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Trial registered on ANZCTR


Registration number
ACTRN12615000981527
Ethics application status
Approved
Date submitted
6/08/2015
Date registered
21/09/2015
Date last updated
21/09/2015
Type of registration
Prospectively registered

Titles & IDs
Public title
Oral paracetamol versus intravenous indomethacin for the treatment of patent ductus arteriosus in premature infants: A Randomised Control Trial (The OVID Trial)
Scientific title
In preterm infants with a haemodynamically significant ductus arteriosus, does oral paracetamol treatment compared to intravenous indomethacin result in greater narrowing or closure of the ductus arteriosus?
Secondary ID [1] 287222 0
None
Universal Trial Number (UTN)
Trial acronym
The OVID Trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Prematurity 295825 0
Patent ductus arteriosus 295915 0
Condition category
Condition code
Reproductive Health and Childbirth 296083 296083 0 0
Complications of newborn
Cardiovascular 296166 296166 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Paracetamol, delivered orally
Dosage: 15 mg/kg 6 hourly for 3 days, per course of treatment.
The assessment for ductal status after the first course will be made by the neonatologist responsible for the infant who will base decision-making based on the echocardiography performed after the first course of treatment (within 72 hours after first treatment). The neonatologist will then decide if a second course of treatment is required (with input from paediatric cardiology).
The second course of treatment will be given if on the second echocardiography (within 72 hours after first treatment) shows the presence of a hemodynamically significant ductus arteriosus and if the attending neonatologist decides.
The maximum number of treatment courses will be two.
Infant randomised to oral paracetamol arm will receive intravenous placebo. The intravenous placebo will be normal saline, which will be administered at 24 hourly interval for 3 days.
Intervention code [1] 292511 0
Treatment: Drugs
Comparator / control treatment
Indomethacin, delivered intravenously
Dosage: 0.2 mg/kg 24 hourly for 3 days, per course of treatment.
Second course of treatment will be given if on second echocardiography (within 72 hours after first treatment) shows the presence of a hemodynamically significant ductus arteriosus.
Infant randomised to intravenous indomethacin arm will receive oral placebo. Oral placebo will consist of water given 6 hourly for 3 days.
Control group
Active

Outcomes
Primary outcome [1] 295757 0
The number of participants with ductus arteriosus (DA) closure OR DA diameter narrowing 50% or more (composite primary outcome) compared to pre-treatment diameter, as assessed echocardiographically.
Timepoint [1] 295757 0
Within 72 hours after completion of first course OR second course of treatment for the ductus arteriosus.
Secondary outcome [1] 316463 0
PDA closure after the first course of medical treatment, as measured by echocardiography.
Timepoint [1] 316463 0
Within 72 hours of completion of the first course of treatment
Secondary outcome [2] 316688 0
Size of PDA after the first course of medical treatment, as measured by echocardiography.
Timepoint [2] 316688 0
Within 72 hours of completion of the first course of treatment
Secondary outcome [3] 316689 0
PDA closure after the second course of medical treatment, as measured by echocardiography.
Timepoint [3] 316689 0
Within 72 hours of completion of second course of treatment
Secondary outcome [4] 316690 0
Size of PDA after the second course of medical treatment, as measured by echocardiography.
Timepoint [4] 316690 0
Within 72 hours of completion of second course of treatment
Secondary outcome [5] 316691 0
Rate of PDA re-opening after the first course of medical treatment, as measured by echocardiography.
Timepoint [5] 316691 0
Within 72 hours of completion of the first course of treatment
Secondary outcome [6] 316692 0
Rate of PDA re-opening after the second course of medical treatment, as measured by echocardiography.
Timepoint [6] 316692 0
Within 72 hours of completion of the second course of treatment
Secondary outcome [7] 316693 0
Need for re-treatment or surgical ligation after 2 completed courses of medical treatment (as decided by clinical team based on clinical and echocardiographic findings).
Timepoint [7] 316693 0
After completion of second course of treatment
Secondary outcome [8] 316694 0
Duration of ventilation, by review of medical records.
Timepoint [8] 316694 0
During the NICU stay
Secondary outcome [9] 316695 0
Time to achieve full enteral feeding, review of medical records
Timepoint [9] 316695 0
From the end of first treatment course to time of full enteral feeding.
Secondary outcome [10] 316696 0
Serum creatinine, by review of medical records.
Timepoint [10] 316696 0
Before entry into trial and within 72 hours of completion of treatment course
Secondary outcome [11] 316697 0
Pulmonary haemorrhage or pneumothorax, by review of medical records.
Timepoint [11] 316697 0
During the NICU stay
Secondary outcome [12] 316698 0
Severe intraventricular haemorrhage (Papille Grade III or IV), by review of medical records
Timepoint [12] 316698 0
During the NICU stay
Secondary outcome [13] 316699 0
Necrotizing enterocolitis (according to Bell classification, Stage 2 or greater), by review of medical records.
Timepoint [13] 316699 0
During the NICU stay
Secondary outcome [14] 316700 0
Abdominal distension or feeding intolerance, by review of medical records
Timepoint [14] 316700 0
During the course of treatment and up to 48 hours after treatment course
Secondary outcome [15] 316701 0
Culture-positive sepsis, by review of medical records.
Timepoint [15] 316701 0
During the course of treatment and up to 48 hours after completion of treatment course
Secondary outcome [16] 316702 0
Oliguria (defined as <1.0 ml/kg/hour), by review of medical records.
Timepoint [16] 316702 0
During the course of treatment
Secondary outcome [17] 316703 0
Chronic lung disease (defined as oxygen dependence at 36 weeks corrected gestation and based on the physiological test described by Walsh et al), by review of medical records.
Timepoint [17] 316703 0
At 36 weeks postmenstrual age
Secondary outcome [18] 316704 0
Retinopathy of prematurity, highest grade, by review of medical records.
Timepoint [18] 316704 0
At any time during the NICU stay
Secondary outcome [19] 316705 0
Duration of hospital stay, by review of medical records.
Timepoint [19] 316705 0
Time until discharge home, i.e. from time of admission to time of discharge home.
Secondary outcome [20] 316706 0
Death (all cause mortality)
Timepoint [20] 316706 0
Death before discharge from hospital during initial NICU admission
Secondary outcome [21] 316893 0
Mode of ventilation, by review of medical records.
Timepoint [21] 316893 0
During NICU stay
Secondary outcome [22] 316894 0
Serum bilirubin, by review of medical records.
Timepoint [22] 316894 0
Before entry into trial and within 72 hours of completion of treatment course.
Secondary outcome [23] 316895 0
Serum aspartate aminotransferase (AST), by review of medical records.
Timepoint [23] 316895 0
Before entry into trial and within 72 hours of completion of treatment course.
Secondary outcome [24] 316896 0
Serum alanine aminotransferase (ALT) levels, by review of medical records.
Timepoint [24] 316896 0
Before entry into trial and within 72 hours of completion of treatment course.

Eligibility
Key inclusion criteria
Gestation: less than 32 weeks (up to 31 weeks 6 days) gestation
Post-natal (or post-gestation) age of greater than/equal to 7 days OR following the second routine cranial ultrasound assessment
Clinical suspicion of a haemodynamically significant PDA, e.g.
Active praecordium, loud murmur or wide pulse pressure
The need for respiratory support (defined as CPAP/NIMV/IMV/HFO) with FiO2 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 equal or greater than 6) comprising transductal diameter, velocity and left atrial aortic root ratio OR
A composite score of greater than or equal to than 16 based on the Sehgal score
Infant is on minimal enteral feed defined as less than or equal to 10ml/kg/day
Minimum age
7 Days
Maximum age
14 Days
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Major congenital abnormalities, including congenital heart disease
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)
Participants will be enrolled after written consent is obtained from parents. An echocardiogram will be performed prior to the study enrolment. Participants will be randomly assigned to treatment groups in a 1:1 ratio using a computer generated list of random allocation schedule.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Random permuted blocks of varying sizes will be employed to ensure approximate balance of treatment allocation within each group. 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; unless there are extenuating clinical reasons.
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
Infant randomised to oral paracetamol arm will receive intravenous placebo
Infant randomised to intravenous indomethacin arm will receive oral placebo
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
There will be a statistician for the trial who will conduct the statistical analyses. The database will be stored in an online database (REDCap). Based on a hypothesis of superiority of oral paracetamol in DA closure, a sample size of 68 babies in each group (136 in total) will provide 80% power at the 5% level of significance to detect a difference increase of 56% in ductal closure rate between groups (i.e. increase to 70% closure rate), based on a closure rate of 45% with indomethacin from a previous NICU audit. Taking into account possible drop-outs, the sample size is adjusted upwards by 10% to get the required number of subjects to be recruited into the trial. Therefore the final sample size will be 150 infants in total (with 75 infants per treatment arm).

An interim analysis will be performed for the main outcome at 50% recruitment.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
2/11/2015
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
150
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 4137 0
Monash Medical Centre - Clayton campus - Clayton

Funding & Sponsors
Funding source category [1] 291795 0
Hospital
Name [1] 291795 0
Pharmacy Department, Monash Health
Country [1] 291795 0
Australia
Primary sponsor type
Hospital
Name
Monash Newborn, Monash Children's Hospital
Address
246 Clayton Road
Clayton
Victoria
VIC 3168
Country
Australia
Secondary sponsor category [1] 290455 0
Hospital
Name [1] 290455 0
Pharmacy Department, Monash Health
Address [1] 290455 0
246 Clayton Road
Clayton
Victoria
VIC 3168
Country [1] 290455 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293538 0
Monash Health Human Research Ethics Committee
Ethics committee address [1] 293538 0
Monash Medical Centre
246 Clayton Road
Clayton
Victoria 3168
Ethics committee country [1] 293538 0
Australia
Date submitted for ethics approval [1] 293538 0
Approval date [1] 293538 0
28/08/2015
Ethics approval number [1] 293538 0
15084A

Summary
Brief summary
This will be a placebo randomised control trial conducted in the neonatal intensive care unit. The trial will compare oral paracetamol against current standard therapy for a haemodynamically significant ductus arteriosus, which is intravenous indomethacin.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 59346 0
Dr Kenneth Tan
Address 59346 0
Monash Newborn
Monash Medical Centre
246 Clayton Road
Clayton
VIC 3168
Country 59346 0
Australia
Phone 59346 0
+61-3-95945191
Fax 59346 0
Email 59346 0
kenneth.tan@monash.edu
Contact person for public queries
Name 59347 0
Kenneth Tan
Address 59347 0
Monash Newborn
Monash Medical Centre
246 Clayton Road
Clayton
VIC 3168
Country 59347 0
Australia
Phone 59347 0
+61-3-95945191
Fax 59347 0
Email 59347 0
kenneth.tan@monash.edu
Contact person for scientific queries
Name 59348 0
Arvind Sehgal
Address 59348 0
Monash Newborn
Monash Medical Centre
246 Clayton Road
Clayton
VIC 3168
Country 59348 0
Australia
Phone 59348 0
+61-3-95945191
Fax 59348 0
Email 59348 0
arvind.sehgal@monash.edu

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

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