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

• Published in: Clinical journal of the American Society of Nephrology Vol. 15; no. 8; pp. 1155 - 1165
• Main Authors: Akizawa, Tadao, Nangaku, Masaomi, Yonekawa, Taeko, Okuda, Nobuhiko, Kawamatsu, Shinya, Onoue, Tomohiro, Endo, Yukihiro, Hara, Katsutoshi, Cobitz, Alexander R
• Format: Journal Article
• Language: English
• Published: United States American Society of Nephrology 07-08-2020
• Subjects: Aged; Anemia - blood; Anemia - diagnosis; Anemia - drug therapy; Anemia - etiology; Barbiturates - adverse effects; Barbiturates - therapeutic use; Biomarkers - blood; Darbepoetin alfa - adverse effects; Darbepoetin alfa - therapeutic use; Double-Blind Method; Female; Glycine - adverse effects; Glycine - analogs & derivatives; Glycine - therapeutic use; Hematinics - adverse effects; Hematinics - therapeutic use; Hemoglobins - metabolism; Humans; Japan; Male; Middle Aged; Original; Renal Dialysis - adverse effects; Renal Insufficiency, Chronic - complications; Renal Insufficiency, Chronic - diagnosis; Renal Insufficiency, Chronic - therapy; Time Factors; Treatment Outcome; Japan; Erythropoiesis; clinical trial; chronic kidney disease; hepcidin; HIF; hemodialysis; daprodustat; anemia; double-blind; hemoglobin; hypoxia-inducible factor prolyl hydroxylase inhibitor
• ISSN: 1555-9041; 1555-905X
• DOI: 10.2215/CJN.16011219

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.
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
g 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.
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.
Oral daprodustat was noninferior to darbepoetin alfa as measured by mean hemoglobin over weeks 40-52 in Japanese patients receiving hemodialysis switched from ESAs.
201754, Clinicaltrials.gov, NCT02969655.