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

• Sponsor: Grifols Therapeutics LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02037555
• Collaborator: Covance (Industry), Clinipace Worldwide (Industry)
• Enrollment: 425
• Locations: 41
• Arms: 2
• Actual Duration (Months): 43
• Patients Per Site: 10.4
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Cardiac Surgery; Cardiopulmonary Bypass	Biological: AT-III (Human); Other: Placebo	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 425 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Jun 26, 2014
• Actual Primary Completion Date: Jan 25, 2018
• Actual Study Completion Date: Jan 25, 2018

Arms and Interventions

Arm	Intervention/Treatment
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); 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 Names: Antithrombin
Placebo Comparator: Placebo Single intravenous administration of placebo at a volume equivalent to the volume for the calculated AT-III (Human) dose.	Other: Placebo; 0.9% Sodium Chloride for Injection, United States Pharmacopeia; Other Names: Saline

Outcome Measures

Primary Outcome Measures

1. Percentage of Subjects With Any Component of a Major Morbidity Composite [Up to Day 30 +/- 4 days]

   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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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).

1. 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

1. this criterion was deleted and noted as "Not applicable - intentionally left blank for data management purposes (consistency in eCRF capture of eligibility criteria historically)."

1. Subject had signed informed consent form.

2. 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.

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

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

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

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

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

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

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

Contacts and Locations

Locations

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

Sponsors and Collaborators

• Grifols Therapeutics LLC
• Covance
• Clinipace Worldwide

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Apr 2, 2015
• Statistical Analysis Plan - May 15, 2018

More Information

Publications

None provided.

• Responsible Party: Grifols Therapeutics LLC
• ClinicalTrials.gov Identifier: NCT02037555
• Other Study ID Numbers: GTI1307
• First Posted: Jan 16, 2014
• Last Update Posted: Mar 15, 2019
• Last Verified: Feb 1, 2019

• Keywords provided by Grifols Therapeutics LLC: Antithrombin; Cardiopulmonary bypass
• Additional relevant MeSH terms: Antithrombins; Antithrombin III

Study Results

Participant Flow

Arm/Group Title	AT-III (Human)	Placebo
Arm/Group Description	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	Single intravenous administration of placebo at a volume equivalent to the volume for the calculated AT-III (Human) dose. Placebo: 0.9% Sodium Chloride for Injection, United States Pharmacopeia
Period Title: Overall Study
STARTED	213	212
Dosed	201	198
Dosed and Operated On	200	196
COMPLETED	190	191
NOT COMPLETED	23	21

Baseline Characteristics

Arm/Group Title	AT-III (Human)	Placebo	Total
Arm/Group Description	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	Single intravenous administration of placebo at a volume equivalent to the volume for the calculated AT-III (Human) dose. Placebo: 0.9% Sodium Chloride for Injection, United States Pharmacopeia	Total of all reporting groups
Overall Participants	201	198	399
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	66.7 (10.4)	65.5 (12.80)	66.1 (11.66)
Age, Customized (Count of Participants)
<65 years	78 38.8%	76 38.4%	154 38.6%
≥65 years	123 61.2%	122 61.6%	245 61.4%
Sex: Female, Male (Count of Participants)
Female	51 25.4%	48 24.2%	99 24.8%
Male	150 74.6%	150 75.8%	300 75.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	9 4.5%	8 4%	17 4.3%
Not Hispanic or Latino	192 95.5%	190 96%	382 95.7%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	2 1%	2 0.5%
Asian	2 1%	2 1%	4 1%
Native Hawaiian or Other Pacific Islander	1 0.5%	0 0%	1 0.3%
Black or African American	4 2%	5 2.5%	9 2.3%
White	194 96.5%	189 95.5%	383 96%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Percentage of Subjects With Any Component of a Major Morbidity Composite
Description	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).
Time Frame	Up to Day 30 +/- 4 days

Outcome Measure Data

Analysis Population Description

All subjects Treated and Operated On Excluding 4 Subjects with Non-verifiable Data

Arm/Group Title	AT-III (Human)	Placebo
Arm/Group Description	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	Single intravenous administration of placebo at a volume equivalent to the volume for the calculated AT-III (Human) dose. Placebo: 0.9% Sodium Chloride for Injection, United States Pharmacopeia
Measure Participants	198	194
Count of Participants [Participants]	68 33.8%	58 29.3%

Adverse Events

Time Frame	Up to Day 30 +/- 4 days
Adverse Event Reporting Description	Four subjects included in the participant flow table are excluded from safety and efficacy reporting. These 4 subjects, 2 from each treatment group, were subtracted from the 399 "Dosed" subjects planned for safety reporting and the 396 "Dosed and Operated on" subjects planned for efficacy reporting. The final population for safety reporting was 395 (AT-III n=199 [ie, 201-2] + Placebo n=196 [ie, 198-2]), and for efficacy reporting was 392 (AT-III n=198 [ie, 200-2] + Placebo n=194 [ie, 196-2]).
Arm/Group Title	AT-III (Human)		Placebo
Arm/Group Description	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		Single intravenous administration of placebo at a volume equivalent to the volume for the calculated AT-III (Human) dose. Placebo: 0.9% Sodium Chloride for Injection, United States Pharmacopeia
All Cause Mortality
	AT-III (Human)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/199 (3.5%)		4/196 (2%)
Serious Adverse Events
	AT-III (Human)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	57/199 (28.6%)		57/196 (29.1%)
Blood and lymphatic system disorders
Coagulopathy	3/199 (1.5%)	3	2/196 (1%)	2
Disseminated intravascular coagulation	1/199 (0.5%)	1	0/196 (0%)	0
Heparin induced thrombocytopenia	1/199 (0.5%)	1	0/196 (0%)	0
Thrombocytopenia	0/199 (0%)	0	1/196 (0.5%)	1
Cardiac disorders
Acute myocardial infarction	1/199 (0.5%)	1	0/196 (0%)	0
Arrhythmia	4/199 (2%)	4	0/196 (0%)	0
Arrhytmia supraventricular	0/199 (0%)	0	1/196 (0.5%)	1
Atrial fibrillation	5/199 (2.5%)	5	6/196 (3.1%)	7
Atrial flutter	0/199 (0%)	0	1/196 (0.5%)	1
Atrioventricular block complete	4/199 (2%)	4	4/196 (2%)	4
Atrioventricular block	0/199 (0%)	0	1/196 (0.5%)	1
Bradycardia	1/199 (0.5%)	1	0/196 (0%)	0
Cardiac arrest	1/199 (0.5%)	1	2/196 (1%)	2
Cardiac failure	2/199 (1%)	2	0/196 (0%)	0
Cardiac failure acute	0/199 (0%)	0	1/196 (0.5%)	1
Cardiac failure congestive	2/199 (1%)	2	1/196 (0.5%)	1
Cardiac tamponade	0/199 (0%)	0	2/196 (1%)	2
Cardiogenic shock	1/199 (0.5%)	1	4/196 (2%)	4
Left ventricular dysfunction	0/199 (0%)	0	1/196 (0.5%)	1
Mitral valve incompetence	1/199 (0.5%)	1	0/196 (0%)	0
Nodal arrhythmia	1/199 (0.5%)	1	0/196 (0%)	0
Pericardial effusion	1/199 (0.5%)	1	0/196 (0%)	0
Pericardial haemorrhage	0/199 (0%)	0	1/196 (0.5%)	1
Pulseless electrical activity	1/199 (0.5%)	1	1/196 (0.5%)	1
Right ventricular dysfunction	0/199 (0%)	0	1/196 (0.5%)	1
Right ventricular failure	0/199 (0%)	0	1/196 (0.5%)	1
Sinus node dysfunction	1/199 (0.5%)	1	0/196 (0%)	0
Ventricular fibrillation	0/199 (0%)	0	2/196 (1%)	2
Ventricular tachycardia	1/199 (0.5%)	1	1/196 (0.5%)	1
Gastrointestinal disorders
Duodenal ulcer haemorrhage	1/199 (0.5%)	1	0/196 (0%)	0
Dysphagia	1/199 (0.5%)	1	1/196 (0.5%)	1
Gastrointestinal haemorrhage	1/199 (0.5%)	1	1/196 (0.5%)	1
Intestinal ischaemia	2/199 (1%)	2	0/196 (0%)	0
Large intestine perforation	0/199 (0%)	0	1/196 (0.5%)	1
Upper gastrointestinal haemorrhage	1/199 (0.5%)	1	0/196 (0%)	0
General disorders
Multiple organ dysfunction syndrome	2/199 (1%)	2	1/196 (0.5%)	1
Non-cardiac chest pain	1/199 (0.5%)	1	0/196 (0%)	0
Systemic inflammatory response syndrome	1/199 (0.5%)	1	0/196 (0%)	0
Hepatobiliary disorders
Hepatic congestion	1/199 (0.5%)	1	0/196 (0%)	0
Hepatic ischaemia	1/199 (0.5%)	1	0/196 (0%)	0
Ischaemic hepatitis	2/199 (1%)	2	0/196 (0%)	0
Liver injury	1/199 (0.5%)	1	0/196 (0%)	0
Immune system disorders
Anaphylactic reaction	0/199 (0%)	0	1/196 (0.5%)	1
Drug hypersensitivity	0/199 (0%)	0	1/196 (0.5%)	1
Infections and infestations
Abscess limb	0/199 (0%)	0	1/196 (0.5%)	1
Bacteraemia	0/199 (0%)	0	1/196 (0.5%)	1
Cellulitis	1/199 (0.5%)	1	1/196 (0.5%)	1
Clostridium difficile colitis	0/199 (0%)	0	1/196 (0.5%)	1
Clostridium difficile infection	1/199 (0.5%)	1	0/196 (0%)	0
Infection	1/199 (0.5%)	1	0/196 (0%)	0
Lower respiratory tract infection	0/199 (0%)	0	1/196 (0.5%)	1
Mediastinitis	0/199 (0%)	0	1/196 (0.5%)	1
Pneumonia	1/199 (0.5%)	1	2/196 (1%)	2
Pseudomonal sepsis	0/199 (0%)	0	1/196 (0.5%)	1
Sepsis	2/199 (1%)	2	1/196 (0.5%)	1
Septic shock	2/199 (1%)	2	2/196 (1%)	2
Wound infection	0/199 (0%)	0	1/196 (0.5%)	1
Injury, poisoning and procedural complications
Cardiac vein perforation	1/199 (0.5%)	1	0/196 (0%)	0
Post procedural haemorrhage	4/199 (2%)	4	1/196 (0.5%)	1
Postoperative delirium	0/199 (0%)	0	1/196 (0.5%)	1
Suture rupture	1/199 (0.5%)	1	0/196 (0%)	0
Transfusion-related acute lung injury	1/199 (0.5%)	1	0/196 (0%)	0
Investigations
Pulmonary arterial pressure increased	0/199 (0%)	0	1/196 (0.5%)	1
Metabolism and nutrition disorders
Fluid overload	1/199 (0.5%)	1	0/196 (0%)	0
Hyperkalaemia	1/199 (0.5%)	1	0/196 (0%)	0
Hypovolaemia	1/199 (0.5%)	1	0/196 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	0/199 (0%)	0	1/196 (0.5%)	1
Nervous system disorders
Aphasia	1/199 (0.5%)	1	0/196 (0%)	0
Cerebral infarction	1/199 (0.5%)	1	1/196 (0.5%)	1
Cerebrovascular accident	0/199 (0%)	0	5/196 (2.6%)	5
Embolic stroke	2/199 (1%)	2	1/196 (0.5%)	1
Encephalopathy	1/199 (0.5%)	1	1/196 (0.5%)	1
Ischaemic stroke	2/199 (1%)	2	1/196 (0.5%)	1
Status epilepticus	0/199 (0%)	0	1/196 (0.5%)	1
Transient ischaemic attack	1/199 (0.5%)	1	0/196 (0%)	0
Product Issues
Device breakage	0/199 (0%)	0	1/196 (0.5%)	1
Psychiatric disorders
Delirium	1/199 (0.5%)	1	2/196 (1%)	2
Mental status changes	1/199 (0.5%)	1	0/196 (0%)	0
Renal and urinary disorders
Acute kidney injury	9/199 (4.5%)	9	2/196 (1%)	2
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	1/199 (0.5%)	1	0/196 (0%)	0
Acute respiratory failure	2/199 (1%)	2	3/196 (1.5%)	3
Haemothorax	0/199 (0%)	0	1/196 (0.5%)	1
Hypoxia	0/199 (0%)	0	1/196 (0.5%)	1
Mediastinal haemorrhage	1/199 (0.5%)	1	0/196 (0%)	0
Pleural effusion	3/199 (1.5%)	3	2/196 (1%)	2
Pneumonia aspiration	0/199 (0%)	0	1/196 (0.5%)	1
Pneumothorax	2/199 (1%)	2	0/196 (0%)	0
Pulmonary embolism	2/199 (1%)	2	1/196 (0.5%)	1
Pulmonary oedema	0/199 (0%)	0	1/196 (0.5%)	1
Respiratory arrest	1/199 (0.5%)	1	1/196 (0.5%)	1
Respiratory distress	2/199 (1%)	2	2/196 (1%)	2
Respiratory failure	4/199 (2%)	4	3/196 (1.5%)	3
Surgical and medical procedures
Decompressive craniectomy	0/199 (0%)	0	1/196 (0.5%)	1
Vascular disorders
Aortic rupture	1/199 (0.5%)	1	0/196 (0%)	0
Deep vein thrombosis	0/199 (0%)	0	2/196 (1%)	2
Extravasation blood	1/199 (0.5%)	1	0/196 (0%)	0
Haemorrhage	0/199 (0%)	0	1/196 (0.5%)	1
Hypotension	1/199 (0.5%)	1	0/196 (0%)	0
Peripheral ischaemia	2/199 (1%)	2	0/196 (0%)	0
Other (Not Including Serious) Adverse Events
	AT-III (Human)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	185/199 (93%)		179/196 (91.3%)
Blood and lymphatic system disorders
Anaemia	48/199 (24.1%)	48	36/196 (18.4%)	36
Coagulopathy	13/199 (6.5%)	13	8/196 (4.1%)	8
Haemorrhagic anaemia	25/199 (12.6%)	25	32/196 (16.3%)	32
Leukocytosis	44/199 (22.1%)	44	50/196 (25.5%)	50
Thrombocytopenia	57/199 (28.6%)	57	64/196 (32.7%)	64
Cardiac disorders
Arrhythmia	10/199 (5%)	10	8/196 (4.1%)	8
Atrial fibrillation	56/199 (28.1%)	61	40/196 (20.4%)	42
Cardiogenic shock	16/199 (8%)	16	18/196 (9.2%)	19
Low cardiac output syndrome	12/199 (6%)	12	10/196 (5.1%)	10
Tachycardia	10/199 (5%)	10	14/196 (7.1%)	14
Gastrointestinal disorders
Constipation	33/199 (16.6%)	34	40/196 (20.4%)	40
Nausea	33/199 (16.6%)	34	39/196 (19.9%)	39
General disorders
Oedema	7/199 (3.5%)	7	11/196 (5.6%)	11
Oedema peripheral	13/199 (6.5%)	16	11/196 (5.6%)	11
Infections and infestations
Urinary tract infection	11/199 (5.5%)	12	5/196 (2.6%)	5
Injury, poisoning and procedural complications
Anaemia postoperative	18/199 (9%)	18	19/196 (9.7%)	19
Postoperative respiratory failure	7/199 (3.5%)	8	11/196 (5.6%)	12
Procedural nausea	11/199 (5.5%)	11	8/196 (4.1%)	8
Procedural pain	54/199 (27.1%)	54	64/196 (32.7%)	64
Investigations
Activated partial thromboplastin time prolonged	11/199 (5.5%)	11	11/196 (5.6%)	11
International normalised ratio increased	19/199 (9.5%)	19	19/196 (9.7%)	19
Myocardial necrosis marker increased	6/199 (3%)	6	10/196 (5.1%)	10
Prothrombin time prolonged	16/199 (8%)	16	19/196 (9.7%)	19
Metabolism and nutrition disorders
Electrolyte imbalance	11/199 (5.5%)	11	11/196 (5.6%)	11
Fluid overload	12/199 (6%)	12	15/196 (7.7%)	15
Hyperchloraemia	10/199 (5%)	10	14/196 (7.1%)	14
Hyperglycaemia	62/199 (31.2%)	63	61/196 (31.1%)	61
Hyperkalaemia	18/199 (9%)	18	11/196 (5.6%)	11
Hypermagnesaemia	14/199 (7%)	14	14/196 (7.1%)	14
Hypervolaemia	17/199 (8.5%)	17	28/196 (14.3%)	28
Hypocalcaemia	19/199 (9.5%)	19	28/196 (14.3%)	28
Hypochloraemia	9/199 (4.5%)	9	11/196 (5.6%)	11
Hypokalaemia	15/199 (7.5%)	15	14/196 (7.1%)	14
Hyponatraemia	11/199 (5.5%)	11	13/196 (6.6%)	13
Hypovolaemia	19/199 (9.5%)	19	14/196 (7.1%)	15
Psychiatric disorders
Insomnia	6/199 (3%)	6	12/196 (6.1%)	12
Renal and urinary disorders
Acute kidney injury	29/199 (14.6%)	30	11/196 (5.6%)	12
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	9/199 (4.5%)	10	11/196 (5.6%)	11
Atelectasis	43/199 (21.6%)	43	48/196 (24.5%)	51
Hypoxia	10/199 (5%)	10	8/196 (4.1%)	8
Pleural effusion	50/199 (25.1%)	51	48/196 (24.5%)	50
Pneumothorax	13/199 (6.5%)	13	11/196 (5.6%)	12
Pulmonary oedema	10/199 (5%)	10	16/196 (8.2%)	16
Respiratory failure	26/199 (13.1%)	29	31/196 (15.8%)	32
Tachypnoea	7/199 (3.5%)	7	12/196 (6.1%)	12
Vascular disorders
Hypertension	15/199 (7.5%)	15	19/196 (9.7%)	19
Hypotension	51/199 (25.6%)	52	58/196 (29.6%)	61
Hypovolaemic shock	9/199 (4.5%)	9	15/196 (7.7%)	15

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

A 12-month post-study period is reserved for a joint, multi-center publication of study results. After this period, individual sites may publish results provided that the Sponsor is allowed 30 days to review any proposed publication for removal of confidential, protected, and trademarked material prior to submission with an option to delay publication up to 60 days if needed to protect its interests. The Sponsor shall retain the option to receive acknowledgment for its sponsorship of the study.