ANZCTR - Registration

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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]

Nil

Universal Trial Number (UTN)

Trial acronym

PDA Trial

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Patent ductus arteriosus

Condition category

Condition code

Cardiovascular

Normal development and function of the cardiovascular system

Reproductive Health and Childbirth

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]

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]

Closure of the PDA confirmed by echocardiography

Timepoint [1]

At 5 days post commencement of treatment

Secondary outcome [1]

Paracetamol serum level - measured in blood using an immunoassay techique

Timepoint [1]

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?

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

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

North Shore Heart Research Foundation

Address [1]

Pacific Highway
St Leonards NSW 2065

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Northern Sydney Central Coast Area Health Service Human Research Ethics Committee (Harbour)

Ethics committee address [1]

Royal North Shore Hospital
Pacific Highway
St Leonards
NSW  2065

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

15/07/2011

Approval date [1]

Ethics approval number [1]

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

Address

Country

Phone

Fax

Contact person for public queries

Name

A/Professor Martin Kluckow

Address

Department of Neonatology
Level 5, Douglas Building
Royal North Shore Hospital
Pacific Highway
St leonards
NSW 2065

Country

Australia

Phone

+61 2 99267509

Fax

mkluckow@med.usyd.edu.au

Contact person for scientific queries

Name

A/Professor Martin Kluckow

Address

Department of Neonatology
Level 5, Douglas Building
Royal North Shore Hospital
Pacific Highway
St leonards
NSW 2065

Country

Australia

Phone

+61 2 99267509

Fax

mkluckow@med.usyd.edu.au

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

Type	Is Peer Reviewed?	DOI	Citations or Other Details	Attachment
Study results article	Yes		Kluckow M, Carlisle H, Broom, M. Woods P, Jeffery ... [More Details]

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	A pilot randomised blinded placebo-controlled trial of paracetamol for later treatment of a patent ductus arteriosus.	2019	https://dx.doi.org/10.1038/s41372-018-0247-z

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

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Documents added manually

Documents added automatically