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Efficacy Study of Recombinant Protein (Ecallantide) to Reduce Blood Loss During Primary Coronary Bypass Grafting or Valve Repair/Replacement

Primary Purpose

Blood Loss, Surgical

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Ecallantide
Placebo
Sponsored by
Cubist Pharmaceuticals LLC
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Blood Loss, Surgical

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • St. Vincent's Hospital
  • Mayo Clinic Hospital
  • University of Colorado
  • Massachusetts General Hospital
  • Brigham and Women's Hospital
  • Caritas St. Elizabeth's Medical Center
  • Beth Israel Deaconess Medical Center
  • Mayo Clinic
  • SUNY Upstate Medical University
  • Duke University Medical Center
  • Gaston Memorial Hospital
  • Cleveland Clinic
  • Hospital of the University of Pennsylvania
  • The Methodist Hospital
  • Texas Heart Institute

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Placebo Comparator

Arm Label

Ecallantide - Low Dose Regimen

Ecallantide - High Dose Regimen

Placebo

Arm Description

Participants received a maximum of 15 milligrams (mg) ecallantide in stages. Intravenous (IV) infusion of 0.6 milligrams per milliliter (mg/mL) ecallantide was administered at 2.92 milliliters per minute (mL/min) for 20 minutes. The infusion rate was then reduced to 0.583 mL/min for 160 minutes, or until the end of cardiopulmonary bypass (CPB), whichever came first. At the termination of the initial infusion, a second infusion of 0.4 mg/mL ecallantide was started at 38 milliliters per hour (mL/hr) for 4 hours.

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 milliliters per hour (mL/hr) for 4 hours.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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)

Full Information

First Posted
March 16, 2007
Last Updated
June 17, 2019
Sponsor
Cubist Pharmaceuticals LLC
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1. Study Identification

Unique Protocol Identification Number
NCT00448864
Brief Title
Efficacy Study of Recombinant Protein (Ecallantide) to Reduce Blood Loss During Primary Coronary Bypass Grafting or Valve Repair/Replacement
Official Title
KALAHARI-1: Kallikrein Antagonist (DX-88 [Ecallantide]) Effect on Blood Loss Associated With Heart Surgery Requiring Institution of Bypass
Study Type
Interventional

2. Study Status

Record Verification Date
June 2019
Overall Recruitment Status
Terminated
Why Stopped
Experience gained from this study is sufficient to design and facilitate the follow-on study.
Study Start Date
May 1, 2007 (Actual)
Primary Completion Date
July 1, 2008 (Actual)
Study Completion Date
August 1, 2008 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Cubist Pharmaceuticals LLC

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Blood Loss, Surgical

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
75 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Ecallantide - Low Dose Regimen
Arm Type
Experimental
Arm Description
Participants received a maximum of 15 milligrams (mg) ecallantide in stages. Intravenous (IV) infusion of 0.6 milligrams per milliliter (mg/mL) ecallantide was administered at 2.92 milliliters per minute (mL/min) for 20 minutes. The infusion rate was then reduced to 0.583 mL/min for 160 minutes, or until the end of cardiopulmonary bypass (CPB), whichever came first. At the termination of the initial infusion, a second infusion of 0.4 mg/mL ecallantide was started at 38 milliliters per hour (mL/hr) for 4 hours.
Arm Title
Ecallantide - High Dose Regimen
Arm Type
Experimental
Arm Description
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 milliliters per hour (mL/hr) for 4 hours.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Ecallantide
Other Intervention Name(s)
DX-88
Intervention Type
Drug
Intervention Name(s)
Placebo
Primary Outcome Measure Information:
Title
Cumulative Chest Tube Drainage During the First 12 Hours Postoperatively
Description
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)
Secondary Outcome Measure Information:
Title
Cumulative Chest Tube Drainage at 24 Hours Postoperatively
Description
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
Title
Number of Participants With Treatment-emergent Adverse Events
Description
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
Title
Pharmacokinetics: Area Under the Concentration Time Curve
Description
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Andrew L Sternlicht, MD
Organizational Affiliation
Dyax Corp.
Official's Role
Study Director
Facility Information:
Facility Name
St. Vincent's Hospital
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35205
Country
United States
Facility Name
Mayo Clinic Hospital
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85054
Country
United States
Facility Name
University of Colorado
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Brigham and Women's Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Caritas St. Elizabeth's Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02135
Country
United States
Facility Name
Beth Israel Deaconess Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
SUNY Upstate Medical University
City
Syracuse
State/Province
New York
ZIP/Postal Code
13210
Country
United States
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
Gaston Memorial Hospital
City
Gastonia
State/Province
North Carolina
ZIP/Postal Code
28054
Country
United States
Facility Name
Cleveland Clinic
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Facility Name
Hospital of the University of Pennsylvania
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
The Methodist Hospital
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Texas Heart Institute
City
Houston
State/Province
Texas
ZIP/Postal Code
77225
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
IPD Sharing URL
http://engagezone.msd.com/ds_documentation.php

Learn more about this trial

Efficacy Study of Recombinant Protein (Ecallantide) to Reduce Blood Loss During Primary Coronary Bypass Grafting or Valve Repair/Replacement

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