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Amikacin Pharmacokinetics to Optimize Dosing Recommendations in Neonates With Perinatal Asphyxia Treated With Hypothermia (Amicool)

Primary Purpose

Asphyxia Neonatorum

Status
Unknown status
Phase
Not Applicable
Locations
Bosnia and Herzegovina
Study Type
Interventional
Intervention
Amikacin
Sponsored by
University of Sarajevo
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Asphyxia Neonatorum focused on measuring Amikacin, Pharmacokinetics, Hypothermia, Newborn

Eligibility Criteria

undefined - 1 Day (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Inclusion criteria for hypothermia group (University Clinical Centre Sarajevo)

  • signed parental informed written consent
  • newborn with GA ≥36 weeks
  • newborn to whom amikacin is administered by intravenous route for clinical indications
  • newborn with perinatal asphyxia treated with hypothermia

Inclusion criteria for control group (University Clinical Centre Tuzla)

  • signed parental informed written consent
  • newborn to whom amikacin is administered by intravenous route for clinical indications
  • newborn with GA ≥36 weeks
  • newborn with perinatal asphyxia defined following Bristol hypothermia protocol from 2015

    • Apgar score of ≤5 at 10 minutes after birth OR
    • Continued need for resuscitation, including endotracheal or mask ventilation, at 10 min after birth OR
    • Acidosis defined as either umbilical cord pH or any arterial, venous or capillary pH within 60 min of birth pH<7.00 OR
    • Base deficit ≥-16 mmol/L in umbilical cord blood sample or any blood sample within 60 minutes of birth (arterial or venous blood)

Non-inclusion criteria for both groups

  • no parental informed consent
  • the presence of congenital hepatic or renal pathology
  • no central venous or arterial line in situ for non-invasive blood sampling procedures

Exclusion criteria for both groups

  • parental informed consent withdrawal
  • the occurrence of clinical reasons to stop blood sampling

Sites / Locations

  • Pediatric Clinic, University Clinical Centre SarajevoRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

asphyxiated neonates treated with amikacin and hypothermia

asphyxiated neonates treated with amikacin

Arm Description

Amikacin (Likacin®; 500 mg/2mL vial; Lisapharma S.p.A., Erba, Italy) is given to the neonate, as an IV infusion via umbilical vein over 20 min by use of a syringe-pump (Braun; B. Braun Medical Inc., Bethlehem, PA USA). Infusion is followed by slow 0.5 mL Sodium chloride 0.9% flush.

Amikacin (Likacin®; 500m g/2mL vial; Lisapharma S.p.A., Erba, Italy) is given to the neonate, as an IV infusion via umbilical vein over 20 min by use of a syringe-pump (Braun; B. Braun Medical Inc., Bethlehem, PA USA). Infusion is followed by slow 0.5 mL Sodium chloride 0.9% flush.

Outcomes

Primary Outcome Measures

Maximum Plasma Concentration [Cmax]
the first plasma concentration measured after the dosing
Minimum Plasma concentration (Ctrough)
the last plasma concentration measured after the dosing
Area under the plasma concentration versus time curve (AUC)
Area under the plasma concentration versus time curve calculated based on a trapezoidal rule
Clearance (CL)
Clearance of the drug, seen from the last part of the concentration-time curve
Volume of distribution (Vd)
Volume of distribution of the drug, seen from the early part of the concentration-time curve
Minumum inhibitory concentration (MIC 90)
concentration of the drug needed to inhibit the growth of 90% of isolates
Creatinine clearance
clearance of the creatinine calculated by different formulas

Secondary Outcome Measures

adverse effects of hypothermia
adverse outcomes of hypothermia

Full Information

First Posted
February 24, 2021
Last Updated
April 27, 2021
Sponsor
University of Sarajevo
Collaborators
KU Leuven, Amsterdam UMC, location VUmc, Leiden University Medical Center, University Clinical Center Tuzla
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1. Study Identification

Unique Protocol Identification Number
NCT04867993
Brief Title
Amikacin Pharmacokinetics to Optimize Dosing Recommendations in Neonates With Perinatal Asphyxia Treated With Hypothermia
Acronym
Amicool
Official Title
Amikacin Pharmacokinetics to Optimize Dosing Recommendations and Patho(Physiological) Considerations in Neonates With Perinatal Asphyxia Treated With Hypothermia
Study Type
Interventional

2. Study Status

Record Verification Date
April 2021
Overall Recruitment Status
Unknown status
Study Start Date
August 28, 2018 (Actual)
Primary Completion Date
August 2022 (Anticipated)
Study Completion Date
December 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Sarajevo
Collaborators
KU Leuven, Amsterdam UMC, location VUmc, Leiden University Medical Center, University Clinical Center Tuzla

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
As a part of a project on perinatal clinical pharmacology, the primary aim of the present project is to study amikacin pharmacokinetics (PK) and physiology in asphyxiated neonates treated with therapeutic hypothermia and to provide amikacin dosing recommendations, which will be validated prospectively. For this purpose, we aim to first collect retrospective data on amikacin available in neonates treated with hypothermia in the neonatal intensive care unit (NICU)s in Leuven and Amsterdam, and consequently to propose the dosing regimen to be used in the prospective amikacin PK study at our NICU in University Clinical Center (UCC) Sarajevo. At our NICU we aim to collect amikacin PK observations and other covariates in at least 40 neonates while treated with hypothermia and after re-warming period (a paired analysis), and in asphyxiated neonates not treated with hypothermia (control group). We hereby will use a stepwise approach, as initially used to develop and to validate an amikacin dosing regimen in preterm and term neonates (De Cock RFW et al., 2012, Smits A et al, 2015). A 3-step approach will be used, of which different parts will be conducted in different contributing hospitals: Retrospective evaluation of amikacin therapeutic drug monitoring (TDM) in asphyxiated neonates treated with hypothermia (University hospital Leuven, VUmc Amsterdam) Development of population PK model derived amikacin dosing recommendation Prospective PK study with validation of the new dosing regimen (UCC Sarajevo, UCC Tuzla)
Detailed Description
Step 1: Retrospective evaluation of amikacin TDM in asphyxiated neonates treated with hypothermia (University hospital Leuven, VUmc Amsterdam) 1.1 Study patients All neonates admitted to the NICUs of the VUmc Amsterdam and University hospital Leuven who underwent treatment with hypothermia for perinatal asphyxia and who received amikacin during routine care were considered for inclusion in this retrospective analysis if TDM observations were available. Patients hospitalized between January 2010 and December 2015 were eligible for inclusion. Neonates already included in the Pharmacool trial (de Haan et al BMC Pediatrics 2012), were excluded. Clinical characteristics at birth [gestational age (GA, weeks), birth bodyweight (grams), Apgar score at 1, 5 and 10 minutes after birth, as well as characteristics at the moment of amikacin TDM [postmenstrual age (PMA, weeks), postnatal age (PNA, days), current bodyweight (grams), concurrent ibuprofen (yes/no) or inotropic drugs (yes/no), respiratory support (i.e. continuous positive airway pressure or mechanical ventilation, yes/no), mechanical ventilation (conventional or high-frequency, yes/no) were retrospectively extracted from the patient files. Additionally, blood culture results at the start of amikacin therapy were collected from the individual laboratory reports. The daily nursing progress reports were used to collect amikacin prescription (dose and interval) data. 1.2 Amikacin dosing regimen University hospital Leuven: Up to July 2011, amikacin dosing was based on Langendries JP et al, 1998. Since July 2011, the simplified model-based dosing regimen published by De Cock RFM et al, 2012) was used. Since July 2014, an adapted dosing regimen based on prospective validation is applied (Smits A et al, 2015). In both regimens, the dosing interval was prolonged with 10 hours when ibuprofen was co-administered or when asphyxia was diagnosed/considered by the treating physician. Vumc Amsterdam: Up to 24 March 2015 amikacin dosing was 12 mg/kg/dose. Interval (24 hours or 36 hours) was determined based on TDM value and subsequent clearance calculation (see below). From 24 March 2015 amikacin dosing was 15 mg/kg/dose. 1.3 Drug administration and TDM sampling University hospital Leuven: amikacine (Bristol-Myers Squibb) is administered intravenously over 20 minutes. As part of routine clinical care, blood samples for amikacin TDM are collected just before (trough) administration of the second dose. In a case of unexpected results or after dosing adaptation, additional TDM samples are collected, based on the decision of the treating physician. Vumc: Amikacine (Bristol-Meyers Squib, and recently amikacine Hospira) is administered intravenously over 60 minutes. As part of routine clinical care, the first amikacin TDM sample is taken at least 6 h - but preferably 12-18 h - after the first amikacin administration. This blood sampling is preferably performed during fixed moments at the neonatal department. Based on the amikacin dosing and TDM plasma concentration of the patient, a dosing adaptation is suggested by the pharmacy department, according to the maximum a posteriori Bayesian fitting method, using the MW/Pharm computer program version 3.6 (Mediware, Groningen, the Netherlands). This approach allows variability in TDM sampling time, between and within patients. The predicted target trough level is < 5 mg/L (http://tdm-monografie.org/monografie/amikacine). 1.4 Amikacin assay University hospital Leuven: Until 31 May 2012, amikacin concentrations were measured with fluorescence polarization immunoassay (Abbott TDx kit, Abbott Laboratories, Diagnostics Division, Abbott Park, IL, USA). The lower limit of quantification (LLOQ) was 0.8 mg/L. The coefficient of variation (CV) was < 5% (assessed at 5, 15, and 30mg/L). From 31 May 2012, amikacin quantification was based on a kinetic interaction of microparticles in solution (KIMS) immunoassay (Roche/Hitachi Cobas c systems, Roche Diagnostics GmbH, Mannheim, Germany). Also in this essay, the LLOQ was 0.8 mg/L. The CV was < 4%. Vumc: Until September 2011, amikacin plasma concentrations were measured with fluorescence polarization immunoassay (Abbott TDx-FLx, Abbott Diagnostics, Abbott Park, IL, USA). The LLOQ was 0.8 mg/L. The CV was < 5% (assessed at 5, 15 and 30m g/L). From September 2011, amikacin quantification was based on a particle-enhanced turbidimetric inhibition immunoassay (PETINIA) (ARCHITECT cSystems, Abbott, Abbott Laboratories Inc, Abbott Park, IL, USA). The limit of quantification for this amikacin assay was 2.0 µg/mL. The coefficient of variation was < 4%. 1.5 Pharmacokinetic analysis The retrospectively collected amikacin TDM values of University hospital Leuven and VUmc Amsterdam will be added to a previously collected dataset of (near)term neonates receiving amikacin but not underwent hypothermia treatment (Smits A et al, 2015). All data will be implemented in the previously developed amikacin population PK model (De Cock R et al, 2012). Step 2: Development of population PK model derived amikacin dosing recommendation Since a relevant number of neonates treated with hypothermia will be included, we hereby aim to compare pharmacokinetic parameters (clearance, CL, volume of distribution, Vd) of this subgroup of neonates with those of term cases not treated with hypothermia (Smits A et al, 2015). Subsequently, we aim to derive an appropriate model-based dosing regimen to be considered during hypothermia in (near) term cases. Step 3. Prospective PK study with validation of the new dosing regimen (UCC Sarajevo and UCC Tuzla) A prospective observational cohort study conducted in NICU with the following aims: Primary aims: to collect amikacin PK observations, renal elimination characteristics and other covariates in at least 40 asphyxiated neonates while treated with hypothermia and after the re-warming period (a paired analysis) (UCC Sarajevo) and in 40 asphyxiated neonates treated with amikacin but not treated with hypothermia (control group, UCC Tuzla) validation of the new dosing regimen Secondary aims of this prospective study are: to evaluate amikacin pharmacodynamics (PD) characteristics (minimal inhibitory concentration, MIC90) to document the adverse effects of hypothermia (UCC Sarajevo) 3.1 Study patients Asphyxiated neonates routinely treated with IV amikacin and therapeutic hypothermia (NICU UCC Sarajevo) and asphyxiated neonates treated with IV amikacin but not treated with hypothermia (control group, NICU UCC Tuzla) will be included in the study after parental informed written consent is obtained. 3.2 Amikacin dosing regimen The amikacin dosing regimen that is routinely used in our unit is based on NeoFax® (2009 version) and depends on PMA as follows: • PMA of equal or more than 35 weeks, 15 mg/kg/24 h with an additional dosing interval increase of 6 h for all ages if ibuprofen was co-administered or in the setting of perinatal asphyxia The dosing regimen (current dosing interval +12 h, 15 mg/kg/36h) derived from asphyxiated neonates treated with hypothermia in Leuven and Amsterdam (step 1-2) will be used in the prospective part of this study (step 3). 3.3 Drug administration and blood sampling Amikacin (Likacin®; 500 mg/2mL vial; Lisapharma S.p.A., Erba, Italy) is given to the neonate, as an IV infusion via umbilical vein over 20 min by use of a syringe-pump (Braun; B. Braun Medical Inc., Bethlehem, PA USA). Infusion is followed by slow 0.5 mL Sodium chloride 0.9% flush. The collection of samples will be obtained to the current clinical and nursing standard procedures at both NICUs. Blood samples for amikacin TDM and corresponding creatinine concentrations will be collected by venous line via umbilical catheter while collecting the sample for other laboratory findings according to the protocol, 6 minutes before ("trough", the Ctrough) the second, third, fourth and fifth dose of amikacin, than 1h after the initiation of administration ("near peak", the maximal concentration, Cmax) of the second, third and fourth dose of amikacin, approximately 40 min after the 20-min IV infusion (Allegaert K, 2004; Langhendries JP, 1998). Blood samples (<0.5 mL) will be collected in heparinized tubes. The recommendations for the maximum predefined total amount of blood available for research purposes in a single neonate is 1.0 mL/kg and will be respected. Blood samples will be centrifuged immediately after collection and subsequently stored at -80°C until analysis. Paired amikacin and creatinine concentrations will be determined. 3.5 Amikacin and creatinine assays Amikacin serum will be determined based on a particle-enhanced turbidimetric inhibition immunoassay (PETINIA) (ARCHITECT cSystems, Abbott, Abbott Laboratories Inc, Abbott Park, IL, USA). Plasma/serum creatinin concentration will be quantified either by using the "Jaffa method" in Sarajevo or by using the "corrected Jaffa method" in Tuzla. MIC90 for amikacin will be determined in each Sarajevo and Tuzla NICU before the dosing. 3.6 Pharmacokinetic analysis A compartmental pharmacokinetics approach will be performed at the Department of Pharmacology, Clinical Pharmacology and Toxicology, Medical faculty, University of Sarajevo, B&H. The population pharmacokinetics approach, comparing the data on PK already reported in neonates will be performed at Leiden Academic Centre for drug research, Leiden University, The Netherlands.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Asphyxia Neonatorum
Keywords
Amikacin, Pharmacokinetics, Hypothermia, Newborn

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
80 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
asphyxiated neonates treated with amikacin and hypothermia
Arm Type
Active Comparator
Arm Description
Amikacin (Likacin®; 500 mg/2mL vial; Lisapharma S.p.A., Erba, Italy) is given to the neonate, as an IV infusion via umbilical vein over 20 min by use of a syringe-pump (Braun; B. Braun Medical Inc., Bethlehem, PA USA). Infusion is followed by slow 0.5 mL Sodium chloride 0.9% flush.
Arm Title
asphyxiated neonates treated with amikacin
Arm Type
Placebo Comparator
Arm Description
Amikacin (Likacin®; 500m g/2mL vial; Lisapharma S.p.A., Erba, Italy) is given to the neonate, as an IV infusion via umbilical vein over 20 min by use of a syringe-pump (Braun; B. Braun Medical Inc., Bethlehem, PA USA). Infusion is followed by slow 0.5 mL Sodium chloride 0.9% flush.
Intervention Type
Drug
Intervention Name(s)
Amikacin
Intervention Description
15 mg/kg/36h
Primary Outcome Measure Information:
Title
Maximum Plasma Concentration [Cmax]
Description
the first plasma concentration measured after the dosing
Time Frame
5 years
Title
Minimum Plasma concentration (Ctrough)
Description
the last plasma concentration measured after the dosing
Time Frame
5 years
Title
Area under the plasma concentration versus time curve (AUC)
Description
Area under the plasma concentration versus time curve calculated based on a trapezoidal rule
Time Frame
5 years
Title
Clearance (CL)
Description
Clearance of the drug, seen from the last part of the concentration-time curve
Time Frame
5 years
Title
Volume of distribution (Vd)
Description
Volume of distribution of the drug, seen from the early part of the concentration-time curve
Time Frame
5 years
Title
Minumum inhibitory concentration (MIC 90)
Description
concentration of the drug needed to inhibit the growth of 90% of isolates
Time Frame
5 years
Title
Creatinine clearance
Description
clearance of the creatinine calculated by different formulas
Time Frame
5 years
Secondary Outcome Measure Information:
Title
adverse effects of hypothermia
Description
adverse outcomes of hypothermia
Time Frame
5 years

10. Eligibility

Sex
All
Maximum Age & Unit of Time
1 Day
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Inclusion criteria for hypothermia group (University Clinical Centre Sarajevo) signed parental informed written consent newborn with GA ≥36 weeks newborn to whom amikacin is administered by intravenous route for clinical indications newborn with perinatal asphyxia treated with hypothermia Inclusion criteria for control group (University Clinical Centre Tuzla) signed parental informed written consent newborn to whom amikacin is administered by intravenous route for clinical indications newborn with GA ≥36 weeks newborn with perinatal asphyxia defined following Bristol hypothermia protocol from 2015 Apgar score of ≤5 at 10 minutes after birth OR Continued need for resuscitation, including endotracheal or mask ventilation, at 10 min after birth OR Acidosis defined as either umbilical cord pH or any arterial, venous or capillary pH within 60 min of birth pH<7.00 OR Base deficit ≥-16 mmol/L in umbilical cord blood sample or any blood sample within 60 minutes of birth (arterial or venous blood) Non-inclusion criteria for both groups no parental informed consent the presence of congenital hepatic or renal pathology no central venous or arterial line in situ for non-invasive blood sampling procedures Exclusion criteria for both groups parental informed consent withdrawal the occurrence of clinical reasons to stop blood sampling
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Sabina Terzic, MD PhD
Phone
+38761207051
Email
sterzic1974@gmail.com
First Name & Middle Initial & Last Name or Official Title & Degree
Aida Kulo Cesic, MD PhD
Phone
+38761566169
Email
aida.kulo@mf.unsa.ba
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Karel Allegaert, MD PhD
Organizational Affiliation
Catholic University Leuven, Belgium
Official's Role
Study Chair
Facility Information:
Facility Name
Pediatric Clinic, University Clinical Centre Sarajevo
City
Sarajevo
ZIP/Postal Code
71000
Country
Bosnia and Herzegovina
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Muniba Omerovic
Phone
+38733566428
Email
pedijatrija@kcus.ba
First Name & Middle Initial & Last Name & Degree
Sabina Terzic, MD PhD
First Name & Middle Initial & Last Name & Degree
Aida Kulo Ćesić, MD PhD

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
22229883
Citation
De Cock RF, Allegaert K, Schreuder MF, Sherwin CM, de Hoog M, van den Anker JN, Danhof M, Knibbe CA. Maturation of the glomerular filtration rate in neonates, as reflected by amikacin clearance. Clin Pharmacokinet. 2012 Feb 1;51(2):105-17. doi: 10.2165/11595640-000000000-00000.
Results Reference
background
PubMed Identifier
26248375
Citation
Smits A, De Cock RF, Allegaert K, Vanhaesebrouck S, Danhof M, Knibbe CA. Prospective Evaluation of a Model-Based Dosing Regimen for Amikacin in Preterm and Term Neonates in Clinical Practice. Antimicrob Agents Chemother. 2015 Oct;59(10):6344-51. doi: 10.1128/AAC.01157-15. Epub 2015 Jul 27.
Results Reference
background
Links:
URL
https://pubmed.ncbi.nlm.nih.gov/22229883-maturation-of-the-glomerular-filtration-rate-in-neonates-as-reflected-by-amikacin-clearance/?from_single_result=De+Cock+RFW%2C+Allegaert+K%2C+Schreuder+MF.%2C+Sherwin+CM%2C+de+Hoog+M%2C+van+den+Anker+JN.%2C+Danhof+Mand+Knibbe+CAJ.+Maturation+of+the+Glomerular+Filtration+Rate+in+Neonates%2C+as+Reflected+by+Amikacin+Clearance.+Clin+Pharmacokinet.+2012%3B+51%282%29%3A105-17.+doi%3A+10.2165%2F11595640-000000000-00000.
Description
Related Info
URL
https://pubmed.ncbi.nlm.nih.gov/26248375-prospective-evaluation-of-a-model-based-dosing-regimen-for-amikacin-in-preterm-and-term-neonates-in-clinical-practice/?from_single_result=Smits+A%2C+De+Cock+RF%2C+Allegaert+K%2C+Vanhaesebrouck+S%2C+Danhof+M%2C+Knibbe+CA.+Prospective+Evaluation+of+a+Model+Based+Dosing+Regimen+for+Amikacin+in+Preterm+and+Term+Neonates+in+Clinical+Practice.+Antimicrob+Agents+Chemother.+2015%3B+59%2810%29%3A6344-51.
Description
Related Info

Learn more about this trial

Amikacin Pharmacokinetics to Optimize Dosing Recommendations in Neonates With Perinatal Asphyxia Treated With Hypothermia

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