Anti-thrombin III (ATIII) vs Placebo in Children (<7mo) Undergoing Open Congenital Cardiac Surgery

• Sponsor: Duke University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02103114
• Collaborator: Grifols Biologicals, LLC (Industry)
• Enrollment: 45
• Location: 1
• Arms: 2
• Duration (Months): 25
• Patients Per Site Per Month: 1.8

Study Details

Study Description

Brief Summary

The purpose of this study is to test whether the administration of ATIII during the intra-operative period results in improved anticoagulation for cardiopulmonary bypass (CPB) and an attenuation of the activation of the coagulation cascade, as represented by a decrease in fibrin degradation products. The investigators believe this benefit would extend into the post-operative period resulting in a decreased incidence of thrombosis generation, as represented by a decrease in fibrin degradation products in the ICU period.

Condition or Disease	Intervention/Treatment	Phase
ATIII Deficiency	Drug: Anti-thrombin III; Other: Placebo	Phase 2

Detailed Description

If Preoperative ATIII functional assay level is less than 70% patients would be enrolled and randomized to either Placebo (normal saline) or ATIII.

Study Design

• Study Type: Interventional
• Actual Enrollment: 45 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Double Blind Randomized Placebo-controlled Study in Children (<6mo) Comparing the Effects of Anti-thrombin III (ATIII) or Placebo on the Coagulation System in Infants With Known Low ATIII Levels Undergoing Open Congenital Cardiac Surgery
• Study Start Date: Jun 1, 2014
• Actual Primary Completion Date: Jun 27, 2016
• Actual Study Completion Date: Jul 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Anti-thrombin III	Drug: Anti-thrombin III; Intraoperatively- (correcting to 100%) according to the following formula: Units required = ((100%- baseline ATIII level*%) X body weight)/1.4 expressed as a % normal level based on functional ATIII assay; Other Names: Thrombate III
Placebo Comparator: Placebo	Other: Placebo; Normal saline placebo

Outcome Measures

Primary Outcome Measures

1. Difference in the Mean and Standard Deviation (SD) of the Calibrated Automated Thrombography (CAT) Measurements of the Control and ATIII Groups at Time 5 (on Arrival in ICU) [Time 5 (on arrival in ICU)]

   Evidence of decreased activation of the coagulation and fibrinolytic systems represented by a difference in the mean and Standard Deviation (SD) of the Calibrated Automated Thrombography (CAT) measurements of the control and ATIII groups at Time 5 (on arrival in ICU).

Secondary Outcome Measures

1. Difference in the Mean and SD of the Calibrated Automated Thrombography (CAT) Measurements of the Control and ATIII Groups at Times 5-Time 7 (ICU Arrival to Post Operative Day 4) [ICU arrival (Time 5) to Time 7 (Post-operative Day 4)]

   Evidence of decreased activation of the coagulation and fibrinolytic systems represented by a difference in the mean and SD of the Calibrated Automated Thrombography (CAT) measurements of the control and ATIII groups at times 5-Time 7 (ICU arrival to Post Operative Day 4)

2. Difference in the Mean the ATIII (Functional Assay) of the Control and ATIII Groups at T1, T2, T3, T5, T6 and T7 [T1, T2, T3, T5, T6 and T7]

   Evidence of decreased activation of the coagulation and fibrinolytic systems represented by a difference in the mean of the ATIII (functional assay) of the control and ATIII groups at T1, T2, T3, T5, T6 and T7 (Baseline, 30 min after study drug, 30 min on CPB, Arrival in ICU, POD 2, and POD 4). Data reported as % Functional Activity, which is calculated as the ability of Antithrombin (AT) to suppress FIIa or FXa in the presence of heparin compared to normograms, and expressed as a percentage.

3. Difference in the Median of the ATIII (Functional Assay) of the Control and ATIII Groups at T4 [T4 (just prior to coming off of CPB)]

   Evidence of decreased activation of the coagulation and fibrinolytic systems represented by a difference in the median of the ATIII (functional assay) of the control and ATIII groups at T4 (just prior to coming off of CPB). Data reported as % Functional Activity, which is calculated as the ability of Antithrombin (AT) to suppress FIIa or FXa in the presence of heparin compared to normograms, and expressed as a percentage.

4. Difference in the Median of the D Dimer of the Control and ATIII Groups at T1, T5, T6 and T7 [T1, T5, T6 and T7]

   Evidence of decreased activation of the coagulation and fibrinolytic systems represented by a difference in the median of the D dimer of the control and ATIII groups at T1 (Baseline), T5 (Arrival in Intensive Care Unit), T6 (Post-Operative Day 2) and T7 (Post-Operative Day 4).

5. Residual Heparin at the ICU Arrival Time Point Represented by a Decreased Anti Factor Xa Level. [T5 (Intensive Care Unit Arrival)]

   Evidence of a decreased amount of residual heparin at the Intensive Care Unit arrival time point (T5) represented by a decreased anti factor Xa level.

6. Evidence of Decreased Inflammation Represented by a Decrease in Inflammatory Markers in the ATIII Group [Baseline (T1) to Post-Operative Day 4 (T7)]

   Evidence of decreased inflammation represented by a decrease in inflammatory markers in the ATIII group.

7. Total Dose of Heparin While on Cardiopulmonary Bypass [T1 (Baseline) to T5 (Arrival in ICU)]

   Total dose of Heparin while on Cardiopulmonary Bypass

8. Protamine Dose Determined by Hemostasis Management System Machine (mg/kg) [T1 (Baseline) to T5 (Arrival in ICU)]

   Protamine dose determined by Hemostasis Management system machine (mg/kg)

9. Total Volume of Blood Products While on CPB [Baseline (intraoperatively) (Time 1) to before termination of bypass (Time 4)]

   Total volume of blood products exposed intraoperatively including the pump prime (ml/kg)

10. Time From Protamine Administration to Skin Dressing [Baseline (intraoperatively) (Time 1) to before termination of bypass (Time 4)]

    Time from protamine administration to skin dressing

11. Total Volume of Fresh Frozen Plasma Given Prior to CPB [Baseline (intraoperatively) (Time 1) to before termination of bypass (Time 4)]

    Total volume of Fresh Frozen Plasma given prior to CPB, including the pump prime (ml/kg)

12. Incidence of Recombinant Factor 7a (VIIa) Use Intraoperatively [Baseline (Intraoperatively)]

    Incidence of Recombinant Factor 7a (VIIa) Use Intraoperatively

13. Volume of Postoperative Blood Loss [From 10min post protamine administration to 24 hour post protamine administration]

    Volume of postoperative blood loss from 10min post protamine administration to 24 hour post protamine administration- (ml/kg)

14. Chest Tube Output (Protamine Time Plus 24 Hours) in Milliliters [protamine time plus 24 hours]

    Chest Tube output (protamine time plus 24 hours) in milliliters

15. Number of Total Blood Product Units Transfused by Type 24-hours Post-operatively by Group [24 Hours Post-Operatively]

    Number of packed Fresh frozen plasma units, Platelet Units, cryo-precipitate units, and Red Blood Cell units transfused 24 hours post-operatively for each group (not total units transfused for each subject)

16. Number of Total Blood Product Units Transfused 24-hours Post-operatively by Group [24 Hours Post-Operatively]

    Number of total blood product units (including packed Fresh frozen plasma units, Platelet Units, cryo-precipitate units, and Red Blood Cell units) transfused 24 hours post-operatively for each group (not total units transfused for each subject)

17. Total Dose of Recombinant Factor 7a (VIIa) Used Intraoperatively [Intraoperatively]

    Total Dose of rescue recombinant factor 7a (VIIa) used intraoperatively

18. Length of Post Operative Ventilation in Days [ICU arrival (Time 5) to Time 7 (Post-Operative Day 4)]

    Length of post operative ventilation in days

19. Incidence of Extracorporeal Membrane Oxygenation (ECMO) Support Within 24 Hours Postoperatively [Baseline (intraoperatively) (Time 1) to Time 7 (Post OP Day 4)]

    Study the safety profile of dosing the ATIII by monitoring the incidence of extracorporeal membrane oxygenation (ECMO) support within 24 hours postoperatively.

20. Incidence of Mediastinal Exploration Within 24 Hours Postoperatively [Baseline (intraoperatively) (Time 1) to Time 7 (Post OP Day 4)]

    Study the safety profile of dosing the ATIII by monitoring the incidence of mediastinal exploration within 24 hours postoperatively

21. Incidence (Number) of Thrombotic Events Documented [Baseline (intraoperatively) (Time 1) to Time 7 (Post OP Day 4)]

    Study the safety profile of dosing the ATIII by monitoring the incidence (number) of thrombotic events documented.

22. Incidence of New Onset Renal Failure, Defined by Stage 3 of the AKIN Criteria [Baseline (intraoperatively) (Time 1) to Time 7 (Post OP Day 4)]

    Study the safety profile of dosing the ATIII by monitoring the incidence of new onset renal failure, defined by stage 3 of the Acute Kidney Injury Network (AKIN) criteria. Serum creatinine increase ≥26.5 μmol/l (≥0.3 mg/dl) or increase to 1.5-2.0-fold from baseline, urine output <0.5 ml/kg/h for 6 hours Serum creatinine increase >2.0-3.0-fold from baseline, urine output <0.5 ml/kg/h for 12 hours Serum creatinine increase >3.0-fold from baseline or serum creatinine ≥354 μmol/l (≥4.0 mg/dl) with an acute increase of at least 44 μmol/l (0.5 mg/dl) or need for Renal replacement therapy (RRT), urine output <0.3 ml/kg/h for 24 h or anuria for 12 hours or need for RRT

23. Incidence (Number) of Newly Diagnosed Intracranial Hemorrhage [Baseline (intraoperatively) (Time 1) to Time 7 (Post OP Day 4)]

    Study the safety profile of dosing the ATIII by monitoring the incidence (number) of newly diagnosed intracranial hemorrhage

24. Length of Time to Delayed Sternal Closure Measured in Days [Baseline (intraoperatively) (Time 1) to Time 7 (Post OP Day 4)]

    Study the safety profile of dosing the ATIII by monitoring the length of time to delayed sternal closure measured in days

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 7 Months
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• All patients less than 7 months of age going for cardiac surgery that will require cardiopulmonary bypass (CPB) with a documented ATIII level below 70%

Exclusion Criteria:

• Less than 2.5kg

• Known or suspected hereditary ATIII deficiency (family history of venous thrombosis with decreased plasma levels of ATIII and no other potential causes of acquired decreased ATIII)

• On Ecmo (extracorporeal membrane oxygenation ) at time of surgery

• Known history of thrombosis

• Renal failure as described by the pediatric RIFLE criteria

• H/o intracranial hemorrhage

• Prematurity less than 37 weeks estimated gestational age

• Previously diagnosed pro-thrombotic or hemorrhagic disorder

• Prior ATIII supplementation

• Prior therapeutic anticoagulant use

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Duke University	Durham	North Carolina	United States	27708

Sponsors and Collaborators

• Duke University
• Grifols Biologicals, LLC

Investigators

• Principal Investigator: Edmund Jooste, MD, Duke University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Duke University
• ClinicalTrials.gov Identifier: NCT02103114
• Other Study ID Numbers: Pro00051186
• First Posted: Apr 3, 2014
• Last Update Posted: Nov 25, 2019
• Last Verified: Nov 1, 2019

• Additional relevant MeSH terms: Antithrombin III Deficiency; Antithrombin III; Antithrombins; Thrombin

Study Results

Participant Flow

Recruitment Details	Five subjects enrolled but withdrew prior to randomization

Arm/Group Title	Anti-thrombin III	Placebo
Arm/Group Description	Intraoperatively- (correcting to 100%) according to the following formula: Units required = ((100%- baseline ATIII level*%) X body weight)/1.4 * expressed as a % normal level based on functional ATIII assay	Normal saline placebo
Period Title: Overall Study
STARTED	20	20
COMPLETED	20	19
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Anti-thrombin III	Placebo	Total
Arm/Group Description	Intraoperatively- (correcting to 100%) according to the following formula: Units required = ((100%- baseline ATIII level*%) X body weight)/1.4 * expressed as a % normal level based on functional ATIII assay	Placebo: Normal saline placebo	Total of all reporting groups
Overall Participants	20	20	40
Age (days) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [days]	9.8 (19.7)	17.2 (30.2)	14.6 (26.1)
Sex: Female, Male (Count of Participants)
Female	6 30%	7 35%	13 32.5%
Male	14 70%	13 65%	27 67.5%
Region of Enrollment (participants) [Number]
United States	20 100%	20 100%	40 100%

Outcome Measures

1. Primary Outcome

Title	Difference in the Mean and Standard Deviation (SD) of the Calibrated Automated Thrombography (CAT) Measurements of the Control and ATIII Groups at Time 5 (on Arrival in ICU)
Description	Evidence of decreased activation of the coagulation and fibrinolytic systems represented by a difference in the mean and Standard Deviation (SD) of the Calibrated Automated Thrombography (CAT) measurements of the control and ATIII groups at Time 5 (on arrival in ICU).
Time Frame	Time 5 (on arrival in ICU)

Outcome Measure Data

Analysis Population Description

The laboratory was unable to perform this blood assay due to technical issues and no results were generated.

Arm/Group Title	Anti-thrombin III	Placebo
Arm/Group Description	Intraoperatively- (correcting to 100%) according to the following formula: Units required = ((100%- baseline ATIII level*%) X body weight)/1.4 * expressed as a % normal level based on functional ATIII assay	Normal saline placebo
Measure Participants	0	0

2. Secondary Outcome

Title	Difference in the Mean and SD of the Calibrated Automated Thrombography (CAT) Measurements of the Control and ATIII Groups at Times 5-Time 7 (ICU Arrival to Post Operative Day 4)
Description	Evidence of decreased activation of the coagulation and fibrinolytic systems represented by a difference in the mean and SD of the Calibrated Automated Thrombography (CAT) measurements of the control and ATIII groups at times 5-Time 7 (ICU arrival to Post Operative Day 4)
Time Frame	ICU arrival (Time 5) to Time 7 (Post-operative Day 4)

Outcome Measure Data

Analysis Population Description

The laboratory was unable to perform this blood assay due to technical difficulties and no results were generated.

Arm/Group Title	Anti-thrombin III	Placebo
Arm/Group Description	Intraoperatively- (correcting to 100%) according to the following formula: Units required = ((100%- baseline ATIII level*%) X body weight)/1.4 * expressed as a % normal level based on functional ATIII assay	Normal saline placebo
Measure Participants	0	0

3. Secondary Outcome

Title	Difference in the Mean the ATIII (Functional Assay) of the Control and ATIII Groups at T1, T2, T3, T5, T6 and T7
Description	Evidence of decreased activation of the coagulation and fibrinolytic systems represented by a difference in the mean of the ATIII (functional assay) of the control and ATIII groups at T1, T2, T3, T5, T6 and T7 (Baseline, 30 min after study drug, 30 min on CPB, Arrival in ICU, POD 2, and POD 4). Data reported as % Functional Activity, which is calculated as the ability of Antithrombin (AT) to suppress FIIa or FXa in the presence of heparin compared to normograms, and expressed as a percentage.
Time Frame	T1, T2, T3, T5, T6 and T7

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Anti-thrombin III	Placebo
Arm/Group Description	Intraoperatively- (correcting to 100%) according to the following formula: Units required = ((100%- baseline ATIII level*%) X body weight)/1.4 * expressed as a % normal level based on functional ATIII assay	Normal saline placebo
Measure Participants	20	19
T1 (Baseline)	54 (12)	54 (13)
T2 (30 minutes post study drug)	99 (19)	49 (16)
T3 (30 minutes on CPB)	83 (20)	55 (27)
T5 (Arrival in ICU)	82 (18)	63 (19)
T6 (POD 2)	58 (15)	57 (14)
T7 (POD 4)	70.7 (20)	66 (17)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Anti-thrombin III, Placebo
	Comments
	Type of Statistical Test	Equivalence
	Comments	T1 (Baseline)
Statistical Test of Hypothesis	p-Value	0.982
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Anti-thrombin III, Placebo
	Comments
	Type of Statistical Test	Equivalence
	Comments	T2 (30 minutes after study drug)
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Anti-thrombin III, Placebo
	Comments
	Type of Statistical Test	Equivalence
	Comments	T3 (30 minutes on CPB)
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Anti-thrombin III, Placebo
	Comments
	Type of Statistical Test	Equivalence
	Comments	T5 (Arrival in ICU)
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Anti-thrombin III, Placebo
	Comments
	Type of Statistical Test	Equivalence
	Comments	T6 (POD 2)
Statistical Test of Hypothesis	p-Value	0.840
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Anti-thrombin III, Placebo
	Comments
	Type of Statistical Test	Equivalence
	Comments	T7 (POD 4)
Statistical Test of Hypothesis	p-Value	0.475
	Comments
	Method	t-test, 2 sided
	Comments

4. Secondary Outcome

Title	Difference in the Median of the ATIII (Functional Assay) of the Control and ATIII Groups at T4
Description	Evidence of decreased activation of the coagulation and fibrinolytic systems represented by a difference in the median of the ATIII (functional assay) of the control and ATIII groups at T4 (just prior to coming off of CPB). Data reported as % Functional Activity, which is calculated as the ability of Antithrombin (AT) to suppress FIIa or FXa in the presence of heparin compared to normograms, and expressed as a percentage.
Time Frame	T4 (just prior to coming off of CPB)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Anti-thrombin III	Placebo
Arm/Group Description	Intraoperatively- (correcting to 100%) according to the following formula: Units required = ((100%- baseline ATIII level*%) X body weight)/1.4 * expressed as a % normal level based on functional ATIII assay	Placebo: Normal saline placebo
Measure Participants	20	19
Median (Inter-Quartile Range) [% Functional Activity]	78.0	69.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Anti-thrombin III, Placebo
	Comments
	Type of Statistical Test	Equivalence
	Comments	T4 (just prior to coming off of CPB)
Statistical Test of Hypothesis	p-Value	0.048
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

5. Secondary Outcome

Title	Difference in the Median of the D Dimer of the Control and ATIII Groups at T1, T5, T6 and T7
Description	Evidence of decreased activation of the coagulation and fibrinolytic systems represented by a difference in the median of the D dimer of the control and ATIII groups at T1 (Baseline), T5 (Arrival in Intensive Care Unit), T6 (Post-Operative Day 2) and T7 (Post-Operative Day 4).
Time Frame	T1, T5, T6 and T7

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Anti-thrombin III	Placebo
Arm/Group Description	Intraoperatively- (correcting to 100%) according to the following formula: Units required = ((100%- baseline ATIII level*%) X body weight)/1.4 * expressed as a % normal level based on functional ATIII assay	Normal saline placebo
Measure Participants	20	19
T1 (Baseline)	1.1	0.9
T5 (Arrival in ICU)	0.6	1.0
T6 (POD 2)	1.3	1.7
T7 (POD 4)	3.2	5.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Anti-thrombin III, Placebo
	Comments
	Type of Statistical Test	Equivalence
	Comments	T1 (Baseline)
Statistical Test of Hypothesis	p-Value	0.855
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Anti-thrombin III, Placebo
	Comments
	Type of Statistical Test	Equivalence
	Comments	T5 (Arrival in ICU)
Statistical Test of Hypothesis	p-Value	0.225
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Anti-thrombin III, Placebo
	Comments
	Type of Statistical Test	Equivalence
	Comments	T6 (POD 2)
Statistical Test of Hypothesis	p-Value	0.313
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Anti-thrombin III, Placebo
	Comments
	Type of Statistical Test	Equivalence
	Comments	T7 (POD 4)
Statistical Test of Hypothesis	p-Value	0.008
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

6. Secondary Outcome

Title	Residual Heparin at the ICU Arrival Time Point Represented by a Decreased Anti Factor Xa Level.
Description	Evidence of a decreased amount of residual heparin at the Intensive Care Unit arrival time point (T5) represented by a decreased anti factor Xa level.
Time Frame	T5 (Intensive Care Unit Arrival)

Outcome Measure Data

Analysis Population Description

In both arms, heparin level was undetectable as Anti factor Xa level was less than or equal to 0.1 IU/ml in all subjects.

Arm/Group Title	Anti-thrombin III	Placebo
Arm/Group Description	Intraoperatively- (correcting to 100%) according to the following formula: Units required = ((100%- baseline ATIII level*%) X body weight)/1.4 * expressed as a % normal level based on functional ATIII assay	Placebo: Normal saline placebo
Measure Participants	20	19
Mean (Standard Deviation) [International Units/milliter]	0.1 (0)	0.1 (0)

7. Secondary Outcome

Title	Evidence of Decreased Inflammation Represented by a Decrease in Inflammatory Markers in the ATIII Group
Description	Evidence of decreased inflammation represented by a decrease in inflammatory markers in the ATIII group.
Time Frame	Baseline (T1) to Post-Operative Day 4 (T7)

Outcome Measure Data

Analysis Population Description

Laboratory testing not performed.

Arm/Group Title	Anti-thrombin III	Placebo
Arm/Group Description	Intraoperatively- (correcting to 100%) according to the following formula: Units required = ((100%- baseline ATIII level*%) X body weight)/1.4 * expressed as a % normal level based on functional ATIII assay	Placebo: Normal saline placebo
Measure Participants	0	0

8. Secondary Outcome

Title	Total Dose of Heparin While on Cardiopulmonary Bypass
Description	Total dose of Heparin while on Cardiopulmonary Bypass
Time Frame	T1 (Baseline) to T5 (Arrival in ICU)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Anti-thrombin III	Placebo
Arm/Group Description	Intraoperatively- (correcting to 100%) according to the following formula: Units required = ((100%- baseline ATIII level*%) X body weight)/1.4 * expressed as a % normal level based on functional ATIII assay	Normal saline placebo
Measure Participants	20	19
Median (Inter-Quartile Range) [units]	3775	5000

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Anti-thrombin III, Placebo
	Comments
	Type of Statistical Test	Equivalence
	Comments	T1 (Baseline) to T5 (Arrival in ICU)
Statistical Test of Hypothesis	p-Value	0.056
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

9. Secondary Outcome

Title	Protamine Dose Determined by Hemostasis Management System Machine (mg/kg)
Description	Protamine dose determined by Hemostasis Management system machine (mg/kg)
Time Frame	T1 (Baseline) to T5 (Arrival in ICU)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Anti-thrombin III	Placebo
Arm/Group Description	Intraoperatively- (correcting to 100%) according to the following formula: Units required = ((100%- baseline ATIII level*%) X body weight)/1.4 * expressed as a % normal level based on functional ATIII assay	Normal saline placebo
Measure Participants	20	19
Median (Inter-Quartile Range) [mg/kg]	9.8	10.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Anti-thrombin III, Placebo
	Comments
	Type of Statistical Test	Equivalence
	Comments	T1 (Baseline) to T5 (Arrival in ICU)
Statistical Test of Hypothesis	p-Value	0.545
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

10. Secondary Outcome

Title	Total Volume of Blood Products While on CPB
Description	Total volume of blood products exposed intraoperatively including the pump prime (ml/kg)
Time Frame	Baseline (intraoperatively) (Time 1) to before termination of bypass (Time 4)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Anti-thrombin III	Placebo
Arm/Group Description	Intraoperatively- (correcting to 100%) according to the following formula: Units required = ((100%- baseline ATIII level*%) X body weight)/1.4 * expressed as a % normal level based on functional ATIII assay	Normal saline placebo
Measure Participants	20	19
Total Volume Red Blood Cells	57 (103.9)	101.5 (128.9)
Total Volume Fresh Frozen Plasma	68.5 (121.5)	141.9 (133.6)
Total volume ultrafiltration Platelet transfusion	89.7 (44.2)	72.6 (54)
Total volume Cryoprecipitate transfusion	35.4 (22.8)	33.8 (32.5)

11. Secondary Outcome

Title	Time From Protamine Administration to Skin Dressing
Description	Time from protamine administration to skin dressing
Time Frame	Baseline (intraoperatively) (Time 1) to before termination of bypass (Time 4)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Anti-thrombin III	Placebo
Arm/Group Description	Intraoperatively- (correcting to 100%) according to the following formula: Units required = ((100%- baseline ATIII level*%) X body weight)/1.4 * expressed as a % normal level based on functional ATIII assay	Normal saline placebo
Measure Participants	20	19
Median (Inter-Quartile Range) [minutes]	107.0	89.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Anti-thrombin III, Placebo
	Comments
	Type of Statistical Test	Equivalence
	Comments	Baseline (intraoperatively) (Time 1) to before termination of bypass (Time 4)
Statistical Test of Hypothesis	p-Value	0.757
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

12. Secondary Outcome

Title	Total Volume of Fresh Frozen Plasma Given Prior to CPB
Description	Total volume of Fresh Frozen Plasma given prior to CPB, including the pump prime (ml/kg)
Time Frame	Baseline (intraoperatively) (Time 1) to before termination of bypass (Time 4)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Anti-thrombin III	Placebo
Arm/Group Description	Intraoperatively- (correcting to 100%) according to the following formula: Units required = ((100%- baseline ATIII level*%) X body weight)/1.4 * expressed as a % normal level based on functional ATIII assay	Placebo: Normal saline placebo
Measure Participants	20	19
Mean (Standard Deviation) [ml/kg]	15 (67.1)	5.8 (25.5)

13. Secondary Outcome

Title	Incidence of Recombinant Factor 7a (VIIa) Use Intraoperatively
Description	Incidence of Recombinant Factor 7a (VIIa) Use Intraoperatively
Time Frame	Baseline (Intraoperatively)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Anti-thrombin III	Placebo
Arm/Group Description	Intraoperatively- (correcting to 100%) according to the following formula: Units required = ((100%- baseline ATIII level*%) X body weight)/1.4 * expressed as a % normal level based on functional ATIII assay	Placebo: Normal saline placebo
Measure Participants	20	19
Number [count of participants]	5 25%	5 25%

14. Secondary Outcome

Title	Volume of Postoperative Blood Loss
Description	Volume of postoperative blood loss from 10min post protamine administration to 24 hour post protamine administration- (ml/kg)
Time Frame	From 10min post protamine administration to 24 hour post protamine administration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Anti-thrombin III	Placebo
Arm/Group Description	Intraoperatively- (correcting to 100%) according to the following formula: Units required = ((100%- baseline ATIII level*%) X body weight)/1.4 * expressed as a % normal level based on functional ATIII assay	Normal saline placebo
Measure Participants	20	19
24 hour postop Fresh Frozen Plasma exposures	0.8 (3.4)	2.8 (7.3)
24 hour postop Platelet exposures	0 (0)	2.7 (5.6)
24 hour postop Cryoprecipitate exposures	0 (0)	2.1 (5.4)
24 hour postop Red Blood Cell exposures	3.9 (7.3)	10.1 (16.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Anti-thrombin III, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.2741
	Comments
	Method	t-test, 2 sided
	Comments	24 hour postop Fresh Frozen Plasma exposures

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Anti-thrombin III, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0351
	Comments
	Method	t-test, 2 sided
	Comments	24 hour postop Platelet exposures

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Anti-thrombin III, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.073
	Comments
	Method	t-test, 2 sided
	Comments	24 hour postop Cryoprecipitate exposures

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Anti-thrombin III, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0196
	Comments
	Method	t-test, 2 sided
	Comments	24 hour postop Red Blood Cell exposures

15. Secondary Outcome

Title	Chest Tube Output (Protamine Time Plus 24 Hours) in Milliliters
Description	Chest Tube output (protamine time plus 24 hours) in milliliters
Time Frame	protamine time plus 24 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Anti-thrombin III	Placebo
Arm/Group Description	Intraoperatively- (correcting to 100%) according to the following formula: Units required = ((100%- baseline ATIII level*%) X body weight)/1.4 * expressed as a % normal level based on functional ATIII assay	Placebo: Normal saline placebo
Measure Participants	20	19
Median (Inter-Quartile Range) [milliters]	59.0	113.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Anti-thrombin III, Placebo
	Comments
	Type of Statistical Test	Equivalence
	Comments	protamine time plus 24 hours
Statistical Test of Hypothesis	p-Value	0.016
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

16. Secondary Outcome

Title	Number of Total Blood Product Units Transfused by Type 24-hours Post-operatively by Group
Description	Number of packed Fresh frozen plasma units, Platelet Units, cryo-precipitate units, and Red Blood Cell units transfused 24 hours post-operatively for each group (not total units transfused for each subject)
Time Frame	24 Hours Post-Operatively

Outcome Measure Data

Analysis Population Description

Unable to be calculated accurately as blood products given in CPB prime were only designated in Units administered and not mls (no record of how many mls present in each unit). Therefore unable to back calculate total mls given from start of surgery to 24 hours postop

Arm/Group Title	Anti-thrombin III	Placebo
Arm/Group Description	Intraoperatively- (correcting to 100%) according to the following formula: Units required = ((100%- baseline ATIII level*%) X body weight)/1.4 * expressed as a % normal level based on functional ATIII assay	Normal saline placebo
Measure Participants	20	19
Fresh Frozen Plasma Units	1	3
Platelet Units	0	4
Cryo-Precipitate Units	0	3
Red Blood Cell Units	5	9

17. Secondary Outcome

Title	Number of Total Blood Product Units Transfused 24-hours Post-operatively by Group
Description	Number of total blood product units (including packed Fresh frozen plasma units, Platelet Units, cryo-precipitate units, and Red Blood Cell units) transfused 24 hours post-operatively for each group (not total units transfused for each subject)
Time Frame	24 Hours Post-Operatively

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Anti-thrombin III	Placebo
Arm/Group Description	Intraoperatively- (correcting to 100%) according to the following formula: Units required = ((100%- baseline ATIII level*%) X body weight)/1.4 * expressed as a % normal level based on functional ATIII assay	Placebo: Normal saline placebo
Measure Participants	20	19
Number [Units]	6	19

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Anti-thrombin III, Placebo
	Comments
	Type of Statistical Test	Equivalence
	Comments	24 Hours Post-Operatively
Statistical Test of Hypothesis	p-Value	0.0004
	Comments
	Method	Fisher Exact
	Comments

18. Secondary Outcome

Title	Total Dose of Recombinant Factor 7a (VIIa) Used Intraoperatively
Description	Total Dose of rescue recombinant factor 7a (VIIa) used intraoperatively
Time Frame	Intraoperatively

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Anti-thrombin III	Placebo
Arm/Group Description	Intraoperatively- (correcting to 100%) according to the following formula: Units required = ((100%- baseline ATIII level*%) X body weight)/1.4 * expressed as a % normal level based on functional ATIII assay	Normal saline placebo
Measure Participants	20	19
Mean (Standard Deviation) [mcg]	56.1 (118.2)	70.6 (174.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Anti-thrombin III, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.927
	Comments
	Method	t-test, 2 sided
	Comments

19. Secondary Outcome

Title	Length of Post Operative Ventilation in Days
Description	Length of post operative ventilation in days
Time Frame	ICU arrival (Time 5) to Time 7 (Post-Operative Day 4)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Anti-thrombin III	Placebo
Arm/Group Description	Intraoperatively- (correcting to 100%) according to the following formula: Units required = ((100%- baseline ATIII level*%) X body weight)/1.4 * expressed as a % normal level based on functional ATIII assay	Normal saline placebo
Measure Participants	20	19
Mean (Standard Deviation) [days]	3.9 (2)	3.6 (1.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Anti-thrombin III, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.738
	Comments
	Method	t-test, 2 sided
	Comments

20. Secondary Outcome

Title	Incidence of Extracorporeal Membrane Oxygenation (ECMO) Support Within 24 Hours Postoperatively
Description	Study the safety profile of dosing the ATIII by monitoring the incidence of extracorporeal membrane oxygenation (ECMO) support within 24 hours postoperatively.
Time Frame	Baseline (intraoperatively) (Time 1) to Time 7 (Post OP Day 4)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Anti-thrombin III	Placebo
Arm/Group Description	Intraoperatively- (correcting to 100%) according to the following formula: Units required = ((100%- baseline ATIII level*%) X body weight)/1.4 * expressed as a % normal level based on functional ATIII assay	Normal saline placebo
Measure Participants	20	19
Number [number]	0	2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Anti-thrombin III, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.231
	Comments
	Method	Fisher Exact
	Comments

21. Secondary Outcome

Title	Incidence of Mediastinal Exploration Within 24 Hours Postoperatively
Description	Study the safety profile of dosing the ATIII by monitoring the incidence of mediastinal exploration within 24 hours postoperatively
Time Frame	Baseline (intraoperatively) (Time 1) to Time 7 (Post OP Day 4)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Anti-thrombin III	Placebo
Arm/Group Description	Intraoperatively- (correcting to 100%) according to the following formula: Units required = ((100%- baseline ATIII level*%) X body weight)/1.4 * expressed as a % normal level based on functional ATIII assay	Normal saline placebo
Measure Participants	20	19
Number [count of participants]	2 10%	3 15%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Anti-thrombin III, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.661
	Comments
	Method	Fisher Exact
	Comments

22. Secondary Outcome

Title	Incidence (Number) of Thrombotic Events Documented
Description	Study the safety profile of dosing the ATIII by monitoring the incidence (number) of thrombotic events documented.
Time Frame	Baseline (intraoperatively) (Time 1) to Time 7 (Post OP Day 4)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Anti-thrombin III	Placebo
Arm/Group Description	Intraoperatively- (correcting to 100%) according to the following formula: Units required = ((100%- baseline ATIII level*%) X body weight)/1.4 * expressed as a % normal level based on functional ATIII assay	Normal saline placebo
Measure Participants	20	19
Number [events]	0	0

23. Secondary Outcome

Title	Incidence of New Onset Renal Failure, Defined by Stage 3 of the AKIN Criteria
Description	Study the safety profile of dosing the ATIII by monitoring the incidence of new onset renal failure, defined by stage 3 of the Acute Kidney Injury Network (AKIN) criteria. Serum creatinine increase ≥26.5 μmol/l (≥0.3 mg/dl) or increase to 1.5-2.0-fold from baseline, urine output <0.5 ml/kg/h for 6 hours Serum creatinine increase >2.0-3.0-fold from baseline, urine output <0.5 ml/kg/h for 12 hours Serum creatinine increase >3.0-fold from baseline or serum creatinine ≥354 μmol/l (≥4.0 mg/dl) with an acute increase of at least 44 μmol/l (0.5 mg/dl) or need for Renal replacement therapy (RRT), urine output <0.3 ml/kg/h for 24 h or anuria for 12 hours or need for RRT
Time Frame	Baseline (intraoperatively) (Time 1) to Time 7 (Post OP Day 4)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Anti-thrombin III	Placebo
Arm/Group Description	Intraoperatively- (correcting to 100%) according to the following formula: Units required = ((100%- baseline ATIII level*%) X body weight)/1.4 * expressed as a % normal level based on functional ATIII assay	Normal saline placebo
Measure Participants	20	19
Number [count of participants]	1 5%	1 5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Anti-thrombin III, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	1.0
	Comments
	Method	Fisher Exact
	Comments

24. Secondary Outcome

Title	Incidence (Number) of Newly Diagnosed Intracranial Hemorrhage
Description	Study the safety profile of dosing the ATIII by monitoring the incidence (number) of newly diagnosed intracranial hemorrhage
Time Frame	Baseline (intraoperatively) (Time 1) to Time 7 (Post OP Day 4)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Anti-thrombin III	Placebo
Arm/Group Description	Intraoperatively- (correcting to 100%) according to the following formula: Units required = ((100%- baseline ATIII level*%) X body weight)/1.4 * expressed as a % normal level based on functional ATIII assay	Normal saline placebo
Measure Participants	20	19
Number [participants]	1 5%	3 15%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Anti-thrombin III, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.342
	Comments
	Method	Fisher Exact
	Comments

25. Secondary Outcome

Title	Length of Time to Delayed Sternal Closure Measured in Days
Description	Study the safety profile of dosing the ATIII by monitoring the length of time to delayed sternal closure measured in days
Time Frame	Baseline (intraoperatively) (Time 1) to Time 7 (Post OP Day 4)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Anti-thrombin III	Placebo
Arm/Group Description	Intraoperatively- (correcting to 100%) according to the following formula: Units required = ((100%- baseline ATIII level*%) X body weight)/1.4 * expressed as a % normal level based on functional ATIII assay	Normal saline placebo
Measure Participants	20	19
Mean (Standard Deviation) [days]	2.7 (2.1)	2.7 (2.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Anti-thrombin III, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.961
	Comments
	Method	t-test, 2 sided
	Comments

Adverse Events

Time Frame	Adverse events were collected from Baseline (intraoperatively) until post-operative day four.
Arm/Group Title	Anti-thrombin III		Placebo
Arm/Group Description	Intraoperatively- (correcting to 100%) according to the following formula: Units required = ((100%- baseline ATIII level*%) X body weight)/1.4 * expressed as a % normal level based on functional ATIII assay		Normal saline placebo
All Cause Mortality
	Anti-thrombin III		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Anti-thrombin III		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/20 (15%)		8/20 (40%)
Blood and lymphatic system disorders
Hypotension R/T bleeding	0/20 (0%)	0	1/20 (5%)	1
Shock	0/20 (0%)	0	1/20 (5%)	1
Intraop Bleeding	0/20 (0%)	0	4/20 (20%)	4
Cardiac disorders
Hypotension R/T chest fluid retention (not bleeding)	1/20 (5%)	1	0/20 (0%)	0
Cardiac arrest	0/20 (0%)	0	1/20 (5%)	1
Nervous system disorders
Right-sided tonic clonic seizure	1/20 (5%)	1	0/20 (0%)	0
Right-sided subdural hematoma	0/20 (0%)	0	1/20 (5%)	1
Respiratory, thoracic and mediastinal disorders
ECMO	1/20 (5%)	1	0/20 (0%)	0
Surgical and medical procedures
Hemorrhage	1/20 (5%)	1	1/20 (5%)	1
Bradycardia	1/20 (5%)	1	0/20 (0%)	0
Hypotension	1/20 (5%)	1	0/20 (0%)	0
Other (Not Including Serious) Adverse Events
	Anti-thrombin III		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/20 (15%)		7/20 (35%)
Blood and lymphatic system disorders
Anemia	0/20 (0%)		1/20 (5%)
Low Hematocrit	1/20 (5%)		0/20 (0%)
Desaturation	0/20 (0%)		1/20 (5%)
Intermittent PVCs R/T Low K, Low Mg	0/20 (0%)		1/20 (5%)
Hemoparitoneum	0/20 (0%)		1/20 (5%)
Cardiac disorders
Junctional ectopic tachycardia	1/20 (5%)		0/20 (0%)
Junctional rhythm tachycardia	0/20 (0%)		1/20 (5%)
SVTs	0/20 (0%)		1/20 (5%)
Hypotension	0/20 (0%)		1/20 (5%)
Gastrointestinal disorders
Hematochezia	0/20 (0%)		1/20 (5%)
Nervous system disorders
Echogenic focus in occipital parietal region	0/20 (0%)		1/20 (5%)
Posterior subdural hematoma	0/20 (0%)		1/20 (5%)
Renal and urinary disorders
Acute kidney injury	0/20 (0%)		1/20 (5%)
Respiratory, thoracic and mediastinal disorders
Right Lung Collapse	1/20 (5%)		0/20 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT 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.