| Ecallantide High Dose | Treatment-emergent Adverse Events | At least 1 Treatment-related AE | 4 participants |
| Ecallantide High Dose | Treatment-emergent Adverse Events | Treatment-related TEAE Resulting in Death | 0 participants |
| Ecallantide High Dose | Treatment-emergent Adverse Events | At least 1 AE of Severe Intensity | 15 participants |
| Ecallantide High Dose | Treatment-emergent Adverse Events | At least 1 TEAE | 62 participants |
| Ecallantide High Dose | Treatment-emergent Adverse Events | At least 1 Treatment-emergent SAE | 19 participants |
| Ecallantide High Dose | Treatment-emergent Adverse Events | At least 1 Treatment-related SAE | 1 participants |
| Placebo | Treatment-emergent Adverse Events | Treatment-related TEAE Resulting in Death | 0 participants |
| Placebo | Treatment-emergent Adverse Events | At least 1 TEAE | 63 participants |
| Placebo | Treatment-emergent Adverse Events | At least 1 Treatment-related AE | 7 participants |
| Placebo | Treatment-emergent Adverse Events | At least 1 AE of Severe Intensity | 16 participants |
| Placebo | Treatment-emergent Adverse Events | At least 1 Treatment-emergent SAE | 15 participants |
| Placebo | Treatment-emergent Adverse Events | At least 1 Treatment-related SAE | 1 participants |
| Placebo | Treatment-emergent Adverse Events | TEAE Resulting on Discontinuation of Study Drug | 0 participants |
| Placebo | Treatment-emergent Adverse Events | TEAE Resulting in Death | 0 participants |