A Randomized Trial of Roxadustat in Anemia of Kidney Failure: SIERRAS Study.
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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.
SUBMITTER: Charytan C
PROVIDER: S-EPMC8258588 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:INTRODUCTION:This study evaluated efficacy and safety/tolerability of roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, in Japanese anemic non-dialysis-dependent chronic kidney disease (NDD-CKD) patients. METHODS:In this phase 2, double-blind, 24-week study, NDD-CKD patients were randomized to oral placebo or roxadustat (50, 70, or 100 mg) three times weekly (TIW) for 6 weeks followed by dose adjustments to maintain hemoglobin (Hb) at 10-12 g/dL for 18 weeks; patients meeting pre-defined criteria were re-randomized to TIW or once-weekly dosing. The primary end point was rate of rise of Hb (g/dL/week) during the first 6 weeks; secondary end points included response rate (Hb???10.0 g/dL and increase in Hb from baseline???1 g/dL) and mean Hb and change from baseline in Hb at weeks 18-24. The main safety outcomes were vital signs, laboratory test results, electrocardiograms, and frequency of treatment-emergent adverse events. RESULTS:Of 107 patients randomized, 83 completed the study. The mean (SD) rate of rise of Hb during the first 6 weeks was -?0.052 (0.142) for placebo and +?0.200 (0.160), +?0.453 (0.256), and +?0.570 (0.240) for roxadustat 50-, 70-, and 100-mg TIW groups, respectively (p?<?0.001). Response rate was 14.8% for placebo and 81.5%, 100%, and 100% for roxadustat TIW groups (p?<?0.001). Change in Hb from baseline at weeks 18-24 was -?0.17 (0.61) for placebo and +?1.10 (0.71), +?1.33 (0.82), and +?1.55 (0.88) g/dL for roxadustat TIW groups (p?<?0.001). No deaths or major adverse cardiac events occurred with roxadustat. CONCLUSION:Roxadustat was well tolerated and effective in correcting Hb levels within 6 weeks in Japanese anemic NDD-CKD patients. TRIAL REGISTRATION:ClinicalTrials.gov: NCT01964196. Registered 15 October 2013 (retrospectively registered). FUNDING:Astellas Pharma Inc.
| S-EPMC6824366 | biostudies-literature
Project description:Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor developed to treat anemia in chronic kidney disease (CKD) patients. This Phase 3, randomized, open-label, 24-week study investigated the efficacy and safety of roxadustat in Japanese CKD patients with anemia on peritoneal dialysis (PD) who were previously treated or not treated with erythropoiesis stimulating agents (ESAs). Patients not previously receiving ESA (ESA-Naïve group) were randomized to roxadustat at a starting dose of 50 or 70?mg three times weekly; patients previously receiving ESA (ESA-Converted group) switched from ESA to roxadustat 70 or 100?mg three times weekly depending on the prior ESA dose. Outcomes included maintenance rate of average hemoglobin (Hb) level within 10-12?g/dL at weeks 18-24, cumulative response rate at end of treatment (Hb thresholds, 10.0?g/dL or 10.5?g/dL; Hb increase, ?1.0?g/dL), and average Hb levels at weeks 18-24. Safety was assessed by occurrence of treatment-emergent adverse events (TEAEs). Fifty-six patients were enrolled (ESA-Naïve, n = 13; ESA-Converted, n = 43). Maintenance rates (weeks 18-24) were 92.3% (95% CI: 64.0-99.8; ESA-Naïve) and 74.4% (95% CI: 58.8-86.5; ESA-Converted). Cumulative response rate was 100.0% in the ESA-Naïve group. Average Hb levels (weeks 18-24) were 11.05?g/dL (95% CI: 10.67-11.42; ESA-Naïve) and 10.93?g/dL (95% CI: 10.73-11.13; ESA-Converted). Common TEAEs included nasopharyngitis and back pain. Roxadustat was well tolerated and effective in maintaining target Hb levels in CKD patients on PD who were previously treated or not treated with ESA.
| S-EPMC7079122 | biostudies-literature
Project description:Roxadustat (FG-4592) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis. This Phase 2a study tested efficacy (Hb response) and safety of roxadustat in anemic nondialysis-dependent chronic kidney disease (NDD-CKD) subjects.NDD-CKD subjects with hemoglobin (Hb) ?11.0 g/dL were sequentially enrolled into four dose cohorts and randomized to roxadustat or placebo two times weekly (BIW) or three times weekly (TIW) for 4 weeks, in an approximate roxadustat:placebo ratio of 3:1. Efficacy was assessed by (i) mean Hb change (?Hb) from baseline (BL) and (ii) proportion of Hb responders (?Hb ? 1.0 g/dL). Pharmacodynamic evaluation was performed in a subset of subjects. Safety was evaluated by adverse event frequency/severity.Of 116 subjects receiving treatment, 104 completed 4 weeks of dosing and 96 were evaluable for efficacy. BL characteristics for roxadustat and placebo groups were comparable. In roxadustat-treated subjects, Hb levels increased from BL in a dose-related manner in the 0.7, 1.0, 1.5 and 2.0 mg/kg groups. Maximum ?Hb within the first 6 weeks was significantly higher in the 1.5 and 2.0 mg/kg groups than in the placebo subjects. Hb responder rates were dose dependent and ranged from 30% in the 0.7 mg/kg BIW group to 100% in the 2.0 mg/kg BIW and TIW groups versus 13% in placebo.Roxadustat transiently and moderately increased endogenous erythropoietin and reduced hepcidin. Adverse events were similar in the roxadustat and placebo groups. Roxadustat produced dose-dependent increases in blood Hb among anemic NDD-CKD patients in a placebo-controlled trial.Clintrials.gov #NCT00761657.
| S-EPMC4569392 | biostudies-literature
Project description:BackgroundRoxadustat is an orally active hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of chronic kidney disease (CKD) anemia.MethodsThis Phase 3, multicenter, randomized, double-blind, placebo-controlled study examined patients with Stages 3-5 CKD, not on dialysis (NCT01887600). Patients were randomized (2:1) to oral roxadustat or placebo three times weekly for 52-104 weeks. This study examined two primary efficacy endpoints: European Union (European Medicines Agency)-hemoglobin (Hb) response, defined as Hb ≥11.0 g/dL that increased from baseline (BL) by ≥1.0 g/dL in patients with Hb >8.0 g/dL or ≥2.0 g/dL in patients with BL Hb ≤8.0 g/dL, without rescue therapy, during the first 24 weeks of treatment; US Food and Drug Administration-change in Hb from BL to the average Hb level during Weeks 28-52, regardless of rescue therapy. Secondary efficacy endpoints and safety were examined.ResultsA total of 594 patients were analyzed (roxadustat: 391; placebo: 203). Superiority of roxadustat versus placebo was demonstrated for both primary efficacy endpoints: Hb response [odds ratio = 34.74, 95% confidence interval (CI) 20.48-58.93] and change in Hb from BL [roxadustat - placebo: +1.692 (95% CI 1.52-1.86); both P < 0.001]. Superiority of roxadustat was demonstrated for low-density lipoprotein cholesterol change from BL, and time to first use of rescue medication (both P < 0.001). The incidences of treatment-emergent adverse events were comparable between groups (roxadustat: 87.7%, placebo: 86.7%).ConclusionsRoxadustat demonstrated superior efficacy versus placebo in terms of both Hb response rate and change in Hb from BL. The safety profiles of roxadustat and placebo were comparable.
| S-EPMC8397511 | biostudies-literature
Project description:Background: Roxadustat, a hypoxia-inducible factor prolyl-hydroxylase inhibitor (HIF-PHI), has been used to treat anemia in patients with chronic kidney disease (CKD). However, its safety and efficacy remain controversial. Methods: The PubMed, EMBASE, Science Citation Index, Cochrane Central Register of Controlled Trials, and Clinical Trial Registries databases were searched for relevant studies published up to April 2021. We identified randomized controlled trials (RCTs) comparing roxadustat with placebo or erythropoiesis-stimulating agents (ESAs) in anemia patients with CKD with or without dialysis. Results: Eleven studies including 6,631 patients met the inclusion criteria. In non-dialysis-dependent (NDD-) and dialysis-dependent (DD-) CKD patients, the total adverse events were not significantly different between the roxadustat and control (placebo for NDD-CKD patients and ESA for DD-CKD patients) groups [relative risk (RR) = 1.02, 95% confidence interval (CI) = 1.00, 1.04, P = 0.08, and RR = 1.22, 95% CI = 0.91, 1.64, P = 0.18, respectively], and the trial sequential analysis (TSA) confirmed the result in the NDD-CKD groups. No significant differences in hyperkalemia and infection incidences were found between roxadustat and placebo in the DD-CKD groups. The pooled results showed that roxadustat significantly increased the hemoglobin response rate compared with placebo in the NDD-CKD group and had an effect similar to that of ESA in the DD-CKD group. However, iron metabolism parameters did not seem to be obviously optimized by roxadustat. Conclusion: Roxadustat can be safely used in CKD patients. Oral roxadustat was more effective than placebo as a therapy for anemia in NDD-CKD patients and non-inferior to ESA in correcting anemia in DD-CKD patients. However, additional clinical trials are still needed to further prove whether roxadustat can optimize iron metabolism.
| S-EPMC8438137 | biostudies-literature
Project description:BackgroundAnemia is a common complication of chronic kidney disease (CKD). Treating renal anemia with erythropoiesis-stimulating agents (ESAs) or erythropoietin analogs is effective but has side effects. Therefore, we performed a meta-analysis to assess the efficacy and safety of roxadustat in treating CKD-induced anemia.MethodsWe searched publications online and conducted a meta-analysis and calculated relative risks with 95% confidence intervals (CIs) for dichotomous data and mean differences (MD) with 95% CIs for continuous data.ResultsOf 110 articles, nine were included that contained 12 data sets and 11 randomized control trials on roxadustat. In the non-dialysis-dependent (NDD) high-dose/low-dose subgroups, the change in hemoglobin (Hb) levels was significantly higher in the roxadustat group than in the placebo group (P<0.0001, P=0.001, respectively). The Hb response rate of the roxadustat is higher in the NDD subgroup than in the placebo group (P<0.00001, MD=6.92, 95% CI: 4.03, 11.89). However, in the dialysis-dependent subgroup, there was no significant difference in the change in Hb levels or the Hb response rate between the roxadustat and ESA groups. There was no change in the mortality in the roxadustat group compared to that in the placebo/ESA group. Hyperkalemia may be a side effect of roxadustat.ConclusionsRoxadustat elevated the serum Hb levels in a manner similar to that observed for ESAs. Roxadustat raised the Hb levels more significantly than the placebo and showed a higher Hb response rate than the placebo group in NDD patients. Roxadustat is a safe and effective drug for anemia in CKD patients.
| S-EPMC8312415 | biostudies-literature
Project description:IntroductionRoxadustat is an orally administered hypoxia-inducible factor prolyl hydroxylase inhibitor being developed for the treatment of anemia of chronic kidney disease (CKD). This European, phase 3, randomized, open-label, active-controlled study investigated efficacy and safety of roxadustat in patients with end-stage kidney disease on dialysis for at least 4 months.MethodsPatients were randomized to switch from an erythropoiesis-stimulating agent (ESA) (epoetin alfa or darbepoetin alfa) to roxadustat three times/week or to continue their previous ESA. Roxadustat and ESA doses were adjusted to maintain hemoglobin within 10.0-12.0 g/dL during the treatment period (day 1 up to 52-104 weeks). Primary endpoints were hemoglobin change from baseline (CFB) to the average of weeks 28-36 without rescue therapy and hemoglobin CFB to the average of weeks 28-52 regardless of rescue therapy. Treatment-emergent adverse events (TEAEs) were assessed descriptively.ResultsOf 1081 screened patients, 836 were randomized and received treatment (roxadustat, n = 415; ESA, n = 421). The least squares means (95% CI) of the treatment difference (roxadustat - ESA) for hemoglobin CFB to weeks 28-36 (without rescue therapy) and CFB to weeks 28-52 (regardless of rescue therapy) were 0.235 (0.132, 0.339) g/dL and 0.171 (0.082, 0.261) g/dL, respectively, demonstrating non-inferiority of roxadustat to ESA (non-inferiority margin of - 0.75 g/dL). The proportions of patients who achieved target hemoglobin without rescue therapy during weeks 28-36 were 84.2% (roxadustat) and 82.4% (ESA). Roxadustat was superior to ESA in decreasing LDL cholesterol from baseline to the average of weeks 12-28. Serious TEAEs occurred in 50.7% (roxadustat) and 45.0% (ESA) of patients. Common TEAEs in both treatment groups included hypertension, arteriovenous fistula thrombosis, headache, and diarrhea.ConclusionRoxadustat was non-inferior to ESAs in maintaining hemoglobin levels in this cohort of patients with anemia of CKD on dialysis for at least 4 months who were previously treated with ESAs. Observed TEAEs were consistent with previous studies.
| S-EPMC8478768 | biostudies-literature
Project description:IntroductionRoxadustat 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).MethodsThis 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.ResultsIn 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.ConclusionRoxadustat 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.
| S-EPMC8258605 | biostudies-literature
Project description:BackgroundAlthough renal anemia has attracted widespread attention, a large proportion of chronic kidney disease (CKD) patients with anemia still do not meet the hemoglobin (Hb) targets. The discovery of prolyl hydroxylase domain (PHD) enzymes as regulators of hypoxia-inducible factor (HIF)-dependent erythropoiesis has led to the development of novel therapeutic agents for renal anemia. Roxadustat, the first small-molecule HIF-PHD inhibitor, has completed the phase 3 trials. There are currently more than 15 phase 3 clinical trials worldwide assessing the efficacy and safety of roxadustat in CKD patients with anemia. This review will summarize recent findings of roxadustat in the treatment of renal anemia.SummaryAlthough the administration of erythropoiesis-stimulating agents (ESAs) and iron supplementation are a well-established and highly effective therapeutic approach for renal anemia, there are several safety concerns. Current findings from phase 2 and 3 trials suggest that roxadustat is clinically effective and well tolerated. On the one hand, roxadustat could increase endogenous erythropoietin (EPO) levels within or near physiological range in a titratable manner by inducing HIF pathway activation transiently. On the other hand, roxadustat also improves iron metabolism by decreasing serum hepcidin and increasing intestinal iron absorption, which is beneficial to functional iron deficiency and absolute iron deficiency. More importantly, the erythropoietic response of roxadustat is independent of baseline inflammatory state of CKD patients. Thus, the discovery of roxadustat will revolutionize the treatment strategy for renal anemia.Key messagesRoxadustat is an emerging and promising therapeutic approach against anemia in CKD patients, which differs from those of conventional ESAs. Roxadustat corrects anemia of CKD patients through multiple pathways, beyond elevating EPO levels within physiological range, and also by handling iron metabolism (particularly decreasing the hepcidin levels). Furthermore, the Hb response of roxadustat is independent of the inflammatory microenvironment.
| S-EPMC7154284 | biostudies-literature
Project description:BackgroundRoxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved in China for dialysis-dependent CKD anemia.MethodsThis 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 (∆Hb18-24). 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.ResultsWe randomly assigned 303 patients to roxadustat (n=151) or darbepoetin alfa (n=152). The difference between roxadustat and darbepoetin alfa in ∆Hb18-24 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.ConclusionsRoxadustat 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 numberA Study of Intermittent Oral Dosing of ASP1517 in Hemodialysis Chronic Kidney Disease Patients with Anemia, NCT02952092 (ClinicalTrials.gov).
| S-EPMC7350993 | biostudies-literature