A Prospective, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Preoperative Antithrombin Supplementation in Patients Undergoing High-Risk Cardiac Surgery With Cardiopulmonary Bypass
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 425
- 试验地点
- 82
- 主要终点
- Percentage of Subjects With Any Component of a Major Morbidity Composite
研究概览
简要总结
This is a prospective, multicenter, randomized, double-blind, placebo-controlled study. The purpose of this study is to determine the safety and effectiveness of human-derived antithrombin III (AT-III [Human]) supplementation prior to high-risk, non-emergency, cardiac surgery with cardiopulmonary bypass (CPB). A total of 404 adult subjects undergoing CPB who meet the study eligibility criteria were planned to be randomized to receive either AT-III (Human) or placebo.
详细描述
The primary objective of this clinical study was to compare the percentage of subjects with any component of a 7 item major morbidity composite (postoperative mortality, stroke, acute kidney injury ([AKI]), surgical re-exploration, arterial or venous thromboembolic event, prolonged mechanical ventilation, or infection) between 2 groups of subjects randomly allocated to receive preoperative supplementation of AT-III (Human) (Antithrombin-III ([Human ]) or Placebo.
The secondary objectives of this clinical study were the following:
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To compare postoperative antithrombin III (AT) levels at the Intensive Care Unit (ICU) admission between the AT-III (Human) treatment group and Placebo control group
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To compare the following perioperative outcomes between the AT-III (Human) treatment group and Placebo control group:
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Postoperative chest-drain blood loss in the first 12 and 24 hours after surgery
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Transfusion requirements
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Need for surgical re-exploration
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Low cardiac output syndrome
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Myocardial Infarction (MI)
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Stroke
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AKI
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Arterial or venous thromboembolic events
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Infections
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Prolonged mechanical ventilation (>24 hours)
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All-cause postoperative mortality
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ICU stay duration
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Prolonged ICU stay (>6 days)
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Length of hospital stay
Additionally, safety objectives included the evaluation of AT III (Human) for clinical safety including adverse events (AEs), risks for bleeding, clinical laboratory testing, physical exam, and vital signs.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female.
- •At least 18 years of age.
- •Subject needed non-emergency cardiac surgery with CPB.
- •Types of cardiac operations permitted: complex/combined procedures (CABG+valve), double/triple valve repair/replacement, ascending aorta/aortic arch surgeries. Isolated CABG or single valve repair/replacements were allowed only if subject had received preoperative heparin >2 days.
- •Following the incorporation of Protocol Version 4.0 (Amendment 3 dated 02 Apr 2015), this criterion was revised to include complex/combined procedures (CABG+valve), double/triple valve repair/replacements, ascending aorta/aortic arch surgeries (without baseline AT level restriction or preoperative heparin requirement). OR isolated CABG or single valve repair/replacements were allowed only if either (a) AT level was less than 80% OR (b) preoperative heparin was received ([UFH for at least 12 hours; LMWH for more than 5 days).
- •Subject had a baseline AT level of less than 80%.
- •Following incorporation of Protocol Version 3.0 (Amendment 2 dated 02 Sep 2014) this was changed to Subject had a Prescreening/Screening and baseline local lab AT level of less than 80%.
- •Following the incorporation of Protocol Version 4.0 (Amendment 3 dated 02 Apr 2015) this criterion was deleted and noted as "Not applicable - intentionally left blank for data management purposes (consistency in eCRF capture of eligibility criteria historically)."
- •Subject had signed informed consent form.
- •Subject was willing to comply with all aspects of the protocol, including blood sampling, for the total duration of the study.
排除标准
- •Subject needed emergency surgery.
- •Subject needed heart transplantation.
- •Subject needed the use of minimally invasive surgery.
- •Subject had previous cardiac operation.
- •Subject had infective endocarditis.
- •Subject had thromboembolic events, stroke, or ST-elevated MI within 7 days of surgery.
- •Subject had cardiogenic shock at the time of surgery.
- •Subject had renal dysfunction: creatinine levels >2 mg/dL or chronic dialysis.
- •Subject had liver dysfunction: aspartate aminotransferase (AST), alanine aminotransferase (ALT) increase ≥2-fold above the upper-limit of local lab normal ranges.
- •Subject had treatment with Clopidogrel® and Ticagrelor® within 5 days before surgery, Prasugrel® within 7 days before surgery, glycoprotein IIb/IIIa receptor blockers within 24 hours of surgery.
- •Subject had treatment with new oral anticoagulants (Apixaban®, Rivaroxaban®, Dabigatran®) within 48 hours before surgery.
- •Subject had Vitamin K antagonist therapy and an international normalized ratio (INR) >1.3 on the day of surgery.
- •Subject had platelet count <120,000/μL.
- •Subject had history or suspicion of a congenital or acquired coagulation disorder.
- •Subject had history of anaphylactic reaction(s) to blood or blood components.
- •Subject had allergies to excipients in the study drug.
- •Subject had refused to receive allogenic transfusion of blood-derived products.
- •Subject had received AT treatment within the last 3 months prior to Screening Visit.
- •Subject was pregnant. Subject had participated in any another investigational study within the last 3 months prior to Screening Visit.
研究组 & 干预措施
AT-III (Human)
Single intravenous dose of AT-III (Human) sufficient to achieve an absolute increase of 20% (percentage points) above pretreatment AT levels according the following formula:
AT-III (Human) dose (IU) required = (20) × (subject weight in kg) / 1.4
干预措施: AT-III (Human) (Biological)
Placebo
Single intravenous administration of placebo at a volume equivalent to the volume for the calculated AT-III (Human) dose.
干预措施: Placebo (Other)
结局指标
主要结局
Percentage of Subjects With Any Component of a Major Morbidity Composite
时间窗: Up to Day 30 +/- 4 days
Major morbidity composite defined as a composite of any one or more of the following: 1. Postoperative mortality (deaths occurring within 30 days of the operation or occurring during the primary hospitalization). 2. Stroke (clinical diagnosis of focal or global neurological deficit of abrupt onset caused by disturbance in cerebral blood supply). 3. Acute kidney injury (increase of serum creatinine levels to \>2.0 mg/dL and twice the baseline level or a new requirement for dialysis postoperatively). 4. Surgical reexploration (return to operating room because of bleeding, tamponade, graft occlusion or other cardiac reason). 5. Arterial or venous thromboembolic event (perioperative myocardial or mesenteric infarction, peripheral thromboembolism, acute coronary graft thrombosis, intracardiac thrombosis, deep vein thrombosis, pulmonary embolism). 6. Prolonged mechanical ventilation (\>24 hours). 7. Infection (deep sternal-wound infection and/or bloodstream infections).
次要结局
未报告次要终点