Ohls 2013

Methods	Randomised masked controlled clinical trial Study location: University of New Mexico, Albuquerque, New Mexico, University of Colorado, Aurora, Colorado and Intermountin Health Care, Salt Lake City, Utah, USA Study period: July 2006 to May 2010
Participants	102 infants with BW 500 to 1250 grams and ≤ 48 hours of age. Infants with trisomies, significant congenital anomalies, hypertension, seizures, thromboses, haemolytic disease, or receiving EPO clinically were ineligible for the study.
Interventions	Infants were randomised in masked fashion to 1 of 3 groups: EPO, 400 U/kg (1200 U/kg/week ‐ high dose), given subcutaneously 3 times a week (Monday, Wednesday, and Friday); Darbe, 10 µg/kg, given subcutaneously once a week, with sham dosing 2 other times per week; or placebo, consisting of 3 sham doses per week. Dosing continued until 35 completed weeks’ gestation, discharge, transfer to another hospital, or death. Doses of Darbe and EPO were initially based on study entry weight and were adjusted weekly. Study drug concentrations were chosen to give equivalent volumes (0.1 mL/kg body weight) of Darbe or EPO. All infants (regardless of treatment arm) received supplemental iron, folate (50 mg per day oral), and vitamin E (15 IU per day oral). Iron dextran, 3 mg/kg once a week, was added to parenteral nutrition while infants were receiving, 60 mL/kg per day enteral feedings. Oral iron 3 mg/kg per day was started when feedings were ≥ 60 mL/kg per day, and was increased to 6 mg/kg per day when feedings reached 120 mL/kg per day (high dose). Serum ferritin concentrations were used to adjust iron dosing. For infants in whom ferritin concentrations were > 400 ng/mL, the parenteral or enteral dose of iron was decreased by 50%; for infants in whom ferritin concentrations were < 50 ng/mL, the parenteral or enteral dose was doubled.
Outcomes	Use of 1 or more red blood cell transfusions Total volume (mL/kg) of blood transfused per infant Number of blood transfusions per infant Number of donors the infant was exposed to Mortality during initial hospital stay ROP all stages and stages ≥ 3 Late‐onset sepsis NEC stage > 2 IVH grade ≥ 3 PVL Length of hospital stay BPD (oxygen dependency at 36 weeks' PMA) Neutropenia Hypertension Cognitive scores on Bayley Scales of Infant Development (BSID‐III) at 18 to 22 months were reported initially in abstract form, but later in a full publication, in which cognitive, language, social/emotional, and OP scores were reported, as were CP, visual deficit, and NDI or death. We used the numbers reported in the 2014 report for these outcomes. Some infants (n = 53) were again assessed at 3.5 years of age (24 EPO‐treated infants, 15 Darbe‐treated infants, and 14 placebo‐treated infants). They were assessed by Wechsler Preschool and Primary Scale of Intelligence, Third Edition, and by an overall measure of executive function, on the basis of tests evaluating inhibitory control and spatial working memory. Rates of neurodevelopmental impairment were reported. A further reduced sample (n = 45 infants) was assessed via behavioural measures at an approximate mean age of 48 months.
Notes	In the previous version of the review, we obtained additional information from Dr. Ohls regarding several outcomes; this explains why some of the data we have entered in RevMan 5.3 differ from the original publication. 17 infants (17%) were transfused before treatment was initiated.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation lists for each pharmacist were computer generated.
Allocation concealment (selection bias)	Low risk	All caregivers were blinded to treatment groups, except research pharmacists at each site, who drew up study medications to be administered by the research nurse.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	All caregivers were blinded to treatment groups, except research pharmacists at each site, who drew up study medications to be administered by the research nurse. The placebo group received sham injections.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	All caregivers were blinded to treatment groups, except research pharmacists at each site, who drew up study medications to be administered by the research nurse. The placebo group received sham injection.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Three participants (1 who had the study drug mistakenly held at the start of the study and subsequently never received any study drug; 1 who was found to be ineligible based on congenital neurological anomaly on head ultrasound noted before receiving study drug; and 1 who died of a pulmonary haemorrhage before receiving study drug) were excluded from analysis. One infant had the study drug stopped at 34 weeks’ corrected gestation at the request of parents. All infants who received at least 1 dose of study drug were included in the analysis (n = 33 in each group). Bayley Scales of Infant Development (BSID‐III) cognitive scores at 18 to 22 months are reported in E‐PAS2013:2924, but not PDI scores. A full report was published in 2014 (Ohls 2014). At the end of hospitalisation, 94 infants were evaluated. Five hospital deaths occurred, and 14 children did not return for follow‐up. Eighty children were evaluated at follow‐up at a corrected age of 18 to 22 months (Darbe n = 27 (84%), EPO n = 29 (91%), placebo/sham injection n = 24 (80%)). A report of preschool assessment (at age 3.5 to 4 years) was published in 2016 (Ohls 2016), and the study assessed 53 children (Darbe n = 15 (47%), EPO n = 24 (75%), placebo n =14 (47%)). In 2017, an additional study (Lowe 2017) reported on behavioural measures in 49 children (Darbe or EPO n = 35 (55%), placebo n = 14 (47%)). The 2 groups of Darbe and EPO were combined to create an erythropoiesis‐stimulating agent (ESA) group. Percentages are based on the number of infants evaluated at the end of hospitalisation. Follow‐up rates beyond 18 to 22 months were low.
Selective reporting (reporting bias)	Low risk	Study was registered as NCT00334737 in June 2006. No major deviations from the protocol are apparent, except that primary outcomes included MDI at 18 to 22 months and PDI as a secondary outcome. MDI and PDI are not reported in the primary publication.
Other bias	Low risk	Appears free of other bias