Canadian EPO 1990.

Study characteristics
Methods	Study design Parallel RCT Study dates Duration of follow‐up: 6 months Time frame: not reported
Participants	Study characteristics Setting: multicentre (13 hospitals in 8 Canadian university HD centres) Country: Canada Inclusion criteria: 18 to 75 years; medically stable on HD for > 3 months; HD 3 times/week in a hospital or self‐care unit; Hb < 9.0 g/dL Exclusion criteria: anaemia was not caused by EPO deficiency; QoL or exercise capacity was affected by factors other than kidney failure; unable to perform a 6MWT; not be able to understand the questionnaires due to language or intellectual difficulties; unwilling or unable to give informed consent; history of DM; ischaemic heart disease; severe or uncontrolled hypertension; androgen or corticosteroid therapy Baseline characteristics Number Completed the SIP/randomised: intervention group 1 (34/40); intervention group 2 (33/38); control group (32/40) Completed the KDQ/randomised; intervention group 1 (34/40); intervention group 2 (33/38); control group (31/40) Mean age ± SD (years): intervention group 1 (44 ± 16); intervention group 2 (43 ± 15); control group (48 ± 16) Sex (M/F): intervention group 1 (19/21); intervention group 2 (26/12); control group (25/15) Dialysis type: HD Mean dialysis vintage ± SD (years): intervention group 1 (4.6 ± 4.7); intervention group 2 (4.4 ± 5.1); control group (2.5 ± 3.1) Comorbidities CVD: not reported Diabetes: intervention group 1 (0/40); intervention group 2 (0/38); control group (0/40) Hypertension: not reported Depression (clinician diagnosis): not reported
Interventions	Intervention classification Pharmacological intervention Indication: study targeting fatigue intervention group 1 Epoetin alfa (IV): to achieve a target HB of 9.5–11.0 g/dL (low‐target group), initial dose was 100 U/kg ‐ outcomes were reported for intervention 1 + 2 Intervention group 2 Epoetin alfa (IV): to achieve a target Hb of 11.5–13.0 g/dL (high‐target group), initial dose was 100 U/kg ‐ outcomes were reported for intervention 1 + 2 Control group Placebo (did not receive EPO alfa) Co‐interventions Not reported
Outcomes	Outcomes reported Fatigue outcome measures used: validation data available Exercise capacity Treadmill stress test (assessed at baseline, and 2, 4, and 6 months) Time trade‐off technique: score between 0 and 1, in which 1 represents perfect health and 0 a state in which the patient is indifferent between life and death (assessed at baseline, and 2 and 6 months) 6MWT: assessed at baseline, and 2, 4, and 6 months HRQoL KDQ: assessed at baseline, and 2, 4, and 6 months (Appendix 3) Physical Fatigue Relationship Frustration Depression SIP: assessed at baseline, and 2, 4, and 6 months Global Physical Ambulation Body care and movement Home management Psychosocial Communication Work Sleep and rest Eating Recreation and pastimes Mobility Change in KDQ symptoms: assessed at baseline, and 2, 4, and 6 months Energy Weakness Shortness of Breath Fatigue Depression Other problems associated with ESKD (sexuality): assessed at baseline, 2 and 6 months Change in Hb: from baseline to 2, 4 and 6 months Change in potassium, phosphorus, calcium, urea, creatinine, white cell count, platelet count: assessed at baseline, 2 and 6 months Change in functional capacity Minutes walked: assessed at baseline, 2 and 6 months Change in BP: assessed at baseline, 2 and 6 months Adverse events: assessed at baseline, 2 and 6 months Hypertension: assessed at baseline, 2 and 6 months Death: assessed at end of treatment
Notes	Additional information Funding: Amgen Inc. Conflicts of interest/disclosures: T. J. M. were Amgen Inc. employees. The authors thank Ortho Pharmaceutical (Canada) who sponsored this study, and Johnson and Johnson Pharmaceutical Research and Development for providing the data for the reanalysis. The authors also thank Y. Mikyas (Amgen Inc.) for editorial support in preparation of this manuscript Trial registration identification number: not applicable A priori published protocol: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote from Canadian EPO 1990: "Patients were stratified by hospital and randomised in blocks to receive placebo; erythropoietin at a dose adjusted to maintain the haemoglobin concentration at 95‐110 g/l (low erythropoietin group); or erythropoietin at a dose adjusted to maintain the haemoglobin concentration at 115‐130 g/l (high erythropoietin group)." Comment: sequence generation methods were not reported in sufficient detail to permit judgement
Allocation concealment (selection bias)	Unclear risk	Quote from Canadian EPO 1990: "Patients were stratified by hospital." Comment: method of allocation concealment was not reported in sufficient detail to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote from Canadian EPO 1990: "To ensure that the study was double blind we established two teams of staff at each study centre. The unblinded team consisted of a doctor, a pharmacist, and a data clerk and was responsible for adjusting the dose of erythropoietin, prescribing iron supplements or transfusions, and sending haematological data to the coordinating centre. The blinded team consisted of nurses in the dialysis unit and our study group and all doctors in the dialysis unit other than those in the unblinded team; this team carried out routine clinical care and recorded adverse reactions and other clinical events but did not have access to the results of haematological tests or know the dose of erythropoietin or placebo that each patient was receiving." Comment: a clear explanation of the double‐blind study was provided
Blinding of outcome assessment (detection bias) All outcomes	High risk	Quote from Canadian EPO 1990: "The nurses in the study group administered tests to assess quality of life and exercise capacity." Quote from Keown 2010: "Health‐related quality of life was measured by the Kidney Disease Questionnaire (KDQ) and Sickness Impact Profile (SIP) between the placebo group and the combined Epoetin alfa‐treated group." Comment: the outcomes were assessed with an appropriate measure, without differences between groups. However, subjective measures were used (although nurses were part of the blinded team) it was not stated whether outcomes were assessed without knowledge of treatment allocation, and knowledge of treatment assignment may have influenced reporting. Participant 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. However, objective and subjective outcomes were assessed
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Quote from Canadian EPO 1990: "Nineteen patients were withdrawn during the study: eight in the placebo group (because of transplantation (five), non‐compliance (one), reaction to transfusion (one), seizure and death (one)); six in the low erythropoietin group (transplantation (two), hypertension (one), hypertension and seizure (one), subarachnoid haemorrhage and seizure (one), pregnancy (one)); and five in the high erythropoietin group (transplantation (three), hypertension (two)). Six patients were withdrawn before the follow‐up at two months, and the 13 others were withdrawn before the follow‐up at four months. The patient who became pregnant continued to receive erythropoietin but had a spontaneous miscarriage at 11‐ 1 2 weeks' gestation." Quote from Muirhead 2008: "Analysis was conducted using ITT." Comment: 11/78 in the two intervention groups and 8/40 in the placebo group did not completed the study. However, ITT analyses was performed
Selective reporting (reporting bias)	High 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 not reported
Other bias	High risk	There was no evidence of different baseline characteristics, or different non‐randomised co‐interventions between groups. Funding (pharmaceutical company) could influenced the data analysis and authors had conflicts of interest