Does selective early treatment of patent ductus arteriosus in extreme preterm infants reduce the complications and improve their long-term outcome?

Current primary outcome measures as of 03/08/2023:
The primary outcome is defined as a composite outcome of death by 36 weeks postmenstrual age or moderate or severe BPD at 36 weeks post-menstrual age.
Severity-Based Diagnostic Criteria for BPD is defined as:
Therapy with oxygen >21% and/or respiratory support for ≥28 days and the following:
Mild BPD: Baby is breathing room air
Moderate BPD: Baby is in 22–29% oxygen, or 0.01–1.0 L/min
Severe BPD: FiO2 ≥0.3, or low flow oxygen ≥1.1 L/min, or the baby is receiving any respiratory support (ventilation, CPAP, or high flow oxygen therapy) to achieve saturations of ≥ 91%

The need for oxygen is subjective and hence oxygen dependency is confirmed using an ‘oxygen reduction test’. This is based on the threshold at which the baby is able to maintain oxygen saturations ≥91% whilst breathing in air or at a given minimum FiO2. Babies unable to achieve this are considered to be oxygen-dependent. This test only applies to those babies whose oxygen requirements are <0.3, or low flow oxygen <1.1L/min, and who have not received any additional respiratory support in the previous 24h. Babies outside of this are not tested, but data on their oxygen requirements will be collected.
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Previous primary outcome measures as of 10/04/2014:
The primary outcome is defined as a composite outcome of death or BPD at 36 weeks post-menstrual age. BPD is defined as the need for respiratory support and/or oxygen for 28 days or more and at 36 weeks post-menstrual age. The need for oxygen is subjective and hence oxygen dependency will be confirmed using an ‘oxygen reduction test’. This is based on whether the baby is able to maintain oxygen saturations over 90% for 1 hour whilst breathing air. Babies unable to achieve this will be considered to be oxygen dependant.

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Previous primary outcome measures:
Death or severe neuro-developmental disability at 2 years corrected age.
The Bayley's scale of infant development III will be used to assess outcomes.

Current secondary outcome measures as of 03/08/2023:
Short-term outcomes:
1. Death by 36 weeks postmenstrual age
2. Moderate or severe BPD at 36 weeks postmenstrual age
3. Severity of BPD at 36 weeks postmenstrual age
4. Incidence or duration of the following up to discharge:
4.1. Severe intraventricular haemorrhage (IVH) (grade III/IV with ventricular dilatation or intraparenchymal abnormality)
4.2. Cystic periventricular leukomalacia (PVL)
4.3. Non-cystic PVL
4.4. Hydrocephalus
4.5. Babies treated for retinopathy of prematurity (ROP)
4.6. Significant pulmonary haemorrhage (fresh blood in endotracheal tube with increase in respiratory support)
4.7. Treated for pulmonary hypertension with pulmonary vasodilator
4.8. NEC definitive and/or complicated (Bell stage II and above) confirmed by radiology and/or histopathology
4.9. NEC requiring surgery
4.10. Gastrointestinal bleeding (leading to investigation or clinical treatment) within 7 days of the first dose of trial drug administration
4.11. Spontaneous intestinal perforation
4.12. Closed or non-significant PDA (<1.5mm) at around 3 weeks of age (range of 18–24 days), confirmed by ECHO
4.13. PDA ≥1.5mm at around 3 weeks of age (range of 18–24 days)
4.14. Medical open-label treatment of a symptomatic PDA with a COX inhibitor
4.15. Open-label treatment of a symptomatic PDA by surgical treatment
4.16. Administration and duration of inotropic support
4.17. Total duration of respiratory support:
4.17.1. Invasive ventilation through an endotracheal tube
4.17.2. Non-invasive support through nasal CPAP, nasal ventilation, humidified high-flow nasal cannula therapy, or low-flow oxygen ≥1.1L/min
4.18. Discharge home on oxygen
4.19. Duration of initial hospitalisation (birth to discharge home)
4.20. Postnatal steroid use for chronic lung disease
4.21. Tolerance of ibuprofen treatment within the foreseeable SAE reporting range
4.22. Weight gain: a change in z score between birth and discharge (or death if sooner)
4.23. Head circumference: a change in head size z score between randomisation and discharge (or death if sooner)

Long-term outcomes assessed at 2 years of age corrected for prematurity:
5. Survival without moderate or severe neurodevelopmental disability (main long-term outcome)
6. Survival
7. Individual components of survival without moderate or severe neurodevelopmental disability (in the four domains of motor, cognitive, hearing and visual function). Cognitive disability will be assessed by determining the standardised non-verbal cognitive subscale and language subscale scores obtained through the Parent Report of Cognitive Abilities–Revised (PARCA-R) assessment. The PARCA-R assessment will be adapted to include questions to assess gross
motor, hearing and visual function.
8. Survival without respiratory morbidity. Respiratory morbidity will be assessed by the need for oxygen or respiratory support; presence of persistent cough and/or wheeze; need for regular treatment for respiratory illness; unscheduled attendances at hospital/GP; readmission to hospital for respiratory problems
9. Duration of oxygen supplementation from randomisation
10. A cost-effectiveness analysis will be conducted of deaths and BPD events avoided and national health services used up to 2 years of age corrected for prematurity

Process outcomes:
11. Number of doses of trial medication received
12. Adherence to protocol (e.g. protocol violations, incidence of non-symptomatic open-label treatment etc)
13. Study withdrawals

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Previous secondary outcome measures as of 10/04/2014:
Secondary outcomes are divided into short- and long-term outcomes:
1. Short-term outcomes:
1.1. Death before discharge
2. Incidence or duration of the following up to time of neonatal unit discharge:
2.1. Severity of BPD at 36 weeks postmenstrual age
2.2. Severe IVH (grade 3/4 with ventricular dilation or intraparenchymal bleeding)
2.3. Cystic periventricular leukomalacia (PVL)
2.4. Retinopathy of prematurity (ROP) requiring treatment
2.5. Pulmonary haemorrhage
2.6. Pulmonary hypertension
2.7. NEC definitive and/or complicated (Bell stage II and above) confirmed by radiology or histopathology
2.8. NEC requiring surgery
2.9. Gastrointestinal bleeding within 7 days of the first dose of study drug administration
2.10. Spontaneous intestinal perforation
2.11. PDA closure at 3 weeks of age (or hospital discharge, if discharged before this age)
2.12. Medical rescue treatment with a COX inhibitor of a symptomatic PDA
2.13. Administration and duration of inotropic support
2.14. Duration of mechanical ventilation
2.15. Total duration of respiratory support (ventilation + nCPAP/high flow oxygen therapy)
2.16. Discharge home on oxygen
2.17. Duration of initial hospitalisation (birth to neonatal unit discharge home)
2.18. Postnatal steroid use
2.19. Safety and tolerability of ibuprofen treatment
2.20. Number of doses of trial medication received during intervention period
3. Secondary long-term clinical outcomes assessed at 2 years of age corrected for prematurity
3.1. Survival without moderate or severe neurodevelopmental disability
3.2. Individual components of survival without moderate or severe neurodevelopmental disability (in the four domains of motor, cognitive, hearing and visual function)
3.3. Survival without respiratory morbidity
3.4. A cost-effectiveness analysis will be conducted of deaths and BPD events avoided and national health services used up to 2 years of age corrected for prematurity

Previous secondary outcome measures:
1. Mortality
2. Complications of prematurity
3. Cardiovascular effects
4. Respiratory outcomes
5. Acute abdominal problems
6. Side effects of medicine
7. Length of hospital stay
8. Developmental outcome at 2 years