Safety and Efficacy of Preoperative Antithrombin Supplementation in Patients Undergoing High-Risk Cardiopulmonary Bypass

Study Overview
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Brief Summary
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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.

Detailed Description
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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: 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 To compare the following perioperative outcomes between the AT-III (Human) treatment group and Placebo control group: Postoperative chest-drain blood loss in the first 12 and 24 hours after surgery Transfusion requirements Need for surgical re-exploration Low cardiac output syndrome Myocardial Infarction (MI) Stroke AKI Arterial or venous thromboembolic events Infections Prolonged mechanical ventilation (>24 hours) All-cause postoperative mortality ICU stay duration Prolonged ICU stay (>6 days) 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.

Official Title
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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

Conditions
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Cardiac Surgery, Cardiopulmonary Bypass

Intervention / Treatment
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* Biological: AT-III (Human)
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AT-III (Human)<br>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 | Biological: AT-III (Human)<br>* AT-III (Human) is an antithrombin concentrate prepared from pooled human plasma. AT-III (Human) is provided as a freeze-dried preparation for intravenous use. The AT-III (Human) preparation is reconstituted in 10 or 20 mL of sterile water for injection prior to intravenous administration.<br>* Other names: Antithrombin;|
| Placebo Comparator: Placebo<br>Single intravenous administration of placebo at a volume equivalent to the volume for the calculated AT-III (Human) dose. | Other: Placebo<br>* 0.9% Sodium Chloride for Injection, United States Pharmacopeia<br>* Other names: Saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects With Any Component of a Major Morbidity Composite | Major morbidity composite defined as a composite of any one or more of the following: Postoperative mortality (deaths occurring within 30 days of the operation or occurring during the primary hospitalization). Stroke (clinical diagnosis of focal or global neurological deficit of abrupt onset caused by disturbance in cerebral blood supply). 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). Surgical reexploration (return to operating room because of bleeding, tamponade, graft occlusion or other cardiac reason). Arterial or venous thromboembolic event (perioperative myocardial or mesenteric infarction, peripheral thromboembolism, acute coronary graft thrombosis, intracardiac thrombosis, deep vein thrombosis, pulmonary embolism). Prolonged mechanical ventilation (>24 hours). Infection (deep sternal-wound infection and/or bloodstream infections). | Up to Day 30 +/- 4 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Antithrombin, Cardiopulmonary bypass