Back to resultsAnti-thrombin III (ATIII) vs Placebo in Children (<7mo) Undergoing Open Congenital Cardiac Surgery
Primary Purpose
ATIII Deficiency
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Anti-thrombin III
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for ATIII Deficiency
Eligibility Criteria
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
Sites / Locations
- Duke University
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Anti-thrombin III
Placebo
Arm Description
Outcomes
Primary Outcome Measures
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)
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
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)
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)
Difference in the Mean the ATIII (Functional Assay) of the Control and ATIII Groups at 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.
Difference in the Median of the ATIII (Functional Assay) of the Control and ATIII Groups at T4
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.
Difference in the Median of the D Dimer of the Control and ATIII Groups at 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).
Residual Heparin at the ICU Arrival Time Point Represented by a Decreased Anti Factor Xa Level.
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.
Evidence of Decreased Inflammation Represented by a Decrease in Inflammatory Markers in the ATIII Group
Evidence of decreased inflammation represented by a decrease in inflammatory markers in the ATIII group.
Total Dose of Heparin While on Cardiopulmonary Bypass
Total dose of Heparin while on Cardiopulmonary Bypass
Protamine Dose Determined by Hemostasis Management System Machine (mg/kg)
Protamine dose determined by Hemostasis Management system machine (mg/kg)
Total Volume of Blood Products While on CPB
Total volume of blood products exposed intraoperatively including the pump prime (ml/kg)
Time From Protamine Administration to Skin Dressing
Time from protamine administration to skin dressing
Total Volume of Fresh Frozen Plasma Given Prior to CPB
Total volume of Fresh Frozen Plasma given prior to CPB, including the pump prime (ml/kg)
Incidence of Recombinant Factor 7a (VIIa) Use Intraoperatively
Incidence of Recombinant Factor 7a (VIIa) Use Intraoperatively
Volume of Postoperative Blood Loss
Volume of postoperative blood loss from 10min post protamine administration to 24 hour post protamine administration- (ml/kg)
Chest Tube Output (Protamine Time Plus 24 Hours) in Milliliters
Chest Tube output (protamine time plus 24 hours) in milliliters
Number of Total Blood Product Units Transfused by Type 24-hours Post-operatively by Group
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)
Number of Total Blood Product Units Transfused 24-hours Post-operatively by Group
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)
Total Dose of Recombinant Factor 7a (VIIa) Used Intraoperatively
Total Dose of rescue recombinant factor 7a (VIIa) used intraoperatively
Length of Post Operative Ventilation in Days
Length of post operative ventilation in days
Incidence of Extracorporeal Membrane Oxygenation (ECMO) Support Within 24 Hours Postoperatively
Study the safety profile of dosing the ATIII by monitoring the incidence of extracorporeal membrane oxygenation (ECMO) support within 24 hours postoperatively.
Incidence of Mediastinal Exploration Within 24 Hours Postoperatively
Study the safety profile of dosing the ATIII by monitoring the incidence of mediastinal exploration within 24 hours postoperatively
Incidence (Number) of Thrombotic Events Documented
Study the safety profile of dosing the ATIII by monitoring the incidence (number) of thrombotic events documented.
Incidence of New Onset Renal Failure, Defined by Stage 3 of the AKIN Criteria
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
Incidence (Number) of Newly Diagnosed Intracranial Hemorrhage
Study the safety profile of dosing the ATIII by monitoring the incidence (number) of newly diagnosed intracranial hemorrhage
Length of Time to Delayed Sternal Closure Measured in Days
Study the safety profile of dosing the ATIII by monitoring the length of time to delayed sternal closure measured in days
Full Information
NCT ID
NCT02103114
First Posted
April 1, 2014
Last Updated
November 21, 2019
Sponsor
Duke University
Collaborators
Grifols Biologicals, LLC
1. Study Identification
Unique Protocol Identification Number
NCT02103114
Brief Title
Anti-thrombin III (ATIII) vs Placebo in Children (<7mo) Undergoing Open Congenital Cardiac Surgery
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 Type
Interventional
2. Study Status
Record Verification Date
November 2019
Overall Recruitment Status
Completed
Study Start Date
June 2014 (undefined)
Primary Completion Date
June 27, 2016 (Actual)
Study Completion Date
July 1, 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Duke University
Collaborators
Grifols Biologicals, LLC
4. Oversight
Data Monitoring Committee
No
5. 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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
ATIII Deficiency
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
45 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Anti-thrombin III
Arm Type
Experimental
Arm Title
Placebo
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
Anti-thrombin III
Other Intervention Name(s)
Thrombate III
Intervention 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
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Normal saline placebo
Primary Outcome Measure Information:
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)
Secondary Outcome Measure Information:
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)
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
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)
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
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)
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)
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)
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)
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)
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)
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)
Title
Incidence of Recombinant Factor 7a (VIIa) Use Intraoperatively
Description
Incidence of Recombinant Factor 7a (VIIa) Use Intraoperatively
Time Frame
Baseline (Intraoperatively)
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
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
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
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
Title
Total Dose of Recombinant Factor 7a (VIIa) Used Intraoperatively
Description
Total Dose of rescue recombinant factor 7a (VIIa) used intraoperatively
Time Frame
Intraoperatively
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)
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)
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)
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)
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)
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)
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)
10. Eligibility
Sex
All
Maximum Age & Unit of Time
7 Months
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Edmund Jooste, MD
Organizational Affiliation
Duke University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Duke University
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27708
Country
United States
12. IPD Sharing Statement
Learn more about this trial
Anti-thrombin III (ATIII) vs Placebo in Children (<7mo) Undergoing Open Congenital Cardiac Surgery
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