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

Phase 2

Completed

• Conditions: ATIII Deficiency
• Interventions: Drug: Anti-thrombin III; Other: Placebo

• Registration Number: NCT02103114
• Lead Sponsor: Duke University

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.

Study Timeline

• Study First Submitted: 2014-04-01
• Study First Submitted QC: 2014-04-01
• Study First Posted: 2014-04-03
• Study Start: 2014-06
• Primary Completion: 2016-06-27
• Study Completion: 2016-07-01
• Results First Submitted: 2017-04-26
• Results First Submitted QC: 2017-06-27
• Results First Posted: 2017-07-26
• Status Verified: 2019-11
• Last Update Submitted: 2019-11-21
• Last Update Posted: 2019-11-25

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 45

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%

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Anti-thrombin III	Anti-thrombin III	-
Placebo	Placebo	-

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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)
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.
Incidence of Recombinant Factor 7a (VIIa) Use Intraoperatively	Baseline (Intraoperatively)	Incidence of Recombinant Factor 7a (VIIa) Use Intraoperatively
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)
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.
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.
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.
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).
Total Dose of Heparin While on Cardiopulmonary Bypass	T1 (Baseline) to T5 (Arrival in ICU)	Total dose of Heparin while on Cardiopulmonary Bypass
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)
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)
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
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)
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
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)
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)
Total Dose of Recombinant Factor 7a (VIIa) Used Intraoperatively	Intraoperatively	Total Dose of rescue recombinant factor 7a (VIIa) used intraoperatively
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
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.
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
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.
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.; 1. 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; 2. Serum creatinine increase \>2.0-3.0-fold from baseline, urine output \<0.5 ml/kg/h for 12 hours; 3. 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	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
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

Trial Locations

Locations (1)

Duke University; 🇺🇸 Durham, North Carolina, United States