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

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

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.

Study Overview

• Status: Completed
• Conditions: ATIII Deficiency
• Intervention / Treatment: Drug: Anti-thrombin III; Other: Placebo

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 Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27708
      • Duke University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 7 months (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Other: Placebo; Normal saline placebo
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	Time 5 (on arrival in ICU)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	ICU arrival (Time 5) to Time 7 (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.	T1, T2, T3, T5, T6 and T7
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.	T4 (just prior to coming off of CPB)
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).	T1, T5, T6 and T7
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.	T5 (Intensive Care Unit Arrival)
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.	Baseline (T1) to Post-Operative Day 4 (T7)
Total Dose of Heparin While on Cardiopulmonary Bypass	Total dose of Heparin while on Cardiopulmonary Bypass	T1 (Baseline) to T5 (Arrival in ICU)
Protamine Dose Determined by Hemostasis Management System Machine (mg/kg)	Protamine dose determined by Hemostasis Management system machine (mg/kg)	T1 (Baseline) to T5 (Arrival in ICU)
Total Volume of Blood Products While on CPB	Total volume of blood products exposed intraoperatively including the pump prime (ml/kg)	Baseline (intraoperatively) (Time 1) to before termination of bypass (Time 4)
Time From Protamine Administration to Skin Dressing	Time from protamine administration to skin dressing	Baseline (intraoperatively) (Time 1) to before termination of bypass (Time 4)
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)	Baseline (intraoperatively) (Time 1) to before termination of bypass (Time 4)
Incidence of Recombinant Factor 7a (VIIa) Use Intraoperatively	Incidence of Recombinant Factor 7a (VIIa) Use Intraoperatively	Baseline (Intraoperatively)
Volume of Postoperative Blood Loss	Volume of postoperative blood loss from 10min post protamine administration to 24 hour post protamine administration- (ml/kg)	From 10min post protamine administration to 24 hour post protamine administration
Chest Tube Output (Protamine Time Plus 24 Hours) in Milliliters	Chest Tube output (protamine time plus 24 hours) in milliliters	protamine time plus 24 hours
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)	24 Hours Post-Operatively
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)	24 Hours Post-Operatively
Total Dose of Recombinant Factor 7a (VIIa) Used Intraoperatively	Total Dose of rescue recombinant factor 7a (VIIa) used intraoperatively	Intraoperatively
Length of Post Operative Ventilation in Days	Length of post operative ventilation in days	ICU arrival (Time 5) to Time 7 (Post-Operative Day 4)
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.	Baseline (intraoperatively) (Time 1) to Time 7 (Post OP Day 4)
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	Baseline (intraoperatively) (Time 1) to Time 7 (Post OP Day 4)
Incidence (Number) of Thrombotic Events Documented	Study the safety profile of dosing the ATIII by monitoring the incidence (number) of thrombotic events documented.	Baseline (intraoperatively) (Time 1) to Time 7 (Post OP Day 4)
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	Baseline (intraoperatively) (Time 1) to Time 7 (Post OP Day 4)
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	Baseline (intraoperatively) (Time 1) to Time 7 (Post OP Day 4)
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	Baseline (intraoperatively) (Time 1) to Time 7 (Post OP Day 4)

Collaborators and Investigators

• Sponsor: Duke University
• Collaborators: Grifols Biologicals, LLC
• Investigators: Principal Investigator: Edmund Jooste, MD, Duke University

Study record dates

Study Major Dates

• Study Start: June 1, 2014
• Primary Completion (Actual): June 27, 2016
• Study Completion (Actual): July 1, 2016

Study Registration Dates

• First Submitted: April 1, 2014
• First Submitted That Met QC Criteria: April 1, 2014
• First Posted (Estimate): April 3, 2014

Study Record Updates

• Last Update Posted (Actual): November 25, 2019
• Last Update Submitted That Met QC Criteria: November 21, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Genetic Diseases, Inborn; Blood Protein Disorders; Blood Coagulation Disorders; Thrombophilia; Antithrombin III Deficiency; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Serine Proteinase Inhibitors; Anticoagulants; Hemostatics; Coagulants; Thrombin; Antithrombins; Antithrombin III
• Other Study ID Numbers: Pro00051186