PROTOS Study 2007.

Methods	Study design: open‐label, parallel group, comparator controlled, phase III RCT Study duration: March 2004 to September 2005 Duration of follow‐up: 1 year
Participants	Countries: international Setting: 92 centres Aged ≥18 years; PD or HD ≥ 12 weeks; Kt/V≥ 1.2 or URR ≥ 65% for HD; weekly Kt/V ≥1.8 for PD patients; Hb concentration 10.5 to 13.0 g/dL; SC rHuEPO maintenance therapy; ferritin ≥ 100 ng/mL or TSAT ≥ 20% Number: treatment group 1 (190); treatment group 2 (191); treatment group 3 (191) Mean age ± SD (years): treatment group 1 (62.3 ± 15.4); treatment group 2 (60.59 ± 15.4); treatment group 3 (60.4 ± 14.7) Sex (M/F): treatment group 1 (117/74); treatment group 2 (108/82); treatment group 3 (110/81) Exclusion criteria: GI bleeding or bleeding requiring transfusion < 8 weeks before screening; non‐renal causes of anaemia; uncontrolled or symptomatic inflammatory disease, e.g. SLE, RA; CRP > 30 mg/L; platelets > 500 x 10⁹/L; PRCA; CHF; poorly controlled hypertension; high likelihood of withdrawal/interruption of the study (MI, stroke); Life expectancy < 12 months
Interventions	Treatment group 1 CERA: every 2 weeks Starting dose: SC 60 μg/2 wk Treatment group 2 CERA: every 4 weeks Starting dose: SC 120 μg/4 wk Treatment group 3 rHuEPO: given one to three/wk with dose based on approved recommendations to maintain Hb as above Other information During titration and evaluation periods CERA dose was adjusted to maintain Hb within ± 1.0 g/dL of baseline and 10.0 to 13.5 g/dL. CERA dose adjustments were performed according to a predefined protocol and no more frequently than once every 4 weeks Co‐interventions Iron supplementations were performed according to each centre's practice and adjusted to maintain adequate stores
Outcomes	Mean change in Hb Adverse effects: hypertension, AV fistula thrombosis, AE leading to withdrawal and death
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Central randomisation with geographic stratification
Allocation concealment (selection bias)	Low risk	Central randomisation
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Open‐label study but laboratory endpoint unlikely to be influenced by lack of blinding
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Open‐label study but laboratory endpoint unlikely to be influenced by lack of blinding
Incomplete outcome data (attrition bias) All outcomes	Low risk	All participants accounted
Selective reporting (reporting bias)	High risk	Data provided for PP not ITT population. ITT data only available graphically so PP data only included in meta‐analyses (98 excluded from ITT population). Withdrawal/loss to follow‐up: 111/572. Death (41), kidney transplantation (39), treatment refusal (13), AEs (2), insufficient therapeutic response (2), other (13)
Other bias	High risk	Funding F. Hoffman La Roche Ltd