Phase 3, Randomized, Double-Blind, Active-Comparator (Darbepoetin Alfa) Study of Oral Roxadustat in CKD Patients with Anemia on Hemodialysis in Japan

Abstract

Background: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved in China for dialysis-dependent CKD anemia.

Methods: This phase 3, 24-week, double-blind, double-dummy study evaluated roxadustat's noninferiority to darbepoetin alfa for hemodialysis-dependent CKD anemia. We randomly assigned Japanese patients to oral roxadustat three times weekly or to darbepoetin alfa injections once weekly, titrating doses to maintain hemoglobin between 10-12 g/dl. The primary end point was change of average hemoglobin from baseline to weeks 18-24 (∆Hb_18-24). Secondary end points were average hemoglobin and proportion of patients with hemoglobin between 10-12 g/dl (maintenance rate) at weeks 18-24, and iron parameters. Safety assessments included treatment-emergent adverse events and adjudicated ophthalmologic findings.

Results: We randomly assigned 303 patients to roxadustat (n=151) or darbepoetin alfa (n=152). The difference between roxadustat and darbepoetin alfa in ∆Hb_18-24 was -0.02 g/dl (95% confidence interval, -0.18 to 0.15), confirming roxadustat's noninferiority to darbepoetin alfa. Average hemoglobin at weeks 18-24 with roxadustat was 10.99 g/dl (95% confidence interval: 10.88 to 11.10), confirming its efficacy. Among patients with one or more hemoglobin value during weeks 18-24, the maintenance rate was 95.2% with roxadustat and 91.3% with darbepoetin alfa. Serum iron, ferritin, and transferrin saturation remained clinically stable with roxadustat; transferrin and total iron binding capacity increased through week 4 before stabilizing. Common treatment-emergent adverse events were nasopharyngitis, shunt stenosis, diarrhea, contusion, and vomiting. The proportion of patients with new or worsening retinal hemorrhage was 32.4% with roxadustat and 36.6% with darbepoetin alfa. We observed no clinically meaningful changes in retinal thickness groups.

Conclusions: Roxadustat maintained hemoglobin within 10-12 g/dl in patients on hemodialysis and was noninferior to darbepoetin alfa. Treatment-emergent adverse events were consistent with previous reports.

Clinical trial registry name and registration number: A Study of Intermittent Oral Dosing of ASP1517 in Hemodialysis Chronic Kidney Disease Patients with Anemia, NCT02952092 (ClinicalTrials.gov).

Keywords: anemia; chronic kidney disease; clinical trial; darbepoetin alfa; hemodialysis; roxadustat.

Figure 1.

Characteristics of patients. For screen failures, “other” generally indicates that a patient was excluded based on inclusion/exclusion criteria. For patients who discontinued after randomization, other refers to cancer (n=1), met withdrawal criteria (n=1), withdrew due to lack of study drug (n=1), and rheumatoid arthritis (n=1) in patients on DA; and met withdrawal criteria (n=2), eye surgery (n=2), and safety (n=1) in patients on roxadustat.

Figure 2.

Mean (SD) Hb levels were comparable between groups throughout the study (FAS). EoT, end of treatment; PSC, prescreening; SC, screening.

Figure 3.

Mean (SD) Hb levels were similar between groups throughout the study when stratified by hs-CRP (FAS). EoT, end of treatment; PSC, prescreening; SC, screening.

Figure 4.

Median (interquartile range) allocated dose of study drug per administration required to maintain target Hb levels was similar in the roxadustat group and slightly different in the DA group when stratified by hs-CRP (FAS). DA was IV administered once per week to patients at the completion of dialysis, on the dialysis day after the longest dialysis interval, for a maximum of 24 weeks. The last dose was administered at completion of dialysis on the day of the week 23 visit.