KALAHARI-1: Kallikrein Antagonist (DX-88 [Ecallantide]) Effect on Blood Loss Associated With Heart Surgery Requiring Institution of Bypass
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 发起方
- 入组人数
- 75
- 试验地点
- 15
- 主要终点
- Cumulative Chest Tube Drainage During the First 12 Hours Postoperatively
研究概览
简要总结
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.
详细描述
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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:
- •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
研究组 & 干预措施
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.
干预措施: Ecallantide (Drug)
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.
干预措施: Ecallantide (Drug)
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.
干预措施: Placebo (Drug)
结局指标
主要结局
Cumulative Chest Tube Drainage During the First 12 Hours Postoperatively
时间窗: 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.
次要结局
- Pharmacokinetics: Area Under the Concentration Time Curve(1, 2, 4, and 8 hours after end of study drug infusion)
- Cumulative Chest Tube Drainage at 24 Hours Postoperatively(Up to 24 hours post admission to ICU)
- Number of Participants With Treatment-emergent Adverse Events(up to 28 days post admission to ICU)