Table 2.

Study treatments and management strategies

Study treatments	Initiation	Protocol-specified dose adjustment algorithma
Daprodustat	● Starting dose 4–12 mg based on prior ESA dose at randomization ● Nine dose steps available (1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg, 16 mg and 24 mg)	● Dose adjustments (i.e. increase, decrease, maintain, or withhold if Hb ≥ 12 g/dL) are implemented by the IRT system to maintain Hb concentrations within the range of 10–11 g/dLb - Hb value measured at least every 4 weeks (Day 1 through Week 52) or at least every 12 weeks (post-Week 52 until the end of treatment) - From Week 52 onward, additional 4-weekly study visits to check Hb and dispense randomized treatment are required if 1. Hb is outside the target range 2. Dose has changed 3. A moderate CYP2C8 inhibitor has been started/stopped/changed 4. Participant has transitioned to dialysis 5. Participant has changed from HD to PD 6. Per investigator discretion allows for an early dose adjustment
Darbepoetin alfa	● Starting dose based on patients’ prior ESA dose (converted to darbepoetin alfa) and Hb at the time of randomization ● Pre-defined dose-stepsc: stepwise increases or decreases in weekly dose from 20 to 33% for most steps (20–400 µg as a total 4-weekly dose; doses ≤150 µg are administered every 4 weeks; 200 µg and 300 µg are divided and administered every 2 weeks; 400 µg is divided and administered once a week)
Iron	● Started if TSAT is ≤20% and/or ferritin is ≤100 ng/mL - Type of iron, dose and route is determined by the investigator based on local clinical practice and the patient's iron status	● Iron must be stopped if values of ferritin > 800 ng/mL and TSAT > 20% or if TSAT > 40% are present - Investigators are to be guided by local/regional guidelines and may stop administration of iron at a lower ferritin or TSAT level if clinically indicated - The framework for starting and stopping iron is based on a review of global and regional iron guidelines, as well as input from the ASCEND Steering Committees
The Hb and Iron Subcommittee of the Steering Committee is monitoring blinded patient Hb and iron data during the trial. Assessment of the quality of clinical care provided to patients was monitored by the Standard of Care Subcommittee of the Steering Committee.

ESA, erythropoiesis-stimulating agent; Hb, haemoglobin; HD, haemodialysis; IRT, interactive response technology; IV, intravenous; PD, peritoneal dialysis; TSAT, transferrin saturation.

^aDuring the trial, overrides of the dose adjustment algorithm for exceptional circumstances associated with a safety concern are permitted if approved by the sponsor.

^bBased on the HemoCue Hb value.

^cComplete details of darbepoetin alfa dose steps (dose and frequency) are outlined in Supplementary data, Table S5.