Nangaku 2021.

Study characteristics
Methods	Study design: RCT, 2‐arm, parallel, phase III Time frame: not reported Duration of follow‐up: 52 weeks ‐ data were reported at 24 weeks (preliminary analysis)
Participants	General information Setting: multicentre (number of sites not reported) Country: Japan Inclusion criteria: CKD receiving HD or HDF 3 times/week for more than 12 weeks prior to the screening period, excluding receiving home dialysis or combination of PD; treated with ESAs for the recent 8 weeks prior to the screening period; mean of the two screening Hb levels closest in time to the baseline visit is ≥ 9.5 g/dL and ≤ 12.0 g/dL; fluctuation between the 2 Hb levels closest in time to the baseline visit during the screening period < 1.5 g/dL; serum ferritin ≥ 100 ng/mL, or TSAT ≥ 20% during the screening period; folate and vitamin B12 ≥ LLN during the screening period Exclusion criteria: anaemia due to a main cause other than CKD: sickle cell disease, myelodysplastic syndrome, bone marrow fibrosis, haematologic malignancy, haemolytic anaemia, thalassaemia, or PRCA; active bleeding or recent blood loss within 8 weeks prior to the screening period; RBC transfusion within 8 weeks prior to the screening period; received testosterone enanthate or mepitiostane within 8 weeks prior to the screening period; AST, ALT, or total bilirubin >2.5 times ULN during the screening period; uncontrolled hypertension (DBP > 110 mm Hg or SBP >180 mm Hg) at the first day of the screening period and day 1; ophthalmic examinations during the screening period correspond to either of the following criteria; 1) no available fundal findings, 2) findings indicating the presence of active fundal disease; severe heart failure (NYHA class IV); cerebrovascular disorder or acute coronary syndrome (hospitalisation due to unstable angina or MI), requiring hospitalisation due to urgent percutaneous intervention for coronary or heart failure within 12 weeks prior to the screening period; current or history of malignancy; history of malignancy with no recurrence for the recent 5 years is not an exclusion criterion; new onset or recurrent event of DVT or pulmonary embolism within 12 weeks prior to the screening period; current or history of haemosiderosis or haemochromatosis; history of prior organ transplantation or scheduled organ transplant, or prior transplantation of hematopoietic stem cell or bone marrow; males and females of childbearing potential who are unwilling to use an acceptable method of contraception during the designated period (males: during the study and 90 days after the last dose; females: during study and 30 days after the last dose); pregnant or breast feeding, or are predicted to be pregnant Target Hb: 10 to 12 g/dL Baseline characteristics CKD stage: HD Number (randomised/analysed): treatment group (162/120); control group (161/135) Mean age ± SD (years): treatment group (66.0 ± 11.3); control group (64.9 ± 11.7) Sex (M, %): treatment group (104, 64.2%); control group (109, 67.7%) Time on dialysis (years): treatment group (7.4 ± 6.7); control group (7.6 ± 7.6) eGFR: not reported Comorbidities CV disease: not reported Heart disease: not reported Hypertension: treatment group (152/162); control group (147/161) Diabetes (number, %): treatment group (35/162); control group (49/161) Prior agents used (number, %) Epoetin: treatment group (49/162); control group (53/161) Darbepoetin alfa: treatment group (97/162); control group (90/161) EBP: treatment group (16/162); control group (18/161)
Interventions	Treatment group (medium dose)* Vadadustat (MT‐6548), initial dose 300 mg daily, orally, then doses were adjusted to achieve a Hb target within 150–600 mg (mean dose 375 mg) Control group Darbepoetin alfa, intravenous administration Co‐interventions Not reported *Note: assessed as medium dose according to NDD‐CKD 2020
Outcomes	Primary outcomes Average Hb at weeks 20 and 24 Secondary outcomes Iron parameters were measured during the study period Safety was assessed up to 24 weeks Mean Hb weeks 48 and 52 Hb level at each assessment time point (up to week 52) Proportion with Hb level at each assessment time point within the target range (up to week 52)
Notes	Funding: Mitsubishi Tanabe Pharma Corporation Conflicts of interest: 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. It was not possible to assess if there was imbalance between intervention groups
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment was not reported in sufficient detail to permit judgement. It was not possible to assess if there was imbalance between intervention groups
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: "Double‐blind phase" Although author reported that the study used a double‐blind design, information about blinding of participants and investigators were not clearly stated. However, since interventions were different, it was possible that investigators and/or participants were aware of treatment allocation. Possible deviations from the intended intervention that arose from the trial context were not reported
Blinding of outcome assessment (detection bias) All outcomes	High risk	Outcomes were principally laboratory measures and were at low risk of detection bias regardless of whether blinding of investigators or outcome assessors occurred. However, some outcomes (adverse events) could be influenced by knowledge of treatment assignment
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Quote: "Of the 323 randomized patients, 120 and 135 completed the 52‐week treatment period in the vadadustat and darbepoetin alfa groups, respectively." Reasons for discontinuation were provided and some of them were related to the intervention ITT analyses were performed for some outcomes
Selective reporting (reporting bias)	High risk	Not all of the planned outcomes on ClincialTrials.gov have been measured and reported on in the final report. No reasoning provided Clinically‐relevant outcomes that would be expected for this type of intervention were not reported
Other bias	High risk	Similar baseline characteristics, or different non‐randomised co‐interventions were reported between groups Funding was reported and authors' disclosure were not reported Funder was likely to influence data analysis and study reporting or interpretation