Maier 1994

Methods	Double‐blind randomised controlled trial Study location: 12 centres in 6 European countries Study period: September 1991 to December 1992
Participants	244 infants with birth weight of 750 to 1499 grams; 3 infants excluded after randomisation
Interventions	120 infants in the EPO group received 250 IU of epoetin beta (Boehringer‐Mannheim, Germany) per kilogram; injections on Monday, Wednesday, and Friday (750 IU/kg/week, high dose). Treatment continued until day 40 to 42, for a total of 17 doses. 121 infants in the control group did not receive placebo, but adhesive tape was placed on both thighs and remained there until the next visit. Oral iron supplementation 2 mg/kg/d was started on day 14 in all infants (low dose). Vitamin E supplementation was not part of the protocol.
Outcomes	Use of 1 or more red blood cell transfusions Number of transfusions per infant Mortality ROP Sepsis NEC IVH all grades IVH grades III and IV Neutropenia Hypertension Side effects
Notes	Infants who had received transfusions before study entry were included (28 in the EPO group and 17 in the control group). Transfusion guidelines were in place. 33 infants in the EPO group and 28 in the control group were withdrawn. Results are reported as per ITT.
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	Numbered sealed envelopes
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Most participating doctors were reluctant to administer repeated subcutaneous injections of placebo to low birth weight infants. Therefoere, 2 teams were formed at each centre: Treating physicians determined whether infants could be enrolled or withdrawn from the study, decided whether they should receive transfusions, and monitored them without knowing their treatment group; "dosing investigators" performed randomisation and administered epoetin beta but were not involved in the infants' care. When treatment was to be given, a dosing investigator carrying a "black box" containing appropriate equipment visited each infant, administered study medication, and placed adhesive strips on both thighs (of both epoetin recipients and controls), which remained there until the next visit. During this procedure, staff and parents had to leave. A treating physician or a dosing investigator assigned to an infant had to serve in that capacity as long as the infant was studied.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	See information in the box above.
Incomplete outcome data (attrition bias) All outcomes	High risk	Complete follow‐up: no 33 infants in the EPO group and 28 in the control group were withdrawn. Results are reported as per ITT. Three of the 244 infants who underwent randomisation were excluded; all data on 2 infants were lost, and treatment (EPO) was inadvertently omitted for 1 infant, whose records were not completed. The remaining 241 infants were evaluated in an ITT analysis.
Selective reporting (reporting bias)	Unclear risk	The protocol for the study was not available to us; therefore we cannot ascertain whether deviations from the protocol occurred.
Other bias	Low risk	Appears free of other bias