PRO2TECT‐CONVERSION 2021.

Study characteristics
Methods	Study design: phase III, parallel RCT Time frame: not reported Duration of follow‐up: 53 weeks + 4 weeks of follow‐up
Participants	General information Setting: multicentre (503 sites) Country: multinational (Argentina, Australia, Austria, Brazil, Bulgaria, Canada, Chile, Colombia, Czech Republic, France, Germany, Hungary, Israel, Italy, Korea, Malaysia, Mexico, New Zealand, Poland, Puerto Rico, Romania, Russia, Serbia, Slovakia, South Africa, Spain, Turkey, Ukraine, UK; USA) Inclusion criteria: ≥ 18 years; diagnosis of CKD with an eGFR ≤ 60 mL/min/1.73 m² at screening and not expected to start dialysis within 6 months of screening; currently maintained on ESA therapy, with a dose received within 6 weeks prior to or during screening; mean screening Hb between 8.0 and 11.0 g/dL in the USA and between 9.0 and 12.0 g/dL outside of the USA Exclusion criteria: uncontrolled hypertension; severe heart failure at screening (NYHA class IV); acute coronary syndrome (hospitalisation for unstable angina or MI), surgical or percutaneous intervention for coronary, cerebrovascular, or peripheral artery disease (aortic or lower extremity), surgical or percutaneous valvular replacement or repair, sustained ventricular tachycardia, hospitalisation for heart failure, or stroke within 12 weeks prior to or during screening; hypersensitivity to darbepoetin or vadadustat or to any of their excipients Target Hb: USA: 10 to 11 g/dL non‐USA: 10 to 12 g/dL Baseline characteristics CKD stage: CKD stages 3 to 5 Number (randomised/analysed): treatment group (862/811); control group (863/811) Mean age ± SD (years): treatment group (67.3 ± 13.1); control group (66.5 ± 13.5) Sex (M, %): treatment group (394, 45.7%); control group (375, 43.6) Time on dialysis: not applicable Mean eGFR ± SD (mL/min/1.73 m²): treatment group (22.6 ± 11.6); control group (22.8 ± 12.0) Comorbidities CV disease: treatment group (375/862); control group (402/863) Heart disease: not reported Hypertension: treatment group (462/862); control group (466/863) Diabetes: treatment group (517/862); control group (518/863) Prior agents used (number, %) IV iron: treatment group (43/862); control group (49/863) ESA: treatment group (833/862); control group (843/863)
Interventions	Treatment group (medium dose)* Vadadustat (AKB‐6548) (oral): dose staring with 300 mg once/day, with flexible titration 150 to 600 mg/day based on Hb level (maximum 600 mg) Control group Darbepoetin alfa (Aranesp) (SC) Co‐interventions Not reported *Note: assessed as medium dose according to NDD‐CKD 2020
Outcomes	Primary outcomes Mean change in Hb between baseline and the primary evaluation period (week 36) MACE from baseline visit to end of study (event‐driven, minimum 1 year) Secondary outcomes Mean change in Hb value between baseline and the secondary evaluation period (week 52) Proportion with Hb values within the target range during the primary evaluation period (week 36) Adverse events and serious adverse events to end of study (event‐driven, minimum 1 year) Proportion of time with Hb values within the target range during the primary evaluation period (week 36) Proportion of time with Hb values within the target range during the secondary evaluation period ( week 52) Proportion with Hb values within the target range during the secondary evaluation period (week 52) Proportion with Hb increase of > 1.0 g/dL from baseline to end of study (event‐driven, minimum 36 weeks) Time to achieve Hb increase of 1.0 g/dL from baseline visit to end of study (event‐driven, minimum 36 weeks) Mean change in Hb between baseline (mean pretreatment Hb) and the primary evaluation period (mean Hb from weeks 24 to 36) stratified pre‐baseline ESA exposure (week 36) Proportion receiving IV iron therapy (week 52) Mean monthly dose of IV elemental iron administered in subjects who have received IV iron (week 52) Proportion of subjects receiving RBC transfusion(s) (week 52)
Notes	Funding: Akebia Therapeutics Conflicts of interest: "GMC reports grants from NIDDK and Amgen and personal fees from Akebia Therapeutics, Inc., Satellite Healthcare, Ardelyx, AstraZeneca, Baxter, Cricket, DiaMedica, Gilead, Reata, Sanifit, Vertex, Angion, Bayer, and ReCor. PEP reports personal fees from Akebia Therapeutics, Inc., Astra‐Zeneca, Bayer, Reata, Gilead, Corvidia, FibroGen, Tricida, and Ardelyx. PEP’s institution, Renal Associates (PA), has received support from multiple pharmaceutical companies, including Akebia Therapeutics, Inc. RA reports personal fees from Akebia Therapeutics, Inc., Relypsa Inc., a Vifor Pharma Group Company, AbbVie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Gilead, GlaxoSmithKline, Johnson & Johnson, Merck, Novartis, Sandoz, ZS Pharma, Takeda, Sanofi, Reata, Iron‐wood Pharmaceuticals, Otsuka, OPKO Health, and Bird Rock Bio. RA has also served as associate editor of the American Journal of Nephrology and Nephrology, Dialysis, Transplantation and has received research grants from the USA Veterans Administration and the National Institutes of Health. GAB reports grants, personal fees, and non financial support from Akebia Therapeutics, Inc., Keryx Biopharmaceuticals, Inc., Astra‐Zeneca, Kirin, and Ardelyx, Inc., as well as personal fees from U.S. Renal Care. YMKF reports personal fees and other from Akebia Therapeutics, Inc. AGJ has nothing to disclose. MJK reports personal fees from Akebia Therapeutics, Inc., FibroGen, Inc., and Micelle BioPharma, Inc. WL was an employee of Akebia Therapeutics, Inc., during the conduct of this study. ZK was an employee of Akebia Therapeutics, Inc., during the conduct of this study. EFL reports grants from Akebia Therapeutics, Inc. KM reports grants from NIH and personal fees from Akebia Therapeutics, Inc.; KM also reports grants and personal fees from Kyowa Kirin and Fukuda Denshi. PAM reports personal fees from Akebia Therapeutics, Inc. PSP reports personal fees from Akebia Therapeutics, Inc.; PSP was also a member of an advisory committee for Vifor Pharma and was a member of the data monitoring committee for the CREDANCE trial for Janssen. JW and KAW are employees of Statistics Collaborative, Inc., which received fees from Akebia Therapeutics, Inc. for conduction of study analyses. CT and TL are employees of Firma Clinical Research, which received fees from Akebia Therapeutics, Inc. for data analyses. MJS was a member of the steering committee for Akebia Therapeutics, Inc.; MJS also reports personal fees from Bayer and Carurian. DLV is an employee of Akebia Therapeutics, Inc. WCW reports personal fees from Akebia Therapeutics, Inc., Amgen, and Relypsa. and personal fees and non financial support from AstraZeneca, Bayer, Daiichi‐Sankyo, Janssen, Merck, and Vifor Fresenius Medical Care Renal Pharma. KUE reports grants from Amgen, Astra Zeneca, Bayer, Fresenius, Genzyme, and Vifor and personal fees from Akebia Therapeutics, Inc., Bayer, and Boehringer Ingelheim."
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. There were no imbalance between intervention groups
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment was not reported in sufficient detail to permit judgement. There were no imbalance between intervention groups
Blinding of participants and personnel (performance bias) All outcomes	High risk	Quote: "Open label"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "An independent clinical end‐points committee, whose members were unaware of the treatment assignments, adjudicated MACE."
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	In the pooled data from NCT02648347 + NCT02680574 3471/3476 participants were included in the analyses Some outcomes were reported in 821/879 participants in the intervention groups and 811/872 participants in the control group
Selective reporting (reporting bias)	Low risk	All planned outcomes on ClincialTrials.gov were measured and reported Clinically‐relevant outcomes that would be expected for this type of intervention (death and CV events) were reported
Other bias	High risk	There was no evidence of different baseline characteristics, or different non‐randomised co‐interventions between groups Funding and authors' disclosure were reported Funder was likely to influence data analysis and study reporting or interpretation