Foley 2000.

Study characteristics
Methods	Study design Parallel RCT Study dates Duration of follow‐up: 48 weeks Time frame: May 1995 to December 1996
Participants	Study characteristics Setting: multicentre Country: Canada Inclusion criteria: > 17 years; maintenance HD > 3 months; LV hypertrophy (LV mass indexed to a body surface area > 131 g/m2 in males and 100 g/m2 in females) or LV dilation; a Hb between 9 and 11 g/dL in the month prior to randomisation; stable vascular access for the previous 3months; and life expectancy > 18 months Exclusion criteria: angina pectoris, MI, coronary artery bypass surgery, percutaneous transluminal angioplasty or congestive heart failure within the previous 12 months; active bleeding; uncorrected iron deficiency; valvular heart disease for which surgical intervention was planned within 1 year; and IV iron dextran intolerance Baseline characteristics Number (analysed/randomised): intervention group 1 (68/73); intervention group 2 (66/73) Mean age ± SD (years): overall (61.5, SD not reported) Sex (M/F): intervention group 1 (44/29); intervention group 2 (47/26) Dialysis type: HD Dialysis vintage (years) (mean ± SD): not reported 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 Epoetin alpha (SC) to achieve Hb levels of 9.5 to 10.5 g/dL Intervention group 2 Epoetin alpha (SC) to achieve Hb levels of 13 to 14 g/dL Co‐interventions Epoetin alpha (SC) was administered in all patients Dosing guidelines were similar in the high‐ and low‐target Hb groups
Outcomes	Outcomes reported Fatigue outcome measures used: validation data available Change in LV mass index in those with concentric LV hypertrophy: assessed from baseline to 48 weeks Change in cavity volume index in those with LV dilation: assessed from baseline to 48 weeks Pre‐dialysis Hb: assessed every week for 24 weeks and then every 2 weeks BP: assessed every week for 24 weeks and then every 2 weeks TSAT: assessed every 2 weeks for 24 weeks and then every 4 weeks Serum chemistry (including Kt/V): assessed monthly ECG carried out on the day after a HD session, with the patients within 1 kg of dry weight): assessed at baseline and at 48 weeks HRQoL KDQ: assessed at baseline and at 12, 24, and 48 weeks (the assessment on week 12 was decided by investigator due to logistic difficulties) Fatigue Depression Relationships with others Frustration Physical symptoms SF‐36: assessed at baseline and at 12, 24, and 48 weeks (the assessment on week 12 was decided by investigator due to logistic difficulties) Physical function Social function Physical role Emotional role Mental health Energy Pain General health perception Health Utilities Index (Appendix 3): assessed at baseline and at 12, 24, and 48 weeks (the assessment on week 12 was decided by investigator due to logistic difficulties) Sensation Mobility Emotion Cognition Self‐care Pain Fertility Incidence of arteriovenous access thrombosis: assessed until the end of treatment Cardiac events (including ischaemic heart disease): assessed until the end of treatment Death: assessed until the end of treatment Hospitalisation (admissions and time spent in the hospital): evaluated over a mean duration of 309 days
Notes	Additional information Funding: Janssen‐Ortho Inc., Toronto, Canada. Dr. Foley and Dr. Parfrey designed and analysed this study Conflicts of interest/disclosures: Dr Foley and several of the other authors have received grant/research support, consultant positions, and/or speaker's bureau affiliations with Janssen Ortho, Amgen and Roche 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)	Unclear risk	Sequence generation methods were not reported in sufficient detail to permit judgement
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment was not reported in sufficient detail to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	High risk	Quote from Foley 2000: "This was a 48‐week, open‐label, randomised, controlled trial." Comment: An open‐label study was considered as high risk of bias
Blinding of outcome assessment (detection bias) All outcomes	High risk	Quote: "A study monitoring group (R.N.F., P.S.P., and J.M.) at the coordinating centre in St. John’s met weekly to review each patient’s haemoglobin level, epoetin dose, iron saturation, and blood pressure level." 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 (bot sure if the committee assessed also 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 monitoring group was blinded to the treatment assigned. However, objective and subjective outcomes were assessed
Incomplete outcome data (attrition bias) All outcomes	High risk	Quote: "Follow‐up studies were unavailable in 12 patients, 5 in the low target and 7 in the high target group. The reasons included transplantation (3), death (3), withdrawal of consent (3), Ischaemic heart disease (1) and other causes (1)." Comment: 68/73 participants in the intervention group 1 (epoetin alpha to achieve HB of 9.5‐10.5 g/dL) and 66/73 participants in the intervention group 2 (epoetin alpha to achieve Hb of 13‐14 g/dL) completed the study (> 5% lost to follow‐up, with differences between groups). Some reasons for discontinuations appeared to be related with the intervention. However, analyses were performed in 45 and 49 participants, respectively
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 not extractable for meta‐analysis. All outcomes that should be addressed (fatigue, cardiovascular disease, and death) were reported, but fatigue was not extractable
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 interests