Blood Loss, Surgical
Conditions
Brief summary
The primary objective of this study was to assess the efficacy and safety of 2 dose levels of ecallantide versus placebo in reducing blood loss following cardiopulmonary bypass (CPB), as measured by chest tube drainage during the first 12 hours postoperatively or until the chest tube was removed, whichever came first, in patients undergoing primary coronary artery bypass grafting (CABG), single valve repair, or single valve replacement. The secondary objective was to compare the efficacy of all ecallantide-treated participants (pooled high and low-doses) to placebo and to compare the high-dose to the low-dose ecallantide group. Other secondary objectives were to evaluate pharmacokinetics and antibody formation.
Detailed description
This was a Phase 2, randomized, double-blind, placebo-controlled, multi-center study designed to assess the efficacy and safety of 2 dose levels of ecallantide compared to placebo in reducing chest tube drainage in participants requiring CPB for primary CABG, single valve repair, or single valve replacement. Participants were randomized in a 3:3:2 ratio to ecallantide high-dose regimen (maximum 91 mg), ecallantide low-dose regimen (maximum 15 mg), or placebo. Randomization was stratified by surgical procedure so that participants undergoing valve replacement would be evenly distributed across treatment arms. Each participant received active drug or placebo administered in stages on the day of the surgical procedure after induction of anesthesia (Day 1). Participants were screened up to 14 days prior to surgery. Additional study procedures were conducted on Day -1 or 1, peri-operatively, during the immediate postoperative period, and on Days 2, 4, and 7 (or at the time of discharge from the hospital), and between Days 28 and 43 (follow-up).
Interventions
DRUGEcallantide
DRUGPlacebo
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
* Men and women ≥18 to ≤85 years of age * Elective primary coronary artery bypass grafting (CABG), single valve repair, or single valve replacement requiring CPB and full sternotomy * No plan to use desmopressin acetate (DDAVP), atrial natriuretic hormone, E-aminocaproic acid (EACA), tranexamic acid, or aprotinin during or postoperatively * Female participants must be non-lactating and not pregnant * If of childbearing potential, female participants must agree to use adequate contraception for 1 month after receiving study drug
Exclusion criteria
* Concomitant surgery including but not limited to atrial septal defect repair, multiple valve replacement, carotid endarterectomy, and combined CABG and valve procedure * Planned hypothermic CPB using temperatures less than 28 degrees Celsius * Weight \<55 kilograms (kg) * Major end organ dysfunction, defined as: * Cardiac: * Left ventricular ejection fraction (LVEF) \< 30% by left ventriculography, echocardiogram, or catheterization (within 90 days prior to screening) * Use of positive IV inotropic agents within 12 hours prior to surgery * Preoperative use of intra-aortic balloon pump (IABP), left ventricular assist device (LVAD), or extracorporeal membrane oxygenation (ECMO) * Renal: Serum creatinine \> 1.5 milligrams per deciliter (mg/dL) * Hepatic: Aspartate aminotransferase (AST) or alanine transferase (ALT) \> 2.5 x upper limit normal * Hematologic: * Preoperative hematocrit (Hct) \< 30% * Platelet count \< 100,000/mm\^3 * Planned transfusion during surgical procedure * History or family history of bleeding or clotting disorder (for example, von Willebrand's Disease, idiopathic thrombocytopenia purpura (ITP), thrombotic thrombocytopenia purpura (TTP), hematologic malignancy) * Prothrombin time (PT) or activated partial thromboplastin time * (aPTT) \> 1.5 x normal range; if receiving unfractionated heparin preoperatively, then abnormal preoperative PT/aPTT permitted * Serious intercurrent illness or active infection * Previous exposure to ecallantide * Known allergy to ecallantide or any of its components, fentanyl, midazolam, isoflurane, propofol, morphine, heparin, or protamine * Autologous blood donation ≤ 30 days month prior to surgery * Known substance abuse within 6 months prior to surgery * Receipt of an investigational drug or device within 30 days prior to participation in the current study * Administration of: * Eptifibatide \< 12 hours prior to surgery * Tirofiban hydrochloride (HCl) \< 12 hours prior to surgery * Enoxaparin sodium or other low- molecular-weight heparin \< 24 hours prior to surgery * Clopidogrel \<5 days prior to surgery * Warfarin \<5 days prior to surgery (Warfarin must be discontinued 5 days prior to surgery and PT must be \< 18 seconds) * Ticlopidine \<7 days prior to surgery * Abciximab \<24 hours prior to surgery
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative Chest Tube Drainage During the First 12 Hours Postoperatively | Up to 12 hours post admission to intensive care unit (ICU) | Mean volume of chest tube drainage during the first 12 hours postoperatively or until chest tube removal, whichever occurred first, is presented for each treatment group. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events | up to 28 days post admission to ICU | A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. |
| Cumulative Chest Tube Drainage at 24 Hours Postoperatively | Up to 24 hours post admission to ICU | Mean volume of chest tube drainage during the first 24 hours postoperatively or until chest tube removal, whichever occurred first, is presented for each treatment group. |
| Pharmacokinetics: Area Under the Concentration Time Curve | 1, 2, 4, and 8 hours after end of study drug infusion | Results are reported in terms of the Area Under Plasma Concentration Time Curve (AUC), measured as milligram hour per liter (mg\*h/L) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ecallantide - Low Dose Regimen Participants received a maximum of 15 mg ecallantide in stages. IV infusion of 0.6 mg/mL ecallantide was administered at 2.92 mL/min for 20 minutes. The infusion rate was then reduced to 0.583 mL/min for 160 minutes, or until the end of CPB, whichever came first. At the termination of the initial infusion, a second infusion of 0.4 mg/mL ecallantide was started at 38 mL/hr for 4 hours. | 26 |
| Ecallantide - High Dose Regimen Participants received a maximum of 91 mg ecallantide in stages. IV infusion of 0.6 mg/mL ecallantide was administered at 2.92 mL/min for 20 minutes. The infusion rate was then reduced to 0.583 mL/min for 160 minutes, or until the end of CPB, whichever came first. At the termination of the initial infusion, an infusion of normal saline was started at 38 mL/hr for 4 hours. | 25 |
| Placebo Participants received placebo in stages. IV infusion placebo was administered at 2.92 mL/min for 20 minutes. The infusion rate was then reduced to 0.583 mL/min for 160 minutes, or until the end of CPB, whichever came first. At the termination of the initial infusion, a second infusion of placebo was started at 38 mL/hr for 4 hours. | 18 |
| Total | 69 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 3 | 1 | 0 |
| Overall Study | Physician Decision | 1 | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 2 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 2 | 0 |
Baseline characteristics
| Characteristic | Total | Ecallantide - Low Dose Regimen | Ecallantide - High Dose Regimen | Placebo |
|---|---|---|---|---|
| Age, Categorical BTWN | 44 Participants | 17 Participants | 16 Participants | 11 Participants |
| Age, Categorical GTE65 | 25 Participants | 9 Participants | 9 Participants | 7 Participants |
| Age, Categorical LTE18 | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 14 Participants | 4 Participants | 7 Participants | 3 Participants |
| Sex: Female, Male Male | 55 Participants | 22 Participants | 18 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 25 / 26 | 23 / 25 | 18 / 18 |
| serious Total, serious adverse events | 9 / 26 | 4 / 25 | 7 / 18 |
Outcome results
Primary
Cumulative Chest Tube Drainage During the First 12 Hours Postoperatively
Mean volume of chest tube drainage during the first 12 hours postoperatively or until chest tube removal, whichever occurred first, is presented for each treatment group.
Time frame: Up to 12 hours post admission to intensive care unit (ICU)
Population: All participants who received at least 1 dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ecallantide - Low Dose Regimen | Cumulative Chest Tube Drainage During the First 12 Hours Postoperatively | 729.9 Milliliters | Standard Deviation 432.03 |
| Ecallantide - High Dose Regimen | Cumulative Chest Tube Drainage During the First 12 Hours Postoperatively | 935.8 Milliliters | Standard Deviation 510.18 |
| Placebo | Cumulative Chest Tube Drainage During the First 12 Hours Postoperatively | 1400.7 Milliliters | Standard Deviation 1371.65 |
Secondary
Cumulative Chest Tube Drainage at 24 Hours Postoperatively
Mean volume of chest tube drainage during the first 24 hours postoperatively or until chest tube removal, whichever occurred first, is presented for each treatment group.
Time frame: Up to 24 hours post admission to ICU
Population: All participants who received at least 1 dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ecallantide - Low Dose Regimen | Cumulative Chest Tube Drainage at 24 Hours Postoperatively | 82.9 Milliliters | Standard Deviation 74.99 |
| Ecallantide - High Dose Regimen | Cumulative Chest Tube Drainage at 24 Hours Postoperatively | 149.8 Milliliters | Standard Deviation 132.27 |
| Placebo | Cumulative Chest Tube Drainage at 24 Hours Postoperatively | 225.3 Milliliters | Standard Deviation 453.6 |
Secondary
Number of Participants With Treatment-emergent Adverse Events
A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.
Time frame: up to 28 days post admission to ICU
Population: All participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ecallantide - Low Dose Regimen | Number of Participants With Treatment-emergent Adverse Events | 25 participants |
| Ecallantide - High Dose Regimen | Number of Participants With Treatment-emergent Adverse Events | 23 participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events | 18 participants |
Secondary
Pharmacokinetics: Area Under the Concentration Time Curve
Results are reported in terms of the Area Under Plasma Concentration Time Curve (AUC), measured as milligram hour per liter (mg\*h/L)
Time frame: 1, 2, 4, and 8 hours after end of study drug infusion
Population: All participants who received at least 1 dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ecallantide - Low Dose Regimen | Pharmacokinetics: Area Under the Concentration Time Curve | 1.39 mg*h/L | Standard Deviation 0.589 |
| Ecallantide - High Dose Regimen | Pharmacokinetics: Area Under the Concentration Time Curve | 13.6 mg*h/L | Standard Deviation 3.58 |