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Trial registered on ANZCTR


Registration number
ACTRN12623001197628
Ethics application status
Approved
Date submitted
18/08/2023
Date registered
20/11/2023
Date last updated
20/11/2023
Date data sharing statement initially provided
20/11/2023
Type of registration
Retrospectively registered

Titles & IDs
Public title
Paracetamol and Patent Ductus Arteriosus closure: Pharmacokinetic-Pharmacodynamic study
Scientific title
Paracetamol and Patent Ductus Arteriosus closure: Pharmacokinetic-Pharmacodynamic study
Secondary ID [1] 310338 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Patent Ductus Arteriosus (PDA) in preterm neonates 331165 0
Paracetamol therapy for PDA closure. 331166 0
Condition category
Condition code
Cardiovascular 327938 327938 0 0
Diseases of the vasculature and circulation including the lymphatic system

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
Paracetamol administration for PDA closure is a standard of care for all preterm neonates at Monash Newborn.
Paracetamol will be used for PDA closure after confirming haemodynamically significant PDA on echocardiography
Dose: First course- 15 mg/kg every 6 h for three days, administered either intravenously or orally for infants tolerating trophic feeds (>10ml/kg/day).
The second ECHO assessment is done within 24 h of the completion of first course.
A second course of paracetamol for three days (15mg/kg every 6 h) is given if there is ductal patency

The following is the baseline blood testing as standard of care before paracetamol therapy is commenced at Monash Newborn-
Baseline creatinine, liver function test and platelet count will be checked before the commencement of paracetamol therapy. The therapy will be withheld when alanine transaminase and gamma glutamyl transferase levels >100 U/l and/or >200 U/l, respectively, or serum creatinine >100 mmol/l or platelet count <100 X109/l; and will be restarted if levels normalized 24–72 h later.
Repeat serum creatinine, liver function test and platelet count will be checked at the same time of checking paracetamol trough concentration before 12th dose

Additional blood testing as part of this study-
Paracetamol concentrations will be collected either as ‘peak’ or ‘trough’, whereby ‘peak’ is 30 minutes after the end of the 30-minute IV infusion, and ‘trough’ is immediately prior to the next 6 hourly dose. On the first day of dosing, 2 samples will be taken after the first dose, both ‘peak’ and ‘trough’. Subsequently, a daily sample will be taken, alternating between ‘trough’ and ‘peak’ concentration. Following completion of 3-day course, a daily ‘washout’ sample will be taken for 2 subsequent days
Sampling schedule:
• Day 1:
o Peak 30m after end of 1st dose
o Trough just before 2nd dose on Day 1
• Day 2
o Peak 30m after end of 5th dose
• Day 3
o Trough just before the 12th dose
• Day 4 (washout)
o Random sample
• Day 5 (washout)
o Random sample
If participant undergoes a second course of paracetamol treatment, the sampling procedure will start over as above.
• Day 1:
o Peak 30m after end of 1st dose
o Trough just before 2nd dose on Day 1
• Day 2
o Peak 30m after end of 5th dose
• Day 3
o Trough just before the 12th dose
• Day 4 (Second Course)
o Peak 30m after end of 1st dose (cumulative 13th dose)
o Trough just before 2nd dose (cumulative 14th dose)
• Day 5
o Peak 30m after end of 5th dose (cumulative 17th dose)
• Day 6
o Trough just before the 12th dose (cumulative 24th dose)
• Day 7 (washout)
o Random sample
• Day 8 (washout)
o Random sample
Additional ‘scavenged’ samples will be taken in an opportunistic manner whenever blood is taken as part of clinical care (with a small aliquot used for paracetamol concentration along with documentation of time taken).
• Every day 1-6:
o All possible scavenged samples will be sent for analysis (additional volume from clinical draws) will be sent for analysis.
Throughout the study, paracetamol concentrations will be assayed in real time, with identification of outliers in exposure allowing for empiric (PK uninformed) dose adjustment.
Total volume: A minimum sample volume for a stand-alone test is a blood volume 120 µL providing 50µL serum/plasma (assay volume 10 µL plus 40µL dead space). If testing is ‘opportunistic’ at the time of other clinical tests additional serum/plasma volume is 10µL.
Intervention code [1] 326808 0
Not applicable
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 335803 0
Testing of paracetamol concentration will be conducted on blood sample (either serum or plasma depending on sample) during paracetamol therapy.
Timepoint [1] 335803 0
This will be assessed during the first and second course of paracetamol and up to 48hrs after completion of therapy as detailed below..
Sampling schedule:
• Day 1:
o Peak 30m after end of 1st dose
o Trough just before 2nd dose on Day 1
• Day 2
o Peak 30m after end of 5th dose
• Day 3
o Trough just before the 12th dose
• Day 4 (washout)
o Random sample
• Day 5 (washout)
o Random sample
If participant undergoes a second course of paracetamol treatment, the sampling procedure will start over as above.
• Day 1:
o Peak 30m after end of 1st dose
o Trough just before 2nd dose on Day 1
• Day 2
o Peak 30m after end of 5th dose
• Day 3
o Trough just before the 12th dose
• Day 4 (Second Course)
o Peak 30m after end of 1st dose (cumulative 13th dose)
o Trough just before 2nd dose (cumulative 14th dose)
• Day 5
o Peak 30m after end of 5th dose (cumulative 17th dose)
• Day 6
o Trough just before the 12th dose (cumulative 24th dose)
• Day 7 (washout)
o Random sample
• Day 8 (washout)
o Random sample

Additional ‘scavenged’ samples will be taken in an opportunistic manner whenever blood is taken as part of clinical care (with a small aliquot used for paracetamol concentration along with documentation of time taken)
• Every day 1-6:
o All possible scavenged samples will be sent for analysis (additional volume from clinical draws) will be sent for analysis.
Primary outcome [2] 335804 0
Successful PDA therapy will be assessed by echocardiography.
Successful treatment is defined a priori as complete closure or greater than or equal to 50% reduction in the composite PDA score, which would represent a significant change in hemodynamic significance of PDA.
Timepoint [2] 335804 0
At the end of each course of paracetamol therapy
Secondary outcome [1] 425712 0
Safety of paracetamol therapy in relation to paracetamol concentration and creatinine, liver function and platelet count. These tests are performed on blood sample before starting each paracetamol course.
Timepoint [1] 425712 0
These tests are performed on blood sample before starting each paracetamol course.

Eligibility
Key inclusion criteria
Preterm neonate (<28 weeks GA) with haemodynamically significant PDA (hsPDA) determined by echocardiography.
An echocardiography will be performed using Vivid E95 equipment (GE Vingmed Ultrasound, Horten, Norway). A PDA scoring schema will be calculated using the parameters: PDA size and velocity, PDA:left pulmonary artery ratio, diastolic flow in main and left pulmonary artery, left atria:aortic (LA:Ao) ratio and left ventricular:aortic ratio. Each parameter scores a maximum 3 points, the maximum score being 21
Minimum age
No limit
Maximum age
28 Weeks
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Preterm neonates (<28wks) without haemodynamically significant PDA

Study design
Purpose
Screening
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
To develop population PKPD model of paracetamol for PDA in ELBW infants (<28weeks’ GA). This can be subsequently used to optimise paracetamol dose by maximum a posteriori Bayesian estimation (MAPBE), where dose can be optimised based on drug concentration after the 1st paracetamol dose.
The statistical analyses will be performed using IBM SPSS Statistics, version 26 (IBM Corporation, New York, NY, USA). Descriptive statistics will be used to summarise baseline clinical characteristics. Linear regression will be performed to study the correlation of serum paracetamol concentrations with successful ductal treatment, birth weight, gestational age, age at therapy, liver transaminases, creatinine and platelet count.
PKPD modelling:
Population PKPD analysis will be performed in NONMEM the industry standard nonlinear mixed effects modelling tool for population PKPD analysis.
Model building involves stepwise additions to the base model supported by mechanistic considerations (e.g. compartmental structural components), with comparison of the nth and (n+1)th models. Stepwise testing will include the range of structural models (compartmental PK), along with linear and nonlinear kinetics. Residual unexplained variability (RUV) will be tested using additive, proportional, combined (proportional and additive) error models with the assumption of random effects following a normal distribution with a mean of zero. Between-subject variability (BSV) and between-occasion variability (BOV) will be modelled under the assumption of log-normally distributed random variability.
Modelled concentration-time course will be linked with time to event analysis of PDA closure, as a measure of paracetamol effect.
A statistically significant improvement of fit is based on the likelihood ratio test whereby a reduction in minus 2 times the log-likelihood (the OFV) by 3.84 in a nested model is equivalent to a p-value of 0.05 under the assumption that the difference is chi-square distributed with 1 degree of freedom. A reduction in OFV 7.879 units to a p-value of 0.005 and a reduction of 10.8 units to a p-value of 0.001.
In addition to statistical improvement in fit, model suitability will also be informed by visualisation of model fit. This includes graphical representation of fit and residuals . A non-parametric bootstrap procedure will be used for internal evaluation and to assess uncertainty of parameter estimates. Finally, a visual predictive check will be used to evaluate model predictions, a technique to assess whether repeated simulations from the model reproduce the central trend and variability of the observed data.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
17/08/2023
Date of last participant enrolment
Anticipated
3/08/2026
Actual
Date of last data collection
Anticipated
31/08/2026
Actual
Sample size
Target
50
Accrual to date
2
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 25407 0
Monash Children’s Hospital - Clayton
Recruitment postcode(s) [1] 41146 0
3168 - Clayton

Funding & Sponsors
Funding source category [1] 314949 0
Hospital
Name [1] 314949 0
Monash Children's Hospital (Monash Health Network)
Country [1] 314949 0
Australia
Primary sponsor type
Other
Name
Monash Health
Address
246 Clayton Road Clayton VIC 3168
Country
Australia
Secondary sponsor category [1] 316948 0
None
Name [1] 316948 0
Address [1] 316948 0
Country [1] 316948 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313584 0
Monash Health HREC
Ethics committee address [1] 313584 0
Research Support ServicesMonash HealthLevel 2, I BlockMonash Medical Centre246 Clayton RoadClayton Victoria 3168
Ethics committee country [1] 313584 0
Australia
Date submitted for ethics approval [1] 313584 0
11/05/2023
Approval date [1] 313584 0
07/08/2023
Ethics approval number [1] 313584 0
HREC/97624/MonH-2023-381075(v2)

Summary
Brief summary
Preterm babies are born with a patent ductus arteriosus (PDA), a blood vessel which connects major blood vessels of heart (aorta) and lung (pulmonary artery). PDA can be associated with complications in preterm babies. Therefore, we try to close it with medications, like paracetamol. However, we still don’t succeed in closing a PDA in 30-35% babies. It is possible, that the dose, which we currently provide, may not be enough for some babies. It is still unknown how much paracetamol concentration (level) is needed to achieve a PDA closure.
The aim of this study is to measure the concentration and develop a pharmacokinetic-pharmacodynamic (PK-PD) model of paracetamol in preterm babies. This study will enable us to find the appropriate target concentration necessary for PDA closure. We will be able to use this information to vary the dose of paracetamol to achieve higher success rate in preterm babies in future.
Trial website
Trial related presentations / publications
Public notes
Preterm babies are born with a patent ductus arteriosus (PDA), a blood vessel which connects major blood vessels of heart (aorta) and lung (pulmonary artery). PDA is a medical condition in which the fetal blood vessel, ductus arteriosus, fails to close after birth. This results in a portion of oxygenated blood from the heart to flow back to the lungs leading to breathing and heart difficulties. PDA in some preterm babies can be associated with complications like prolonged need for ventilation, chronic lung disease and necrotising enterocolitis. Therefore, we try to close it with medications, like paracetamol. Paracetamol is safe and effective in closing PDA. However, we still don’t succeed in closing a PDA in 30-35% preterm babies with a PDA. This may be related to the variation in the interaction of the medication and the body (pharmacokinetics and pharmacodynamics). It is possible, that the dose, which we currently provide, may not be enough for some babies. It is still unknown how much paracetamol concentration (level) is needed to achieve a PDA closure.
At Monash Newborn, we routinely treat preterm babies with paracetamol for PDA closure. However, we do not routinely measure the level of paracetamol in these babies. Very few studies have measured the concentration of paracetamol in babies’ blood. This has been done in more mature preterm babies and show inconsistent results. We are still unsure about the appropriate dose for immature preterm babies as we don’t know what should be the most appropriate target level necessary for PDA closure.
The aim of this study is to measure the concentration and develop a pharmacokinetic-pharmacodynamic (PK-PD) model of paracetamol in preterm babies. This study will enable us to find the appropriate target concentration necessary for PDA closure. We will be able to use this information to vary the dose of paracetamol to achieve higher success rate in preterm babies in future.
This research study is not funded by any grants. This participant information and consent form will be signed prior to any study assessments being carried out. We are enrolling preterm babies born before 28 weeks of gestation who need paracetamol treatment for PDA closure for this study. We routinely do three blood tests on an average per day in preterm babies during their initial stay in the nursery (NICU) to check their gas exchange, blood sugar, electrolytes and jaundice level. Our PDA management protocol is as follows: we check kidney function, liver function and platelet count in preterm babies prior to starting paracetamol therapy for PDA. We give paracetamol (15 mg/kg/dose every 6 hourly) for 3 days. At the end of this first course, we perform Echo (ultrasound of heart) and if PDA is still open; we give another course of paracetamol for 3 days after checking their kidney function, liver function and platelet count.

Contacts
Principal investigator
Name 128642 0
Dr Pramod Pharande
Address 128642 0
Monash Children's Hospital246 Clayton RoadClayton, VIC, 3168
Country 128642 0
Australia
Phone 128642 0
+613 8572 3650
Fax 128642 0
+613 8572 3649
Email 128642 0
[email protected]
Contact person for public queries
Name 128643 0
Pramod Pharande
Address 128643 0
Monash Children's Hospital246 Clayton RoadClayton, VIC, 3168
Country 128643 0
Australia
Phone 128643 0
+613 8572 3650
Fax 128643 0
+613 8572 3649
Email 128643 0
[email protected]
Contact person for scientific queries
Name 128644 0
Pramod Pharande
Address 128644 0
Monash Children's Hospital246 Clayton RoadClayton, VIC, 3168
Country 128644 0
Australia
Phone 128644 0
+613 8572 3650
Fax 128644 0
+613 8572 3649
Email 128644 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All the information collected for this study can be shared de-identified.
When will data be available (start and end dates)?
After the end of the study until the youngest participant is 25years old
Available to whom?
Researchers who are interetsed in paracetamol and its PK-PD model.
Available for what types of analyses?
Building PK-PD model, systematic review and meta-analysis
How or where can data be obtained?
We will be happy to share de-identified data for future research after taking Monash Health HREC approval.This data will be made available after an email request to the principal investigator Dr Pramod Pharande (Email ID: [email protected])


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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