Efficacy and Safety of Daprodustat Compared with Darbepoetin Alfa in Japanese Hemodialysis Patients with Anemia: A Randomized, Double-Blind, Phase 3 Trial

Abstract

Background and objectives: Daprodustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis and regulates genes related to iron metabolism. The efficacy (noninferiority) and safety of daprodustat compared with standard therapy (darbepoetin alfa) was evaluated.

Design, setting, participants, & measurements: This was a randomized, phase 3, double-blind, active-control study in Japanese patients receiving hemodialysis with anemia of CKD. Participants' treatment was switched from current erythropoiesis-stimulating agents (ESAs) to daprodustat 4 mg once daily or darbepoetin alfa 10-60 μg once weekly (on the basis of the prestudy ESA dose). Dose was adjusted every 4 weeks for daprodustat or every 2 weeks for darbepoetin alfa, according to a protocol-specified algorithm. The primary end point was mean hemoglobin during weeks 40-52 in the intent-to-treat population.

Results: Of 332 participants screened, 271 participants were randomized (safety evaluation: 271 participants; efficacy evaluation: 267 intent-to-treat population). The mean hemoglobin during weeks 40-52 were maintained within the target range in both groups (10.9 g/dl [95% confidence interval (95% CI), 10.8 to 11.0] for daprodustat, and 10.8 g/dl [95% CI, 10.7 to 11.0] for darbepoetin alfa). Daprodustat was noninferior to darbepoetin alfa, as the lower bound of the confidence interval for the treatment difference (0.1 g/dl; 95% CI, -0.1 to 0.2 g/dl) was greater than the noninferiority criterion of -1.0 g/dl. For most participants, hemoglobin was maintained within the target range (10.0-12.0 g/dl) during weeks 40-52 (88% daprodustat; 90% darbepoetin alfa). Geometric mean hepcidin levels decreased more at week 52 with daprodustat (-37%; 95% CI, -49 to -23) than with darbepoetin alfa (-20%; 95% CI, -36 to -1), and an increase in total iron-binding capacity was observed in the daprodustat group. Frequency of adverse events were generally similar between daprodustat and darbepoetin alfa.

Conclusions: Oral daprodustat was noninferior to darbepoetin alfa as measured by mean hemoglobin over weeks 40-52 in Japanese patients receiving hemodialysis switched from ESAs.

Clinical trial registry name and registration number: 201754, Clinicaltrials.gov, NCT02969655.

Keywords: Erythropoiesis; HIF; anemia; chronic kidney disease; clinical trial; daprodustat; double-blind; hemodialysis; hemoglobin; hepcidin; hypoxia-inducible factor prolyl hydroxylase inhibitor.

Graphical abstract

Figure 1.

Two hundred seventy-one participants were randomized (136 participants in the daprodustat group, 135 participants in the darbepoetin alfa group) in this study. Hgb, hemoglobin; ITT, intent-to-treat.

Figure 2.

The mean hemoglobin levels were maintained within the target range for the daprodustat and the darbepoetin alfa groups during the treatment period. Area between dashed lines indicates hemoglobin target range. Error bars represent 95% confidence intervals. Data shown are nonadjusted values.

Figure 3.

Daprodustat dose was increased by week 12 in the tertile 2 and 3 ERI subgroups. Daprodustat median dose during weeks 40–52 were 4.0 mg, 6.0 mg, and 6.0 mg for the tertile 1, 2, and 3 ERI subgroups, respectively. Error bars represent 25th percentile, 75th percentile for median dose. Median dose by ERI subgroup of darbepoetin alfa was a post hoc analysis. ERI, erythropoietin resistance index; W, week.

Figure 4.

Iron parameters over time. In the daprodustat group, serum iron and TIBC increased, ferritin and hepcidin decreased, and TSAT remained near baseline. Error bars represent 95% CIs. 95% CI, 95% confidence interval; TIBC, total iron-binding capacity; TSAT, transferrin saturation.