Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12611000741987
Ethics application status
Approved
Date submitted
14/07/2011
Date registered
14/07/2011
Date last updated
18/06/2012
Type of registration
Prospectively registered

Titles & IDs
Public title
Paracetamol Duct Action(PDA) Trial: Does paracetamol close a patent ductus arteriosus in premature infants?
Scientific title
Paracetamol Duct Action(PDA) Trial: The effect of paracetamol vs placebo on ductal closure in premature infants with a late patent ductus arterious
Secondary ID [1] 262629 0
Nil
Universal Trial Number (UTN)
Trial acronym
PDA Trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Patent ductus arteriosus 268328 0
Condition category
Condition code
Cardiovascular 268465 268465 0 0
Normal development and function of the cardiovascular system
Reproductive Health and Childbirth 268467 268467 0 0
Complications of newborn

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A clinician performed ultrasound (CPU) by qualified neonatal medical staff will assess ductal size and haemodynamic significance. This will be documented utilising the standard measures of flow pattern, diastolic flow in the descending aorta, left atrium / aortic ratio (LA/AO), left pulmonary artery diastolic velocity (LPAD), left ventricular end diastolic diameter (LVEDD) and left ventricular output (LVO).
If not routinely collected in the previous week, a blood sample of 0.5ml will then be collected for elevated Liver Function Tests (LFTs): alanine transaminase and aspartate transaminase, plus conjugated SBR levels, to detect any abnormal liver function prior to commencement of study medication.
After randomisation, the study group will receive paracetamol as per Neofax guidelines with an oral loading dose of 25mg/kg/dose, followed by a maintenance dose of 15mg/kg/dose. The maintenance dosing interval will be 8 hourly in preterm infants more than or equal to 32 weeks postmenstrual age, 12 hourly in preterm less than 32 weeks postmenstrual age, and 6 hourly in term infants. The total duration of treatment will be 5 days in all groups.
Intervention code [1] 266978 0
Treatment: Drugs
Comparator / control treatment
A clinician performed ultrasound (CPU) by qualified neonatal medical staff will assess ductal size and haemodynamic significance. This will be documented utilising the standard measures of flow pattern, diastolic flow in the descending aorta, left atrium / aortic ratio (LA/AO), left pulmonary artery diastolic velocity (LPAD), left ventricular end diastolic diameter (LVEDD) and left ventricular output (LVO).
If not routinely collected in the previous week, a blood sample of 0.5ml will then be collected for elevated Liver Function Tests (LFTs): alanine transaminase and aspartate transaminase, plus conjugated SBR levels, to detect any abnormal liver function prior to commencement of study medication.
After randomisation, the placebo group will receive the same volume of oral sucrose solution. Sucrose was chosen for placebo due to its similarity to paracetamol in consistency and colour.
Control group
Placebo

Outcomes
Primary outcome [1] 269216 0
Closure of the PDA confirmed by echocardiography
Timepoint [1] 269216 0
At 5 days post commencement of treatment
Secondary outcome [1] 279139 0
Paracetamol serum level - measured in blood using an immunoassay techique
Timepoint [1] 279139 0
Day 2 and Day 5

Eligibility
Key inclusion criteria
1. Babies with a persistent PDA born <33 weeks gestational age who are >4 weeks of postnatal age and tolerating at least 50% (i.e. 80ml/kg/day) of enteral feeds
2. Echocardiographic findings of a PDA with a Colour Doppler duct size more than 1.5mm with pulsatile pattern with or without oxygen and/or CPAP support.
3. Informed written parental consent
Minimum age
4 Weeks
Maximum age
20 Weeks
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. PDA with evidence of congestive cardiac failure, signs include tachycardia; venous congestion; high catecholamine levels; and, ultimately, insufficient cardiac output with poor perfusion and end-organ compromise.
2. Abnormal liver function tests :
a. Elevated alanine transaminase (twice normal level for corrected gestation)
b. Elevated aspartate transaminase (twice normal level for corrected gestation)
c. Elevated conjugated bilirubin (>80mmol/L)

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
At randomisation, 50% of the infants will be allocated to the active treatment of oral paracetamol, while the other 50% will have the placebo medication: the oral sucrose solution used in our unit for pain relief. Allocation concealment will be achieved by the use of a random number table that is only available to the clinical trials pharmacist who will allocate the treatment group independent of clinical staff who will see only a trial number. Clinicians enroling participants will not be involved with allocation to a treatment group.
Treatment allocation will be blinded to nursing staff administering the dose, the medical staff performing the diagnostic clinician performed ultrasound (CPU) and the senior clinician reviewing the CPU results. Pathology staff will also be blinded to treatment allocation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Babies in each group will be randomised to either paracetamol or placebo group using a random number table with a variable block size. Stratification will be into two groups: that of gestation less than 29 weeks and that of gestation 29 to less than 33 weeks.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/09/2011
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
60
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)

Funding & Sponsors
Funding source category [1] 267452 0
Charities/Societies/Foundations
Name [1] 267452 0
North Shore Heart Research Foundation
Country [1] 267452 0
Australia
Primary sponsor type
Individual
Name
A/Professor Martin Kluckow
Address
Department of Neonatology
Royal North Shore Hospital
Pacific Highway
St Leonards NSW 2065
Country
Australia
Secondary sponsor category [1] 266497 0
None
Name [1] 266497 0
Address [1] 266497 0
Country [1] 266497 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 269418 0
Northern Sydney Central Coast Area Health Service Human Research Ethics Committee (Harbour)
Ethics committee address [1] 269418 0
Royal North Shore Hospital
Pacific Highway
St Leonards
NSW 2065
Ethics committee country [1] 269418 0
Australia
Date submitted for ethics approval [1] 269418 0
15/07/2011
Approval date [1] 269418 0
Ethics approval number [1] 269418 0

Summary
Brief summary
Background: In term infants functional closure of the PDA usually occurs in the first 72 hours, but may take longer in
preterm infants. The primary rationale for treatment of the duct is that the left to right shunt across the PDA can cause
deleterious systemic and pulmonary haemodynamic effects. This potentially leads to excessive pulmonary blood
flow that may result in pulmonary haemorrhage or a need for increased respiratory support (oxygen and/or positive
pressure) and systemic circulatory compromise causing abnormal organ function and tissue injury.
The need to treat a PDA at a later stage when acute complications are less likely is currently controversial. Though
the data on the outcome of preterm infants with persistent ductus arteriosus have been scarce, there has been a
study addressing this issue which reports eightfold increase in mortality of VLBW neonates with persistent PDA.
A recent abstract publication described a case series of 5 infants who appeared to have spontaneous late PDA
closure following the use of paracetamol for unrelated indications. Paracetamol is a commonly used medication in
infants with a relatively benign side effect profile, so if found to be efficacious, could provide a useful alternative for
treatment of PDA.
Aim: 1.To study the effect of paracetamol given orally in closure of late PDA in premature neonates; 2. Examine the
safety and efficacy profile of paracetamol.
Study design: a prospective randomised, blinded, placebo controlled trial.
Population: Preterm infants born <33 weeks gestational age with a persistent PDA who are >4 weeks of postnatal
age and tolerating at least 50% enteral feeds.
Method: A clinician performed ultrasound (CPU) by qualified neonatal medical staff will assess ductal size and
haemodynamic significance at 4 weeks of age.
Any abnormal liver function will be excluded prior to commencement of study medication using routine blood tests.
After randomisation, the study group will receive paracetamol as per Australian guidelines for neonates(25mg/kg
loading dose, followed by maintenance dose of 15mg/kg at an interval appropriate for gestational age. The placebo
group will receive the same volume of oral placebo solution, most likely sucrose. The study medication course will
be for 5 days.
A CPU by a clinician blinded to study medication allocation will be performed after 48 hours of medication
administration and again after 5 days to document ductal patency and haemodynamic significance.
0.5ml of blood will be collected in a lithium heparin tube for repeat liver function tests and paracetamol serum levels
48 hours after commencement of study medication and again at completion of study medication on day 5. Some of
these tests may overlap with required routine blood tests and therefore may not be extra.
The primary outcome will be succesful closure of PDA as documented on clinician performed ultrasound.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 32878 0
Address 32878 0
Country 32878 0
Phone 32878 0
Fax 32878 0
Email 32878 0
Contact person for public queries
Name 16125 0
A/Professor Martin Kluckow
Address 16125 0
Department of Neonatology
Level 5, Douglas Building
Royal North Shore Hospital
Pacific Highway
St leonards
NSW 2065
Country 16125 0
Australia
Phone 16125 0
+61 2 99267509
Fax 16125 0
Email 16125 0
[email protected]
Contact person for scientific queries
Name 7053 0
A/Professor Martin Kluckow
Address 7053 0
Department of Neonatology
Level 5, Douglas Building
Royal North Shore Hospital
Pacific Highway
St leonards
NSW 2065
Country 7053 0
Australia
Phone 7053 0
+61 2 99267509
Fax 7053 0
Email 7053 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
Current Study Results
No documents have been uploaded by study researchers.

Update to Study Results
Doc. No.TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
4313Study results articleYes Kluckow M, Carlisle H, Broom, M. Woods P, Jeffery ... [More Details]

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseA pilot randomised blinded placebo-controlled trial of paracetamol for later treatment of a patent ductus arteriosus.2019https://dx.doi.org/10.1038/s41372-018-0247-z
N.B. These documents automatically identified may not have been verified by the study sponsor.