A Randomized Trial of Roxadustat in Anemia of Kidney Failure: SIERRAS Study

Abstract

Introduction: Erythropoiesis-stimulating agents, standard of care for anemia of end-stage kidney disease, are associated with cardiovascular events. We evaluated the efficacy and safety of roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis.

Methods: SIERRAS was a phase 3, randomized, open-label, active-controlled study enrolled adults on dialysis for end-stage kidney disease receiving erythropoiesis-stimulating agents for anemia. Patients were randomized (1:1) to thrice-weekly roxadustat or epoetin alfa. Doses were based on previous epoetin alfa dose and adjusted in the roxadustat arm to maintain hemoglobin at ∼11 g/dl during treatment. Epoetin alfa dosing was adjusted per US package insert. Primary efficacy endpoint was mean hemoglobin (g/dl) change from baseline averaged over weeks 28 to 52. Treatment-emergent adverse events were monitored.

Results: Enrolled patients (roxadustat, n = 370 and epoetin alfa, n = 371) had similar mean (SD) baseline hemoglobin levels (10.30 [0.66] g/dl). Mean (SD) hemoglobin changes for weeks 28 to 52 were 0.39 (0.93) and -0.09 (0.84) in roxadustat and epoetin alfa, respectively. Roxadustat was noninferior (least squares mean difference: 0.48 [95% confidence interval: 0.37, 0.59]; P < 0.001) to epoetin alfa. Tolerability was comparable between treatments.

Conclusion: In end-stage kidney disease, roxadustat was noninferior to epoetin alfa in up to 52 weeks of treatment in this erythropoietin-stimulating agent conversion study. Roxadustat had an acceptable tolerability profile.

Keywords: dialysis; epoetin alfa; hemoglobin; kidney failure; roxadustat.

Figure 1

CONSORT flow diagram.

Figure 2

Mean hemoglobin levels (g/dl) ± SD in roxadustat-treated patients (red) compared with epoetin alfa-treated patients (blue) were significantly increased from baseline to week 52 (full analysis set). The number of patients (n) with nonmissing values is indicated for each treatment.

Figure 3

Primary efficacy endpoint treatment differences by subgroup.

Figure 4

Mean low-density lipoprotein cholesterol levels in roxadustat-treated patients (red) compared with epoetin alfa–treated patients (blue) were significantly decreased from baseline to week 48 (full analysis set).

Figure 5

Mean monthly i.v. iron use in roxadustat-treated patients (red) compared with epoetin alfa-treated patients (blue) was significantly reduced from baseline to week 52 (full analysis set).

Figure 6

Cumulative percentage of in roxadustat-treated patients (red) compared with epoetin alfa–treated patients (blue) having a first blood/red blood cell transfusion was significantly reduced from baseline to week 52 (full analysis set).

Figure 7

Levels of hepcidin (A), ferritin (B), iron (C), and transferrin saturation (TSAT) (D) in the roxadustat group were lower (hepcidin, iron, and TSAT) or similar (ferritin) to the epoetin alfa group from baseline to week 52 (full analysis set). Total iron binding capacity for roxadustat significantly increased from baseline to week 52 compared with epoetin alfa (least squares mean [SEM] 36.28 [2.32], 95% confidence interval 31.73, 40.82; P < 0.001).