Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12614000754640
Ethics application status
Approved
Date submitted
26/06/2014
Date registered
16/07/2014
Date last updated
9/07/2015
Type of registration
Prospectively registered

Titles & IDs
Public title
Oral paracetamol versus intravenous Ibuprofen for the treatment of patent Ductus arteriosus in premature infants: A Pilot Randomised Trial (The OVID Trial)
Scientific title
Patent Ductus Arteriosus in preterm infants treated by oral paracetamol versus intravenous ibuprofen and ductal closure.
Secondary ID [1] 284566 0
Nil
Universal Trial Number (UTN)
Trial acronym
The OVID Trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Patent ductus arteriosus 291839 0
Prematurity 291840 0
Condition category
Condition code
Reproductive Health and Childbirth 292204 292204 0 0
Childbirth and postnatal care
Cardiovascular 292780 292780 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Paracetamol: 15 mg/kg administered every 6 hours for a total of 3 days via nasogastric tube. This is defined as a treatment course of paracetamol.
Intervention code [1] 289338 0
Treatment: Drugs
Comparator / control treatment
Ibuprofen: 10 mg/kg intravenously, followed by 5 mg/kg 24 hours and 48 hours later. This is defined as a treatment course of ibuprofen.
Control group
Active

Outcomes
Primary outcome [1] 292072 0
PDA closure OR reduction in size by >50%; assessed by echocardiography.
Timepoint [1] 292072 0
Within 72 hours after completion of first medical treatment course
Secondary outcome [1] 308163 0
Rate of PDA closure after the first course of medical treatment, assessed by echocardiography.
Timepoint [1] 308163 0
Within 72 hours after completion of first medical treatment course
Secondary outcome [2] 308228 0
Size of PDA after the first course of medical treatment, assessed by echocardiography.
Timepoint [2] 308228 0
Within 72 hours after completion of first medical treatment course
Secondary outcome [3] 308229 0
Rate of PDA closure after the second course of medical treatment, assessed by echocardiography.
Timepoint [3] 308229 0
Within 72 hours after completion of the second medical treatment course
Secondary outcome [4] 308230 0
Need for re-treatment or surgical ligation after 2 completed courses of medical treatment
Timepoint [4] 308230 0
During NICU admission

Eligibility
Key inclusion criteria
Gestation: < 30 weeks completed gestation
Post-natal age of greater than or equal to 7 days OR following the second routine cranial ultrasound assessment
Clinical suspicion of a haemodynamically significant PDA
Active praecordium, loud murmur or wide pulse pressure
The need for respiratory support (defined as CPAP/NIMV/IMV/HFO) with FiO2 of greater than or equal to 30%. These infants should have an echocardiographic assessment to confirm the presence of PDA
Echocardiographic evidence of either:
Significant left-to-right shunting across PDA (hsDA score of of greater than or equal to 6) comprising transductal diameter, velocity and left atrial aortic root ratio (10) OR
A composite score of of greater than or equal to 16 based on our earlier publication
Infant is on minimal enteral feed defined as of greater than or equal to 10ml/kg/day
Minimum age
7 Days
Maximum age
10 Days
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Major congenital abnormalities
Severe intraventricular haemorrhage (IVH) (grade 3 or 4)
Evidence of coagulation dysfunction: Platelet count < 100,000/microlitre or presence of blood in endotracheal/gastric aspirate, haematuria
Intrauterine growth restriction defined as <3rd centile and/or reverse end diastolic flow on antenatal Dopplers.
Echocardiographic evidence of significant right-to-left shunting across PDA
Elevated serum creatinine > 100 micromol/L
Concerns about abdominal problems (feeding intolerance aspirates > feeding volume, bilious colour, abdominal distension)
Life threatening sepsis
Urine output of less than 1ml/kg/hour during the preceding 8 hours
Evidence of liver dysfunction or hyperbilirubinaemia requiring exchange transfusion
Decision not-to-treat by the attending neonatologist

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)
Allocation of patients to treatment arm will be concealed at all times from the treating team, as it will be performed independently by the pharmacy department research section who will maintain the allocation key.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomly assigned to treatment groups in a 1:1 ratio using a computer generated list of random allocation schedule. Random permuted blocks of varying sizes will be employed to ensure approximate balance of treatment allocation within each group.
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 3 / Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
Statistics
The study aims to recruit 60 babies, based on ductal closure rate or reduction in size of 50% as the primary efficacy measure. A sample size of 30 babies in each group will provide 80% power at the 5% level of significance to detect a difference of 37% in ductal closure rate between groups, assuming a closure rate of 13% with Ibuprofen based on NICU audit. An interim analysis will be performed for the main outcome at 50% recruitment. The study would be terminated if a difference of 37% or more in the main outcome were found.

Statistical analysis
We will estimate the ductal closure rate in each treatment group. Difference between groups will be assessed and 95% confidence interval for the difference will be determined. Comparisons between groups will be made using Student’s t test. For parametric continuous data, Wilcoxon rank-sum test for nonparametric continuous data and chi-square or Fisher’s exact test as appropriate for categorical data. A two-sided p value of 0.05 will be chosen to indicate statistical significance. All analysis will be performed on an Intention-to-treat (ITT) basis.

Recruitment
Recruitment status
Withdrawn
Reason for early stopping/withdrawal
Date of first participant enrolment
Anticipated
1/08/2014
Actual
Date of last participant enrolment
Anticipated
31/07/2015
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
60
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 2445 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment postcode(s) [1] 8063 0
3168 - Clayton

Funding & Sponsors
Funding source category [1] 289199 0
Hospital
Name [1] 289199 0
Monash Health
Country [1] 289199 0
Australia
Primary sponsor type
Hospital
Name
Monash Newborn
Address
246 Clayton Road
Clayton
VIC 3168
Country
Australia
Secondary sponsor category [1] 287872 0
None
Name [1] 287872 0
Address [1] 287872 0
Country [1] 287872 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290974 0
Human Research Ethics Committee B
Ethics committee address [1] 290974 0
Monash Medical Centre
246 Clayton Road
Clayton
VIC 3168
Ethics committee country [1] 290974 0
Australia
Date submitted for ethics approval [1] 290974 0
Approval date [1] 290974 0
20/03/2014
Ethics approval number [1] 290974 0
14066B

Summary
Brief summary
The ductus arteriosus DA is a blood vessel that connecting the two major vessels exiting the heart. It is a normal structure that is present in every baby before birth and closes very soon after birth in healthy term babies. In babies born prematurely before 32 weeks gestation, the DA can continue to remain open (or patent –PDA). The continual presence of the PDA in preterm infants may cause ongoing breathing difficulties, feeding problems or blood pressure issues. The doctors looking after your baby will generally want to give medication to close the PDA. The standard treatment is to use a medication called ibuprofen given as an intravenous injection. Recently, doctors is Australia have become aware of reports from other centres overseas that suggest paracetamol (a common medication for fever and pain) may be as effective as intravenous ibuprofen to help close the PDA. However, these reports currently do not provide sufficient scientific proof yet to guide doctors here to use to paracetamol routinely to treat PDAs. Therefore we propose to conduct a research study to compare whether oral paracetamol is as effective as intravenous ibuprofen in treating PDAs.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 48210 0
Dr Kenneth Tan
Address 48210 0
Monash Newborn
Monash Medical Centre
246 Clayton Road
Clayton
VIC 3168
Country 48210 0
Australia
Phone 48210 0
+61-3-95945191
Fax 48210 0
+61-3-95946115
Email 48210 0
[email protected]
Contact person for public queries
Name 48211 0
Kenneth Tan
Address 48211 0
Monash Newborn
Monash Medical Centre
246 Clayton Road
Clayton
VIC 3168
Country 48211 0
Australia
Phone 48211 0
+61-3-95945191
Fax 48211 0
+61-3-95946115
Email 48211 0
[email protected]
Contact person for scientific queries
Name 48212 0
Arvind Sehgal
Address 48212 0
Monash Newborn
Monash Medical Centre
246 Clayton Road
Clayton
VIC 3168
Country 48212 0
Australia
Phone 48212 0
+61-3-95945191
Fax 48212 0
+61-3-95946115
Email 48212 0
[email protected]

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No Supporting Document Provided



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