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Trial registered on ANZCTR


Registration number
ACTRN12616000195459
Ethics application status
Approved
Date submitted
8/02/2016
Date registered
15/02/2016
Date last updated
20/11/2018
Date data sharing statement initially provided
20/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Early pharmacological treatment with supportive care versus supportive care alone in preterm infants with a patent ductus arteriosus
Scientific title
Early pharmacological treatment with supportive care versus supportive care alone in preterm infants with a patent ductus arteriosus
Secondary ID [1] 288499 0
nil
Secondary ID [2] 288508 0
nil
Universal Trial Number (UTN)
Trial acronym
uPDA
Linked study record

Health condition
Health condition(s) or problem(s) studied:
patent ductus arteriosus 297558 0
preterm infants 297559 0
Condition category
Condition code
Reproductive Health and Childbirth 297759 297759 0 0
Complications of newborn
Cardiovascular 297760 297760 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Non steroidal anti inflammatory drugs (NSAID) combined with supportive care

This is a pragmatic study evaluating NSAID therapy with supportive care versus supportive care alone in the management of PDA. Both commonly used NSAID preparations will be eligible and can be used according to current local guidelines. Indomethacin is known to be more effective in very early treatment (<24h). Ibuprofen has a better side effect profile when used in early treatment (24-72h). The standard recommended dose and interval are
Indomethacin iv 0.2-0.1-0.1 mg/kg with 24 hour intervals
Ibuprofen iv 10-5-5 mg/kg with 24 hour intervals

Supportive care includes optimizing airway pressure, careful fluid management with or without the use of diuretics as per current standard practice. No directive guideline is provided with this study, as none of these supportive care measures have been rigorously tested.
Intervention code [1] 293859 0
Treatment: Drugs
Comparator / control treatment
Placebo (comparable volume as 0.9% saline in 24 hour intervals) combined with supportive care

Supportive care includes optimizing airway pressure, careful fluid management with or without the use of diuretics as per current standard practice. No directive guideline is provided with this study, as none of these supportive care measures have been rigorously tested.
Control group
Placebo

Outcomes
Primary outcome [1] 297288 0
composite chronic lung disease and/or death
assessed by review of medical records
Timepoint [1] 297288 0
36 weeks corrected gestational age
Secondary outcome [1] 320628 0
pulmonary hemorrhage
assessed by review of medical records
Timepoint [1] 320628 0
discharge
Secondary outcome [2] 320629 0
abnormal cranial ultrasound (intraventricular hemorrhage and/or periventricular leucomalacia)
assessed by review of medical records
Timepoint [2] 320629 0
discharge
Secondary outcome [3] 320656 0
necrotizing enterocolitis
assessed by review of medical records
Timepoint [3] 320656 0
discharge
Secondary outcome [4] 320657 0
surgical ligation
assessed by review of medical records
Timepoint [4] 320657 0
discharge
Secondary outcome [5] 320658 0
retinopathy of prematurity
assessed by retinal scan and review of medical records
Timepoint [5] 320658 0
discharge
Secondary outcome [6] 320659 0
neurodevelopmental impairment
assessed by standard Bayley developmental test
Timepoint [6] 320659 0
2 years corrected age
Secondary outcome [7] 320660 0
duration of respiratory support (mechanical ventilation, CPAP, oxygen)
assessed by review of medical records
Timepoint [7] 320660 0
from birth until 36 weeks corrected

Eligibility
Key inclusion criteria
Preterm infants less than 29 weeks gestation
PDA diameter > 1.5 mm
<72 hours of age
Minimum age
0 Hours
Maximum age
72 Hours
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
significant active haemorrhage (pulmonary, IVH grade 3 or 4, other) at randomization
major congenital heart disease
significant other congenital abnormalities
absolute contraindications for indomethacin or ibuprofen

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)
central randomisation
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software
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
Phase
Phase 4
Type of endpoint(s)
Efficacy
Statistical methods / analysis
This is a pilot study with intention to include around 70 patients in a 2 year period. As no study thus far has explored NSAIDs with supportive care versus supportive care alone in the management of a PDA, we feel that this sample will be enough to provide data that can help decide on continuing the study as a larger multi-center trial. Our successful collaboration with several similar sized neonatal units in Australia with interest in hemodynamics and the capability of providing cardiac ultrasounds will help complete the full sample size after further funding has been obtained.
The calculated full sample size needed using a non-inferiority design (death or chronic lung disease incidence 43%, accepting 10% difference, alpha 5%, beta 20%) is 594 patients.


Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
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)
NSW
Recruitment hospital [1] 5245 0
John Hunter Children's Hospital - New Lambton
Recruitment hospital [2] 5246 0
Royal North Shore Hospital - St Leonards
Recruitment postcode(s) [1] 12713 0
2305 - New Lambton
Recruitment postcode(s) [2] 12714 0
2065 - St Leonards

Funding & Sponsors
Funding source category [1] 292849 0
Charities/Societies/Foundations
Name [1] 292849 0
John Hunter Charitable trust fund
Address [1] 292849 0
John Hunter Hospital
Lookout Road
New Lambton NSW 2305
Country [1] 292849 0
Australia
Funding source category [2] 292850 0
Other
Name [2] 292850 0
Hunter Medical Research Institute
Address [2] 292850 0
Locked Bag 1000, New Lambton, NSW, Australia, 2305
Country [2] 292850 0
Australia
Funding source category [3] 292851 0
Charities/Societies/Foundations
Name [3] 292851 0
Heart Research Australia
Address [3] 292851 0
Level 4, Building 35
Reserve Road
Royal North Shore Hospital
St Leonards, NSW 2065
Country [3] 292851 0
Australia
Primary sponsor type
Other
Name
Hunter Medical Research Institute
Address
Locked Bag 1000, New Lambton, NSW, Australia, 2305
Country
Australia
Secondary sponsor category [1] 291594 0
None
Name [1] 291594 0
Address [1] 291594 0
Country [1] 291594 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294350 0
Hunter New England Ethics
Ethics committee address [1] 294350 0
Hunter New England Human Research Ethics Committee
Hunter New England Local Health District
Locked Bag 1
New Lambton NSW 2305
Ethics committee country [1] 294350 0
Australia
Date submitted for ethics approval [1] 294350 0
19/11/2015
Approval date [1] 294350 0
02/02/2016
Ethics approval number [1] 294350 0
HREC/15/HNE/498

Summary
Brief summary
Preterm birth continues to be a major health problem throughout the world. Very preterm babies have to adapt to their new extra uterine environment to be able to survive, often with increased risks of abnormal neurodevelopmental outcomes in later life.
A patent ductus arteriosus (PDA) is a frequent cardiovascular complication in this patient group, and many would receive treatment with either medication or surgical closure. However, meta-analysis of trials showed no improvement in clinical outcomes, even though PDA was reduced. It is possible that the treatment received is causing more harm than benefit or treatment is being directed at the wrong patient subgroups.
A definitive trial, comparing current standard treatment (pharmacological treatment with supportive care) versus supportive care alone, is necessary to resolve doubts regarding the quality or conduct of prior studies. We hypothesise that there will be comparable outcomes between the 2 approaches, and that this data will support the start of a larger trial using neonatal and cardiology collaboration networks. The proposed study design where no open label pharmacological treatment is allowed will be able to describe the natural course of a PDA in preterm infants in the current era of perinatal care. It will allow for detailed prospective study of the PDA using conventional and novel echocardiography techniques to address the issue of which patient subgroups may benefit from treatment.
Trial website
na
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 63382 0
Dr Koert de Waal
Address 63382 0
John Hunter Children's Hospital
department of newborn care
Lookout road
New Lambton NSW 2305

Country 63382 0
Australia
Phone 63382 0
+61 2 49855537
Fax 63382 0
Email 63382 0
koert.dewaal@hnehealth.nsw.gov.au
Contact person for public queries
Name 63383 0
Dr Koert de Waal
Address 63383 0
John Hunter Children's Hospital
department of newborn care
Lookout road
New Lambton NSW 2305
Country 63383 0
Australia
Phone 63383 0
+61 2 49855537
Fax 63383 0
Email 63383 0
koert.dewaal@hnehealth.nsw.gov.au
Contact person for scientific queries
Name 63384 0
Dr Koert de Waal
Address 63384 0
John Hunter Children's Hospital
department of newborn care
Lookout road
New Lambton NSW 2305
Country 63384 0
Australia
Phone 63384 0
+61 2 49855537
Fax 63384 0
Email 63384 0
koert.dewaal@hnehealth.nsw.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Undecided
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
Study protocol
Informed consent form
Clinical study report
Ethical approval
Summary results
No Results