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

NCT ID: NCT02037555

Last Updated: 2019-03-15

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 425 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-06-26
• Study Completion Date: 2018-01-25

Brief 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.

Detailed 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.

Conditions

Cardiac Surgery; Cardiopulmonary Bypass

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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

Group Type: EXPERIMENTAL

AT-III (Human)

Intervention Type: BIOLOGICAL

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.

Placebo

Single intravenous administration of placebo at a volume equivalent to the volume for the calculated AT-III (Human) dose.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

0.9% Sodium Chloride for Injection, United States Pharmacopeia

Interventions

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.

Intervention Type: BIOLOGICAL

Placebo

0.9% Sodium Chloride for Injection, United States Pharmacopeia

Intervention Type: OTHER

Other Intervention Names

Antithrombin; Saline

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Covance

INDUSTRY

Sponsor Role: collaborator

Clinipace Worldwide

INDUSTRY

Sponsor Role: collaborator

Grifols Therapeutics LLC

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

UC Irvine

Orange, California, United States

VA Medical Center - San Francisco

San Francisco, California, United States

Stanford University Hospital and Clinics

Stanford, California, United States

University of Colorado

Aurora, Colorado, United States

Yale University School of Medicine

New Haven, Connecticut, United States

University of Florida College of Medicine

Gainesville, Florida, United States

Jackson Memorial Hospital at University of Miami

Miami, Florida, United States

Emory University Hospital

Atlanta, Georgia, United States

Georgia Regents University

Augusta, Georgia, United States

Memorial Medical Center

Springfield, Illinois, United States

Indiana Ohio Heart

Fort Wayne, Indiana, United States

St. Vincent Heart Center of IN, LLC

Indianapolis, Indiana, United States

Kentucky Clinic

Lexington, Kentucky, United States

Tulane University Medical

New Orleans, Louisiana, United States

Maine Medical Center

Portland, Maine, United States

Brigham & Women's Hospital

Boston, Massachusetts, United States

Sparrow Clinical Research Institute

Lansing, Michigan, United States

William Beaumont Hospital

Royal Oak, Michigan, United States

Saint Luke's Hospital

Kansas City, Missouri, United States

Missouri Baptist Medical Center

St Louis, Missouri, United States

CHI Health Nebraska Heart Medical Office

Lincoln, Nebraska, United States

University of Nebraska Medical Center

Omaha, Nebraska, United States

Dartmouth-Hitchcock Medical Center

Lebanon, New Hampshire, United States

North Shore University Hospital

New Hyde Park, New York, United States

Duke University Medical Center

Durham, North Carolina, United States

Sanford Health Fargo

Fargo, North Dakota, United States

Summa Health Hospital

Akron, Ohio, 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

ProMedica Toledo Hospital

Toledo, Ohio, United States

University of Toledo Medical Center

Toledo, Ohio, United States

Oregon Health & Science University

Portland, Oregon, United States

University of Pennsylvania

Philadelphia, Pennsylvania, United States

UPMC Presbyterian Hospital

Pittsburgh, Pennsylvania, United States

Baptist Memorial Hospital Memphis

Memphis, Tennessee, United States

St. Thomas Health

Nashville, Tennessee, United States

Memorial Hermann Memorial City Medical Center

Bellaire, Texas, United States

Texas Heart

Houston, Texas, United States

Cardiothoracic Surgical Associates

Richmond, Virginia, United States

Virginia Commonwealth University Medical Center

Richmond, Virginia, United States

Countries

United States

References

Moront MG, Woodward MK, Essandoh MK, Avery EG, Reece TB, Brzezinski M, Spiess B, Shore-Lesserson L, Chen J, Henriquez W, Barcelo M, Despotis G, Karkouti K, Levy JH, Ranucci M, Mondou E; Clinical Thrombate Study Group. A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Preoperative Antithrombin Supplementation in Patients at Risk for Antithrombin Deficiency After Cardiac Surgery. Anesth Analg. 2022 Oct 1;135(4):757-768. doi: 10.1213/ANE.0000000000006145. Epub 2022 Jul 25.

Reference Type: DERIVED

PMID: 35877927 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

GTI1307

Identifier Type: -

Identifier Source: org_study_id