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

Cardiac Surgery Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02037555
• Other study ID #: GTI1307
• Status: Completed
• Phase: Phase 2
• Start date: June 26, 2014
• Est. completion date: January 25, 2018

Study information

• Verified date: February 2019
• Source: Grifols Therapeutics LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 425
• Est. completion date: January 25, 2018
• Est. primary completion date: January 25, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Male or female.

2. At least 18 years of age.

3. Subject needed non-emergency cardiac surgery with CPB.

4. 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).

5. 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)."

6. Subject had signed informed consent form.

7. Subject was willing to comply with all aspects of the protocol, including blood sampling, for the total duration of the study.

Exclusion Criteria:

1. Subject needed emergency surgery.

2. Subject needed heart transplantation.

3. Subject needed the use of minimally invasive surgery.

4. Subject had previous cardiac operation.

5. Subject had infective endocarditis.

6. Subject had thromboembolic events, stroke, or ST-elevated MI within 7 days of surgery.

7. Subject had cardiogenic shock at the time of surgery.

8. Subject had renal dysfunction: creatinine levels >2 mg/dL or chronic dialysis.

9. Subject had liver dysfunction: aspartate aminotransferase (AST), alanine aminotransferase (ALT) increase =2-fold above the upper-limit of local lab normal ranges.

10. 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.

11. Subject had treatment with new oral anticoagulants (Apixaban®, Rivaroxaban®, Dabigatran®) within 48 hours before surgery.

12. Subject had Vitamin K antagonist therapy and an international normalized ratio (INR) >1.3 on the day of surgery.

13. Subject had platelet count <120,000/µL.

14. Subject had history or suspicion of a congenital or acquired coagulation disorder.

15. Subject had history of anaphylactic reaction(s) to blood or blood components.

16. Subject had allergies to excipients in the study drug.

17. Subject had refused to receive allogenic transfusion of blood-derived products.

18. Subject had received AT treatment within the last 3 months prior to Screening Visit.

19. Subject was pregnant. Subject had participated in any another investigational study within the last 3 months prior to Screening Visit.

Related Conditions & MeSH terms

• Cardiac Surgery
• Cardiopulmonary Bypass

Intervention

Biological:
• AT-III (Human)
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.

Other:
• Placebo
0.9% Sodium Chloride for Injection, United States Pharmacopeia

Locations

Country	Name	City	State
United States	Summa Health Hospital	Akron	Ohio
United States	Emory University Hospital	Atlanta	Georgia
United States	Georgia Regents University	Augusta	Georgia
United States	University of Colorado	Aurora	Colorado
United States	Memorial Hermann Memorial City Medical Center	Bellaire	Texas
United States	Brigham & Women's Hospital	Boston	Massachusetts
United States	The Lindner Center for Research & Education - The Christ Hospital	Cincinnati	Ohio
United States	University Hospitals Case Medical Center	Cleveland	Ohio
United States	The Ohio State University Wexner Medical Center	Columbus	Ohio
United States	Duke University Medical Center	Durham	North Carolina
United States	Sanford Health Fargo	Fargo	North Dakota
United States	Indiana Ohio Heart	Fort Wayne	Indiana
United States	University of Florida College of Medicine	Gainesville	Florida
United States	Texas Heart	Houston	Texas
United States	St. Vincent Heart Center of IN, LLC	Indianapolis	Indiana
United States	Saint Luke's Hospital	Kansas City	Missouri
United States	Sparrow Clinical Research Institute	Lansing	Michigan
United States	Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire
United States	Kentucky Clinic	Lexington	Kentucky
United States	CHI Health Nebraska Heart Medical Office	Lincoln	Nebraska
United States	Baptist Memorial Hospital Memphis	Memphis	Tennessee
United States	Jackson Memorial Hospital at University of Miami	Miami	Florida
United States	St. Thomas Health	Nashville	Tennessee
United States	Yale University School of Medicine	New Haven	Connecticut
United States	North Shore University Hospital	New Hyde Park	New York
United States	Tulane University Medical	New Orleans	Louisiana
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	UC Irvine	Orange	California
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	UPMC Presbyterian Hospital	Pittsburgh	Pennsylvania
United States	Maine Medical Center	Portland	Maine
United States	Oregon Health & Science University	Portland	Oregon
United States	Cardiothoracic Surgical Associates	Richmond	Virginia
United States	Virginia Commonwealth University Medical Center	Richmond	Virginia
United States	William Beaumont Hospital	Royal Oak	Michigan
United States	Missouri Baptist Medical Center	Saint Louis	Missouri
United States	VA Medical Center - San Francisco	San Francisco	California
United States	Memorial Medical Center	Springfield	Illinois
United States	Stanford University Hospital and Clinics	Stanford	California
United States	ProMedica Toledo Hospital	Toledo	Ohio
United States	University of Toledo Medical Center	Toledo	Ohio

Sponsors (3)

Lead Sponsor	Collaborator
Grifols Therapeutics LLC	Clinipace Worldwide, Covance

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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