Phase 3 Study of Roxadustat to Treat Anemia in Non-Dialysis-Dependant CKD

Abstract

Introduction: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that has demonstrated safety and efficacy versus placebo in phase III trials in patients with anemia of chronic kidney disease (CKD) who were not on dialysis (NDD).

Methods: This was a phase III, active-controlled, multicenter, partially randomized, open-label study in Japanese patients with NDD CKD. Patients who had used recombinant human erythropoietin or darbepoetin alfa (DA) before conversion were randomized to roxadustat or DA (comparative arms). Patients who had used epoetin beta pegol before conversion were allocated to roxadustat (reference arm). The primary endpoint was change in average hemoglobin (Hb) level from baseline during the evaluation period (Weeks 18-24). Longer term efficacy and safety were evaluated in roxadustat-treated patients over 52 weeks.

Results: In this study, 334 patients were randomized/allocated to receive treatment (n = 132, roxadustat [comparative]; n = 131, DA [comparative]; n = 71, roxadustat [reference]). The estimated difference between the roxadustat (comparative) and DA (comparative) groups in the least squares mean of change of average Hb levels of Weeks 18 to 24 from baseline was -0.07 g/dl, with the lower limit of 95% confidence interval of -0.23 g/dl, thereby confirming the noninferiority of roxadustat to DA. Common treatment-emergent adverse events (≥3% of patients in any treatment group) observed during the 24-week treatment period included nasopharyngitis, CKD, hyperkalemia, and hypertension.

Conclusion: Roxadustat maintained Hb within 10 to 12 g/dl in NDD CKD patients and was noninferior to DA. The safety profiles observed in this study are consistent with previous studies performed in this patient population.

Keywords: active comparator; anemia; chronic kidney disease; conversion; non–dialysis dependent; roxadustat.

Graphical abstract

Figure 1

Study design. Registration was conducted on the day when the most recent dose of erythropoiesis-stimulating agent was scheduled to be administered within 4 weeks, in principle, based on the assessments that confirmed that all the inclusion/exclusion criteria were satisfied. Conduct of registration was on the same day of the Week 0 visit.

Figure 2

Patient disposition at the end of (a) Week 24 and (b) Week 52. ^aPatients who signed informed consent but discontinued before randomization/registration were screen failures. ^bPatients who did not receive the study drug were included. ^cPatients in the roxadustat (comparative) group and the roxadustat (reference) group continued to receive the study drug for up to 52 weeks.

Figure 3

Mean and SD plot of (a) roxadustat and (b) darbepoetin alfa per intake over time (safety analysis set)

Figure 4

Mean and SD plot of hemoglobin (g/dl) through Week 24 or end of Week 24 for all treatment arms (full analysis set). EOW24, end of Week 24; PSC, prescreening; SC, screening.

Figure 5

Median (interquartile range) of allocated dose of study drug by high-sensitivity C-reactive protein (hs-CRP): (a) darbepoetin alfa (comparative), (b) roxadustat (comparative), (c) roxadustat (reference), (d) roxadustat (pooled).

Figure 5

Median (interquartile range) of allocated dose of study drug by high-sensitivity C-reactive protein (hs-CRP): (a) darbepoetin alfa (comparative), (b) roxadustat (comparative), (c) roxadustat (reference), (d) roxadustat (pooled).

Figure 6

Mean and SD plot of hemoglobin (g/dl) through Week 52 or end of treatment for all treatment arms (full analysis set). EOT, end of treatment; FAS, full analysis set; PSC, prescreening; SC, screening.