ASCEND‐D 2021.

Study characteristics
Methods	Study design: phase 3, parallel RCT Time frame: November 2016 to August 2018 Duration of follow‐up: 52 weeks + 6 weeks follow‐up
Participants	General information Setting: multicentre (431 sites) Country: international (USA, Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Czech Republic, Denmark, Estonia, France, Germany, Greece, Hungary, India, Italy, Korea, Malaysia, Mexico, Netherlands, New Zealand, Norway, Poland, Portugal, Romania, Russian Federation, Singapore, South Africa, Spain, Sweden, Taiwan, Turkey, Ukraine, UK) Inclusion criteria: Aged 18 to 99 years; use of any approved ESA for at least the 6 weeks prior to screening and between screening and randomisation; Hb 8 to 11 g/dL and receiving at least the minimum ESA dose; on dialysis > 90 days prior to screening and continuing on the same mode of dialysis from screening (week 8) through to randomisation (day 1) (HD ≥ 2 times/week and PD ≥ 5 times/week, home HD ≥ 2 times/week); ≥ 80% and ≤ 120% compliance with placebo during run‐in period; informed consent (screening only); capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in this protocol Exclusion criteria: planned living‐related or living‐unrelated kidney transplant within 52 weeks after study start (day 1); ferritin ≤100 ng/mL (≤100 µg/L at screening); TSAT ≤ 20% at screening; history of bone marrow aplasia or PRCA; untreated pernicious anaemia, thalassaemia major, sickle cell disease or myelodysplastic syndrome; evidence of actively bleeding gastric, duodenal, or oesophageal ulcer disease or clinically significant GI bleeding ≤ 4 weeks prior to screening through to randomisation (day 1); MI or acute coronary syndrome ≤ 4 weeks prior to screening through to randomisation (day 1); stroke or TIA ≤ 4 weeks prior to screening through to randomisation (day 1); chronic NYHA Class IV HF; current uncontrolled hypertension as determined by the investigator that would contraindicate the use of rHuEPO; QTcB (day 1) >500 msec, or QTcB > 530 msec in subjects with bundle branch block; ALT >2 times ULN at screening; bilirubin > 1.5 times ULN at screening; current unstable liver or biliary disease per investigator assessment, generally defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, persistent jaundice, or cirrhosis; history of malignancy within the 2 years prior to screening through to randomisation (day 1) or currently receiving treatment for cancer, or complex kidney cyst; history of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product, or epoetin alfa or darbepoetin alfa; use of strong inhibitors of CYP2C8 (e.g. gemfibrozil) or strong inducers of CYP2C8 (e.g. rifampin/rifampicin); use of other investigational agent or device prior to screening through to randomisation (day 1); any prior treatment with daprodustat for treatment duration of > 30 days, subject is pregnant, breastfeeding, or subject is of reproductive potential and does not agree to follow one of the contraceptive options listed in the List of Highly Effective Methods for Avoiding Pregnancy; any other condition, clinical or laboratory abnormality, or examination finding that the investigator considers would put the subject at unacceptable risk, which may affect study compliance (e.g. intolerance to rHuEPO) or prevent understanding of the aims or investigational procedures or possible consequences of the study Target Hb: 10 to 11 g/dL Baseline characteristics CKD stage HD: treatment group (1316, 88.5%); control group (1308, 88.6%) PD: treatment group (171, 11.5%); control group (169, 11.4%) Number (randomised/analysed): treatment group (1487/1487); control group (1477/1477) Mean age ± SD (years): not reported Sex (M, %): treatment group (851, 57.2%); control group (847, 57.3%) Time on dialysis: not reported eGFR: not reported Comorbidities CV disease: treatment group (666/1478); control group (665/1477) Heart disease: not reported Hypertension: not reported Diabetes: treatment group (615/1478); control group (617/1477) Prior agents used (number, %) ESA: treatment group (1478/1478); control group (1477/1477)
Interventions	Treatment group (medium dose)* Daprodustat (oral): once/day The starting dose of daprodustat was between 4 and 12 mg daily, according to the patient’s previous ESA dose, and stepped changes in the dose from 1 to 24 mg were available for dose adjustments Control group rHuEPO: participants on PD will be administered SC darbepoetin alfa and participants on HD will be administered IV epoetin alfa Co‐interventions Supplemental iron therapy if ferritin is ≤ 100 ng/mL or TSAT is ≤ 20%; investigator will choose the route of administration and dose of iron *Note: dose assessed according to Meadowcroft 2019
Outcomes	Primary outcomes Time to the first occurrence of adjudicated MACE to end of study (event‐driven, up to 3.3 years) Mean change in Hb between baseline and efficacy period (mean over weeks 28 to 52) Secondary outcomes Time to first occurrence of adjudicated MACE or a thromboembolic event (vascular access thrombosis, symptomatic DVT or symptomatic pulmonary embolism) (event‐driven, up to 3.3 years) Time to first occurrence of adjudicated MACE or a hospitalisation for HF (event‐driven, up to 3.3 years) Average monthly IV iron dose mg/subject up to and including week 52 Time to first occurrence of death (any cause), CV death, fatal or non‐fatal MI, fatal or non‐fatal stroke (event‐driven, up to 3.3 years) Time to first occurrence of MACE or hospitalisation for HF (recurrent events analysis) (event‐driven, up to 3.3 years) Time to first occurrence of CV death or non‐fatal MI incidences (event‐driven, up to 3.3 years) Time to first occurrence of all‐cause hospitalisation (event‐driven, up to 3.3 years) Time to first occurrence of all‐cause hospital re‐admission within 30 days (event‐driven, up to 3.3 years) Time to first occurrence of MACE or hospitalisation for HF or thromboembolic events (event‐driven, up to 3.3 years) Time to first occurrence of hospitalisation for HF (event‐driven, up to 3.3 years) Time to first occurrence of thromboembolic events (event‐driven, up to 3.3 years) Hb change from baseline to week 52 Percentage of responders, defined as mean Hb within Hb analysis range to week 52 Number of responders, defined as mean Hb within Hb analysis range to week 52 Percentage time for which Hb is in analysis range during the efficacy period (week 28 to 52) and during the maintenance period (week 28 to end of trial) Change from baseline in SBP, DBP and MAP at week 52 and at end of treatment Number of BP exacerbation events/100 patient years (event‐driven, up to 3.3 years) Number of participants with least one BP exacerbation event during study (event‐driven, up to 3.3 years) Percentage of participants with least one BP exacerbation event during study (event‐driven, up to 3.3 years) Time to stopping randomised treatment due to meeting rescue criteria (event‐driven, up to 3.3 years) Mean change in SF‐36 HRQoL scores between baseline and weeks 8, 12, 28, 52, of particular interest are the changes from baseline in the vitality and physical functioning domains at weeks 28 and 52 Change from baseline in EQ‐5D‐5L score up to week 52 Change from baseline in EQ‐5D‐5L VAS at week 52 Change from baseline in PGI‐S at weeks 8, 12, 28 and 52
Notes	Funding: GlaxoSmithKline Conflicts of interest: "A.K.S. reports consultancy fees from GlaxoSmithKline and stock in Gilead. K.C. reports consultancy fees from GlaxoSmithKline. V.J. reports consultancy fees from GlaxoSmithKline. K.L.J. reports consultancy fees from GlaxoSmithKline. R.D.L. reports grants and personal fees from Bristol‐Myers Squibb and Pfizer, personal fees from Boehringer Ingelheim and Bayer AG, and research grants from Amgen Inc., GlaxoSmithKline, Medtronic PLC and Sanofi Aventis. I.C.M.D. reports research grants, consultancy fees and honoraria from GlaxoSmithKline and Vifor Pharma. J.M.M. reports personal fees from Abbott, Hickma, Sun Pharmaceuticals and Servier, and that his employer received fees from Alnylam Amgen, AstraZeneca, Bayer, Bristol‐Myers Squibb, Cardurion, Cytokinetics, Dal‐Cor, GlaxoSmithKline, Ionis, Novartis, Pfizer and Theracos. G.T.O. reports personal fees from Roche Mexico, Johnson & Johnson, Vifor and AbbVie. V.P. reports consultancy agreements with AbbVie, Bayer, Boehringer Ingelheim, Chinook, GlaxoSmithKline, Janssen, Pfizer, Astellas, AstraZeneca, Bayer, Baxter, Bristol‐Myers Squibb, Durect, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Merck, Mitsubishi Tanabe, Mundipharma, Novartis, Novo Nordisk, Pharmalink, Relypsa, Retrophin, Roche, Sanofi, Servier and Vitae; research funding from Pfizer (supplied drug and seed funding for TESTING trial) and GlaxoSmithKline; honoraria from AbbVie, Bayer, Boehringer Ingelheim, GlaxoSmithKline, Janssen, Pfizer, Astellas, AstraZeneca, Bayer, Baxter, Bristol‐Myers Squibb, Chinook, Durect, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Merck, Mitsubishi, Tanabe, Mundipharma, Novartis, Novo Nordisk, Pharmalink, Relypsa, Retrophin, Roche, Sanofi, Servier and Vitae; scientific advisor or membership: serving/served on steering committees for trials funded by AbbVie, AstraZeneca, Bayer, Boehringer Ingelheim, Chinook, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Novartis, Novo Nordisk and Retrophin; other interests/relationships reported include: Board Director: George Clinical, George Institute, Garvan Institute, Mindgardens Network, Childrens Cancer Institute and Victor Chang Cardiac Research Institute. S.S. reports grants and consultancy fees from Alnylam, AstraZeneca, Bayer, Bristol‐MyersSquibb, Cytokinetics, Gilead, GlaxoSmithKline, Lilly, MyoKardia, Novartis, Respicardia, Sanofi Pasteur and Theracos grants from Bellerophon, Celladon, Eidos, Ionis, Lone Star Heart, Mesoblast, NIH/NHLBI and Neurotronik, and consultancy fees from Akros, Amgen, Arena, Cardior, Cardurion, Corvia, Daiichi‐Sankyo, Ironwood, Merck Sharp Dohme, Roche, Takeda, Quantum Genetics, AoBiome, Janssen, Cardiac Dimensions, Tenaya, Dinaqor, Tremeau, CellProThera and Moderna. C.W. reports consultancy fees from Akebia, Astellas, AstraZeneca, Bayer, Chiesi, FMC Idorsia, Mundipharma, GlaxoSmithKline, Merck Sharp Dohme, Reata, Gilead, Tricida, Vifor, Lilly and Takeda, and grants and consultancy fees from Boehringer Ingelheim, Sanofi Genzyme and Shire. S.S.W. reports personal fees from Public Health Advocacy Institute, CVS, Roth Capital Partners, Kantum Pharma, Mallinckrodt, Wolters Kluewer, GE Health Care, GlaxoSmithKline, Mass Medical International, Barron and Budd (versus Fresenius), JNJ, Venbio, Strataca, Takeda, Cerus, Pfizer, Bunch and James, Harvard Clinical Research Institute (aka Baim), Oxidien, Sironax, Metro Biotechnology, Biomarin and Bain, and grants and personal fees from Allena Pharmaceuticals. D.C.W. reports honoraria and/or consultancy fees from AstraZeneca, Amgen, Astellas, Bayer, Boehringer Ingelheim, GlaxoSmithKline, Jansen, Merck Sharp and Dohme, Mundipharma, Napp, Pharmacosmos, Reata, Tricida and Vifor Fresenius. A.W. reports personal fees from Roche, Bayer, Fresenius and Medice. A.R.C., A.B., A.M.M., B.C., L.K. and R.D. are employees of and stockholders in GlaxoSmithKline."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Patients were stratified by dialysis type of HD [including hemodiafiltration (HDF) and hemofiltration (HF)] or PDg, by region, and by participation in the ambulatory blood pressure (BP) monitoring sub‐study. Following stratification, patients were randomized 1:1 to receive oral daprodustat or rhEPO control. A central randomisation approach was used to protect against selection bias due to the open‐label design." Quote: "Investigators used an interactive voice‐ or Web‐response system to determine treatment assignments."
Allocation concealment (selection bias)	Low risk	Quote: "Investigators used an interactive voice‐ or Web‐response system to determine treatment assignments."
Blinding of participants and personnel (performance bias) All outcomes	High risk	Quote: "Open label"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "The safety of trial patients was overseen by an independent data monitoring." Not clearly stated if the data monitoring was blinded to the treatment assigned
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	ITT population Quote: "Eight patients (5 in the daprodustat group and 3 in the ESA group) were excluded from the safety analyses because they did not receive the randomised treatment"
Selective reporting (reporting bias)	Low risk	All of the planned outcomes on ClincialTrials.gov were measured and reported on in the final report Clinically‐relevant outcomes that would be expected for this type of intervention (death and CV events) were reported
Other bias	High risk	Quote: "The trial drug was stopped prematurely." Quote: "The sponsor conducted the analysis." Similar baseline characteristics, or different non‐randomised co‐interventions were reported between groups Funder influenced data analysis and study reporting or interpretation. Conflicts of interest were reported