A randomized, 29-day, dose-ranging, efficacy and safety study of daprodustat, administered three times weekly in patients with anemia on hemodialysis

Abstract

Background: Daprodustat is a hypoxia-inducible factor-prolyl hydroxylase inhibitor currently being investigated as a treatment for anemia of chronic kidney disease (CKD) in both dialysis and nondialysis patients. In clinical studies to date, daprodustat has been administered orally as a once-daily regimen. This randomized, double-blind, placebo-controlled study characterized the initial dose-hemoglobin response as well as the efficacy and safety of three times weekly (TIW) daprodustat in hemodialysis patients switched from stable recombinant human erythropoietin (rhEPO), in accordance with a TIW hemodialysis schedule.

Methods: 103 patients on hemodialysis with baseline hemoglobin of 9.0 to 11.5 g/dL and previously receiving a stable dose of rhEPO or its analogs were randomized 1:1:1:1:1 to receive daprodustat 10, 15, 25, or 30 mg or placebo TIW over 29 days.

Results: Mean baseline hemoglobin was 10.6 g/dL for the placebo group and each daprodustat cohort. Daprodustat produced dose-dependent changes in mean hemoglobin from baseline to day 29. Using a Bayesian approach, the estimated dose conversion ratio between once-daily and TIW daprodustat was ~ 2.0 across the evaluated dose range using an E_max model. Daprodustat was generally well tolerated, with an adverse event (AE) profile consistent with the hemodialysis population.

Conclusions: These data help inform the appropriate dose conversion ratio to be applied to daily doses to obtain equivalent daprodustat TIW doses and suggest TIW treatment with daprodustat can treat anemia of CKD safely, supporting future long-term studies for this indication using a TIW dosing regimen.

Trial registration: ClinicalTrials.gov Identifier: NCT02689206 ; date registered: 02/11/2016.

Keywords: Anemia; Bayesian; Clinical trials; Dose response; Efficacy; Hemodialysis; Safety; Three-times weekly (TIW).

Fig. 1

Study Flow Diagram. AE, adverse event; ITT, intention-to-treat; Hgb, hemoglobin; PK, pharmacokinetics; SAE, serious adverse event; TIW, three times weekly. ^aOne participant randomized to the placebo group erroneously received daprodustat 25 mg. This participant was counted in the placebo group in the ITT population and in the daprodustat 25 mg cohort in the safety and PK populations. ^bThe ITT population comprised all randomized participants who received at least one dose of study treatment, and had a baseline and at least one corresponding on-treatment assessment including hemoglobin

Fig. 2

Mean Change from Baseline and 95% CI for Hemoglobin (g/dL) Over Time (ITT Population). BL, baseline; CI, confidence interval; Hgb, hemoglobin; ITT, intention-to-treat

Fig. 3

Posterior E_max Dose-Response Curve for Hemoglobin (g/dL) Change from Baseline at Day 29 (ITT Population). The two dotted lines are 95% credible bands. E_max, maximal response; Hgb, hemoglobin; ITT, intention-to-treat

Fig. 4

EPO and VEGF Absolute Values and Change From Baseline by Visit and Sample Time (ITT Population; Post-Hoc Analyses). Each boxplot displays the distribution of the parameter indicated on the Y-axis label. The bottom and top edges of the box indicate the intra-quartile range (IQR); that is the range of values between the 25th and 75th percentiles. The line inside the box indicates the median value. The whiskers are drawn from the box to the most extreme point that is less than or equal to 1.5 times the IQR. The dots are outliers that are more extreme than the upper and lower fences (±1.5 IQR). EPO, erythropoietin; ITT, intention-to-treat; VEGF, vascular endothelial growth factor