Gournay 2004.

Methods	Randomised double‐blinded controlled trial I. Blinding of randomisation ‐ yes II. Blinding of intervention ‐ yes III. Complete follow‐up ‐ no (see notes) IV. Blinding of outcome measurement(s): yes
Participants	Study period: March 2001 to December 2001 Multi‐centre trial including 11 NICUs in France Inclusion criteria: 1. GA < 28 weeks 2. Postnatal age < 6 hours Exclusion criteria: 1. Congenital malformations 2. Shock or right‐to‐left ductal shunt evidenced by differential cyanosis 3. Cerebral complications 4. Bleeding disorders Demographic data: values presented as mean ± SD Prophylactic ibuprofen group: N = 65 GA (weeks): 26.3 ± 0.9 BW (g): 844 ± 181 Placebo group: N = 66 GA (weeks): 26.0 ± 0.9 BW (g): 851 ± 164
Interventions	One hundred thirty‐five infants were enrolled in the trial; 131 were randomised to receive either ibuprofen (N = 65) or placebo (N = 66) Both ibuprofen and placebo were given as 3 doses, 24 hours apart, with the first dose given within the first 6 hours of life. The initial dose of ibuprofen was 10 mg/kg, and the 2 following doses were 5 mg/kg, infused IV continuously over 20 minutes
Outcomes	Decreased need for surgical ligation based on presence of significant PDA on echocardiogram Mortality PDA on day 3 by echocardiogram Need for back‐up treatment with indomethacin PVL Grade III or IV IVH NEC Intestinal perforation Duration of mechanical ventilation BPD at 36 weeks' corrected GA Renal function Actuarial curve of survival during the study period
Notes	135 infants were included However, 4 were not randomly assigned because of errors in study drug allocation (3 mistakenly received open‐label ibuprofen prepared for the curative part of the study during their prophylactic course, and one 10‐day‐old with diagnosis of PDA was mistakenly given 2 doses of the randomised test drug (placebo) instead of curative ibuprofen). Per‐protocol analyses were performed on 131 infants. No participants were lost to follow‐up The trial was closed earlier than planned after 3 episodes of refractory hypoxaemia with pulmonary hypertension happened after the first prophylactic injection at 3 different centres. The Agence Francaise du Medicament was notified and requested blinding of treatment received in these 3 cases. Treatment was ibuprofen in all 3 cases, and recruitment was closed on 14 December 2001 The study was supported by the industry (Orphan Europe, Paris, France)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No information provided
Allocation concealment (selection bias)	Low risk	Sealed envelopes used
Blinding (performance bias and detection bias) All outcomes	Low risk	Placebo (saline) used. Low risk of performance and detection bias
Incomplete outcome data (attrition bias) All outcomes	Low risk	135 infants were included However, 4 were not randomly assigned because of errors in study drug allocation (3 mistakenly received open‐label ibuprofen prepared for the curative part of the study during their prophylactic course, and one 10‐day‐old with diagnosis of PDA was mistakenly given 2 doses of the randomised test drug (placebo) instead of curative ibuprofen. Per‐protocol analyses were performed on 131 infants. No participants were lost to follow‐up
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	Low risk	Appears free of other bias