Filippi 2013.

Methods	2‐centre randomised controlled trial performed in Milano and Florence, Italy. Allocation concealment: yes. Randomisation: computer‐based random number generation (blocks of 8). Blinding of caregivers and personnel to intervention: no. Blinding of outcome ascertainment: yes (ophthalmologist). Complete follow‐up: yes.
Participants	Preterm neonates (n = 52 enrolled, n = 51 analysed). Inclusion criteria: gestational age < 32 weeks and stage 2 ROP without plus disease in zone II. Infants were stratified by centre and gestational age (23 to 25 weeks' gestational age and 26 to 31 weeks' gestational age). 1 neonate allocated to the intervention group was relocated to the control group on the first day of using study drug due to serious adverse effects from propranolol. Intervention group: mean (SD) postnatal age, 67 (±14) days; mean (SD) weight 1678 (± 393) grams. Control group: mean (SD) postnatal age, 68 (± 17) days; mean (SD) weight 1559 (± 431) grams. 67.3% of neonates were outborn and the majority of neonates were transferred to the 2 study centres for surgery. 15 (57.7%) participants in the intervention group and 13 (50%) participants in the control group had at least 1 major surgical intervention. Surgery was predominantly performed for closure of patent ductus arteriosus, hydrocephalus, and intestinal disease. Exclusion criteria: neonates with congenital or acquired cardiovascular anomalies, renal failure, cerebral haemorrhage; preterm infants with ROP in zone I or ≥ stage 2 ROP without plus disease in zone II.
Interventions	Intervention group (n = 25 analysed): oral propranolol (2 mg/ml syrup) at a dose of 0.5 mg/kg 6 hourly (n = 18); dosage was reduced to 0.25 mg/kg 6 hourly in 8 infants with a gestational age of 23 to 25 weeks. Duration of treatment: until complete retinal vascularisation, but no more than 90 days. Mean (range) treatment duration 66 (6 to 90) days. Control group (n = 26 analysed): no control treatment. Standard treatment for ROP was offered to all study participants if indicated (laser photocoagulation, rescue therapy with anti‐VEGF agents).
Outcomes	Primary outcome: Progression of ROP to stage 2 ROP with plus disease or to stage 3 ROP with or without plus disease. Secondary outcomes: Incidence of laser therapy, rescue treatment with bevacizumab, progression to stage 4 or 5 ROP, need for vitrectomy. Plasma VEGF and sE‐selectin concentrations.
Notes	Registered with clinicaltrials.gov NCT01079715. Dr Filippi (contact author) provided additional information on study methodology.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated random sequence.
Allocation concealment (selection bias)	Low risk	Allocation was concealed by using sequentially numbered, opaque, sealed envelopes.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Blinding of the intervention was not attempted.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcome assessors (ophthalmologist and data analyst) were blinded.
Incomplete outcome data (attrition bias) All outcomes	High risk	52 patients were randomised. In the intervention group, 1/26 (4%) infants died after 9 days of treatment; in the control group, 2/26 (8%) infants died prior to complete retinal vascularisation. In 6/26 (23%) infants allocated to the intervention group, treatment was discontinued early due to severe adverse effects. Additionally, 1 patient from the intervention group was relocated and analysed in the control group due to severe adverse effects after 1 day of propranolol treatment. Reporting of outcomes from the single deceased infant in the intervention group was incomplete.
Selective reporting (reporting bias)	Low risk	Primary outcome reported as specified in the report. Some of the secondary outcomes specified in the registered trial protocol (blindness and retinal detachment within 6 months from beginning of treatment, see NCT01079715) were not reported.
Other bias	Low risk	None detected.