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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 -
Journal of Pharmaceutical and... Feb 2020Erythropoiesis stimulating agents (ESAs) are a group of therapeutic glycoproteins used to treat anaemia caused by chronic kidney disease or chemotherapy. A variety of...
Erythropoiesis stimulating agents (ESAs) are a group of therapeutic glycoproteins used to treat anaemia caused by chronic kidney disease or chemotherapy. A variety of ESA products are available in the European Union, including innovator, biosimilar and second-generation medicines. Glycosylation is a critical quality attribute of ESA products, as it has a crucial influence upon in vivo biological activity. In this study, a combination of chromatography and mass spectrometry analysis has been used to characterise and compare the glycosylation profiles of five ESA products; Eprex® (epoetin alfa), NeoRecormon® (epoetin beta), Binocrit® (epoetin alfa biosimilar), Silapo (epoetin alfa biosimilar) and Aranesp® (darbepoetin alfa). The methods utilised include mixed-mode anion-exchange/hydrophilic interaction chromatography (AEX/HILIC-MS) for N-glycan identification and quantitation, and HILIC-MS for O-glycan characterisation. The products exhibit notable differences in N- and O-glycosylation, including attributes such as sialic acid occupation, O-acetylation, N-acetyllactosamine extended antennae and sulphated/penta-sialylated N-glycans, which have the potential to cause divergence of therapeutic potencies. The study highlights the need for continued monitoring of ESA product glycosylation, ideally allied to pharmacological data, in order to ensure consistency and therapeutic equivalence between products and enhance our understanding of ESA structure-activity-relationships.
Topics: Acetylation; Amino Sugars; Biosensing Techniques; Chromatography, High Pressure Liquid; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Glycosylation; Hematinics; Molecular Structure; N-Acetylneuraminic Acid; Polysaccharides; Recombinant Proteins; Tandem Mass Spectrometry
PubMed: 31838284
DOI: 10.1016/j.jpba.2019.113031 -
International Urology and Nephrology Feb 2023As a novel oral agent in treating anemia of chronic kidney disease (CKD), several clinical trials of vadadustat have been conducted to compare with darbepoetin alfa.... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
As a novel oral agent in treating anemia of chronic kidney disease (CKD), several clinical trials of vadadustat have been conducted to compare with darbepoetin alfa. This study systematically reviews and investigates the efficacy and safety of vadadustat in the anemia treatment with different duration in both nondialysis-dependent CKD (NDD-CKD) and dialysis-dependent CKD (DD-CKD).
METHODS
Several main databases were searched for randomized controlled trials (RCTs) reporting vadadustat vs darbepoetin alfa for anemia patients with CKD. The outcome indicators were focused on hemoglobin (Hb), the percentage of patients within the target Hb, the need for RBC (Red Blood Cell) transfusions, and serious adverse events (SAEs).
RESULTS
Four eligible studies with 8,026 participants were included. The changes of Hb levels from the baseline in the darbepoetin alfa group were significantly higher than that in the vadadustat group with DD-CKD (mean difference (MD) - 0.19, [95% confidence interval (CI), - 0.21 to - 0.17], p < 0.0001). In NDD-CKD patients, the changes of Hb levels in the two groups are not significantly different (MD = - 0.06, [95% CI, - 0.18 to 0.05], p = 0.006), especially, during the treatment duration of 20-36 weeks (MD = 0.02, [95% CI, - 0.04 to 0.08], p = 0.51). The percentage of patients within the target Hb was significantly lower in the vadadustat group than that in the darbepoetin alfa group in DD-CKD patients (MD = 0.9, [95% CI, 0.86 to 0.94], p < 0.00001), while in NDD-CKD patients, there was no significant difference (MD = 1.05, [95% CI, 0.99 to 1.12], p < 0.00001). In terms of safety, the two agents had no significant difference in the incidence of RBC transfusions and SAEs (RR = 1.26 [95% CI, 0.99 to 1.61], p = 0.52; RR = 0.97, [95% CI, 0.94 to 1.01], p = 0.19; respectively).
CONCLUSION
Compared to darbepoetin alfa, vadadustat had the same effect in raising the hemoglobin level in NDD-CKD patients in the short term. Vadadustat may become an effective and safe alternative for the treatment of patients with anemia and CKD, especially in NDD-CKD patients. As the application of vadadustat is still under exploration, future research should compensate for the limitations of our study to estimate the vadadustat's value.
Topics: Humans; Darbepoetin alfa; Erythropoietin; Hematinics; Anemia; Renal Insufficiency, Chronic; Hemoglobins
PubMed: 35960479
DOI: 10.1007/s11255-022-03316-z -
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 -
Chronic Diseases and Translational... Jun 2022This study was to explore the clinical efficacy and safety of darbepoetin alfa injection replacing epoetin alfa injection (recombinant human erythropoietin injection,...
Efficacy and safety of darbepoetin alfa injection replacing epoetin alfa injection for the treatment of renal anemia in Chinese hemodialysis patients: A randomized, open-label, parallel-group, noninferiority phase III trial.
BACKGROUND
This study was to explore the clinical efficacy and safety of darbepoetin alfa injection replacing epoetin alfa injection (recombinant human erythropoietin injection, rHuEPO) for the treatment of anemia associated with chronic kidney failure in Chinese patients undergoing hemodialysis.
METHOD
This study was a multicenter, randomized, open-label, intergroup parallel control phase III noninferiority trial from April 19, 2013 to September 9, 2014 at 25 sites. In this study, the members of the darbepoetin alfa group underwent intravenous administration once per week or once every two weeks. The members of the control drug epoetin alfa group underwent intravenous administration two or three times per week. All subjects underwent epoetin alfa administration during the 8-week baseline period. After that, subjects were randomly assigned to the darbepoetin alfa group or epoetin alfa group. The noninferiority in the changes of the average Hb concentrations from the baseline to the end of the evaluation period (noninferiority threshold: -1.0 g/dl) was tested between the two treatments. The time-dependent hemoglobin (Hb) concentration and the maintenance rate of the target Hb concentration (the proportion of subjects with Hb concentrations between 10.0 and 12.0 g/dl) were also evaluated. Iron metabolism, including changes in the serum iron, total iron-binding capacity, ferritin, transferrin saturation, and comparisons of the dose adjustments between the two groups during the treatment period were analyzed further. Adverse events (AEs) were also observed and compared, and the safety was analyzed between the two treatment groups. The conversion rate switching from epoetin alfa to darbepoetin alfa was also discussed. SAS® software version 9.2 was used to perform all statistical analyses. Descriptive statistics were used for all efficacy, safety, and demographic variable analyses, including for the primary efficacy indicators.
RESULTS
Four hundred and sixty-six patients were enrolled in this study, and ultimately 384 cases were analyzed for safety, including 267 cases in the darbepoetin alfa group and 117 cases in the epoetin alfa group. There were 211 cases in the per-protocol set, including 152 cases in the darbepoetin alfa group and 59 cases in the epoetin alfa group. The changes in the average Hb concentrations from the baseline to the end of the evaluation period were -0.07 and -0.15 g/dl in the darbepoetin alfa group and epoetin alfa group respectively. The difference between the two groups was 0.08 g/dl (95% confidence interval [CI]: -0.22 to 0.39), and the lower limit of the 95% CI was -0.22 > -1.0 g/dl. The average Hb concentrations of the two groups were 10.88-11.43 g/dl (darbepoetin alfa) and 10.91-11.38 g/dl (epoetin alfa) during the study period of Weeks 0-28, with the maintenance rates of the target Hb concentration ranging within 71%-87% and 78%-95% in the darbepoetin alfa group and epoetin alfa group respectively. During the period of comparison between the two groups, the incidence of AEs in the darbepoetin alfa group was 61.42%, while in the epoetin alfa group it was 56.41%. All of the adverse events and reactions in the study were those commonly associated with hemodialysis.
CONCLUSION
The overall efficacy and safety of darbepoetin alfa for the treatment of Chinese renal anemia patients undergoing hemodialysis are consistent with those of epoetin alfa.
PubMed: 35774427
DOI: 10.1002/cdt3.23 -
Annual Review of Medicine Jan 2023Red blood cells transport O from the lungs to body tissues. Hypoxia stimulates kidney cells to secrete erythropoietin (EPO), which increases red cell mass.... (Review)
Review
Red blood cells transport O from the lungs to body tissues. Hypoxia stimulates kidney cells to secrete erythropoietin (EPO), which increases red cell mass. Hypoxia-inducible factors (HIFs) mediate gene transcriptional activation. HIF-α subunits are subject to O-dependent prolyl hydroxylation and then bound by the von Hippel-Lindau protein (VHL), which triggers their ubiquitination and proteasomal degradation. Mutations in the genes encoding EPO, EPO receptor, HIF-2α, prolyl hydroxylase domain protein 2 (PHD2), or VHL cause familial erythrocytosis. In addition to O, α-ketoglutarate is a substrate for PHD2, and analogs of α-ketoglutarate inhibit hydroxylase activity. In phase III clinical trials evaluating the treatment of anemia in chronic kidney disease, HIF prolyl hydroxylase inhibitors were as efficacious as darbepoetin alfa in stimulating erythropoiesis. However, safety concerns have arisen that are focused on thromboembolism, which is also a phenotypic manifestation of VHL or HIF-2α mutation, suggesting that these events are on-target effects of HIF prolyl hydroxylase inhibitors.
Topics: Humans; Erythropoiesis; Prolyl-Hydroxylase Inhibitors; Ketoglutaric Acids; Hypoxia; Basic Helix-Loop-Helix Transcription Factors
PubMed: 35773226
DOI: 10.1146/annurev-med-042921-102602 -
European Review For Medical and... May 2021The aim of this study was to determine whether prophylactic darbepoetin alpha and/or topiramate administration could prevent bilirubin neurotoxicity (BNTx) in...
OBJECTIVE
The aim of this study was to determine whether prophylactic darbepoetin alpha and/or topiramate administration could prevent bilirubin neurotoxicity (BNTx) in experimental model of kernicterus.
MATERIALS AND METHODS
A total of 60 Wistar albino rat puppies with experimental kernicterus model were included in the study. The Kernicterus was established administering a bilirubin injection via a cisterna magna puncture 30 minutes after ip drug injection. The puppies were divided into five groups with 12 in each group as shown below: a control group, bilirubin group, darbepoetin alpha group, topiramate group and darbepoetin alpha+ topiramate group. Darbepoetin alpha and/or topiramate were administered on day 5 intraperitoneally (ip). At the 6th and 24th hours, bilirubin induced neurological dysfunction (BIND) score was used to assess behavioral changes. Hearing functions were evaluated on days 10 and 28. On day 30, the Water Maze water tank test was implemented to evaluate spatial memory. The rats were sacrificed on days 6 and 34 and apoptosis in the globus pallidus and hippocampus was examined.
RESULTS
The BIND score was improved following darbepoetin alpha treatment. Neither darbepoetin alpha nor topiramate therapy ameliorate spatial memory. There were no significant differences between groups in terms of the auditory brainstem response (ABR). The combined use of darbepoetin alpha and topiramate lead to slight decrease in apoptosis.
CONCLUSIONS
Darbepoetin alpha or topiramate administration ameliorates bilirubin induced neurological dysfunction in experimental model of kernicterus.
Topics: Animals; Apoptosis; Bilirubin; Darbepoetin alfa; Female; Maze Learning; Morris Water Maze Test; Neurons; Rats; Rats, Wistar; Topiramate
PubMed: 34002833
DOI: 10.26355/eurrev_202105_25841 -
Current Drug Safety 2022Anemia is one of the most common complications of Chronic Kidney Disease (CKD). The vast majority of Egyptian CKD patients are interchangeably treated with Darbepoetin... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Anemia is one of the most common complications of Chronic Kidney Disease (CKD). The vast majority of Egyptian CKD patients are interchangeably treated with Darbepoetin Alfa (DPA) and Epoetin Alfa (EPA) to achieve and maintain target hemoglobin levels. Our study aimed to compare the efficacy and safety of DPA versus EPA for managing anemia amongst Egyptian patients with CKD undergoing dialysis.
METHODS
A multicenter, open label, randomized, prospective, parallel study was conducted. Patients with CKD undergoing dialysis with Hb level < 10 g/dl were enrolled. The primary efficacy endpoint was the change in hemoglobin concentration at the evaluation period (weeks 20-24). Prespecified adverse events of interest following administration, including blood transfusions requirement, blood pressure and hemoglobin excursions, the relationship between C - Reactive Protein (CRP) and hemoglobin, were assessed.
RESULTS
Only 98 of 104 enrolled patients completed the study, fifty patients received EPA, and 48 patients received DPA. Our results showed that a significantly higher percentage of patients who achieved target Hb level ≥ 11 g/dL in DPA treated group vs. EPA as well as the meantime to achieve Hb level ≥ 10 g/dL was shorter in DPA treated group. Safety profiles of both treatments were similar. A negative correlation was observed between serum CRP and hemoglobin level in hemodialysis patients.
CONCLUSION
Our study showed that DPA was more effective and well tolerated in achieving and maintaining Hb levels with lower dosing frequency compared to EPA. Furthermore, CRP is recommended to be routinely measured where patients with higher CRP require high ESA doses.
Topics: Anemia; Darbepoetin alfa; Egypt; Epoetin Alfa; Erythropoietin; Hemoglobins; Humans; Kidney Failure, Chronic; Prospective Studies; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic
PubMed: 34814819
DOI: 10.2174/1568009621666211123095129 -
Nephrology, Dialysis, Transplantation :... Oct 2022Anaemia is common in chronic kidney disease (CKD) and assessment of the risks and benefits of new therapies is important. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Anaemia is common in chronic kidney disease (CKD) and assessment of the risks and benefits of new therapies is important.
METHODS
The Anaemia Study in CKD: Erythropoiesis via a Novel prolyl hydroxylase inhibitor Daprodustat-Non-Dialysis (ASCEND-ND) trial includes adult patients with CKD Stages 3-5, not using erythropoiesis-stimulating agents (ESAs) with screening haemoglobin (Hb) 8-10 g/dL or receiving ESAs with screening Hb of 8-12 g/dL. Participants were randomized to daprodustat or darbepoetin alfa (1:1) in an open-label trial (steering committee- and sponsor-blinded), with blinded endpoint assessment. The co-primary endpoints are mean change in Hb between baseline and evaluation period (average over Weeks 28-52) and time to first adjudicated major adverse cardiovascular (CV) event. Baseline characteristics were compared with those of participants in similar anaemia trials.
RESULTS
Overall, 3872 patients were randomized from 39 countries (median age 67 years, 56% female, 56% White, 27% Asian and 10% Black). The median baseline Hb was 9.9 g/dL, blood pressure was 135/74 mmHg and estimated glomerular filtration rate was 18 mL/min/1.73 m2. Among randomized patients, 53% were ESA non-users, 57% had diabetes and 37% had a history of CV disease. At baseline, 61% of participants were using renin-angiotensin system blockers, 55% were taking statins and 49% were taking oral iron. Baseline demographics were similar to those in other large non-dialysis anaemia trials.
CONCLUSION
ASCEND-ND will define the efficacy and safety of daprodustat compared with darbepoetin alfa in the treatment of patients with anaemia associated with CKD not on dialysis.
Topics: Aged; Female; Humans; Male; Anemia; Darbepoetin alfa; Erythropoietin; Hematinics; Hemoglobins; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Iron; Prolyl-Hydroxylase Inhibitors; Renal Dialysis; Renal Insufficiency, Chronic
PubMed: 34865143
DOI: 10.1093/ndt/gfab318 -
Chronic Diseases and Translational... Mar 2022Erythropoietin is a glycoprotein that mainly regulates erythropoiesis. In patients with chronic renal failure with anemia, darbepoetin alfa can stimulate erythropoiesis,...
Darbepoetin alfa injection versus epoetin alfa injection for treating anemia of Chinese hemodialysis patients with chronic kidney failure: A randomized, open-label, parallel-group, non-inferiority Phase III trail.
BACKGROUND
Erythropoietin is a glycoprotein that mainly regulates erythropoiesis. In patients with chronic renal failure with anemia, darbepoetin alfa can stimulate erythropoiesis, correct anemia, and maintain hemoglobin levels. This study was designed to demonstrate the efficacy and safety of darbepoetin alfa injections as being not inferior to epoetin alfa injections (Recombinant Human Erythropoietin injection, rHuEPO) when maintaining hemoglobin (Hb) levels within the target range (10.0-12.0 g/dL) for the treatment of renal anemia.
METHODS
Ninety-five patients were enrolled in this study from April 15, 2013 to April 10, 2014 at 25 sites. In this study, patients ( = 95) aged 18-70 years were randomized into a once per week intravenous darbepoetin alfa group ( = 56) and a twice or three times per week intravenous epoetin alfa group ( = 39) for 28 weeks, who had anemia with hemoglobin levels between 6 g/dL and 10 g/dL due to chronic kidney disease (CKD) and were undergoing hemodialysis or hemofiltration with ESA-naive (erythropoiesis stimulating agent-naive). The primary efficacy profile was the mean Hb level (the non-inferiority margin was -1.0 g/dL, week 21-28); the secondary efficacy profiles were the Hb increase rate (week 0-4), the target Hb achievement cumulative rate and time, the change trends of the Hb levels, and the target Hb maintenance ratio. Adverse events (AEs) were observed and compared, and the efficacy and safety were analyzed between the two treatment groups. Additionally, the frequencies of dose adjustments between the darbepoetin alfa and epoetin alfa groups were compared during the treatment period. SAS® software version 9.2 was used to perform all statistical analyses. Descriptive statistics were used for all efficacy, safety, and demographic variable analyses, including for the primary efficacy indicators.
RESULTS
The mean Hb level was 11.3 g/dL in the darbepoetin alfa group and 10.7 g/dL in the epoetin alfa group, respectively; the difference of the lower limits of the 95% confidence intervals (CI) between the two groups was 0.1 g/dL (>-1.0 g/dL), and non-inferiority was proven; the Hb levels started to increase in the first four weeks at a similar increase rate; no obvious differences were observed between the groups in the target Hb achievement cumulative rates, and the Hb levels as well as the target Hb level maintenance rate changed over time. The incidence of AEs was 62.5% in the darbepoetin alfa group and 76.9% in the epoetin alfa group. All the adverse events observed in the study were those commonly associated with hemodialysis.
CONCLUSION
Darbepoetin alfa intravenously once per week can effectively increase Hb levels and maintain the target Hb levels well, which makes it not inferior to epoetin alfa intravenously twice or three times per week. Darbepoetin alfa shows an efficacy and safety comparable to epoetin alfa for the treatment of renal anemia.
PubMed: 35620165
DOI: 10.1002/cdt3.13