Neonates on ECMOPhase 4NCT01913444
Pharmacokinetic Study of Recombinant AT III in Neonates Undergoing ECMO
A Phase 4 study testing Recombinant Antithrombin in people with Neonates on ECMO, run by Children's Hospital Los Angeles at 1 site in United States.
Trial summary
Maintenance of adequate anticoagulation or blood thinning is of critical importance when patients are placed on extracorporeal life support, such as extracorporeal membrane oxygenation (ECMO). During ECMO, a patient's entire blood volume is constantly exposed to the artificial surfaces of the ECMO circuit. Read more about this study
- Who is it for?
- Ages 1 minute to 30 days
- Conditions the study is for
- Neonates on ECMO
- What is being tested?
- Recombinant Antithrombin
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- 1 siteUnited States
- Study dates
- Jul 2013to Oct 2014
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 minute to 30 days
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- Neonates requiring ECMO
- Must be < or = to 30 days of age
- Must be > or = to 37weeks corrected gestational age
Who cannot join
- Older than or = to 31 days of age
- Preterm neonates < 37weeks corrected gestational age
- Previously diagnosed hereditary coagulopathy or hemorrhagic disorder in the family
- Prior to recent anticoagulation use
- Known or suspected genetic or terminal disorder
- Known family history of hypersensitivity to goat's milk or goat milk products
Trial locations and contacts
1 site in 1 country.
United States1 site
Children's Hospital Los Angeles
Los Angeles, California, 90027
About this study
Official title: Pharmacokinetics of Recombinant Antithrombin III in Neonates Undergoing Extracorporeal Membrane Oxygenation
Maintenance of adequate anticoagulation or blood thinning is of critical importance when patients are placed on extracorporeal life support, such as extracorporeal membrane oxygenation (ECMO). During ECMO, a patient's entire blood volume is constantly exposed to the artificial surfaces of the ECMO circuit. This exposure activates the clotting cascade, and not only is the circuit at risk for clot formation, but the patient is also at risk for clotting within the body. Hence anticoagulation is vital in allowing the ECMO circuit to support a patient for an extended period of time. Anticoagulation on ECMO is achieved primarily by the use of a blood thinning agent called heparin. Heparin's main mechanism of action is to activate an enzyme called antithrombin III (AT III). AT III deficiency has been shown to be a common finding in pediatric patients requiring ECMO. This deficiency may then result in ineffective blood thinning by heparin. The purpose of this study is to determine how a neonate on ECMO, processes and eliminates a medication called ATryn® from their body. ATryn® is a form ATIII that is made from goat's milk. This will ultimately aid in establishing standardized dosing for the use of ATryn® in this patient population.
Read the detailed description
Maintenance of adequate anticoagulation is of critical importance when patients are placed on extracorporeal life support, such as ECMO. During ECMO, a patient's entire blood volume is constantly exposed to the artificial surfaces of the ECMO circuit. This exposure activates the clotting cascade, and not only is the circuit at risk for clot formation, but the patient is also at risk for thromboembolic events. Hence anticoagulation is vital in allowing the ECMO circuit to support a patient's entire cardiopulmonary system for an extended period of time. Anticoagulation on ECMO is achieved primarily by the use of a heparin continuous infusion. Heparin's main mechanism of action is to bind to and activate an enzyme called antithrombin III (AT III). AT III is the principal inhibitor of the blood coagulation serine proteases - Thrombin and Factor Xa. In the presence of, and when bound to heparin, the inhibitory activity of AT III is greatly enhanced. AT III deficiency has been shown to be a common finding in pediatric patients requiring ECMO. Our center has reported that most neonatal patients requiring ECMO also have a significant degree of ATIII deficiency prior to, and during ECMO bypass. This deficiency may lead to challenges in achieving adequate anticoagulation while on ECMO. For this reason, our institution already supplements antithrombin during pre-ECMO circuit priming and for maintaining AT III levels above 70% during the entire length of ECMO support. Optimizing AT III levels may then improve anticoagulation while on ECMO. This study aims to determine the pharmacokinetics of recombinant antithrombin (ATryn®) supplementation. To date, the use of ATryn® has primarily been studied in adults. There is no published data to date, and no current studies on the pharmacokinetics of antithrombin III in neonates, and hence no published data on the pharmacokinetics of antithrombin III in the neonatal ECMO population. Since the use of antithrombin III in the neonatal ECMO patient population has not been thoroughly studied, the use of antithrombin III supplementation varies greatly among different neonatal intensive care units. Therefore, studies that aim at determining the pharmacokinetics of antithrombin III, particularly in ECMO patients, are important because of the lack of data and published studies in this patient population. By determining the pharmacokinetics of ATryn® in our neonatal ECMO patient population, we will aid in establishing standardized dosing and administration protocols for the supplementation of antithrombin in this specific patient population.
Summary of Risks and Benefits: ATryn® is FDA approved for use in the prevention of peri-operative and peri-partum thromboembolic events in hereditary antithrombin III deficient patients. ATryn® is a transgenically produced recombinant antithrombin concentrate from goat milk that is preservative free. It has an identical amino acid structure with minor glycosylation differences to endogenous human AT IIII. When assayed in the presence of excess heparin, the potency and efficacy of ATryn® is not different from that of plasma-derived AT III concentrates.5 ATryn® is administered as a continuous intravenous infusion, with weight-adjusted loading and maintenance dosing regimens as recommended by the medication's package insert. As dosing is specific to a patient's weight, this theoretically minimizes the risk for overdosing. In addition, as dosing is administered as a continuous infusion that is titrated to maintain stable AT III levels, there is the additional potential for less fluctuations in a patient's AT III levels. Not only will anticoagulation be optimized throughout the duration of ECMO support, but theoretically there may be a decreased need for, or less fluctuations in a patient's heparin requirements. This may furthermore minimize the risk for thromboembolic events within the ECMO circuit and the patient. Additionally, ATryn® is preservative free and because it is a recombinant product, it should be free from the risk of viral infection or prion transmission.
- Conditions
- Neonates on ECMO
- Being tested
- Recombinant Antithrombin
- Keywords
- Recombinant Antithrombin, ATryn, Pharmacokinetics, ECMO, Neonates
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Recombinant AntithrombinDrug
Also called ATryn
| Study group | Role | What they receive |
|---|---|---|
| Recombinant Antithrombin Infusion | Experimental | The initial loading dose and maintenance continuous infusion will be calculated according to the following equations which are based on the patient's baseline AT activity level prior to ECMO. Loading dose(IU)=(100-baseline AT activity)/2.3 x Wt(kg). Maintenance Dose(IU/hour)=(100-baseline AT activity)/10.2 x Wt(kg). The loading dose will be administered as a 15-minute IV infusion once the patient is on ECMO. This will be followed by the maintenance continuous infusion. AT levels will be checked 2hours after the initiation of treatment. For AT levels that are <80% or >100%, the infusion rate will be increased or decreased, respectively, by 30% and a follow-up level will be checked 2hours after the adjustment. If the AT level is within goal range (80-100%), follow-up AT levels will be checked every 6hours unless dose adjustments are made. Once the patient is off ECMO, the continuous infusion will be discontinued and AT levels will no longer be checked. Receives: Drug: Recombinant Antithrombin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Antithrombin III Level
ATIII levels will be checked at a minimum of every 6 hours throughout a patient's ECMO course. However, should dose adjustments be made to the ATryn infusion rate, ATIII levels will be checked 2hours after each dose adjustment. Once the ATIII level is again within goal range, ATIII levels will resume to being checked every 6hours.
Measured: Every 6 hours until steady state within first 72 hours on ECMO
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Aug 2013 (estimated)
- Study startJul 2013
- Primary completionOct 2014
- Study completionOct 2014
Why it stopped: Unable to enroll patients into study.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Neonates on ECMOStudies of the same condition, open and under way.
- More trials run by Children's Hospital Los AngelesThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Children's Hospital Los Angeles
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Philippe Samuel Friedlich, M.D, Children's Hospital Los Angeles
- Investigators
- Philippe S Friedlich, MD, MS Epi, MBA, Principal investigator, Children's Hospital Los Angeles
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01913444
- Sponsor's protocol ID
- CCI-12-00147
- Status last verified
- Jan 2015
- First submitted
- 29 Jul 2013
- Last updated
- 13 Jan 2015
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Niebler RA, Christensen M, Berens R, Wellner H, Mikhailov T, Tweddell JS. Antithrombin replacement during extracorporeal membrane oxygenation. Artif Organs. 2011 Nov;35(11):1024-8. doi: 10.1111/j.1525-1594.2011.01384.x.
PubMed 22097980Agati S, Ciccarello G, Salvo D, Turla G, Undar A, Mignosa C. Use of a novel anticoagulation strategy during ECMO in a pediatric population: single-center experience. ASAIO J. 2006 Sep-Oct;52(5):513-6. doi: 10.1097/01.mat.0000242596.92625.a0.
PubMed 16966848Sievert A, Uber W, Laws S, Cochran J. Improvement in long-term ECMO by detailed monitoring of anticoagulation: a case report. Perfusion. 2011 Jan;26(1):59-64. doi: 10.1177/0267659110385513. Epub 2010 Nov 5.
PubMed 21057061Konkle BA, Bauer KA, Weinstein R, Greist A, Holmes HE, Bonfiglio J. Use of recombinant human antithrombin in patients with congenital antithrombin deficiency undergoing surgical procedures. Transfusion. 2003 Mar;43(3):390-4. doi: 10.1046/j.1537-2995.2003.00315.x.
PubMed 12675726
Study at a glance
From the registry record, last updated by the sponsor on 13 Jan 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pharmacokinetics of Recombinant Antithrombin III in Neonates Undergoing Extracorporeal Membrane Oxygenation
- ClinicalTrials.gov ID
- NCT01913444
- Acronym / sponsor ID
- CCI-12-00147
- Conditions
- Neonates on ECMO
- Keywords
- Recombinant Antithrombin, ATryn, Pharmacokinetics, ECMO, Neonates
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: Unable to enroll patients into study.
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Children's Hospital Los AngelesUniversity, hospital or other
- Study start
- Jul 2013
- Primary completion
- Oct 2014 (actual)
- Study completion
- Oct 2014 (actual)
- First posted
- 1 Aug 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Maintenance of adequate anticoagulation or blood thinning is of critical importance when patients are placed on extracorporeal life support, such as extracorporeal membrane oxygenation (ECMO). During ECMO, a patient's entire blood volume is constantly exposed to the artificial surfaces of the ECMO circuit. This exposure activates the clotting cascade, and not only is the circuit at risk for clot formation, but the patient is also at risk for clotting within the body. Hence anticoagulation is vital in allowing the ECMO circuit to support a patient for an extended period of time. Anticoagulation on ECMO is achieved primarily by the use of a blood thinning agent called heparin. Heparin's main mechanism of action is to activate an enzyme called antithrombin III (AT III). AT III deficiency has been shown to be a common finding in pediatric patients requiring ECMO. This deficiency may then result in ineffective blood thinning by heparin. The purpose of this study is to determine how a neonate on ECMO, processes and eliminates a medication called ATryn® from their body. ATryn® is a form ATIII that is made from goat's milk. This will ultimately aid in establishing standardized dosing for the use of ATryn® in this patient population.
Detailed description
Maintenance of adequate anticoagulation is of critical importance when patients are placed on extracorporeal life support, such as ECMO. During ECMO, a patient's entire blood volume is constantly exposed to the artificial surfaces of the ECMO circuit. This exposure activates the clotting cascade, and not only is the circuit at risk for clot formation, but the patient is also at risk for thromboembolic events. Hence anticoagulation is vital in allowing the ECMO circuit to support a patient's entire cardiopulmonary system for an extended period of time. Anticoagulation on ECMO is achieved primarily by the use of a heparin continuous infusion. Heparin's main mechanism of action is to bind to and activate an enzyme called antithrombin III (AT III). AT III is the principal inhibitor of the blood coagulation serine proteases - Thrombin and Factor Xa. In the presence of, and when bound to heparin, the inhibitory activity of AT III is greatly enhanced. AT III deficiency has been shown to be a common finding in pediatric patients requiring ECMO. Our center has reported that most neonatal patients requiring ECMO also have a significant degree of ATIII deficiency prior to, and during ECMO bypass. This deficiency may lead to challenges in achieving adequate anticoagulation while on ECMO. For this reason, our institution already supplements antithrombin during pre-ECMO circuit priming and for maintaining AT III levels above 70% during the entire length of ECMO support. Optimizing AT III levels may then improve anticoagulation while on ECMO. This study aims to determine the pharmacokinetics of recombinant antithrombin (ATryn®) supplementation. To date, the use of ATryn® has primarily been studied in adults. There is no published data to date, and no current studies on the pharmacokinetics of antithrombin III in neonates, and hence no published data on the pharmacokinetics of antithrombin III in the neonatal ECMO population. Since the use of antithrombin III in the neonatal ECMO patient population has not been thoroughly studied, the use of antithrombin III supplementation varies greatly among different neonatal intensive care units. Therefore, studies that aim at determining the pharmacokinetics of antithrombin III, particularly in ECMO patients, are important because of the lack of data and published studies in this patient population. By determining the pharmacokinetics of ATryn® in our neonatal ECMO patient population, we will aid in establishing standardized dosing and administration protocols for the supplementation of antithrombin in this specific patient population.
Summary of Risks and Benefits: ATryn® is FDA approved for use in the prevention of peri-operative and peri-partum thromboembolic events in hereditary antithrombin III deficient patients. ATryn® is a transgenically produced recombinant antithrombin concentrate from goat milk that is preservative free. It has an identical amino acid structure with minor glycosylation differences to endogenous human AT IIII. When assayed in the presence of excess heparin, the potency and efficacy of ATryn® is not different from that of plasma-derived AT III concentrates.5 ATryn® is administered as a continuous intravenous infusion, with weight-adjusted loading and maintenance dosing regimens as recommended by the medication's package insert. As dosing is specific to a patient's weight, this theoretically minimizes the risk for overdosing. In addition, as dosing is administered as a continuous infusion that is titrated to maintain stable AT III levels, there is the additional potential for less fluctuations in a patient's AT III levels. Not only will anticoagulation be optimized throughout the duration of ECMO support, but theoretically there may be a decreased need for, or less fluctuations in a patient's heparin requirements. This may furthermore minimize the risk for thromboembolic events within the ECMO circuit and the patient. Additionally, ATryn® is preservative free and because it is a recombinant product, it should be free from the risk of viral infection or prion transmission.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Recombinant Antithrombin Infusion | Experimental | Drug: Recombinant AntithrombinThe initial loading dose and maintenance continuous infusion will be calculated according to the following equations which are based on the patient's baseline AT activity level prior to ECMO. Loading dose(IU)=(100-baseline AT activity)/2.3 x Wt(kg). Maintenance Dose(IU/hour)=(100-baseline AT activity)/10.2 x Wt(kg). The loading dose will be administered as a 15-minute IV infusion once the patient is on ECMO. This will be followed by the maintenance continuous infusion. AT levels will be checked 2hours after the initiation of treatment. For AT levels that are <80% or >100%, the infusion rate will be increased or decreased, respectively, by 30% and a follow-up level will be checked 2hours after the adjustment. If the AT level is within goal range (80-100%), follow-up AT levels will be checked every 6hours unless dose adjustments are made. Once the patient is off ECMO, the continuous infusion will be discontinued and AT levels will no longer be checked. |
Who may qualify
- Ages
- 1 minute to 30 days
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (3 listed)
- Neonates requiring ECMO
- Must be < or = to 30 days of age
- Must be > or = to 37weeks corrected gestational age
Key exclusion criteria (6 listed)
- Older than or = to 31 days of age
- Preterm neonates < 37weeks corrected gestational age
- Previously diagnosed hereditary coagulopathy or hemorrhagic disorder in the family
- Prior to recent anticoagulation use
- Known or suspected genetic or terminal disorder
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Recombinant AntithrombinAlso: ATryn | Drug | Recombinant Antithrombin Infusion |
Primary outcome
Antithrombin III Level
Time frame: Every 6 hours until steady state within first 72 hours on ECMO
ATIII levels will be checked at a minimum of every 6 hours throughout a patient's ECMO course. However, should dose adjustments be made to the ATryn infusion rate, ATIII levels will be checked 2hours after each dose adjustment. Once the ATIII level is again within goal range, ATIII levels will resume to being checked every 6hours.
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Jan 2015.
- Background: PubMed 22097980Niebler RA, Christensen M, Berens R, Wellner H, Mikhailov T, Tweddell JS. Antithrombin replacement during extracorporeal membrane oxygenation. Artif Organs. 2011 Nov;35(11):1024-8. doi: 10.1111/j.1525-1594.2011.01384.x.
- Background: PubMed 16966848Agati S, Ciccarello G, Salvo D, Turla G, Undar A, Mignosa C. Use of a novel anticoagulation strategy during ECMO in a pediatric population: single-center experience. ASAIO J. 2006 Sep-Oct;52(5):513-6. doi: 10.1097/01.mat.0000242596.92625.a0.
- Background: PubMed 21057061Sievert A, Uber W, Laws S, Cochran J. Improvement in long-term ECMO by detailed monitoring of anticoagulation: a case report. Perfusion. 2011 Jan;26(1):59-64. doi: 10.1177/0267659110385513. Epub 2010 Nov 5.
- Background: PubMed 12675726Konkle BA, Bauer KA, Weinstein R, Greist A, Holmes HE, Bonfiglio J. Use of recombinant human antithrombin in patients with congenital antithrombin deficiency undergoing surgical procedures. Transfusion. 2003 Mar;43(3):390-4. doi: 10.1046/j.1537-2995.2003.00315.x.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Philippe S Friedlich, MD, MS Epi, MBA principal investigator
Children's Hospital Los Angeles
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Recombinant Antithrombin in people with Neonates on ECMO, run by Children's Hospital Los Angeles at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 13 Jan 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Antithrombin III Level (time frame: Every 6 hours until steady state within first 72 hours on ECMO). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01913444, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Jan 2015.