CompletedNCT02037555Updated Mar 15, 2019Results posted

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

A Phase 2 interventional study of AT-III (Human) and Placebo in Cardiac Surgery and Cardiopulmonary Bypass, sponsored by Grifols Therapeutics LLC. Completed at 41 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2019-03-15.

Sponsored by Grifols Therapeutics LLC · Phase 2, Interventional, and Treatment

Phase: Phase 2
Study type: Interventional
Enrollment: 425
Allocation: Randomized
Ages: 18 Years and older
Sex: All

Study 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.

Read the 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 studied

Cardiac Surgery
Cardiopulmonary Bypass

Keywords

Antithrombin
Cardiopulmonary bypass

In context

Lead sponsor

Grifols Therapeutics LLC is the lead sponsor of 43 studies on the registry; 4 are open to participants now.

Of its 12 completed or terminated interventional studies of FDA-regulated products, 11 (92%) have results posted.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years and older
Sexes eligible: All
Accepts healthy volunteers: No

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

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.

Study design

Phase: Phase 2
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel assignment
Masking: Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment: 425 participants (actual)

Study arms

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
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.
Other: Placebo

Interventions

BiologicalAT-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.
Also known as: Antithrombin
OtherPlacebo
0.9% Sodium Chloride for Injection, United States Pharmacopeia
Also known as: Saline

What researchers measure

Primary outcomes

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: 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).
Time frame: Up to Day 30 +/- 4 days

Results

Posted Feb 15, 2019

Participant flow

Participant flow — Overall Study
Milestone	AT-III (Human)	Placebo
Started	213	212
Dosed	201	198
Dosed and operated on	200	196
Completed	190	191
Not completed	23	21

Outcome measures

PrimaryPercentage 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: 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).

Time frame:: Up to Day 30 +/- 4 days
Reported as:: Count of participants · Participants

Percentage of Subjects With Any Component of a Major Morbidity Composite
Participants	AT-III (Human)	Placebo
Percentage of Subjects With Any Component of a Major Morbidity Composite	68	58

Adverse events

Collected over Up to Day 30 +/- 4 days. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
AT-III (Human)	7/199 (3.5%)	57/199 (28.6%)	185/199 (93%)
Placebo	4/196 (2%)	57/196 (29.1%)	179/196 (91.3%)

Most frequent serious events

Showing 10 of 99

Most frequent serious events
Event	AT-III (Human)	Placebo
Acute kidney injuryRenal and urinary disorders	9/199	2/196
Atrial fibrillationCardiac disorders	5/199	6/196
Cerebrovascular accidentNervous system disorders	0/199	5/196
Atrioventricular block completeCardiac disorders	4/199	4/196
Cardiogenic shockCardiac disorders	1/199	4/196
ArrhythmiaCardiac disorders	4/199	0/196
Post procedural haemorrhageInjury, poisoning and procedural complications	4/199	1/196
Respiratory failureRespiratory, thoracic and mediastinal disorders	4/199	3/196
Acute respiratory failureRespiratory, thoracic and mediastinal disorders	2/199	3/196
CoagulopathyBlood and lymphatic system disorders	3/199	2/196

Most frequent other events

Showing 10 of 48

Most frequent other events
Event	AT-III (Human)	Placebo
ThrombocytopeniaBlood and lymphatic system disorders	57/199	64/196
Procedural painInjury, poisoning and procedural complications	54/199	64/196
HyperglycaemiaMetabolism and nutrition disorders	62/199	61/196
HypotensionVascular disorders	51/199	58/196
Atrial fibrillationCardiac disorders	56/199	40/196
LeukocytosisBlood and lymphatic system disorders	44/199	50/196
Pleural effusionRespiratory, thoracic and mediastinal disorders	50/199	48/196
AtelectasisRespiratory, thoracic and mediastinal disorders	43/199	48/196
AnaemiaBlood and lymphatic system disorders	48/199	36/196
ConstipationGastrointestinal disorders	33/199	40/196

Baseline characteristics

All Subjects Receiving Study Treatment

Age, Continuous
Age, Continuous(years)	AT-III (Human)	Placebo	Total
Mean	66.7 ± 10.4	65.5 ± 12.80	66.1 ± 11.66

Age, Customized
Age, Customized(Participants)	AT-III (Human)	Placebo	Total
Age Category — <65 years	78	76	154
Age Category — ≥65 years	123	122	245

Sex: Female, Male
Sex: Female, Male(Participants)	AT-III (Human)	Placebo	Total
Female	51	48	99
Male	150	150	300

Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)	AT-III (Human)	Placebo	Total
Hispanic or Latino	9	8	17
Not Hispanic or Latino	192	190	382
Unknown or Not Reported	0	0	0

Race (NIH/OMB)
Race (NIH/OMB)(Participants)	AT-III (Human)	Placebo	Total
American Indian or Alaska Native	0	2	2
Asian	2	2	4
Native Hawaiian or Other Pacific Islander	1	0	1
Black or African American	4	5	9
White	194	189	383
More than one race	0	0	0
Unknown or Not Reported	0	0	0

Study locations

41 sites

UC Irvine
Orange, California 92868, United States
VA Medical Center - San Francisco
San Francisco, California 94121, United States
Stanford University Hospital and Clinics
Stanford, California 94305, United States
University of Colorado
Aurora, Colorado 80045, United States
Yale University School of Medicine
New Haven, Connecticut 06510, United States
University of Florida College of Medicine
Gainesville, Florida 32610, United States
Jackson Memorial Hospital at University of Miami
Miami, Florida 33136, United States
Emory University Hospital
Atlanta, Georgia 30322, United States
Georgia Regents University
Augusta, Georgia 30912, United States
Memorial Medical Center
Springfield, Illinois 62794, United States
Indiana Ohio Heart
Fort Wayne, Indiana 46804, United States
St. Vincent Heart Center of IN, LLC
Indianapolis, Indiana 46290, United States
Kentucky Clinic
Lexington, Kentucky 40536, United States
Tulane University Medical
New Orleans, Louisiana 70112, United States
Maine Medical Center
Portland, Maine 04102, United States
Brigham & Women's Hospital
Boston, Massachusetts 02115, United States
Sparrow Clinical Research Institute
Lansing, Michigan 48910, United States
William Beaumont Hospital
Royal Oak, Michigan 48073, United States
Saint Luke's Hospital
Kansas City, Missouri 64111, United States
Missouri Baptist Medical Center
Saint Louis, Missouri 63131, United States
CHI Health Nebraska Heart Medical Office
Lincoln, Nebraska 68526, United States
University of Nebraska Medical Center
Omaha, Nebraska 68198, United States
Dartmouth-Hitchcock Medical Center
Lebanon, New Hampshire 03766, United States
North Shore University Hospital
New Hyde Park, New York 11040, United States
Duke University Medical Center
Durham, North Carolina 27710, United States
Sanford Health Fargo
Fargo, North Dakota 58103, United States
Summa Health Hospital
Akron, Ohio 44304, United States
The Lindner Center for Research & Education - The Christ Hospital
Cincinnati, Ohio 45219, United States
University Hospitals Case Medical Center
Cleveland, Ohio 44106, United States
The Ohio State University Wexner Medical Center
Columbus, Ohio 43210, United States
ProMedica Toledo Hospital
Toledo, Ohio 43606, United States
University of Toledo Medical Center
Toledo, Ohio 43614, United States
Oregon Health & Science University
Portland, Oregon 97239, United States
University of Pennsylvania
Philadelphia, Pennsylvania 19104, United States
UPMC Presbyterian Hospital
Pittsburgh, Pennsylvania 15213, United States
Baptist Memorial Hospital Memphis
Memphis, Tennessee 38120, United States
St. Thomas Health
Nashville, Tennessee 37205, United States
Memorial Hermann Memorial City Medical Center
Bellaire, Texas 77401, United States
Texas Heart
Houston, Texas 77030, United States
Cardiothoracic Surgical Associates
Richmond, Virginia 23225, United States
Virginia Commonwealth University Medical Center
Richmond, Virginia 23298, United States

References and documents

Publications

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. PubMed 35877927 ↗

Study documents

Study protocol · Apr 2, 2015
Statistical analysis plan · May 15, 2018

Documents are hosted by the registry — open the source record to download them.

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on Mar 15, 2019, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT02037555
Lead sponsor: Grifols Therapeutics LLC
Collaborators: Covance, Clinipace Worldwide
Responsible party: Sponsor
First posted: Jan 16, 2014
Start date: Jun 26, 2014
Primary completion: Jan 25, 2018
Completion: Jan 25, 2018
Results posted: Feb 15, 2019
Last update: Mar 15, 2019

Oversight

Data monitoring committee: No

View the source record on ClinicalTrials.gov ↗

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