Evaluation Of The Pharmacokinetics Of Antithrombin III In Neonates And Infants Undergoing CPB And ECMO Support

NCT02631174 | Completed Phase 1 DMC

• 1 other identifier: 2014-6716
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 1

Brief Summary

The potential role of ATIII in achieving and maintaining adequate anticoagulation in pediatric patients on the heart-lung machine has recently taken on increased importance as caregivers strive to mitigate the risk for clinically significant clotting problems. It is known that ATIII levels are decreased in normal neonates and infants less than 6 months of age relative to older children and adults and become even further decreased in critically ill neonates and infants, including those with congenital heart disease. The current utilization of ATIII in the context of support on a heart-lung machine is based on pharmacokinetic data derived from adult subjects with congenital ATIII deficiency. There is a gap in knowledge as to the appropriate frequency of ATIII repletion, best method of monitoring, and mode of administration in critically ill neonates and infants receiving support on a heart-lung machine.Our long-term goal is to determine if antithrombin (ATIII) can effectively change the coagulation system in patients undergoing heart-lung machine support. The objective of this proposal, which is our first step in pursuit of that goal, is to determine the pharmacokinetics of ATIII in neonates and infants. Our central hypothesis is that ATIII will have different pharmacokinetic properties in neonates and infants than adults and these properties will be affected by the use of heart-lung machine. This research will result in critical data on the pharmacokinetics of ATIII in neonates and infants receiving heart-lung machine support. This contribution is significant because it is the first step in a continuum of research that is expected to lead to the development of a therapeutic strategy employing ATIII that will facilitate improved modulation of the coagulation cascade to prevent significant clotting and bleeding complications in pediatric patients requiring heart-lung machine support.

Conditions

Extracorporeal Membrane Oxygenation Complication; Cardiopulmonary Bypass

Outcome Measures

Primary Outcomes (3)

• Aim 1:To determine the pharmacokinetics of a single dose of hpATIII in neonates not undergoing ECMO or CPB.

  Blood samples (0.5 mL) for analysis of plasma ATIII concentration will be drawn at specific time points, e.g. before and after the dose of ATIII is given ,together with coagulation labs such as prothrombin/ thrombin anti thrombin complex and CBC, PT/PTT/INR at baseline, 12 and 24 hrs only.If clinical labs exist, those will be used instead for that time point.

  participants in cohort 1 will have sampling up to 36 hrs after receiving their single dose of ATIII

• Aim 2:To determine the pharmacokinetics of a single dose of hpATIII in neonates and infants undergoing ECMO or CPB

  Blood samples (0.5 mL) for analysis of plasma ATIII concentration will be drawn at specific time points, e.g.before and after the dose of ATIII is given,together with coagulation labs such as prothrombin/ thrombin anti thrombin complex and CBC, PT/PTT/INR at baseline, 12 and 24 hrs only. If clinical labs exist, those will be used instead for that time point.

  participants will be followed for 120hrs after recieving their single dose of ATIII

• Aim 3:To determine the pharmacokinetics of hpATIII administered by continuous infusion in neonates and infants undergoing ECMO

  Blood samples (0.5 mL) for analysis of plasma ATIII concentration will be drawn at specific time points, e.g.before and after the dose of ATIII is given,together with coagulation labs such as prothrombin/ thrombin anti thrombin complex and CBC, PT/PTT/INR at baseline, 12 and 24 hrs only. If clinical labs exist, those will be used instead for that timepoint.

  participants will be followed for a period of 120hrs after recieving half the dose as a bolus and the rest as a continuous infusion

Study Arms (5)

cohort 1

NO INTERVENTION

Cohort 1 (Aim 1) - 6 participants Cohort 1 will be comprised of 6 neonates (≤28 days of age) admitted to the CICU or NICU who are neither undergoing ECMO nor CPB. Cohort 1 will receive a single dose of ATIII by short 15 minute infusion.

cohort 2.1

ACTIVE COMPARATOR

• Cohort 2.1 - 6 neonates undergoing ECMO. * Three participants will receive a single dose 15 minute infusion of hpATIII that is dose adjusted to account for additional circuit volume followed by a single dose 15 minute infusion of ATIII that is not dose adjusted to account for circuit volume * Three participants will receive a single dose 15 minute infusion of hpATIII that is not dose adjusted to account for circuit volume followed by a single dose 15 minute infusion of hpATIII that is dose adjusted to account for additional circuit volume

Drug: Antithrombin III

cohort 2.2

ACTIVE COMPARATOR

• Cohort 2.2 - 12 neonates who will undergo open-heart surgery with CPB * Six participants will receive a single dose 15 minute infusion of ATIII that is dose adjusted to account for additional circuit volume. * Six participants will receive a single dose 15 minute infusion of ATIII that is not dose adjusted to account for circuit volume

Drug: Antithrombin III

cohort 2.3

ACTIVE COMPARATOR

• Cohort 2.3 - 12 infants who will undergo open-heart surgery with CPB * Six participants will receive a single dose 15 minute infusion of ATIII that is dose adjusted to account for additional circuit volume. * Six participants will receive a single dose 15 minute infusion of ATIII that is not dose adjusted to account for circuit volume

Drug: Antithrombin III

cohort 3

ACTIVE COMPARATOR

Cohort 3 (Aim 3) - 6 participants Six participants (neonates or infants) who will undergo ECMO and receive ATIII as standard of care will be enrolled and have a baseline ATIII level measured within 6 hours of ATIII administration and repeated within 15 minutes of initiation of extracorporeal support. If post-support level is \< 80% normal activity then an ATIII level will be repeated and participants will be assigned to one of two hpATIII dosing regimens in which one formula accounts for additional circuit volume and one formula does not account for additional circuit volume, as described in section 7.4. Upon completion and 120 hr follow up after the first dose, participants still having ATIII activity less than 80% will then receive a second dose

Drug: Antithrombin III

Interventions

Antithrombin III DRUG

We are comparing neonates and infants on ECMP or CPB receiving ATIII, the dose of which is calculated to account for circuit volume, and compared with those not accounting for circuit volume

cohort 2.1; cohort 2.2; cohort 2.3; cohort 3

Eligibility Criteria

• Age: Up to 1 Year
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)

You may qualify if:

• \. Neonates less than or equal to 28 days of age OR Infants between 29 days and 1 year of age;
• \. ATIII activity less than 80% at time of screening;

You may not qualify if:

• Subjects who meet any of the following criteria will be excluded from the study:
• Known or suspected bleeding disorder;
• Neonates with gestational age \<36 weeks;
• Neonates with evidence of intracranial hemorrhage on routine cranial ultrasound;
• Documented infection (sepsis);
• Patients who require post-cardiotomy ECMO;
• Patients who require E-CPR; and/or
• Neonates or infants deemed to be at increased risk as judged by the investigator or for whom administration of hpATIII is not in their best interest

Sponsors & Collaborators

• Children's Hospital Medical Center, Cincinnati: lead
• Grifols Biologicals, LLC: collaborator

Study Sites (1)

Cincinnati Childrens Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Related Publications (4)

• Guzzetta NA, Bajaj T, Fazlollah T, Szlam F, Wilson E, Kaiser A, Tosone SR, Miller BE. A comparison of heparin management strategies in infants undergoing cardiopulmonary bypass. Anesth Analg. 2008 Feb;106(2):419-25, table of contents. doi: 10.1213/01.ane.0000297290.03501.db.

  PMID: 18227295 BACKGROUND

• D'Argenio DZ. Optimal sampling times for pharmacokinetic experiments. J Pharmacokinet Biopharm. 1981 Dec;9(6):739-56. doi: 10.1007/BF01070904.

  PMID: 7341758 BACKGROUND

• Esmon CT. The interactions between inflammation and coagulation. Br J Haematol. 2005 Nov;131(4):417-30. doi: 10.1111/j.1365-2141.2005.05753.x.

  PMID: 16281932 BACKGROUND

• Avidan MS, Levy JH, van Aken H, Feneck RO, Latimer RD, Ott E, Martin E, Birnbaum DE, Bonfiglio LJ, Kajdasz DK, Despotis GJ. Recombinant human antithrombin III restores heparin responsiveness and decreases activation of coagulation in heparin-resistant patients during cardiopulmonary bypass. J Thorac Cardiovasc Surg. 2005 Jul;130(1):107-13. doi: 10.1016/j.jtcvs.2004.10.045.

  PMID: 15999048 BACKGROUND

MeSH Terms

Interventions

Antithrombin III

Intervention Hierarchy (Ancestors)

Antithrombin Proteins; Serpins; Peptides; Amino Acids, Peptides, and Proteins; Alpha-Globulins; Serum Globulins; Blood Proteins; Proteins; Globulins; Blood Coagulation Factor Inhibitors; Biological Factors

Study Officials

• David Cooper, MD

  Cincinnati Childrens Hospital Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 13, 2015
• First Posted: December 16, 2015
• Study Start: June 1, 2015
• Primary Completion: June 1, 2018
• Study Completion: June 1, 2018
• Last Updated: January 25, 2019

Record last verified: 2019-01

Locations

US (1)