Parfrey 2005.

Study characteristics
Methods	Study design Parallel RCT Study dates Duration of follow‐up: 96 weeks Time frame: February 2000 to June 2001. The last patient completed the study in May 2003
Participants	Study characteristics Setting: multicentre (95 centres) Country: multinational (10 countries, Europe (Australia, Belgium, Canada, France, Germany, Greece, Hungary, Poland, Spain, UK) Inclusion criteria: ≥ 18 years; maintenance HD started within the previous 3 to 18 months without symptomatic cardiac disease; predialysis Hb between 8 and 12 g/dL; LV volume index < 100 mL/m2; and predialysis DBP < 100 mm Hg Exclusion criteria: clinical evidence or history of symptomatic cardiac failure or ischaemic heart disease; daily prednisone dose > 10 mg; medical conditions likely to reduce epoetin responsiveness, including uncorrected iron deficiency; concurrent malignancy; blood transfusion in the preceding month; therapy with cytotoxic agents; seizure in the preceding year; hypersensitivity to IV iron; current pregnancy or breastfeeding Baseline characteristics Number (analysed/randomised): intervention group 1 (164/300); intervention group 2 (160/296) Mean age ± SD (years): intervention group 1 (49.4 ± 15.2); intervention group 2 (52.2 ± 15.6) Sex (M/F): intervention group 1 (180/120); intervention group 2 (178/118) Dialysis type: HD Mean dialysis vintage ± SD (years): intervention group 1 (0.9 ± 0.4); intervention group 2 (0.8 ± 0.4) Comorbidities CVD: not reported Diabetes: not reported Hypertension: not reported Depression (clinician diagnosis): not reported
Interventions	Intervention classification Pharmacological intervention Indication: study targeting fatigue Intervention group 1 SC or IV epoetin alfa to reach low target Hb (9.5 to 11.5 g/dL), for 96 weeks Intervention group 2 SC or IV epoetin alfa to reach high target Hb (13.5 to 14.5 g/dL), for 96 weeks Co‐interventions Not reported
Outcomes	Outcomes reported Fatigue outcome measures used: validation data available HRQoL KDQoL (Appendix 3): assessed at weeks 0, 24, 36, 48, 60, 72, 84, and 96 Energy/fatigue Burden of kidney disease Cognitive function Symptoms/problems Sexual function Sleep Social support Work status Dialysis staff encouragement Patient satisfaction rating Overall health rating Physical functioning Role limitations ‐ physical Pain General health Emotional well‐being Role limitation ‐ emotional Social function Quality of social interaction Vitality SF‐36 (Appendix 3): assessed at weeks 0, 24, 36, 48, 60, 72, 84, and 96 Death: assessed until the end of treatment Laboratory results (BMI, URR, TSAT, albumin, serum concentrations of N terminal pro–B type natriuretic peptide, cardiac troponin T, CRP, IL‐6): assessed every week Hb: assessed weekly for 24 weeks and biweekly thereafter Vital signs (SBP, DBP): assessed every week Adverse events: classified by the World Health Adverse Reactions Terminology (Appendix 3) Transfusion rate: assessed at weeks 0, 24, 36, 48, 60, 72, 84, and 96 Time to first transfusion: assessed at weeks 0, 24, 36, 48, 60, 72, 84, and 96 LV cavity volumes ECG: assessed at 24, 48 and 96 weeks LV mass index: assessed at 24, 48 and 96 weeks Rates of de novo heart failure (defined as dyspnoea): assessed at 24, 48 and 96 weeks Change in functional capacity 6MWT performance: assessed at weeks 0, 24, 48, and 96 Fatigue FACIT‐fatigue: assessed at weeks 0, 24, 36, 48, 60, 72, 84, and 96
Notes	Additional information Funding: Johnson&Johnson Pharmaceutical Research and Development. The study sponsor identified the participating centres, monitored the data collection, and entered the data in a central database Conflicts of interest/disclosures: P.S.P. has received research support and has been an academic advisor to companies that make erythropoietin products: Ortho Biotech, Amgen, and Roche. R.N.F. has received research support and honoraria from Ortho Biotech and honoraria from Affymax, Amgen, Ortho Biotech, and Roche. B.M.C. has received research support and honoraria from Ortho Biotech. P.S.P. declares that he had full access to all of the data in the study and had final responsibility for the decision to submit for publication Trial registration identification number: not applicable (trial was performed before 2005) A priori published protocol: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote from Foley 2008: "The study was centrally coordinated from St. John’s, Canada for Canadian patients and Manchester, England for European patients. Randomization was performed at the coordinating centres with an interactive voice randomisation telephone system using permuted blocks stratified by concurrent epoetin use and sex." Comment: The interactive voice system is likely to be a computer. No imbalance between intervention groups was apparent
Allocation concealment (selection bias)	Low risk	Quote from Foley 2008: "The study was centrally coordinated from St. John’s, Canada for Canadian patients and Manchester, England for European patients. Randomization was performed at the coordinating centres with an interactive voice randomisation telephone system using permuted blocks stratified by concurrent epoetin use and sex." Comment: An interactive voice system is considered as low risk of bias. No imbalance between intervention groups was apparent
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote from Foley 2009: "Patients and attending physicians were masked to treatment assignment. [...] Local investigators and the dialysis unit were also masked to treatment assignment." Quote from Parfley 2005: "A randomised, double‐blind design was used with patients and outcome assessors but not treating physicians, who were blinded to assigned haemoglobin target." Comment: A double‐blind trial is considered as low risk of bias
Blinding of outcome assessment (detection bias) All outcomes	High risk	Quote from Foley 2009: "Quality of life was assessed using the KDQoL questionnaire, with prespecified outcomes being Energy/Fatigue scores, and Quality of Social Interaction Scores." Quote from Foley 2009: "Independent Data Monitoring Committee Members." Comment: The outcomes were assessed with an appropriate measure, without differences between groups. However, subjective measures were used, it was not stated whether outcomes were assessed without knowledge of treatment allocation, and knowledge of treatment assignment may have influenced reporting (not sure that the Independent Data Monitoring Committee Members assessed fatigue). Participant/investigators beliefs about the superiority/inferiority of either intervention could have influenced their assessment of the outcome, but there was no evidence that this was likely. It was not stated if the independent data monitoring was blinded to the treatment assigned. However, objective and subjective outcomes were assessed. It was not stated if the interviewer was blinded to the treatment allocation
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Quote from Parfley 2005: "324 (54%) patients remained in the study for 96 weeks, 160 (54%) in the higher and 164 (55%) in the lower target groups. The reasons for study exit— renal transplantation (n 133, 67 in the higher and 66 in the lower target group), adverse events (n 76, 39 and 37), patient choice (n 28, 9 and 19), loss to follow‐up (n 2, 1 and 1), and other (n 36, 21 and 15)—were similar in the two target groups." Comment: 164/300 participants in intervention group 1 (epoetin alfa to reach low target haemoglobin) and 160/296 participants in intervention group 2 (epoetin alfa to reach high target Hb) completed the study (> 5% lost to follow‐up, without differences between groups). Reasons for discontinuations (adverse events) seemed to be related to the treatment allocation. However, all outcomes have been reported on the ITT population
Selective reporting (reporting bias)	Low risk	Information about the protocol and the statistical analysis plan were not reported. Fatigue was reported using multiple eligible outcome measurements (scales, time points). Fatigue was reported in a format that was extractable for meta‐analysis. All outcomes that should be addressed (fatigue, cardiovascular disease, and death) were reported
Other bias	High risk	Quote from Foley 2009: "Baseline characteristics were similar except for the older age of high target subjects (52.2 versus 49.4 years)." Comment: There was no substantial evidence of different baseline characteristics, or different non‐randomised co‐interventions between groups. Funding (pharmaceutical company) could influence the data analysis and authors reported conflicts of interest