Three Times Weekly Dosing of Daprodustat versus Conventional Epoetin for Treatment of Anemia in Hemodialysis Patients: ASCEND-TD: A Phase 3 Randomized, Double-Blind, Noninferiority Trial

Abstract

Background and objectives: Daprodustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) being investigated for the treatment of anemia of CKD. In this noninferiority trial, we compared daprodustat administered three times weekly with epoetin alfa (epoetin) in patients on prevalent hemodialysis switching from a prior erythropoiesis-stimulating agent (ESA).

Design, setting, participants, & measurements: Patients on hemodialysis with a baseline hemoglobin of 8-11.5 g/dl receiving an ESA were randomized 2:1 to daprodustat three times weekly (n=270) or conventional epoetin (n=137) for 52 weeks. Dosing algorithms aimed to maintain hemoglobin between 10 and 11 g/dl. The primary end point was mean change in hemoglobin from baseline to the average during the evaluation period (weeks 28-52). The principal secondary end point was average monthly intravenous iron dose. Other secondary end points included BP and hemoglobin variability.

Results: Daprodustat three times weekly was noninferior to epoetin for mean change in hemoglobin (model-adjusted mean treatment difference [daprodustat-epoetin], -0.05; 95% confidence interval, -0.21 to 0.10). During the evaluation period, mean (SD) hemoglobin values were 10.45 (0.55) and 10.51 (0.85) g/dl for daprodustat and epoetin groups, respectively. Responders (defined as mean hemoglobin during the evaluation period in the analysis range of 10 to 11.5 g/dl) were 80% in the daprodustat group versus 64% in the epoetin group. Proportionately fewer participants in the daprodustat group versus the epoetin group had hemoglobin values either below 10 g/dl or above 11.5 g/dl during the evaluation period. Mean monthly intravenous iron use was not significantly lower with daprodustat versus epoetin. The effect on BP was similar between groups. The percentage of treatment-emergent adverse events was similar between daprodustat (75%) and epoetin (79%).

Conclusions: Daprodustat was noninferior to epoetin in hemoglobin response and was generally well tolerated.

Clinical trial registry name and registration number: Anemia Studies in Chronic Kidney Disease: Erythropoiesis via a Novel Prolyl Hydroxylase Inhibitor Daprodustat-Three Times Weekly Dosing in Dialysis (ASCEND-TD), NCT03400033.

Keywords: anemia; blood pressure; chronic kidney disease; clinical trial; epoetin; erythropoietin; hemodialysis; hemoglobin; hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI); randomized controlled trials.

Graphical abstract

Figure 1.

Participant disposition. ^aParticipants could have more than one reason for screen failure, so the number of reasons for screen failure may sum to more than the participant total. ^bThe randomized (intent-to-treat) population is defined as all randomized participants. ^cPrimary reason. Participants may have only one primary reason for study withdrawal/study treatment discontinuation. Participants whose primary reason for study treatment discontinuation was protocol-defined stopping criteria may have also reported an adverse event (AE) leading to permanent discontinuation of study treatment; for example, participants who met the stopping criterion of a cancer event may have also reported a cancer-related AE. ^dParticipants who completed the study include (1) those who completed the 52-week treatment, (2) those who continued in the study to week 52 after permanently discontinuing the study treatment, and (3) those who died while in the study.

Figure 2.

Mean postrandomization hemoglobin data by visit showed that hemoglobin levels were similarly stable between groups (intent-to-treat population). Error bars indicate 95% confidence intervals (95% CIs). Baseline and visits on or before day 1 include only pretreatment values. Postrandomization values include all available observed and imputed hemoglobin values (on and off treatment). The dashed vertical lines represent the evaluation period (week 28 to week 52). The horizontal reference lines represent the hemoglobin analysis range (10–11.5 g/dl). The hemoglobin target range for dose changes is 10–11 g/dl. Fup, follow-up; Scr, screening; Wk, week.

Figure 3.

Daprodustat was associated with improved iron kinetics compared with epoetin. Change over time in (A) total iron, (B) total iron binding capacity, (C) transferrin saturation, (D) ferritin, and (E) hepcidin by visit (intent-to-treat population). Error bars indicate 95% CIs. Baseline and visits on or before day 1 include only pretreatment values. The dashed vertical lines represent the evaluation period (week 28 to week 52). EOT, end of trial.

Figure 4.

Mean evaluable hemoglobin and median most recent daprodustat and epoetin dose by visit were stable throughout the trial in both groups (intent-to-treat population). Error bars indicate first and third quartiles.