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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02037555
Recruitment Status : Completed
First Posted : January 16, 2014
Results First Posted : February 15, 2019
Last Update Posted : March 15, 2019
Clinipace Worldwide
Information provided by (Responsible Party):
Grifols Therapeutics LLC

Tracking Information
First Submitted Date  ICMJE January 14, 2014
First Posted Date  ICMJE January 16, 2014
Results First Submitted Date  ICMJE January 24, 2019
Results First Posted Date  ICMJE February 15, 2019
Last Update Posted Date March 15, 2019
Actual Study Start Date  ICMJE June 26, 2014
Actual Primary Completion Date January 25, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 14, 2014)
Percentage of Subjects With Any Component of a Major Morbidity Composite [ Time Frame: 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).
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Safety and Efficacy of Preoperative Antithrombin Supplementation in Patients Undergoing High-Risk Cardiopulmonary Bypass
Official Title  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Cardiac Surgery
  • Cardiopulmonary Bypass
Intervention  ICMJE
  • 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 Name: Antithrombin
  • Other: Placebo
    0.9% Sodium Chloride for Injection, United States Pharmacopeia
    Other Name: Saline
Study Arms  ICMJE
  • Experimental: 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

    Intervention: Biological: AT-III (Human)
  • Placebo Comparator: Placebo
    Single intravenous administration of placebo at a volume equivalent to the volume for the calculated AT-III (Human) dose.
    Intervention: Other: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: February 21, 2018)
Original Estimated Enrollment  ICMJE
 (submitted: January 14, 2014)
Actual Study Completion Date  ICMJE January 25, 2018
Actual Primary Completion Date January 25, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT02037555
Other Study ID Numbers  ICMJE GTI1307
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Grifols Therapeutics LLC
Study Sponsor  ICMJE Grifols Therapeutics LLC
Collaborators  ICMJE
  • Covance
  • Clinipace Worldwide
Investigators  ICMJE Not Provided
PRS Account Grifols Therapeutics LLC
Verification Date February 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP