ASCEND‐NHQ 2021.

Study characteristics
Methods	Study design: parallel RCT Time frame: not reported Duration of follow‐up: 28‐week
Participants	General information Setting: multicentre (168 sites) Country: international (USA, Argentina, Australia, Austria, Brazil, Canada, France, Italy, Korea, Mexico, Poland, Romania, Russian Federation, Spain, UK) Inclusion criteria: ≥ 18 years; CKD stages 3, 4, or 5 defined by eGFR using the CKD‐EPI formula; stable Hb from 8.5 to 10.5 g/dL at screening visit (week ‐4) and from 8.5 to 10.0 g/dL at randomisation (day 1); may receive up to one IV iron dose within the 8 weeks prior to screening and NO IV iron use between screening visit and randomisation (day 1); males and female; not pregnant, not breastfeeding, not a woman of childbearing potential (WOCBP) OR WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 4 weeks after the last dose of study treatment; capable of giving signed informed consent Exclusion criteria: on dialysis or clinical evidence of impending need to initiate dialysis within 180 days after randomisation (day 1); planned living‐related or living‐unrelated kidney transplant within 28 weeks after randomisation (day 1); TSAT < 15% (screening only); ferritin < 50 ng/mL (screening only); history of rHuEPO or rHuEPO analogue use within the 8 weeks prior to screening and rHuEPO use between screening and randomisation (day 1); history of transfusion within the 8 weeks prior to screening and transfusion between screening and randomisation (day 1); history of bone marrow aplasia or PRCA; megaloblastic anaemia (untreated pernicious anaemia and folate deficiency), thalassaemia major, sickle cell disease or myelodysplastic syndrome; evidence of actively bleeding gastric, duodenal, or oesophageal ulcer disease or clinically significant GI bleeding ≤ 8 weeks prior to screening through to randomisation (day 1); history of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product; use of strong inhibitor of CYP2C8 (e.g. gemfibrozil) or strong inducers of CYP2C8 (e.g. rifampin/rifampicin); ferric citrate use within 4 weeks prior to randomisation (day 1); use of other investigational agent or device prior to screening through to randomisation (day 1); any prior treatment with daprodustat for a treatment duration of > 30 days; MI or acute coronary syndrome within the 8 weeks prior to screening through to randomisation (day 1); stroke or TIA within the 8 weeks prior to screening through to randomisation (day 1); chronic NYHA class IV HF; QTcB > 500 msec or QTcB > 530 msec in participants with bundle branch block; ALT > 2 times ULN at screening (week ‐4); bilirubin > 1.5 times ULN at screening (week ‐4); 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 > 3 cm; any other condition, clinical or laboratory abnormality, or examination finding that the investigator considers would put the participant at unacceptable risk, which may affect study compliance or prevent understanding of the aims or investigational procedures or possible consequences of the study; current uncontrolled hypertension as determined by the investigator Target Hb: 11 to 12 g/dL and proportion with ≥ 1 g/dL increase in Hb Baseline characteristics CKD stage: CKD stages 3, 4, or 5 Number (randomised/analysed): overall (614/not reported); treatment group (not reported); control group (not reported) Mean age ± SD (years): not reported Sex (M, %): not reported Time on dialysis: not reported eGFR: not reported Comorbidities CV disease: not reported Heart disease: not reported Hypertension: not reported Diabetes (number, %): not reported Prior agents used (number, %) ESA: treatment group (0); control group (0)
Interventions	Treatment group Daprodustat (GSK1278863) (oral): once/day Control group Placebo Co‐interventions Iron therapy will be administered if ferritin is < 50 ng/mL and/or TSAT is < 15%
Outcomes	Primary outcome Mean change from baseline in Hb up to evaluation period (up to week 28) Secondary outcomes Percentage of participants with Hb increase of ≥ 1.0 g/dL from baseline up to week 28 Mean change from baseline in SF‐36 questionnaire vitality domain score (baseline and week 28) Percentage of Hb responders (baseline and up to week 28) Percentage time Hb in range (up to week 28) Mean change from baseline for additional Hb parameters [(baseline and up to week 28) Time to rescue (up to week 28) Mean change from baseline in CKD ‐ Anemia Questionnaire score (up to week 28) Change from baseline in Patient Global Impression of Severity (PGI‐S) score (baseline and up to week 28) Mean change from baseline in SF‐36 questionnaire vitality domain score (fatigue) (baseline and up to week 28) Mean change from baseline in SF‐36 questionnaire physical function domain score (baseline and up to week 28) Percentage of participants currently employed on the WPAI, anaemia symptoms, clinical practice version scale (up to week 28) Change from baseline in percent mean hours work time missed on the WPAI anaemia symptoms ( baseline and up to week 28) CPV change from baseline in percent impaired on the WPAI anaemia symptoms, clinical practice version questionnaire (baseline and up to week 28] Change from baseline in overall percent work impairment on the WPAI anaemia symptoms, clinical practice version questionnaire ( baseline and up to week 28) Change from baseline in percent activity impairment on the WPAI anaemia symptoms, clinical practice version questionnaire (baseline and at week 28) Change from baseline in EQ‐5D‐5L score (baseline and up to week 28) Change from baseline EQ‐VAS score (baseline and up to week 28) Change from baseline in SBP, DBP and MAP at week 28 (baseline and at week 28) Percentage of participants with at least one BP exacerbation (up to week 28) Incidences and severity of adverse events and serious adverse events (up to week 32)
Notes	Funding: GlaxoSmithKline Conflicts of interest: not reported Abstract‐only publication
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	Unclear risk	Quote: "Double blind"
Blinding of outcome assessment (detection bias) All outcomes	High risk	Objective and subjective outcomes were reported
Incomplete outcome data (attrition bias) All outcomes	High risk	Not reported in sufficient detail to perform adjudication
Selective reporting (reporting bias)	High risk	Clinically‐relevant outcomes that would be expected for this type of intervention were not reported
Other bias	High risk	Baseline characteristics, or different non‐randomised co‐interventions were not reported between groups Funder was likely to influence data analysis and study reporting or interpretation Conflicts of interest were not reported