Efficacy, tolerability and safety of darbepoetin alfa injection for the treatment of anemia associated with chronic kidney disease (CKD) undergoing dialysis: a randomized, phase-III trial.
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SUBMITTER: Sinha SD
PROVIDER: S-EPMC6417108 | biostudies-literature | 2019 Mar
REPOSITORIES: biostudies-literature
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Efficacy, tolerability and safety of darbepoetin alfa injection for the treatment of anemia associated with chronic kidney disease (CKD) undergoing dialysis: a randomized, phase-III trial.
Sinha Shubhadeep D SD Bandi Vamsi Krishna VK Bheemareddy Bala Reddy BR Thakur Pankaj P Chary Sreenivasa S Mehta Kalpana K Pinnamareddy Vikranth Reddy VR Pandey Rajendra R Sreepada Subhramanyam S Durugkar Santosh S
BMC nephrology 20190313 1
<h4>Background</h4>Darbepoetin alfa (DA-α) is a long-acting erythropoiesis-stimulating glycoprotein which has half-life three-fold longer than that of Erythropoietin alfa (EPO). The objective of this study was to compare the efficacy and safety of DA-α injection versus EPO for treating renal anemia amongst Indian patients with end-stage renal disease (ESRD) undergoing dialysis.<h4>Methods</h4>Patients of either gender (aged 18-65 years) with ESRD undergoing dialysis who had hemoglobin (Hb) level ...[more]
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Project description:BackgroundErythropoietin 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.MethodsNinety-five patients were enrolled in this study from April 15, 2013 to April 10, 2014 at 25 sites. In this study, patients (n = 95) aged 18-70 years were randomized into a once per week intravenous darbepoetin alfa group (n = 56) and a twice or three times per week intravenous epoetin alfa group (n = 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.ResultsThe 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.ConclusionDarbepoetin 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.
| S-EPMC9128564 | biostudies-literature
Project description:Standard care for treating anemia in patients with CKD includes use of erythropoiesis-stimulating agents, which sometimes involves increased risks of cardiovascular morbidity and mortality. Previous studies in patients with anemia and nondialysis-dependent CKD (NDD-CKD) found significantly elevated hemoglobin levels with use of vadadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, compared with placebo. In this phase 3, open-label, active-controlled noninferiority trial, we randomized 304 Japanese adults with anemia in NDD-CKD (including erythropoiesis-stimulating agent users and nonusers) to oral vadadustat or subcutaneous darbepoetin alfa for 52 weeks. The primary efficacy end point was average hemoglobin at weeks 20 and 24. Safety data included adverse events (AEs) and serious AEs. A total of 151 participants received vadadustat and 153 received darbepoetin alfa. Least squares mean of the average hemoglobin at weeks 20 and 24 was 11.66 (95% confidence interval [95% CI], 11.49 to 11.84) g/dl for vadadustat and 11.93 (95% CI, 11.76 to 12.10) g/dl for darbepoetin alfa. The 95% CIs for both treatments were within the target hemoglobin range (11.0-13.0 g/dl), and the lower 95% confidence limit for the difference between groups (-0.50 g/dl) was above the predefined noninferiority margin (-0.75 g/dl), demonstrating noninferiority of vadadustat to darbepoetin alfa. Similar proportions of patients in each group reported AEs and serious AEs. The most frequent AEs with vadadustat were nasopharyngitis, diarrhea, and constipation. In Japanese patients with NDD-CKD, vadadustat was noninferior to darbepoetin alfa, was effective up to week 52 in terms of average hemoglobin, and was generally well tolerated. These results suggest that vadadustat may be a potential treatment for anemia in this patient population.
| S-EPMC8425651 | biostudies-literature
Project description:To evaluate the efficacy and safety of darbepoetin alfa dosed every-other-week (Q2W) to treat anemia in subjects with chronic kidney disease (CKD), not receiving dialysis, who were naïve to erythropoiesis-stimulating agent (ESA) therapy.This was an open-label, multicenter, single-arm study enrolling ESA-naïve CKD subjects with baseline hemoglobin (Hb) < 11.0 g/dL. Q2W darbepoetin alfa treatment was initiated at a dose of 0.75 microg/kg and titrated to achieve and maintain Hb levels at 11.0-13.0 g/dL. Treatment was administered from week 1 to week 19.The primary endpoint was the proportion of subjects who achieved Hb > or = 11 g/dL at any study visit, except in week 1. Hb levels, darbepoetin alfa dose, and safety were also assessed.Of the 128 subjects who received at least one dose of darbepoetin alfa and of the subjects who completed the study, 118 (92%) and 112 (97%), respectively, achieved a Hb > or = 11 g/dL in a median time of 5 weeks. Median darbepoetin alfa dose at week 1 and at the time of achieving a Hb > or = 11 g/dL were 60 and 80 microg, respectively. Darbepoetin alfa was well-tolerated, and short-term adverse events were consistent with those expected in CKD subjects.This study demonstrates that de novo Q2W darbepoetin alfa was effective in correcting and maintaining Hb levels in ESA-naïve subjects with CKD who were not receiving dialysis. Study limitations, including lack of a control arm for the study and multiple race information for subjects, must be considered in interpreting the results.ClinicalTrials.gov, NCT00112008.
| S-EPMC3133722 | biostudies-other
Project description:Background and objectivesLarge, randomized, controlled trials targeting higher hemoglobin level with erythropoiesis-stimulating agents for Western patients with CKD showed harm. However, the effect of anemia correction using erythropoiesis-stimulating agents may differ between CKD subpopulations. The Prevention of ESKD by Darbepoetin Alfa in CKD Patients with Non-diabetic Kidney Disease study, a multicenter, randomized, open-label, parallel-group study, aimed to examine the effect of targeting hemoglobin levels of 11-13 g/dl using darbepoetin alfa with reference to a low-hemoglobin target of 9-11 g/dl on kidney outcome in patients with advanced CKD without diabetes in Japan.Design, setting, participants, & measurementsWe enrolled 491 patients with CKD without diabetes, and an eGFR of 8-20 ml/min per 1.73 m2. Of these 491 patients, 239 and 240 were ultimately assigned to the high- and low-hemoglobin groups, respectively (12 patients were excluded). The primary outcome was a kidney composite end point (starting maintenance dialysis, kidney transplantation, eGFR≤6 ml/min per 1.73 m2, and 50% reduction in eGFR).ResultsMean hemoglobin levels were 11.2±1.1 and 10.0±0.9 g/dl in the high- and low-hemoglobin groups, respectively, during the mean study period of 73.5±29.7 weeks. The kidney composite end point occurred in 105 (44%) and 116 (48%) patients in the high- and low-hemoglobin groups, respectively (log-rank test; P=0.32). The adjusted Cox proportional hazards model showed that the hazard ratio for the high- versus low-hemoglobin group was 0.78 (95% confidence interval, 0.60 to 1.03; P=0.08). Cardiovascular events occurred in 19 (8%) and 16 (7%) patients in each group, respectively, with no significant between-group difference (log-rank test; P=0.66).ConclusionsTargeting a higher hemoglobin level (11-13 g/dl) with darbepoetin alfa did not improve kidney outcome compared with targeting a lower hemoglobin level (9-11 g/dl) in patients with advanced CKD without diabetes.Clinical trial registry name and registration numberPrevention of ESKD by Darbepoetin Alfa in CKD Patients with Non-diabetic Kidney Disease (PREDICT), NCT01581073.
| S-EPMC7269223 | biostudies-literature
Project description:BackgroundHyporesponsiveness to erythropoiesis-stimulating agents (ESAs) is associated with cardiovascular events and poor renal outcome in patients with chronic kidney disease (CKD). This study aimed to investigate the initial responsiveness to darbepoetin alfa (DA) and its contributing factors using the data from the BRIGHTEN.MethodsOf 1980 patients enrolled at 168 facilities, 1695 were included in this analysis [285 patients were excluded mainly due to lack of hemoglobin (Hb) values]. The initial ESA response index (iEResI) was defined as a ratio of Hb changes over 12 weeks after DA administration per weight-adjusted total DA dose and contributing factors to iEResI were analyzed.ResultsThe mean age was 70?±?12 years (male 58.8%; diabetic nephropathy 27.6%). The median creatinine and mean Hb levels at DA initiation were 2.62 mg/dL and 9.8 g/dL, respectively. The most frequent number of DA administration during 12 weeks was 3 times (41.1%), followed by 4 (15.6%) times with a wide distribution of the total DA dose (15-900 ?g). Remarkably, 225 patients (13.3%) did not respond to DA. Multivariate analysis showed that male gender, hypoglycemic agent use, iron supplementation, high eGFR, low Hb, low CRP, low NT-proBNP, and low urinary protein-creatinine ratio were independently associated with better initial response to DA (P?=??<?0.0001, 0.0108,?<?0.0001, 0.0476,?<?0.0001, 0.0004, 0.0435, and 0.0009, respectively).ConclusionsNon-responder to DA accounted for 13.3% of patients with non-dialysis CKD. Iron supplementation, low CRP, low NT-proBNP, and less proteinuria were predictive and modifiable factors associated with better initial response to DA.
| S-EPMC7880978 | 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
Project description:BackgroundExposure to high doses or a high cumulative dose of erythropoiesis-stimulating agents (ESAs) may contribute to cardiovascular events in patients with CKD and anemia. Whether using a low fixed ESA dose versus dosing based on a hemoglobin-based, titration-dose algorithm in such patients might reduce risks associated with high ESA doses and decrease the cumulative exposure-while reducing the need for red blood cell transfusions-is unknown.MethodsIn this phase-3, randomized trial involving 756 adults with stage-3 to -5 CKD and anemia, we evaluated incidence of red blood cell transfusions for participants randomized to receive darbepoetin given as a fixed dose (0.45 µg/kg every 4 weeks) versus administered according to a hemoglobin-based, titration-dose algorithm, for up to 2 years. Participants received transfusions as deemed necessary by the treating physician.ResultsThere were 379 patients randomized to the fixed-dose group, and 377 to the titration-dose group. The percentage of participants transfused did not differ (24.1% and 24.4% for the fixed-dose and titration-dose group, respectively), with similar time to first transfusion. The titration-dose group achieved significantly higher median hemoglobin (9.9 g/dl) compared with the fixed-dose group (9.4 g/dl). The fixed-dose group had a significantly lower median cumulative dose of darbepoetin (median monthly dose of 30.9 µg) compared with the titration-dose group (53.6 µg median monthly dose). The FD and TD group received a median (Q1, Q3) cumulative dose per 4 weeks of darbepoetin of 30.9 (21.8, 40.0) µg and 53.6 (31.1, 89.9) µg, respectively; the median of the difference between treatment groups was -22.1 (95% CI, -26.1 to -18.1) µg.ConclusionsThese findings indicate no evidence of difference in incidence of red blood cell transfusion for a titration-dose strategy versus a fixed-dose strategy for darbepoetin. This suggests that a low fixed dose of darbepoetin may be used as an alternative to a dose-titration approach to minimize transfusions, with less cumulative dosing.
| S-EPMC8054895 | biostudies-literature
Project description:IntroductionRoxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for treating anemia of chronic kidney disease (CKD). This post hoc analysis of a Japanese, open-label, partially randomized, phase 3 study in nondialysis-dependent (NDD) CKD patients treated with traditional erythropoiesis-stimulating agents (ESAs) evaluated dosing trends of roxadustat and darbepoetin alfa (DA) required to maintain target hemoglobin concentrations in patients with risk factors associated with ESA hyporesponsiveness.MethodsPatients enrolled in the 1517-CL-0310 study (NCT02988973) that demonstrated noninferiority of roxadustat to DA for change in average hemoglobin levels of week 18-24 from baseline who had used human recombinant erythropoietin or DA before conversion and who were randomized to either roxadustat or DA were included. The endpoints were the average allocated dose of roxadustat and DA per administration in the last 6 weeks (AAD/6W), assessed by subgroups known to be associated with ESA hyporesponsiveness. The analysis of variance was performed by the treatment group to test the influence of subgroup factors on the AAD/6W of study drug. The ratios between the mean AAD/6W in each subgroup category and the within-arm mean AAD/6W were calculated.ResultsTwo hundred and sixty-two patients were randomized to either the roxadustat or DA comparative group and received treatment (roxadustat, n = 131; DA, n = 131). Higher mean (standard deviation) doses of both roxadustat (63.15 [24.84] mg) and DA (47.33 [29.79] μg) were required in the highest ESA resistance index (≥6.8) quartile (p = 0.003 and p < 0.001, respectively). Patients with adequate iron repletion had the lowest doses for both roxadustat (45.54 [18.01] mg) and DA (28.13 [20.98] μg). High-sensitivity C-reactive protein ≥28.57 nmol/L and the estimated glomerular filtration rate <15 mL/min/1.73 m2 were associated with requiring higher DA but not roxadustat doses.Discussion/conclusionThe roxadustat dose required to maintain target hemoglobin in NDD patients in Japan with anemia of CKD relative to DA dose may not be impacted by low-grade inflammation. Roxadustat may be beneficial for ESA-hyporesponsive NDD CKD patients.
| S-EPMC8686708 | biostudies-literature
Project description:BackgroundExtending the administration interval of erythropoiesis-stimulating agents (ESAs) represents an opportunity to improve the efficiency of anaemia management in patients with chronic kidney disease (CKD). However, effective haemoglobin (Hb) maintenance can be challenging with epoetin alfa and epoetin beta administered at extended intervals. C.E.R.A., a continuous erythropoietin receptor activator, has a unique pharmacologic profile and long half-life ( approximately 130 h), allowing administration at extended intervals. Phase III results have demonstrated that C.E.R.A. administered once every 4 weeks effectively maintains stable Hb levels in patients with CKD on dialysis.MethodsSTRIATA (Stabilizing haemoglobin TaRgets in dialysis following IV C.E.R.A. Treatment for Anaemia) was a multicentre, open-label randomized phase III study to evaluate the efficacy and safety of intravenous C.E.R.A. administered once every 2 weeks (Q2W) for Hb maintenance following direct conversion from darbepoetin alfa (DA). Adult patients on dialysis receiving stable intravenous DA once weekly (QW) or Q2W were randomized (1:1) to continue their current DA regimen (n = 156) or receive intravenous C.E.R.A. Q2W (n = 157) for 52 weeks. Doses were adjusted to maintain Hb levels within +/- 1.0 g/dl of baseline and between 10.0 and 13.5 g/dl. The primary endpoint was the mean Hb change between baseline and the evaluation period (weeks 29-36).ResultsMost patients (>80%) received DA QW before randomization. The mean (95% CI) difference between C.E.R.A. and DA in the primary endpoint was 0.18 g/dl (-0.05, 0.41), within a pre-defined non-inferiority limit. C.E.R.A. was clinically non-inferior to DA (P < 0.0001) in maintaining Hb levels. Both treatments were well tolerated.ConclusionsStable Hb levels were successfully maintained in patients on haemodialysis directly converted to Q2W intravenous C.E.R.A. from DA.
| S-EPMC2568005 | biostudies-literature
Project description:Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of anemia in chronic kidney disease (CKD). Emerging evidence suggests that roxadustat may be beneficial for patients who inadequately respond to erythropoiesis-stimulating agents (ESAs). This post-hoc analysis of a Japanese, double-blind, randomized, phase 3 study in hemodialysis-dependent CKD patients treated with traditional ESAs assessed the impact of factors associated with ESA hyporesponsiveness on roxadustat and darbepoetin alfa (DA) doses required to maintain target hemoglobin. Endpoints included mean of average doses of roxadustat and DA per administration in the last 6 weeks (AAD/6W) by prior ESA-resistance index (ERI), iron repletion (transferrin saturation; ferritin), and high-sensitivity C-reactive protein (hs-CRP). Of 415 enrolled patients, 303 were randomized (roxadustat, n = 151; DA, n = 152). Weight-adjusted AAD/6W increased with increasing ERI for roxadustat (ERI <3.3, 0.89 mg/kg; ERI ≥8.4, 1.51 mg/kg) and DA (ERI <3.3, 0.26 μg/kg; ERI ≥8.4, 0.91 μg/kg); the weight-adjusted AAD/6W relative to within-arm mean AAD/6W showed a trend toward increased DA doses for the ERI ≥8.4 category (P = .089). AAD/6W remained stable for roxadustat but increased for DA with decreasing baseline iron repletion markers. The relationship between roxadustat doses and end of treatment (EoT) hs-CRP was not significant (estimated slope, -0.494; P = .814); a trend toward increased DA doses was observed with increasing EoT hs-CRP (estimated slope, 2.973; P = .075). Roxadustat doses required to maintain target hemoglobin appear to be less affected by factors that underlie ESA hyporesponsiveness, relative to DA; roxadustat may be beneficial for patients hyporesponsive to ESAs.
| S-EPMC8451884 | biostudies-literature