Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616001517460
Ethics application status
Approved
Date submitted
1/11/2016
Date registered
3/11/2016
Date last updated
9/02/2021
Date data sharing statement initially provided
9/02/2021
Date results information initially provided
9/02/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Early PARacetamol (EPAR) to promote early closure of the ductus arteriosus in preterm infants
Scientific title
Early PARacetamol (EPAR) to promote early closure of the ductus arteriosus in preterm infants
Secondary ID [1] 290438 0
None
Universal Trial Number (UTN)
U1111-1189-3203
Trial acronym
EPAR study
Linked study record
N/A

Health condition
Health condition(s) or problem(s) studied:
Patent ductus arteriosus 300791 0
Condition category
Condition code
Cardiovascular 300617 300617 0 0
Other cardiovascular diseases
Reproductive Health and Childbirth 300634 300634 0 0
Complications of newborn

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Intravenous paracetamol at a dose of 15 mg/kg (1.5 ml/kg) as a single bolus, followed by 7.5 mg/kg (0.75 ml/kg) every 6 hours for five days
Intervention code [1] 296283 0
Treatment: Drugs
Comparator / control treatment
5% dextrose 1.5 ml/kg as a single bolus, followed by 0.75 ml/kg every 6 hours for five days
Control group
Placebo

Outcomes
Primary outcome [1] 300030 0
Any intervention for management of PDA up to five days
Timepoint [1] 300030 0
The need for medical or surgical intervention will be assessed by review of the medical record at 5 days of life
Secondary outcome [1] 328859 0
Closure of ductus arteriosus at five days
Timepoint [1] 328859 0
Closure of the ductus arteriosus will be assessed by ultrasound scan at 5 days of life
Secondary outcome [2] 328860 0
Size of ductus arteriosus at 48 hours and five days
Timepoint [2] 328860 0
The size of the ductus arteriosus will be measured by ultrasound scan in millimetres at 48 hours and 5 days of life
Secondary outcome [3] 328861 0
Ductal reopening during admission
Timepoint [3] 328861 0
Ductal reopening will be assessed by review of the medical record for each infant at first discharge home
Secondary outcome [4] 328862 0
Ductus arteriosus parameters (excluding size and pattern)
Timepoint [4] 328862 0
This will be assessed using ultrasound at 48 hours and 5 days of life. Diastolic flow in the descending aorta will be assessed and will be categorised into one of retrograde, absent or antegrade. Left pulmonary artery diastolic velocity will be assessed and recorded.
Secondary outcome [5] 328863 0
Systemic blood flow measurements
Timepoint [5] 328863 0
Measures of systemic blood flow will be assessed and measured in ml/kg/min at 48 hours and 5 days of life. This will include the left ventricular outflow, right ventricular outflow and superior vena cava blood flow.
Secondary outcome [6] 328864 0
Mortality
Timepoint [6] 328864 0
Assessed by review of the discharge status in the medical record
Secondary outcome [7] 328906 0
Ductus arteriosus flow pattern
Timepoint [7] 328906 0
The ductus arteriosus flow pattern will be assessed by ultrasound scan at 48 hours and 5 days of life and categorised into one of bidirectional, growing, pulsatile, closing or closed
Secondary outcome [8] 328908 0
Necrotising enterocolitis
Timepoint [8] 328908 0
Assessed by review of the medical record for each infant at time of first hospital discharge to home
Secondary outcome [9] 328909 0
Sepsis
Timepoint [9] 328909 0
Assessed by review of the medical record for each infant at time of first hospital discharge to home
Secondary outcome [10] 328910 0
Intraventricular haemorrhage
Timepoint [10] 328910 0
Assessed by review of the medical record for each infant at time of first hospital discharge to home
Secondary outcome [11] 328911 0
Periventricular leukomalacia
Timepoint [11] 328911 0
Assessed by review of the medical record for each infant at time of first hospital discharge to home
Secondary outcome [12] 328912 0
Chronic lung disease
Timepoint [12] 328912 0
Assessed by review of the medical record for each infant at time of first hospital discharge to home
Secondary outcome [13] 328913 0
Retinopathy of prematurity
Timepoint [13] 328913 0
Assessed by review of the medical record for each infant at time of first hospital discharge to home
Secondary outcome [14] 332368 0
Neurodevelopment using Bayley Scales of Infant and Toddler Development, Third Edition
(Bayley-III) and Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition
(WPPSI- IV)
Timepoint [14] 332368 0
2-3 years corrected age (Bayley-III)
5 years of age (WPPSI-IV

Eligibility
Key inclusion criteria
Preterm infants <6 hours old
Born at <29 weeks gestation
Informed parental consent
Ductus arteriosus characteristics
- Patent >1 mm
- <30% right to left shunt
Minimum age
No limit
Maximum age
6 Hours
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Known congenital anomalies
Haemodynamic instability (>1 ionotropic agent)
Abnormal baseline liver function
- Transaminases >50% above upper reference range
- Bilirubin above local guideline for exchange transfusion
Ductus arteriosus characteristics
- <1 mm
- >30% right to left shunt

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)
Sealed opaque envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using computerised sequence generation
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Randomisation will be stratified based on
Gestation <27 weeks
Duct size >1.5 mm
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
All tests of the effect of treatment on outcomes will be conducted on an intention-to-treat basis. That is, all randomized patients will be analysed in the group to which they were randomised regardless of whether they received the assigned treatment and regardless of any protocol deviations or violations. Analyses of outcome variables will, however, exclude data from infants who withdraw from study treatment and withdraw consent for use of their data. All primary statistical analyses will be unadjusted and tests of significance will be two-sided. Any departures from intention-to-treat will be documented and reported. With regard to sample size calculation for our initial studies we propose the following:
Assuming that approximately 60% of infants in this study would otherwise have required intervention for PDA, a sample size of at least 42 infants per group would be required to detect a 50% reduction in the need for intervention, with a 95% confidence interval and a power of 80%.

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Other reasons/comments
Other reasons
Stopping criteria met at interim analysis
Date of first participant enrolment
Anticipated
14/11/2016
Actual
12/11/2016
Date of last participant enrolment
Anticipated
Actual
23/03/2019
Date of last data collection
Anticipated
Actual
3/07/2019
Sample size
Target
100
Accrual to date
Final
58
Recruitment in Australia
Recruitment state(s)
NSW

Funding & Sponsors
Funding source category [1] 294845 0
Charities/Societies/Foundations
Name [1] 294845 0
Running for Premature Babies
Country [1] 294845 0
Australia
Primary sponsor type
Individual
Name
Timothy Schindler
Address
Department of Newborn Care
Royal Hospital for Women
Barker St
Randwick NSW 2031
Country
Australia
Secondary sponsor category [1] 293683 0
None
Name [1] 293683 0
Address [1] 293683 0
Country [1] 293683 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296230 0
South Eastern Sydney Local Health District (Northern Sector)
Ethics committee address [1] 296230 0
Prince of Wales Hospital
G71 East Wing
Edmund Blacket Building
Prince of Wales Hospital
Cnr High and Avoca Street Randwick NSW 203`1
Ethics committee country [1] 296230 0
Australia
Date submitted for ethics approval [1] 296230 0
26/08/2015
Approval date [1] 296230 0
24/02/2016
Ethics approval number [1] 296230 0
15/232 (HREC/15/POWH/448)

Summary
Brief summary
The optimal management of PDA is highly controversial with a lack of consensus regarding the need to treat, timing of intervention, the most appropriate pharmacological agents (including dose, dose intervals, duration, repeat courses, routes of administration) and the role of surgical intervention. Traditionally, the medications we use to treat PDA are non-steroidal anti-inflammatory drugs (NSAIDs), which decrease prostaglandin production by inhibiting cyclooxygenases (COX). The most commonly used medications, indomethacin and ibuprofen, have a success rate of approximately 70% - 85%. Unfortunately these medications are associated a number of unwanted adverse effects due to decreased blood flow to the brain, gastrointestinal tract and kidneys. Exposure to these medications puts vulnerable preterm infants at risk of significant complications such as intestinal perforation and necrotising enterocolitis. The alternative to medications is surgical intervention, which also carries significant risks, particularly for extreme preterm infants.

Paracetamol is a medication with an excellent safety profile in infants when used to treat mild to moderate pain and fever. Although the mechanism of action of paracetamol is not completely understood, part of its spectrum of activity resembles that of a COX-2 selective inhibitor. Similar to traditional NSAIDs, this results in decreased prostaglandin production. It is therefore intuitive that this may also be effective in promoting ductal closure without the adverse effects associated with NSAIDs. Early experiences with the use of paracetamol for ductal closure have been encouraging. Paracetamol appears to have similar efficacy to NSAIDs, without the gastrointestinal complications associated with NSAIDs, and is well tolerated in the preterm infant population. It has been suggested as a safe alternative medication in situations where other medications have failed or are contraindicated.

The aims of this study are to study the effect of early treatment of patent ductus arteriosus with paracetamol and to examine the safety and efficacy profile of paracetamol during the early postnatal period. We hypothesise that early treatment with paracetamol will reduce the number of infants requiring intervention for PDA and that the use of paracetamol in preterm infants with a patent ductus arteriosus will result in a higher rate of ductal closure compared with placebo. We also am to show that paracetamol can be used safely in preterm infants during the early postnatal period.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 70090 0
Dr Timothy Schindler
Address 70090 0
Department of Newborn Care
Royal Hospital for Women
Barker St
Randwick NSW 2031
Country 70090 0
Australia
Phone 70090 0
+61293826190
Fax 70090 0
+61293826191
Email 70090 0
[email protected]
Contact person for public queries
Name 70091 0
Dr Timothy Schindler
Address 70091 0
Department of Newborn Care
Royal Hospital for Women
Barker St
Randwick NSW 2031
Country 70091 0
Australia
Phone 70091 0
+61293826190
Fax 70091 0
+61293826191
Email 70091 0
[email protected]
Contact person for scientific queries
Name 70092 0
Dr Timothy Schindler
Address 70092 0
Department of Newborn Care
Royal Hospital for Women
Barker St
Randwick NSW 2031
Country 70092 0
Australia
Phone 70092 0
+61293826190
Fax 70092 0
+61293826191
Email 70092 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Risks to individual patient confidentiality


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
10511Study protocolSchindler T, Smyth J, Bolisetty S, Michalowski J, Lui K. Early PARacetamol (EPAR) trial: a study protocol for a randomised controlled trial of early paracetamol to promote closure of the ductus arteriosus in preterm infants. BMJ Open. 2019 Oct 30;9(10):e031428. doi: 10.1136/bmjopen-2019-031428.   
10512Informed consent form  [email protected]
10513Ethical approval  [email protected]



Results publications and other study-related documents

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

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseEarly PARacetamol (EPAR) trial: a study protocol for a randomised controlled trial of early paracetamol to promote closure of the ductus arteriosus in preterm infants.2019https://dx.doi.org/10.1136/bmjopen-2019-031428
EmbaseEarly PARacetamol (EPAR) Trial: A Randomized Controlled Trial of Early Paracetamol to Promote Closure of the Ductus Arteriosus in Preterm Infants.2021https://dx.doi.org/10.1159/000515415
EmbaseEarly treatment versus expectant management of hemodynamically significant patent ductus arteriosus for preterm infants.2020https://dx.doi.org/10.1002/14651858.CD013278.pub2
N.B. These documents automatically identified may not have been verified by the study sponsor.