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

This study has been terminated.
(Experience gained from this study is sufficient to design and facilitate the follow-on study)
Sponsor:
Information provided by (Responsible Party):
Cubist Pharmaceuticals Holdings LLC ( Cubist Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00448864
First received: March 16, 2007
Last updated: June 12, 2015
Last verified: June 2015
  Purpose

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.


Condition Intervention Phase
Blood Loss, Surgical
Drug: Ecallantide
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: KALAHARI-1: Kallikrein Antagonist (DX-88 [Ecallantide]) Effect on Blood Loss Associated With Heart Surgery Requiring Institution of Bypass

Resource links provided by NLM:


Further study details as provided by Cubist Pharmaceuticals Holdings LLC:

Primary Outcome Measures:
  • Cumulative Chest Tube Drainage During the First 12 Hours Postoperatively [ Time Frame: Up to 12 hours post admission to intensive care unit (ICU) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Up to 24 hours post admission to ICU ] [ Designated as safety issue: No ]
    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 [ Time Frame: up to 28 days post admission to ICU ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: 1, 2, 4, and 8 hours after end of study drug infusion ] [ Designated as safety issue: No ]
    Results are reported in terms of the Area Under Plasma Concentration Time Curve (AUC), measured as milligram hour per liter (mg*h/L)


Enrollment: 75
Study Start Date: May 2007
Study Completion Date: August 2008
Primary Completion Date: July 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Ecallantide - Low Dose Regimen
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.
Drug: Ecallantide
Other Name: DX-88
Experimental: 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 milliliters per hour (mL/hr) for 4 hours.
Drug: Ecallantide
Other Name: DX-88
Placebo Comparator: 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.
Drug: Placebo

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).

  Eligibility

Ages Eligible for Study:   18 Years to 85 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00448864

Locations
United States, Alabama
St. Vincent's Hospital
Birmingham, Alabama, United States, 35205
United States, Arizona
Mayo Clinic Hospital
Phoenix, Arizona, United States, 85054
United States, Colorado
University of Colorado
Aurora, Colorado, United States, 80045
United States, Massachusetts
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02215
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02115
Caritas St. Elizabeth's Medical Center
Boston, Massachusetts, United States, 02135
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
United States, New York
SUNY Upstate Medical University
Syracuse, New York, United States, 13210
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
Gaston Memorial Hospital
Gastonia, North Carolina, United States, 28054
United States, Ohio
Cleveland Clinic
Cleveland, Ohio, United States, 44195
United States, Pennsylvania
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
United States, Texas
Texas Heart Institute
Houston, Texas, United States, 77225
The Methodist Hospital
Houston, Texas, United States, 77030
Sponsors and Collaborators
Cubist Pharmaceuticals
Investigators
Study Director: Andrew L Sternlicht, MD Dyax Corp.
  More Information

No publications provided

Responsible Party: Cubist Pharmaceuticals Holdings LLC ( Cubist Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT00448864     History of Changes
Other Study ID Numbers: DX-88/16
Study First Received: March 16, 2007
Results First Received: April 22, 2015
Last Updated: June 12, 2015
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Blood Loss, Surgical
Hemorrhage
Intraoperative Complications
Pathologic Processes

ClinicalTrials.gov processed this record on July 29, 2015