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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.
 
ClinicalTrials.gov Identifier: NCT02037555
Recruitment Status : Completed
First Posted : January 16, 2014
Results First Posted : February 15, 2019
Last Update Posted : March 15, 2019
Sponsor:
Collaborators:
Covance
Clinipace Worldwide
Information provided by (Responsible Party):
Grifols Therapeutics LLC

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions Cardiac Surgery
Cardiopulmonary Bypass
Interventions Biological: AT-III (Human)
Other: Placebo
Enrollment 425
Recruitment Details  
Pre-assignment Details  
Arm/Group Title AT-III (Human) Placebo
Hide 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 [1] 201 198
Dosed and Operated On [2] 200 196
Completed 190 191
Not Completed 23 21
[1]
Reported for Safety Results
[2]
Reported for Efficacy Results
Arm/Group Title AT-III (Human) Placebo Total
Hide 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 Number of Baseline Participants 201 198 399
Hide Baseline Analysis Population Description
All Subjects Receiving Study Treatment
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 201 participants 198 participants 399 participants
66.7  (10.4) 65.5  (12.80) 66.1  (11.66)
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Age Category Number Analyzed 201 participants 198 participants 399 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  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 201 participants 198 participants 399 participants
Female
51
  25.4%
48
  24.2%
99
  24.8%
Male
150
  74.6%
150
  75.8%
300
  75.2%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 201 participants 198 participants 399 participants
Hispanic or Latino
9
   4.5%
8
   4.0%
17
   4.3%
Not Hispanic or Latino
192
  95.5%
190
  96.0%
382
  95.7%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 201 participants 198 participants 399 participants
American Indian or Alaska Native
0
   0.0%
2
   1.0%
2
   0.5%
Asian
2
   1.0%
2
   1.0%
4
   1.0%
Native Hawaiian or Other Pacific Islander
1
   0.5%
0
   0.0%
1
   0.3%
Black or African American
4
   2.0%
5
   2.5%
9
   2.3%
White
194
  96.5%
189
  95.5%
383
  96.0%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
1.Primary Outcome
Title Percentage of Subjects With Any Component of a Major Morbidity Composite
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
All subjects Treated and Operated On Excluding 4 Subjects with Non-verifiable Data
Arm/Group Title AT-III (Human) Placebo
Hide 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

Overall Number of Participants Analyzed 198 194
Measure Type: Count of Participants
Unit of Measure: Participants
68
  34.3%
58
  29.9%
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
Hide 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 (%) Affected / at Risk (%)
Total   7/199 (3.52%)      4/196 (2.04%)    
Hide Serious Adverse Events
AT-III (Human) Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   57/199 (28.64%)      57/196 (29.08%)    
Blood and lymphatic system disorders     
Coagulopathy  1  3/199 (1.51%)  3 2/196 (1.02%)  2
Disseminated intravascular coagulation  1  1/199 (0.50%)  1 0/196 (0.00%)  0
Heparin induced thrombocytopenia  1  1/199 (0.50%)  1 0/196 (0.00%)  0
Thrombocytopenia  1  0/199 (0.00%)  0 1/196 (0.51%)  1
Cardiac disorders     
Acute myocardial infarction  1  1/199 (0.50%)  1 0/196 (0.00%)  0
Arrhythmia  1  4/199 (2.01%)  4 0/196 (0.00%)  0
Arrhytmia supraventricular  1  0/199 (0.00%)  0 1/196 (0.51%)  1
Atrial fibrillation  1  5/199 (2.51%)  5 6/196 (3.06%)  7
Atrial flutter  1  0/199 (0.00%)  0 1/196 (0.51%)  1
Atrioventricular block complete  1  4/199 (2.01%)  4 4/196 (2.04%)  4
Atrioventricular block  1  0/199 (0.00%)  0 1/196 (0.51%)  1
Bradycardia  1  1/199 (0.50%)  1 0/196 (0.00%)  0
Cardiac arrest  1  1/199 (0.50%)  1 2/196 (1.02%)  2
Cardiac failure  1  2/199 (1.01%)  2 0/196 (0.00%)  0
Cardiac failure acute  1  0/199 (0.00%)  0 1/196 (0.51%)  1
Cardiac failure congestive  1  2/199 (1.01%)  2 1/196 (0.51%)  1
Cardiac tamponade  1  0/199 (0.00%)  0 2/196 (1.02%)  2
Cardiogenic shock  1  1/199 (0.50%)  1 4/196 (2.04%)  4
Left ventricular dysfunction  1  0/199 (0.00%)  0 1/196 (0.51%)  1
Mitral valve incompetence  1  1/199 (0.50%)  1 0/196 (0.00%)  0
Nodal arrhythmia  1  1/199 (0.50%)  1 0/196 (0.00%)  0
Pericardial effusion  1  1/199 (0.50%)  1 0/196 (0.00%)  0
Pericardial haemorrhage  1  0/199 (0.00%)  0 1/196 (0.51%)  1
Pulseless electrical activity  1  1/199 (0.50%)  1 1/196 (0.51%)  1
Right ventricular dysfunction  1  0/199 (0.00%)  0 1/196 (0.51%)  1
Right ventricular failure  1  0/199 (0.00%)  0 1/196 (0.51%)  1
Sinus node dysfunction  1  1/199 (0.50%)  1 0/196 (0.00%)  0
Ventricular fibrillation  1  0/199 (0.00%)  0 2/196 (1.02%)  2
Ventricular tachycardia  1  1/199 (0.50%)  1 1/196 (0.51%)  1
Gastrointestinal disorders     
Duodenal ulcer haemorrhage  1  1/199 (0.50%)  1 0/196 (0.00%)  0
Dysphagia  1  1/199 (0.50%)  1 1/196 (0.51%)  1
Gastrointestinal haemorrhage  1  1/199 (0.50%)  1 1/196 (0.51%)  1
Intestinal ischaemia  1  2/199 (1.01%)  2 0/196 (0.00%)  0
Large intestine perforation  1  0/199 (0.00%)  0 1/196 (0.51%)  1
Upper gastrointestinal haemorrhage  1  1/199 (0.50%)  1 0/196 (0.00%)  0
General disorders     
Multiple organ dysfunction syndrome  1  2/199 (1.01%)  2 1/196 (0.51%)  1
Non-cardiac chest pain  1  1/199 (0.50%)  1 0/196 (0.00%)  0
Systemic inflammatory response syndrome  1  1/199 (0.50%)  1 0/196 (0.00%)  0
Hepatobiliary disorders     
Hepatic congestion  1  1/199 (0.50%)  1 0/196 (0.00%)  0
Hepatic ischaemia  1  1/199 (0.50%)  1 0/196 (0.00%)  0
Ischaemic hepatitis  1  2/199 (1.01%)  2 0/196 (0.00%)  0
Liver injury  1  1/199 (0.50%)  1 0/196 (0.00%)  0
Immune system disorders     
Anaphylactic reaction  1  0/199 (0.00%)  0 1/196 (0.51%)  1
Drug hypersensitivity  1  0/199 (0.00%)  0 1/196 (0.51%)  1
Infections and infestations     
Abscess limb  1  0/199 (0.00%)  0 1/196 (0.51%)  1
Bacteraemia  1  0/199 (0.00%)  0 1/196 (0.51%)  1
Cellulitis  1  1/199 (0.50%)  1 1/196 (0.51%)  1
Clostridium difficile colitis  1  0/199 (0.00%)  0 1/196 (0.51%)  1
Clostridium difficile infection  1  1/199 (0.50%)  1 0/196 (0.00%)  0
Infection  1  1/199 (0.50%)  1 0/196 (0.00%)  0
Lower respiratory tract infection  1  0/199 (0.00%)  0 1/196 (0.51%)  1
Mediastinitis  1  0/199 (0.00%)  0 1/196 (0.51%)  1
Pneumonia  1  1/199 (0.50%)  1 2/196 (1.02%)  2
Pseudomonal sepsis  1  0/199 (0.00%)  0 1/196 (0.51%)  1
Sepsis  1  2/199 (1.01%)  2 1/196 (0.51%)  1
Septic shock  1  2/199 (1.01%)  2 2/196 (1.02%)  2
Wound infection  1  0/199 (0.00%)  0 1/196 (0.51%)  1
Injury, poisoning and procedural complications     
Cardiac vein perforation  1  1/199 (0.50%)  1 0/196 (0.00%)  0
Post procedural haemorrhage  1  4/199 (2.01%)  4 1/196 (0.51%)  1
Postoperative delirium  1  0/199 (0.00%)  0 1/196 (0.51%)  1
Suture rupture  1  1/199 (0.50%)  1 0/196 (0.00%)  0
Transfusion-related acute lung injury  1  1/199 (0.50%)  1 0/196 (0.00%)  0
Investigations     
Pulmonary arterial pressure increased  1  0/199 (0.00%)  0 1/196 (0.51%)  1
Metabolism and nutrition disorders     
Fluid overload  1  1/199 (0.50%)  1 0/196 (0.00%)  0
Hyperkalaemia  1  1/199 (0.50%)  1 0/196 (0.00%)  0
Hypovolaemia  1  1/199 (0.50%)  1 0/196 (0.00%)  0
Musculoskeletal and connective tissue disorders     
Back pain  1  0/199 (0.00%)  0 1/196 (0.51%)  1
Nervous system disorders     
Aphasia  1  1/199 (0.50%)  1 0/196 (0.00%)  0
Cerebral infarction  1  1/199 (0.50%)  1 1/196 (0.51%)  1
Cerebrovascular accident  1  0/199 (0.00%)  0 5/196 (2.55%)  5
Embolic stroke  1  2/199 (1.01%)  2 1/196 (0.51%)  1
Encephalopathy  1  1/199 (0.50%)  1 1/196 (0.51%)  1
Ischaemic stroke  1  2/199 (1.01%)  2 1/196 (0.51%)  1
Status epilepticus  1  0/199 (0.00%)  0 1/196 (0.51%)  1
Transient ischaemic attack  1  1/199 (0.50%)  1 0/196 (0.00%)  0
Product Issues     
Device breakage  1  0/199 (0.00%)  0 1/196 (0.51%)  1
Psychiatric disorders     
Delirium  1  1/199 (0.50%)  1 2/196 (1.02%)  2
Mental status changes  1  1/199 (0.50%)  1 0/196 (0.00%)  0
Renal and urinary disorders     
Acute kidney injury  1  9/199 (4.52%)  9 2/196 (1.02%)  2
Respiratory, thoracic and mediastinal disorders     
Acute respiratory distress syndrome  1  1/199 (0.50%)  1 0/196 (0.00%)  0
Acute respiratory failure  1  2/199 (1.01%)  2 3/196 (1.53%)  3
Haemothorax  1  0/199 (0.00%)  0 1/196 (0.51%)  1
Hypoxia  1  0/199 (0.00%)  0 1/196 (0.51%)  1
Mediastinal haemorrhage  1  1/199 (0.50%)  1 0/196 (0.00%)  0
Pleural effusion  1  3/199 (1.51%)  3 2/196 (1.02%)  2
Pneumonia aspiration  1  0/199 (0.00%)  0 1/196 (0.51%)  1
Pneumothorax  1  2/199 (1.01%)  2 0/196 (0.00%)  0
Pulmonary embolism  1  2/199 (1.01%)  2 1/196 (0.51%)  1
Pulmonary oedema  1  0/199 (0.00%)  0 1/196 (0.51%)  1
Respiratory arrest  1  1/199 (0.50%)  1 1/196 (0.51%)  1
Respiratory distress  1  2/199 (1.01%)  2 2/196 (1.02%)  2
Respiratory failure  1  4/199 (2.01%)  4 3/196 (1.53%)  3
Surgical and medical procedures     
Decompressive craniectomy  1  0/199 (0.00%)  0 1/196 (0.51%)  1
Vascular disorders     
Aortic rupture  1  1/199 (0.50%)  1 0/196 (0.00%)  0
Deep vein thrombosis  1  0/199 (0.00%)  0 2/196 (1.02%)  2
Extravasation blood  1  1/199 (0.50%)  1 0/196 (0.00%)  0
Haemorrhage  1  0/199 (0.00%)  0 1/196 (0.51%)  1
Hypotension  1  1/199 (0.50%)  1 0/196 (0.00%)  0
Peripheral ischaemia  1  2/199 (1.01%)  2 0/196 (0.00%)  0
1
Term from vocabulary, MedDRA 19.1
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
AT-III (Human) Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   185/199 (92.96%)      179/196 (91.33%)    
Blood and lymphatic system disorders     
Anaemia  1  48/199 (24.12%)  48 36/196 (18.37%)  36
Coagulopathy  1  13/199 (6.53%)  13 8/196 (4.08%)  8
Haemorrhagic anaemia  1  25/199 (12.56%)  25 32/196 (16.33%)  32
Leukocytosis  1  44/199 (22.11%)  44 50/196 (25.51%)  50
Thrombocytopenia  1  57/199 (28.64%)  57 64/196 (32.65%)  64
Cardiac disorders     
Arrhythmia  1  10/199 (5.03%)  10 8/196 (4.08%)  8
Atrial fibrillation  1  56/199 (28.14%)  61 40/196 (20.41%)  42
Cardiogenic shock  1  16/199 (8.04%)  16 18/196 (9.18%)  19
Low cardiac output syndrome  1  12/199 (6.03%)  12 10/196 (5.10%)  10
Tachycardia  1  10/199 (5.03%)  10 14/196 (7.14%)  14
Gastrointestinal disorders     
Constipation  1  33/199 (16.58%)  34 40/196 (20.41%)  40
Nausea  1  33/199 (16.58%)  34 39/196 (19.90%)  39
General disorders     
Oedema  1  7/199 (3.52%)  7 11/196 (5.61%)  11
Oedema peripheral  1  13/199 (6.53%)  16 11/196 (5.61%)  11
Infections and infestations     
Urinary tract infection  1  11/199 (5.53%)  12 5/196 (2.55%)  5
Injury, poisoning and procedural complications     
Anaemia postoperative  1  18/199 (9.05%)  18 19/196 (9.69%)  19
Postoperative respiratory failure  1  7/199 (3.52%)  8 11/196 (5.61%)  12
Procedural nausea  1  11/199 (5.53%)  11 8/196 (4.08%)  8
Procedural pain  1  54/199 (27.14%)  54 64/196 (32.65%)  64
Investigations     
Activated partial thromboplastin time prolonged  1  11/199 (5.53%)  11 11/196 (5.61%)  11
International normalised ratio increased  1  19/199 (9.55%)  19 19/196 (9.69%)  19
Myocardial necrosis marker increased  1  6/199 (3.02%)  6 10/196 (5.10%)  10
Prothrombin time prolonged  1  16/199 (8.04%)  16 19/196 (9.69%)  19
Metabolism and nutrition disorders     
Electrolyte imbalance  1  11/199 (5.53%)  11 11/196 (5.61%)  11
Fluid overload  1  12/199 (6.03%)  12 15/196 (7.65%)  15
Hyperchloraemia  1  10/199 (5.03%)  10 14/196 (7.14%)  14
Hyperglycaemia  1  62/199 (31.16%)  63 61/196 (31.12%)  61
Hyperkalaemia  1  18/199 (9.05%)  18 11/196 (5.61%)  11
Hypermagnesaemia  1  14/199 (7.04%)  14 14/196 (7.14%)  14
Hypervolaemia  1  17/199 (8.54%)  17 28/196 (14.29%)  28
Hypocalcaemia  1  19/199 (9.55%)  19 28/196 (14.29%)  28
Hypochloraemia  1  9/199 (4.52%)  9 11/196 (5.61%)  11
Hypokalaemia  1  15/199 (7.54%)  15 14/196 (7.14%)  14
Hyponatraemia  1  11/199 (5.53%)  11 13/196 (6.63%)  13
Hypovolaemia  1  19/199 (9.55%)  19 14/196 (7.14%)  15
Psychiatric disorders     
Insomnia  1  6/199 (3.02%)  6 12/196 (6.12%)  12
Renal and urinary disorders     
Acute kidney injury  1  29/199 (14.57%)  30 11/196 (5.61%)  12
Respiratory, thoracic and mediastinal disorders     
Acute respiratory failure  1  9/199 (4.52%)  10 11/196 (5.61%)  11
Atelectasis  1  43/199 (21.61%)  43 48/196 (24.49%)  51
Hypoxia  1  10/199 (5.03%)  10 8/196 (4.08%)  8
Pleural effusion  1  50/199 (25.13%)  51 48/196 (24.49%)  50
Pneumothorax  1  13/199 (6.53%)  13 11/196 (5.61%)  12
Pulmonary oedema  1  10/199 (5.03%)  10 16/196 (8.16%)  16
Respiratory failure  1  26/199 (13.07%)  29 31/196 (15.82%)  32
Tachypnoea  1  7/199 (3.52%)  7 12/196 (6.12%)  12
Vascular disorders     
Hypertension  1  15/199 (7.54%)  15 19/196 (9.69%)  19
Hypotension  1  51/199 (25.63%)  52 58/196 (29.59%)  61
Hypovolaemic shock  1  9/199 (4.52%)  9 15/196 (7.65%)  15
1
Term from vocabulary, MedDRA 19.1
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Miquel Barceló, PhD
Organization: Grifols Therapeutics, LLC
Phone: +34 935.712.368
EMail: Miquel.Barcelo@grifols.com
Layout table for additonal information
Responsible Party: Grifols Therapeutics LLC
ClinicalTrials.gov Identifier: NCT02037555    
Other Study ID Numbers: GTI1307
First Submitted: January 14, 2014
First Posted: January 16, 2014
Results First Submitted: January 24, 2019
Results First Posted: February 15, 2019
Last Update Posted: March 15, 2019