Roxadustat Versus Epoetin Alfa for Treating Anemia in Patients with Chronic Kidney Disease on Dialysis: Results from the Randomized Phase 3 ROCKIES Study

Abstract

Background: Concerns regarding cardiovascular safety with current treatments for anemia in patients with dialysis-dependent (DD)-CKD have encouraged the development of alternatives. Roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, stimulates erythropoiesis by increasing endogenous erythropoietin and iron availability.

Methods: In this open-label phase 3 study, patients with DD-CKD and anemia were randomized 1:1 to oral roxadustat three times weekly or parenteral epoetin alfa per local clinic practice. Initial roxadustat dose depended on erythropoiesis-stimulating agent dose at screening for patients already on them and was weight-based for those not on them. The primary efficacy end point was mean hemoglobin change from baseline averaged over weeks 28‒52 for roxadustat versus epoetin alfa, regardless of rescue therapy use, tested for noninferiority (margin, -0.75 g/dl). Adverse events (AEs) were assessed.

Results: Among 2133 patients randomized (n=1068 roxadustat, n=1065 epoetin alfa), mean age was 54.0 years, and 89.1% and 10.8% were on hemodialysis and peritoneal dialysis, respectively. Mean (95% confidence interval) hemoglobin change from baseline was 0.77 (0.69 to 0.85) g/dl with roxadustat and 0.68 (0.60 to 0.76) g/dl with epoetin alfa, demonstrating noninferiority (least squares mean difference [95% CI], 0.09 [0.01 to 0.18]; P<0.001). The proportion of patients experiencing ≥1 AE and ≥1 serious AE was 85.0% and 57.6% with roxadustat and 84.5% and 57.5% with epoetin alfa, respectively.

Conclusions: Roxadustat effectively increased hemoglobin in patients with DD-CKD, with an AE profile comparable to epoetin alfa.

Clinical trial registry name and registration number: Safety and Efficacy Study of Roxadustat to Treat Anemia in Patients With Chronic Kidney Disease, on Dialysis.

Clinicaltrials: gov Identifier: NCT02174731.

Keywords: HIF-PH inhibitor; anemia; chronic kidney disease; dialysis; roxadustat.

Graphical abstract

Figure 1.

Study design. ^aEOT is defined as the patient’s next scheduled visit after discontinuing study treatment. ^bEOS is defined as the last visit of the last patient undergoing the study. CV, cardiovascular; EOS, end of study; EOT, end of treatment; Hb, hemoglobin; R, randomization; TIW, three times a week.

Figure 2.

Patient disposition. ^aExcluded from the study due to major Good Clinical Practice violations (i.e., significant deviations from best practice in obtaining or recording the data that might affect the validity of the data), or being phantom patients (not physically existing) due to system technical issues. ^bNeed for more than one cycle of ESA in patients treated with roxadustat. ^cKidney transplant (n=63), investigator decision (n=22), patient moved/relocated (n=14), death (n=6), miscellaneous (n=20). ^dKidney transplant (n=80), investigator decision (n=8), patient moved/relocated (n=18), death (n=14), miscellaneous (n=22). The analysis sets used in this study are detailed in Supplemental Table 3.

Figure 3.

Hemoglobin endpoints. (A) Hb change from baseline to the mean Hb in weeks 28–52 by subgroup. P value for superiority is modeled using ANCOVA with baseline Hb as covariate and CV history, geographical region (US versus ex-US), incident versus prevalent dialysis (≤4 versus >4 months), treatment group, subgroup, and treatment by subgroup interaction as fixed effects. ^aCV/cerebrovascular/thromboembolic history defined by MedDRA version 20.0 dictionary-derived terms: cardiac failure congestive, myocardial infarction, percutaneous coronary intervention, coronary artery bypass, ischemic stroke, hemorrhagic stroke, and cerebrovascular accident. (B) Mean Hb over time to week 164. ITT analysis set. Symbol inside box: mean; symbols outside box: outliers. Whiskers extend to the most extreme observation within 1.5 times the IQR from the nearest quartile, so that all outliers >1.5 times the IQR are individually displayed with clear circles. Baseline Hb is defined as the mean of the last three central laboratory Hb values obtained from screening and randomization. ANCOVA, analysis of covariance; BMI, body mass index; PD, peritoneal dialysis; HD, hemodialysis.

Figure 4.

Time-to-first administration of RBC transfusion. RBC transfusion was allowed if rapid correction of anemia was required or if deemed a medical necessity by the investigator. On-treatment + 3 days analysis set. HR, hazard ratio.

Figure 5.

Serum iron parameters by visit. Mean iron levels for (A) ferritin, (B) iron, (C) TIBC, and (D) TSAT. Intent-to-treat analysis set. Error bars are 95% CIs. Baseline is defined as the last measurement before randomization. 95% CI of the mean is based on the normal distribution.