Roxadustat for Treating Anemia in Patients with CKD Not on Dialysis: Results from a Randomized Phase 3 Study

Abstract

Background: Current anemia therapies for patients with non-dialysis-dependent CKD may require injection and medical visits. Roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, stimulates erythropoiesis and improves iron homeostasis.

Methods: In this double-blind phase 3 study, we randomized patients with non-dialysis-dependent CKD stages 3-5 and hemoglobin <10.0 g/dl (1:1) to thrice-weekly 70-mg oral roxadustat or placebo. Doses were titrated throughout the study based on hemoglobin levels. The primary efficacy end point was mean change from baseline in hemoglobin averaged over weeks 28-52 versus placebo, irrespective of rescue therapy use. We assessed patients for adverse events.

Results: The study included 2781 patients, 1393 who received roxadustat and 1388 who received placebo. Mean baseline hemoglobin was 9.1 g/dl for both groups. The mean change in hemoglobin from baseline was 1.75 g/dl (95% confidence interval [95% CI], 1.68 to 1.81) with roxadustat versus 0.40 g/dl (95% CI, 0.33 to 0.47) with placebo, (P<0.001). Among 411 patients with baseline elevated high-sensitivity C-reactive protein, mean change in hemoglobin from baseline was 1.75 g/dl (95% CI, 1.58 to 1.92) with roxadustat versus 0.62 g/dl (95% CI, 0.44 to 0.80) with placebo, (P<0.001). Roxadustat reduced the risk of red blood cell transfusion by 63% (hazard ratio, 0.37; 95% CI, 0.30 to 0.44). The most common adverse events with roxadustat and placebo, respectively, were ESKD (21.0% versus 20.5%), urinary tract infection (12.8% versus 8.0%), pneumonia (11.9% versus 9.4%), and hypertension (11.5% versus 9.1%).

Conclusions: Roxadustat effectively increased hemoglobin in patients with non-dialysis-dependent CKD and reduced the need for red blood cell transfusion, with an adverse event profile comparable to that of placebo.

Clinical trial registry name and registration number: Safety and Efficacy Study of Roxadustat to Treat Anemia in Patients With CKD, Not on Dialysis, NCT02174627.

Keywords: anemia; chronic kidney disease; clinical nephrology; clinical trial; randomized controlled trials.

Copyright © 2021 by the American Society of Nephrology.

Figures

Graphical abstract

Figure 1.

Design of the OLYMPUS study. A minimum of two screening visits were performed at least 7 days apart. The Hb inclusion criteria were on the basis of central laboratory assessment and could be repeated during the screening period. The treatment period began on the first day of dosing with the study drug (day 1, week 0). Patients were contacted by telephone at week 1, and attended study visits every 2 weeks from week 0 to 20. After week 20, study visits occurred every 4 weeks until week 52, and then every 8 weeks until EOT. The next scheduled visit, the EOT visit, occurred as soon as possible after the target number of cardiovascular events was accrued. Treatment duration was variable for individual patients (estimated duration up to 4 years). For patients without premature study drug discontinuation, an EOS visit was performed 4 weeks after the treatment period. CV, cardiovascular; R, randomization; TIW, three times weekly; wk, week(s).

Figure 2.

Patient disposition. aBecause of GCP violations. Study-specific discontinuation criteria included patients who required dialysis initiation and ESA rescue therapy. When possible, patients who discontinued treatment were followed for concomitant medications, AEs, vital status, and hospitalization.

Figure 3.

Time to premature study drug discontinuation by treatment arm and baseline eGFR 2 (OT+28 analysis set). KM percentages were calculated at 24 months. Permanent discontinuation criteria: patient decision or investigator decision (AE, severe noncompliance, need for three or more cycles of ESA rescue therapy, or initiation of dialysis and need for ESA rescue therapy). Assessment of premature study drug discontinuation by baseline eGFR <10 ml/min per 1.73 m2 was performed post hoc. KM, Kaplan–Meier; N, number of patients in that treatment arm.

Figure 4.

Hb end points. (A) change from baseline in Hb averaged over weeks 28–52; (B) change from baseline in Hb averaged over weeks 28–52 by baseline iron replete status; (C) mean Hb levels by visit; (D) proportion of patients achieving Hb response; (E) change from baseline in Hb averaged over weeks 28–52 in patients with elevated hsCRP at baseline. Error bars are 95% CIs. (A) ITT analysis set. Change in Hb from baseline to mean value during weeks 28–52 was analyzed using ANCOVA with the following fixed-effect covariates at baseline: Hb, baseline eGFR, cardiovascular/cerebrovascular/thromboembolic history, geographic region (USA versus ex-USA), and treatment arm. Adjusted LSMs, their difference, and corresponding 95% CI were generated from datasets where missing data were imputed using missing at random–based multiple imputation by treatment arm with baseline Hb, baseline eGFR, cardiovascular/cerebrovascular/thromboembolic history, and geographic region (USA versus ex-USA) as predictor variables. Observed values up to the EOT visit if treatment was completed; the EOS visit if patient discontinued treatment; or date of withdrawal of consent, last contact, or death if patient withdrew consent, was lost to follow-up, or died; and imputed values up to death of patient were used to derive the mean from weeks 28 to 52. (B) ITT analysis set. Iron replete defined as ferritin >100 μg/l and TSAT >20%. (C) ITT analysis set. Week 0 on the x axis refers to the baseline value. (D) FAS. Hb response was defined as Hb ≥11.0 g/dl and Hb increase from baseline by ≥1.0 g/dl for patients with baseline Hb >8.0 g/dl, or Hb increase from baseline by ≥2.0 g/dl for those with baseline Hb ≤8.0 g/dl, at two consecutive visits (with available data) separated by at least 5 days during the first 24 weeks of treatment without having received rescue therapy before Hb response. Statistical analysis was on the basis of the Cochran–Mantel–Haenszel test, adjusting for baseline Hb (≤8, >8 g/dl), baseline eGFR (≤30, >30 ml/min per 1.73 m2), cardiovascular/cerebrovascular/thromboembolic history, and geographic region (USA versus ex-USA). Patients who had discontinued study drug or taken rescue medication before response were considered nonresponders. (E) ITT analysis set. hsCRP was quantified from available stored biomarker samples obtained at randomization. ULN is 5 mg/l (0.5 mg/dl). Data were analyzed analogously to the primary analysis.

Figure 5.

Rescue therapy end points. OT+28 analysis set. Data shown are for first rescue therapy (composite of individual rescue therapies). Event rates are presented per 100 patient-years. For the overall (composite) end point, rescue therapy refers to iv iron, RBC transfusion, or ESA. RBC transfusion was allowed if rapid correction of anemia was required or if deemed a medical necessity by the investigator. The HR, 95% CI, and P value comparing the treatment arms were estimated using a Cox proportional hazards model with baseline Hb, baseline eGFR, cardiovascular/cerebrovascular/thromboembolic history, and geographic region (USA versus ex-USA) included in the model. 95% CIs were from Wald and ties and were calculated using the Efron method. Time to first rescue therapy was calculated as (date of first rescue therapy, or date of censoring if no rescue therapy was taken)−(date of first dose of study drug)+1. Patients who did not take any rescue therapy were censored at the earliest occurrence of 28 days after their last intake of study drug, or the date of withdrawal of consent or last study contact if the patient withdrew consent or was lost to follow-up, or the date of death.

Figure 6.

Change from baseline in Hb (g/dl) averaged over weeks 28–52, by patient subgroups (ITT analysis set). Treatment difference is for roxadustat versus placebo. Error bars are 95% CIs. Change in Hb from baseline to average over weeks 28–52 was analyzed using an ANCOVA model with the following fixed-effect covariates at baseline: Hb and eGFR values in continuous scales; cardiovascular/cerebrovascular/thromboembolic history (yes/no); geographic region (USA versus ex-USA); and treatment arm, subgroup, and treatment by subgroup interaction as fixed effects. Adjusted LS means, their difference, and corresponding 95% CI were generated from datasets where missing data were imputed using missing at random-based multiple imputation with baseline Hb, baseline eGFR, cardiovascular/cerebrovascular/thromboembolic history, and geographic region (USA versus ex-USA) as predictor variables. hsCRP was quantified from available stored biomarker samples obtained at randomization; ULN is 5 mg/l (0.5 mg/dl); iron replete defined as ferritin >100 μg/l and TSAT >20%. LS, least squares.

Figure 7.

Serum iron parameters by visit. (A) Iron; (B) ferritin; (C) TIBC; (D) TSAT (ITT analysis set). Error bars are 95% CIs. Baseline is defined as the last measurement before randomization. 95% CI of the mean is on the basis of the normal distribution.