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

Blood Loss, Surgical Clinical Trial

Official title:

KALAHARI-1: Kallikrein Antagonist (DX-88 [Ecallantide]) Effect on Blood Loss Associated With Heart Surgery Requiring Institution of Bypass

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00448864
• Other study ID #: 1501-001
• Secondary ID: DX-88/16
• Status: Terminated
• Phase: Phase 2
• Start date: May 1, 2007
• Est. completion date: August 1, 2008

Study information

• Verified date: June 2019
• Source: Cubist Pharmaceuticals LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 75
• Est. completion date: August 1, 2008
• Est. primary completion date: July 1, 2008
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

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

Related Conditions & MeSH terms

• Blood Loss, Surgical
• Hemorrhage

Intervention

Drug:
• Ecallantide

• Placebo

Locations

Country	Name	City	State
United States	University of Colorado	Aurora	Colorado
United States	St. Vincent's Hospital	Birmingham	Alabama
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Caritas St. Elizabeth's Medical Center	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Cleveland Clinic	Cleveland	Ohio
United States	Duke University Medical Center	Durham	North Carolina
United States	Gaston Memorial Hospital	Gastonia	North Carolina
United States	Texas Heart Institute	Houston	Texas
United States	The Methodist Hospital	Houston	Texas
United States	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania
United States	Mayo Clinic Hospital	Phoenix	Arizona
United States	Mayo Clinic	Rochester	Minnesota
United States	SUNY Upstate Medical University	Syracuse	New York

Sponsors (1)

Lead Sponsor	Collaborator
Cubist Pharmaceuticals LLC

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	Up to 12 hours post admission to intensive care unit (ICU)
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.	Up to 24 hours post admission to ICU
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.	up to 28 days post admission to ICU
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)	1, 2, 4, and 8 hours after end of study drug infusion