Van Overmeire 2004.

Methods	Seven‐centre randomised double blinded controlled trial I. Blinding of randomisation ‐ yes II. Blinding of intervention ‐ yes III. Blinding of outcome measurement(s) ‐ yes IV. Complete follow‐up ‐ yes
Participants	Study period: 1 February 1999 to 30 September 2001 7 centres; Belgium Inclusion criteria: gestational age 24 to 30 weeks Exclusion criteria: major congenital malformation or chromosomal anomaly, intraventricular haemorrhage higher than grade I already detected during baseline cranial ultrasonography, Apgar score at 5 minutes < 5, signs of congenital infection or life‐threatening septicaemia, uncontrolled hypotension, contraindications to administration of ibuprofen Demographic data: values presented as mean ± SD or as number (percentage) Prophylaxis group: N = 205 Gestational age (weeks): 28.1 ± 1.7 Birth weight (g): 1048 ± 315 Placebo group: N = 210 Gestational age (weeks): 28.1 ± 1.6 Birth weight (g): 1065 ± 324
Interventions	205 infants received ibuprofen‐lysine and 210 infants received placebo (saline). First dose of medication was given within 6 hours of birth, and second and third doses were given at 24 hours and 48 hours after the first dose. The dose of IV ibuprofen used was 10 mg/kg for the first dose and 5 mg/kg for subsequent doses. The dose of saline was 1 mL/kg for first dose and 0.5 mL/kg for subsequent doses
Outcomes	The primary outcome variable was IVH grade III or IV Secondary outcomes included echocardiographically confirmed PDA after day 3 of life and the need for its pharmacological rescue treatment or surgical ligation, occurrence of renal dysfunction measured by urine production, NEC, and death
Notes	The study was published as an abstract when 358 infants had been enrolled. There is no mention of this interim analysis in the final publication
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation was done independently by the chief pharmacist in a 1‐to‐1 ratio between ibuprofen and placebo
Allocation concealment (selection bias)	Low risk	Identical looking ibuprofen‐lysine and normal saline as placebo provided by the pharmacy
Blinding (performance bias and detection bias) All outcomes	Low risk	Attending and consulting physicians, nurses, study collaborators, and parents were unaware of treatment allocation. Risk for performance and detection bias was low
Incomplete outcome data (attrition bias) All outcomes	Low risk	Outcomes reported for all randomised infants
Selective reporting (reporting bias)	Unclear risk	The trial was not registered in a trials registry, and we could not ascertain if there were deviations from the original protocol in the final publication
Other bias	Unclear risk	The study was published as an abstract when 358 infants had been enrolled. There is no mention of this interim analysis in the final publication

Abbreviations:
 BPD: bronchopulmonary dysplasia.
 BUN: blood urea nitrogen.
 BW: birth weight.
 CGA: corrected gestational age.
 CLD: chronic lung disease.
 FiO₂: fraction of inspired oxygen.
 GA: gestational age.
 GI: gastrointestinal.
 IQR: interquartile ratio.
 IV: intravenous(ly).
 IVH: intraventricular haemorrhage.
 NEC: necrotising enterocolitis.
 NICU: neonatal intensive care unit.
 PDA: patent ductus arteriosus.
 PMA: postmenstrual age.
 PPHN: persistent pulmonary hypertension of the newborn.
 PVL: periventricular leukomalacia.
 RCT: randomised controlled trial.
 RDS: respiratory distress syndrome.
 ROP: retinopathy of prematurity.
 SD: standard deviation.