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Advances in Therapy Oct 2021This integrated phase 3 analysis examined efficacy and cardiovascular safety for roxadustat vs erythropoiesis-stimulating agents (ESAs) in dialysis-dependent patients. (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
This integrated phase 3 analysis examined efficacy and cardiovascular safety for roxadustat vs erythropoiesis-stimulating agents (ESAs) in dialysis-dependent patients.
METHODS
Efficacy and safety results from four phase 3, randomized, open-label studies comparing roxadustat to ESAs (PYRENEES, SIERRAS, HIMALAYAS, ROCKIES) in dialysis-dependent patients with anemia of chronic kidney disease (CKD) were evaluated by study, pooled population and in two subgroups: incident dialysis and stable dialysis. The primary efficacy endpoint per study was hemoglobin change from baseline (CFB) to weeks 28-36 using least-squares mean difference (LSMD) without rescue therapy. Pooled safety endpoints included time to major adverse cardiovascular event (MACE; myocardial infarction, stroke, and all-cause mortality [ACM]) and MACE+ (MACE plus congestive heart failure or unstable angina requiring hospitalization), ACM, and treatment-emergent adverse events (TEAEs). MACE and MACE+ were evaluated for non-inferiority at 1.8 and 1.3 margins using hazard ratios (HRs) and 95% confidence intervals (CIs). TEAEs were descriptively summarized.
RESULTS
In total, 4714 patients were randomized (2354 roxadustat; 2360 ESA). Hemoglobin CFB to weeks 28-36 achieved non-inferiority for roxadustat vs ESA in each study. Roxadustat was non-inferior to ESA for risks for MACE and MACE+ in the entire cohort (MACE: HR 1.09, 95% CI 0.95-1.26; MACE+ : HR 0.98, 95% CI 0.86-1.11) and similar to the incident dialysis and stable dialysis subgroups; ACM results were consistent with MACE and MACE+ (HR 1.13, 95% CI 0.95-1.34). TEAEs were generally comparable between groups.
CONCLUSION
Roxadustat improved hemoglobin similarly to ESA while demonstrating comparable cardiovascular and overall safety profiles in a wide spectrum of dialysis-dependent patients with anemia of CKD. Roxadustat represents an oral alternative to ESAs for achieving a target hemoglobin for anemia of CKD in dialysis-dependent patients.
Topics: Erythropoietin; Glycine; Hematinics; Hemoglobins; Humans; Isoquinolines; Renal Dialysis; Renal Insufficiency, Chronic
PubMed: 34523074
DOI: 10.1007/s12325-021-01903-7 -
Journal of the American Society of... Jul 2020Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved in China for dialysis-dependent CKD anemia. (Comparative Study)
Comparative Study
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). 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 (=151) or darbepoetin alfa (=152). The difference between roxadustat and darbepoetin alfa in Hb 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).
Topics: Adult; Aged; Aged, 80 and over; Anemia; Contusions; Darbepoetin alfa; Diarrhea; Double-Blind Method; Female; Ferritins; Glycine; Hematinics; Hemoglobins; Hepcidins; Humans; Iron; Isoquinolines; Japan; Male; Middle Aged; Nasopharyngitis; Renal Dialysis; Renal Insufficiency, Chronic; Retinal Hemorrhage; Time Factors; Transferrin; Vomiting; Young Adult
PubMed: 32493693
DOI: 10.1681/ASN.2019060623 -
Clinical and Experimental Nephrology Sep 2023In the primary analysis of the PREDICT trial, a higher hemoglobin target (11-13 g/dl) with darbepoetin alfa did not improve renal outcomes compared with a lower... (Randomized Controlled Trial)
Randomized Controlled Trial
Higher hemoglobin levels using darbepoetin alfa and kidney outcomes in advanced chronic kidney disease without diabetes: a prespecified secondary analysis of the PREDICT trial.
BACKGROUND
In the primary analysis of the PREDICT trial, a higher hemoglobin target (11-13 g/dl) with darbepoetin alfa did not improve renal outcomes compared with a lower hemoglobin target (9-11 g/dl) in advanced chronic kidney disease (CKD) without diabetes. Prespecified secondary analyses were performed to further study the effects of targeting higher hemoglobin levels on renal outcomes.
METHODS
Patients with an estimated glomerular filtration rate (eGFR) 8-20 ml/min/1.73 m without diabetes were randomly assigned 1:1 to the high- and low-hemoglobin groups. The differences between the groups were evaluated for the following endpoints and cohort sets: eGFR and proteinuria slopes, assessed using a mixed-effects model in the full analysis set and the per-protocol set that excluded patients with off-target hemoglobin levels; the primary endpoint of composite renal outcome, evaluated in the per-protocol set using the Cox model.
RESULTS
In the full analysis set (high hemoglobin, n = 239; low hemoglobin, n = 240), eGFR and proteinuria slopes were not significantly different between the groups. In the per-protocol set (high hemoglobin, n = 136; low hemoglobin, n = 171), the high-hemoglobin group was associated with reduced composite renal outcome (adjusted hazard ratio: 0.64; 95% confidence interval: 0.43-0.96) and an improved eGFR slope (coefficient: + 1.00 ml/min/1.73 m/year; 95% confidence interval: 0.38-1.63), while the proteinuria slope did not differ between the groups.
CONCLUSIONS
In the per-protocol set, the high-hemoglobin group demonstrated better kidney outcomes than the low-hemoglobin group, suggesting a potential benefit of maintaining higher hemoglobin levels in patients with advanced CKD without diabetes.
CLINICAL TRIAL REGISTRATION
Clinicaltrials.gov (identifier: NCT01581073).
Topics: Humans; Darbepoetin alfa; Anemia; Renal Insufficiency, Chronic; Kidney; Hemoglobins; Proteinuria; Neoplasms; Diabetes Mellitus
PubMed: 37289335
DOI: 10.1007/s10157-023-02362-w -
Clinical Kidney Journal May 2021Hypoxia-inducible factor prolyl-hydroxylase inhibitors belong to a new class of orally administered drugs for treating anemia in patients with chronic kidney disease...
Hypoxia-inducible factor prolyl-hydroxylase inhibitors belong to a new class of orally administered drugs for treating anemia in patients with chronic kidney disease (CKD). The prevalence of hypothyroidism is disproportionately high in patients with CKD on hemodialysis. We report a rapid suppression of thyroid-stimulating hormone (TSH) and decrease in free triiodothyronine (T3) and free tetraiodothyronine levels after switching from darbepoetin alfa to roxadustat in a hemodialysis patient with hypothyroidism on levothyroxine therapy. This was reversed after stopping roxadustat. Roxadustat has structural similarity with T3 and is a selective activating ligand for thyroid hormone receptor-β possibly suppressing TSH release.
PubMed: 33959275
DOI: 10.1093/ckj/sfab007 -
Journal of the American Society of... Nov 2020
Topics: Anemia; Darbepoetin alfa; Double-Blind Method; Glycine; Humans; Isoquinolines; Japan; Renal Dialysis; Renal Insufficiency, Chronic
PubMed: 32915765
DOI: 10.1681/ASN.2020071096 -
The Journal of Veterinary Medical... Apr 2021Iron metabolism, hepcidin and some blood profiles were investigated in 13 healthy and 31 chronic kidney disease (CKD) dogs. The study consisted of 2 experiments,...
Iron metabolism, hepcidin and some blood profiles were investigated in 13 healthy and 31 chronic kidney disease (CKD) dogs. The study consisted of 2 experiments, experiment I included healthy dogs (CONT) and CKD dogs (stage 2, 3 and 4), while experiment II consisted of anemic CKD dogs subjected to 28-day darbepoetin alfa treatment. The response to darbepoetin alfa could divide anemic CKD dogs into responder (RP) and non-responder (NRP) subgroups. The results from experiment I showed that packed cell volume (PCV) and plasma albumin concentration were significantly lower in CKD dogs of all stages while the total iron binding capacity (TIBC) was lower in only CKD stage 3 and 4 compared with dogs in CONT group. The PCV was related to both TIBC and albumin when considering among all dogs or only in CKD dogs. The hepcidin concentration in CKD dogs with anemia was lower than those without anemia (P<0.05). In experiment II before darbepoetin alfa treatment, RP subgroup had significantly higher iron and TIBC compared with NRP subgroup (P<0.05), the iron concentration was decreased only in RP subgroup after darbepoetin alfa treatment (P<0.05). The percent increase in PCV was correlated with initial TIBC (P<0.01). Plasma hepcidin concentration was not different between CONT and CKD groups and between RP and NRP subgroups both before and after darbepoetin alfa treatment. It is concluded that TIBC and plasma iron concentration play role on anemia and erythropoietic response to darbepoetin alfa treatment in CKD dogs.
Topics: Animals; Darbepoetin alfa; Dog Diseases; Dogs; Erythropoiesis; Erythropoietin; Hemoglobins; Iron; Renal Insufficiency, Chronic
PubMed: 33563860
DOI: 10.1292/jvms.20-0574 -
Journal of the American Society of... Jun 2019Despite the widespread use of erythropoietin-stimulating agents (ESAs) to treat anemia in patients undergoing hemodialysis, the relative mortality risks associated with... (Comparative Study)
Comparative Study
BACKGROUND
Despite the widespread use of erythropoietin-stimulating agents (ESAs) to treat anemia in patients undergoing hemodialysis, the relative mortality risks associated with use of different types of ESAs are unknown.
METHODS
To compare the mortality risk associated with use of short-acting ESAs versus long-acting ESAs, we conducted a nationwide cohort study of 194,698 hemodialysis patients in Japan who received either a short-acting (epoetin / or epoetin ) or a long-acting (darbepoetin or epoetin β pegol) ESA. Study outcomes were 2-year all-cause and cause-specific mortality. In addition to Cox proportional hazards models, we performed an instrumental variable analysis in which facility-level long-acting ESA prescription rates were taken as the instrumental variable.
RESULTS
During the 2-year follow-up period, 31,557 deaths occurred. In a multivariable Cox model, long-acting ESA users had a 13% higher rate of deaths compared with short-acting ESA users, a significant difference (<0.001). Similar results were obtained in other analyses. This difference in risk was pronounced among patients receiving high doses of ESA (for whom the adjusted 2-year number needed to harm for death was 30.8). Long-acting ESA use was associated with an increased rate of death from cardiovascular diseases, infection, and malignancies. In the instrumental variable analysis, long-acting ESA users remained at a significantly higher risk of death. Compared with anemic (hemoglobin 9.0-9.9 g/dl) short-acting ESA users, long-acting ESA users who achieved more optimal hemoglobin levels (10.0-10.9 g/dl) showed a higher mortality rate.
CONCLUSIONS
Among patients undergoing hemodialysis, use of long-acting ESAs might be associated with a higher risk of death than use of short-acting ESAs.
Topics: Aged; Anemia; Cause of Death; Cohort Studies; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Administration Schedule; Epoetin Alfa; Female; Humans; Japan; Kidney Failure, Chronic; Male; Middle Aged; Multivariate Analysis; Prognosis; Proportional Hazards Models; Registries; Renal Dialysis; Retrospective Studies; Risk Assessment; Survival Analysis; Treatment Outcome
PubMed: 31015255
DOI: 10.1681/ASN.2018101007 -
American Journal of Kidney Diseases :... Jul 2015Epoetin alfa (EPO) and darbepoetin alfa (DPO) are erythropoiesis-stimulating agents that are widely and interchangeably used for the treatment of anemia in patients with... (Comparative Study)
Comparative Study Meta-Analysis Review
BACKGROUND
Epoetin alfa (EPO) and darbepoetin alfa (DPO) are erythropoiesis-stimulating agents that are widely and interchangeably used for the treatment of anemia in patients with advanced chronic kidney disease and end-stage renal disease. No study has specifically compared the risks of hard study outcomes between EPO and DPO, including mortality.
STUDY DESIGN
Systematic review of the literature and meta-analysis.
SETTING & POPULATION
Patients enrolled in randomized trials comparing EPO versus DPO for the treatment of anemia in adults with chronic kidney disease, including those requiring dialysis.
SELECTION CRITERIA FOR STUDIES
We conducted a systematic search of the literature (PubMed, CENTRAL, SCOPUS, and EMBASE, all years) and industry resources, using predefined search terms and data abstraction tools. We then summarized key characteristics and findings of these trials and performed a random-effects meta-analysis of trials with at least 3 months' duration to identify the summary OR of mortality between patients randomly assigned to DPO versus EPO.
INTERVENTION
DPO versus EPO.
OUTCOME
All-cause mortality.
RESULTS
We identified 9 trials that met the stated inclusion criteria. Overall, 2,024 patients were included in the meta-analysis, of whom 126 died during follow-up, which ranged from 20 to 52 weeks. We found no significant difference in mortality between patients randomly assigned to DPO versus EPO (OR, 1.33; 95% CI, 0.88-2.01). No treatment heterogeneity across studies was detected (Q statistic=4.60; P=0.8).
LIMITATIONS
Generalizability to nontrial populations is uncertain.
CONCLUSIONS
Few trials directly comparing DPO and EPO have been conducted and follow-up was limited. In aggregate, no effect of specific erythropoiesis-stimulating agent on mortality was identified, but the confidence limits were wide and remained compatible with considerable harm from DPO. Absent adequately powered randomized trials, observational postmarketing comparative effectiveness studies comparing these erythropoiesis-stimulating agents are required to better characterize the long-term safety profiles of these agents.
Topics: Anemia; Cause of Death; Darbepoetin alfa; Double-Blind Method; Epoetin Alfa; Erythropoietin; Half-Life; Hematinics; Humans; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic
PubMed: 25636816
DOI: 10.1053/j.ajkd.2014.12.012 -
Erythropoietic effects of vadadustat in patients with anemia associated with chronic kidney disease.American Journal of Hematology Sep 2022Patients with chronic kidney disease (CKD) develop anemia largely because of inappropriately low erythropoietin (EPO) production and insufficient iron available to...
Patients with chronic kidney disease (CKD) develop anemia largely because of inappropriately low erythropoietin (EPO) production and insufficient iron available to erythroid precursors. In four phase 3, randomized, open-label, clinical trials in dialysis-dependent and non-dialysis-dependent patients with CKD and anemia, the hypoxia-inducible factor prolyl hydroxylase inhibitor, vadadustat, was noninferior to the erythropoiesis-stimulating agent, darbepoetin alfa, in increasing and maintaining target hemoglobin concentrations. In these trials, vadadustat increased the concentrations of serum EPO, the numbers of circulating erythrocytes, and the numbers of circulating reticulocytes. Achieved hemoglobin concentrations were similar in patients treated with either vadadustat or darbepoetin alfa, but compared with patients receiving darbepoetin alfa, those receiving vadadustat had erythrocytes with increased mean corpuscular volume and mean corpuscular hemoglobin, while the red cell distribution width was decreased. Increased serum transferrin concentrations, as measured by total iron-binding capacity, combined with stable serum iron concentrations, resulted in decreased transferrin saturation in patients randomized to vadadustat compared with patients randomized to darbepoetin alfa. The decreases in transferrin saturation were associated with relatively greater declines in serum hepcidin and ferritin in patients receiving vadadustat compared with those receiving darbepoetin alfa. These results for serum transferrin saturation, hepcidin, ferritin, and erythrocyte indices were consistent with improved iron availability in the patients receiving vadadustat. Thus, overall, vadadustat had beneficial effects on three aspects of erythropoiesis in patients with anemia associated with CKD: increased endogenous EPO production, improved iron availability to erythroid cells, and increased reticulocytes in the circulation.
Topics: Anemia; Clinical Trials, Phase III as Topic; Darbepoetin alfa; Erythropoiesis; Erythropoietin; Ferritins; Glycine; Hematinics; Hemoglobins; Hepcidins; Humans; Iron; Picolinic Acids; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Transferrins
PubMed: 35751858
DOI: 10.1002/ajh.26644 -
Oncology (Williston Park, N.Y.) Oct 2002Studies on human erythropoietin (EPO) demonstrated that there is a direct relationship between the sialic acid-containing carbohydrate content of the molecule and its... (Review)
Review
Studies on human erythropoietin (EPO) demonstrated that there is a direct relationship between the sialic acid-containing carbohydrate content of the molecule and its serum half-life and in vivo biological activity, but an inverse relationship with its receptor-binding affinity. These observations led to the hypothesis that increasing the carbohydrate content, beyond that found naturally, would lead to a molecule with enhanced biological activity. Hyperglycosylated recombinant human EPO (rHuEPO) analogs were developed to test this hypothesis. Darbepoetin alfa (Aranesp), which was engineered to contain five N-linked carbohydrate chains (two more than rHuEPO), has been evaluated in preclinical animal studies. Due to its increased sialic acid-containing carbohydrate content, darbepoetin alfa is biochemically distinct from rHuEPO, having an increased molecular weight and greater negative charge. Compared with rHuEPO, it has an approximate threefold longer serum half-life, greater in vivo potency, and can be administered less frequently to obtain the same biological response. Darbepoetin alfa is currently being evaluated in human clinical trials for treatment of anemia and reduction in its incidence.
Topics: Animals; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Design; Erythropoietin; Humans; Quantitative Structure-Activity Relationship
PubMed: 12435169
DOI: No ID Found