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

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT02103114
First Posted: April 3, 2014
Last Update Posted: July 26, 2017
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.
Collaborator:
Grifols Biologicals Inc.
Information provided by (Responsible Party):
Duke University
  Purpose
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 Intervention Phase
ATIII Deficiency Drug: Anti-thrombin III Other: Placebo Phase 2

Study Type: Interventional
Study Design: 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

Resource links provided by NLM:


Further study details as provided by Duke University:

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) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.

  • Difference in the Median of the D Dimer of the Control and ATIII Groups at T1, T5, T6 and T7 [ Time Frame: 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. [ Time Frame: 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 [ Time Frame: Baseline (T1) to Post-Operative Day 4 (T7) ]
    Evidence of decreased inflammation represented by a decrease in inflammatory markers in the ATIII group.

  • Total Dose of Heparin While on Cardiopulmonary Bypass [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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)

  • Incidence of Recombinant Factor 7a (VIIa) Use Intraoperatively [ Time Frame: Baseline (Intraoperatively) ]
    Incidence of Recombinant Factor 7a (VIIa) Use Intraoperatively

  • Volume of Postoperative Blood Loss [ Time Frame: 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)

  • Chest Tube Output (Protamine Time Plus 24 Hours) in Milliliters [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Intraoperatively ]
    Total Dose of rescue recombinant factor 7a (VIIa) used intraoperatively

  • Length of Post Operative Ventilation in Days [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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


Enrollment: 45
Study Start Date: June 2014
Study Completion Date: July 1, 2016
Primary Completion Date: June 27, 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: Thrombate III
Placebo Comparator: Placebo Other: Placebo
Normal saline 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.
  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   up to 7 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02103114


Locations
United States, North Carolina
Duke University
Durham, North Carolina, United States, 27708
Sponsors and Collaborators
Duke University
Grifols Biologicals Inc.
Investigators
Principal Investigator: Edmund Jooste, MD Duke University
  More Information

Responsible Party: Duke University
ClinicalTrials.gov Identifier: NCT02103114     History of Changes
Other Study ID Numbers: Pro00051186
First Submitted: April 1, 2014
First Posted: April 3, 2014
Results First Submitted: April 26, 2017
Results First Posted: July 26, 2017
Last Update Posted: July 26, 2017
Last Verified: June 2017

Additional relevant MeSH terms:
Antithrombin III Deficiency
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Blood Protein Disorders
Thrombophilia
Genetic Diseases, Inborn
Thrombin
Antithrombins
Antithrombin III
Hemostatics
Coagulants
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anticoagulants