Linde 2001.

Study characteristics
Methods	Study design Parallel RCT Study dates Duration of follow‐up: 48 to 76 weeks (the study duration was extended from 48 weeks to 76 weeks in Sweden (48 study centres) due to a slower increase in Hb values than anticipated. Since the withdrawal rate was high, results at week 48 are presented for many variables) Time frame: 1995 to 1996 (the months were not reported)
Participants	Study characteristics Setting: multicentre (62 hospital centres: Sweden (48), Norway (8), Finland (5) and Iceland (1)) Country: multinational (Sweden, Norway, Finland, Iceland) Inclusion criteria: renal anaemia; stratified into 3 groups: pre‐dialysis, HD and PD patients; pre‐dialysis patients (SCr 300 mmol/L or CrCl < 30 mL/min) were not expected to become dialysis‐dependent within 1 year; Hb values in the subnormal range (90 to 120 g/L) for at least 3 months with or without epoetin therapy prior to entering the study Exclusion criteria: anaemia from causes other than CKD; DBP repeatedly at least 100 mmHg; uncontrolled diabetes (HbA1c > 10%); clinically relevant abnormal liver function; severe secondary hyperparathyroidism (cystic bone disease, PTH >3 00 ng/L); clinical signs of aluminium intoxication (serum aluminium > 100 mg/L) or treatment with desferrioxamine; uncontrolled overhydration in Hb patients (requiring repeatedly ultrafiltration of at least 4 L); active infection, inflammation or malignancy An amendment added new exclusion criteria: angina pectoris and/or congestive heart failure corresponding to NYHA classes III and IV; history of a coronary‐artery by‐pass grafting and/or percutaneous transluminal coronary angioplasty < 2 years ago; history of transmural MI < 3 years ago; permanent atrial fibrillation or uncontrolled arterial hypertension Baseline characteristics Number (analysed/randomised): intervention group (73/180); control group (83/164) HD: intervention group (63/157); control group (71/136) PD: intervention group (10/23); control group (12/28) Mean age ± SD (years) HD: intervention group (65 ± 12); control group (64 ± 15) PD: intervention group (60 ± 9); control group (60 ± 13) Sex (M/F): intervention group (125/55); control group (106/53) HD: intervention group (108/49); control group (92/44) PD: intervention group (17/6); control group (14/9) Dialysis type: HD, PD Dialysis vintage (years) (mean ± SD) HD: intervention group (2.6 ± 3.3); control group (3.0 ± 3.9) PD: treatment group (1.1 ± 1); control group (2.4 ± 4.4) Comorbidities CVD: not reported Diabetes: intervention group (33/180); control group (33/159) HD: intervention group (28/157); control group (27/136) PD: intervention group (5/23); control group (6/28) Hypertension: not reported Depression (clinician diagnosis): not reported
Interventions	Intervention classification Pharmacological intervention Indication: study targeting fatigue Intervention group Epo alfa (SC): to reach normal Hb 135 to 150 g/L in females and 145 to 160 g/L in males Patients randomised to N‐Hb not already receiving epoetin initially received 50 U/kg of epoetin alfa 3 times/week. For patients already receiving epoetin, the initial dose increment was 50%. The dose was increased by 25% if reticulocytes had not increased by at least 75% after 2 weeks of treatment. Epoetin alfa was increased by a further 25%, if the increase in Hb was < 10 g/L after 4 weeks. The dose was then adjusted every 2 weeks, aiming at a monthly increase in Hb of 10 to 15 g/L to reach the target Hb level within 3 months Control group Subnormal Hb of 90 to 120 g/L with or without epoetin alfa Co‐interventions Patients received iron supplementation with oral iron sulphate or IV iron sucrose to keep TSAT > 20% and serum ferritin levels between 400 to 800 mg/L during the correction phase and > 250 mg/L during the maintenance phase
Outcomes	Outcomes reported Fatigue outcome measures used: validation data available Change in HRQoL KDQ: assessed at baseline and at week 48 Physical symptoms Fatigue Depression Frustration Relations with others Self‐Image Scales: assessed at baseline and at week 48 Leicester Uremic Symptoms Scale: assessed at baseline and at week 48 ESKD‐DL scales: assessed at baseline and at week 48 VAS: assessed at baseline and at week 48 Adverse events: assessed until the end of treatment Vascular access: assessed until the end of the study Serious adverse events: assessed until the end of treatment Vital signs (including SBP, DBP): assessed weekly until the end of the study Progression rate of CKD Endogenous CrCL (24 hours urine collection) in pre‐dialysis patients: assessed at weeks 0 and 48 Iohexol clearance in pre‐dialysis patients: assessed at weeks 0 and 48 Cr‐EDTA clearance in pre‐dialysis patients: assessed at weeks 0 and 48 All‐cause death (included sepsis, infection, uraemia NUD and malignancy): assessed until 48 weeks Laboratory results (TSAT, serum ferritin, creatinine, Hb, GFR): assessed at week 0 and 48 Epo alfa dose: assessed at weeks 0 and 48 Iron sucrose dose: assessed at weeks 1 to 4 and 45 to 48 Fraction functioning grafts: assessed at days 1, 7, 14 and months 3 and 6 Hospitalisation: assessed until the end of treatment Cardiovascular death: included MI, atherosclerotic disease of the coronary arteries, aorta and peripheral arteries, congestive heart failure, sudden death and cerebrovascular disease): assessed until the end of treatment ESKD (for pre‐dialysis patients): assessed until the end of the study Transplant: assessed at 6 months Transplant acute rejection: assessed at 6 months
Notes	Additional information Funding: not reported Conflicts of interest/disclosures: not reported 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 Furuland 2003: "This was a multicenter, randomised, open‐label trial in patients with renal anaemia." Comment: An open‐label study is considered as high risk of bias
Blinding of outcome assessment (detection bias) All outcomes	High risk	Quote from Furuland 2003: "Thrombovascular events and vascular access thrombosis were recorded and categorized centrally by one coordinator based on a WHO classification." Comment: Some outcomes were recorded centrally (not sure that it was valid also for fatigue). 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. 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	High risk	As reported in table 2, overall 73/180 participants in the intervention group and 83/164 participants in the control group completed the study (> 5% lost to follow‐up, with differences between groups). Some reasons for discontinuations (adverse events) seemed to be related to the treatment allocation
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	Unclear risk	There was no evidence of different baseline characteristics, or different non‐randomised co‐interventions between groups. Funding and conflicts of interest were not reported