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1.
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
Liu B, Chen N, Zhao J, Yin A, Wu X, Xing C, Jiang G, Fu J, Wang M, Wang R, et al
Chronic diseases and translational medicine. 2022;8(2):134-144
Abstract
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.
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2.
Comparison of darbepoetin alpha and recombinant human erythropoietin for treatment of anemia in pediatric chronic kidney disease: a non-inferiority trial from India
Mazahir R, Anand K, Pruthi PK
European journal of pediatrics. 2022
Abstract
To determine whether or not Darbepoetin alpha (DA) was non-inferior to recombinant human erythropoietin (rHuEPO) in the treatment of anemia in children with chronic kidney disease (CKD) stage 3-5 (on or not on dialysis). This was a randomized, open-label, two-arm, parallel group, active-controlled, non-inferiority trial conducted at a tertiary care center in New Delhi, India. Fifty patients of either gender (aged 1-18 years) with CKD stage 3-5 (on or not on dialysis) who had baseline hemoglobin (Hb) between 9 and 12 g/dL and were on stable erythropoietin therapy for at least 8 weeks were randomized (1:1) to either continue rHuEPO or switch to DA therapy for a period of 28 weeks. Doses were titrated in the initial 23 weeks to maintain the Hb between 11 and 12 g/dL, and efficacy was assessed between weeks 24 and 28. The primary efficacy outcome was the mean change in Hb between baseline and the evaluation period. In the intention-to-treat population (n = 50), the adjusted between-group difference in mean Hb change between the baseline and the evaluation period was 0.131 g/dL (95% CI: - 0.439 to 0.719, p = 0.629). The lower limit of the two-sided 95% CI for the difference in the mean change in Hb between the two treatment groups was well above the pre-specified non-inferiority margin of - 1.0 g/dL. Similar pattern of non-inferiority was seen for per protocol population. The safety profile of DA and rHuEPO was also comparable (injection site pain:rHuEPO-3, DA-7; p-0.296). Conclusion: DA is non-inferior to rHuEPO for the treatment of anemia of CKD (stage 3-5) in pediatric population with a comparable safety profile. Trial registration: ClinicalTrials.gov Identifier: NCT04959578 (retrospectively registered), Date: July 13, 2021. What is Known: • Limited studies showing darbepoetin alpha is effective in children as an erythropoiesis stimulating agent. • No RCT from Indian subcontinent addressing this topic. What is New: • Darbepoetin alpha is non inferior to recombinant human erythropoietin for treatment of anemia in children with CKD stage 3-5 (on or not on dialysis) with safety comparable to recombinant human erythropoietin. • A cost reduction of approximately 8.6% per patient by shifting to darbepoetin alpha.
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3.
De novo weekly and biweekly darbepoetin alfa dosing in pediatric patients with chronic kidney disease
Warady BA, Barcia J, Benador N, Jankauskiene A, Olson K, Podracka L, Shavkin A, Srivaths P, Wong CJ, Petersen J
Pediatric Nephrology (Berlin, Germany). 2017;33((1):):125-137
Abstract
BACKGROUND Darbepoetin alfa is a commonly prescribed erythropoiesis-stimulating agent (ESA) for correcting anemia in pediatric chronic kidney disease (CKD) patients. However, little information exists on its use in ESA-naive patients. This study evaluated the efficacy and safety of darbepoetin alfa in pediatric patients initiating ESA therapy. METHODS One-hundred sixteen pediatric ESA-naive subjects (aged 1-18 years) with CKD stages 3-5D and hemoglobin (Hb) <10 g/dl from 43 centers in the US, Europe, and Mexico were randomized by age (three groups) and dialysis status (yes vs. no) to receive darbepoetin alfa once weekly (QW) or every 2 weeks (Q2W) subcutaneously (not on dialysis and peritoneal dialysis subjects) and intravenously (hemodialysis subjects). The drug was titrated to achieve Hb levels of 10.0-12.0 g/dl over 25 weeks. Patient- and parent-reported health-related outcomes were measured by the Pediatric Quality of Life Inventory (PedsQL) in children ≥2 years. RESULTS In both groups, mean Hb concentrations increased to ≥11.0 g/dl over the first 3 months of treatment and remained stable within the 10.0-12.0 g/dl target range. The median time to achieve hemoglobin ≥10 g/dl was slightly longer for subjects <12 years (QW and Q2W, both 28 days) vs. those ≥12 years (23 and 22 days, respectively). Adverse event profiles were similar between groups, with QW, four (7%) and Q2W, five (9%). PedsQL scores showed modest increases. CONCLUSIONS Darbepoetin alfa can be safely administered either QW or Q2W to ESA-naive pediatric patients with CKD-related anemia to achieve Hb targets of 10.0-12.0 g/dl.
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4.
Early erythropoietin reduced the need for red blood cell transfusion in childhood hemolytic uremic syndrome: a randomized prospective pilot trial
Pape L, Ahlenstiel T, Kreuzer M, Drube J, Froede K, Franke D, Ehrich JH, Haubitz M
Pediatric Nephrology (Berlin, Germany). 2009;24((5):):1061-4.
Abstract
Childhood hemolytic uremic syndrome (HUS) is most often caused by enterohemorrhagic Escherichia coli (EHEC). Due to severe hemolysis, red blood cell (RBC) transfusions are often necessary, and anemia is aggravated by low erythropoietin (EPO) levels caused by acute renal failure. In a single center, prospective study, we randomized ten children with EHEC-positive HUS into two therapeutic groups: one receiving EPO treatment (median age 2 years, age range 1-3 years) and the other receiving standard therapy (median age 2 years, age range 1-6 years). Red blood cell transfusions were performed when the hemoglobin level (Hb) fell below 5 mg/dl. The number of RBC transfusions was compared in both groups. The Hb level at admission was comparable between both groups (6. 4 vs. 8. 1 mg/dl, P > 0. 05, t-test). However, children in the EPO group required a significantly lower mean number of RBCs than those in the non-EPO group (0. 2 vs. 1. 4, P < 0. 04, t-test). Based on these results, we suggest that the early administration of EPO at the time of hemolytic anemia and beginning renal failure may attenuate renal anemia in children with EHEC-induced HUS and thereby reduce the number of RBC transfusions required. The results of this pilot study will have to be confirmed in a larger multicenter trial.
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5.
Randomized cross-over trial comparing albumin and frusemide infusions in nephrotic syndrome
Dharmaraj R, Hari P, Bagga A
Pediatric Nephrology (Berlin, Germany). 2009;24((4):):775-82.
Abstract
The contribution of hypoalbuminemia to impaired diuretic responsiveness can be overcome by administering larger doses of loop diuretics. However, the clinical efficacy of the combination of loop-acting diuretics with human albumin remains controversial. In the study reported here, 16 children with nephrotic syndrome and refractory edema were randomized in a cross-over trial to receive either the combination of 20% human albumin and frusemide infusion (HA+FU infusion group) or frusemide infusion alone (FU infusion group). At the end of study, median urine volume was 3. 27 [95% confidence interval (CI) 2. 04-4. 50] ml/kg per hour in the HA+FU infusion group and 1. 33 (95% CI 0. 79-1. 88) ml/kg per hour in the FU infusion group (P = 0. 01); the median daily sodium excretion was 58 (95% CI 30-366) mEq and 30 (95% CI 10-122) mEq (P = 0. 08), respectively The changes in other variables included weight loss [HA+FU 5. 2% (95% CI 3. 1-8. 8); FU 0. 8% (95% CI -1. 9 to 4. 1); P = 0. 006]; urine osmolality [HA+FU 315 (95% CI 220-426) mOsm/kg; FU 368 (95% CI 318-446) mOsm/kg; P = 0. 13]; osmolal clearance [HA+FU 1600 (95% CI 916-4140) ml/day; FU 880 (95% CI 510-2105) ml/day; P = 0. 01; free water clearance [HA+FU -190 (95% CI -960 to 280) ml/day; FU -162 (95% CI -446 to -70) ml/day; P = 0. 18]. The findings from this study suggest that the co-administration of albumin and frusemide infusions is more effective than the administration of frusemide infusion alone in inducing diuresis and natriuresis in patients with nephrotic syndrome.
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6.
Population pharmacokinetic modeling of epoetin delta in pediatric patients with chronic kidney disease
Knebel W, Palmen M, Dowell JA, Gastonguay M
Journal of Clinical Pharmacology. 2008;48((7):):837-48.
Abstract
This analysis quantifies the population pharmacokinetics of subcutaneous and intravenous epoetin delta, an epoetin produced in a human cell line, in pediatric patients with chronic kidney disease and estimates the effects of covariate factors on epoetin delta and epoetin alfa pharmacokinetic parameters. Erythropoietin serum concentration data, taken from a phase III study conducted in 60 patients aged 1 to 17 years, were best described by a 1-compartment model with first-order absorption and elimination. The typical point estimates were clearance (0. 268 L/h), central volume of distribution (1. 03 L), absorption rate constant (0. 0554 h(-1)), and bioavailability (0. 708) for a 35-kg male < or = 10 years who was predialysis and on subcutaneous epoetin delta treatment. Erythropoietin pharmacokinetic parameters were similar in pediatric patients as compared with adults when scaled by weight. The subcutaneous administration of epoetin alfa exhibited lower systemic bioavailability than subcutaneous administration of epoetin delta.
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7.
Increased injection pain with darbepoetin-alpha compared to epoetin-beta in paediatric dialysis patients
Schmitt CP, Nau B, Brummer C, Rosenkranz J, Schaefer F
Nephrology, Dialysis, Transplantation. 2006;21((12):):3520-4.
Abstract
BACKGROUND Darbepoetin-alpha is applicable at longer injection intervals. Our early experience in children on peritoneal dialysis suggested increased injection pain compared to epoetin-beta, possibly due to technical differences or patient anxiety. METHODS To verify a possible difference in the painfulness of the injected fluids per se, we performed a prospective, randomized, double-blind trial in 13 paediatric end-stage renal disease patients. They received three injections of equivalent doses of darbepoetin-alpha or epoetin-beta in 0. 6 ml saline, using neutral syringes and 27G needles, at 4 week intervals. Pain perception was recorded immediately and after 30 min on a visual analogue scale (VAS, 0 = no pain, 10 = maximal pain; complemented by 5 faces for young children). RESULTS The patients perceived more intense immediate injection pain with darbepoetin-alpha than with epoetin-beta (5. 4 +/- 1 vs 2. 3 +/- 0. 6, P < 0. 05). This was confirmed by the impression of the parents (5. 3 +/- 1 vs 2. 0 +/- 0. 9, P < 0. 05) and the nurses (4. 4 +/- 1 vs 2. 2 +/- 0. 6, P < 0. 05). General injection pain was inversely related to patient age (R = -0. 77, P = 0. 001). Six patients perceived no or a mild difference in injection pain, whereas 7 subjects reported a markedly higher pain score (> or =4 VAS points) with darbepoetin-alpha. After 30 min, the injection site was largely painless with both drugs. No significant local reactions occurred with either medication (0. 3 +/- 0. 1 vs 0. 3 +/- 0. 1 on a 5-score scale). CONCLUSIONS Subcutaneous injections of darbepoetin-alpha are more painful than those of epoetin-beta in the majority of paediatric patients. The observed difference in painfulness is related to the nature of the injected compounds and may limit the subcutaneous applicability of darbepoetin-alpha in children.
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8.
Darbepoetin alfa for the treatment of anemia in pediatric patients with chronic kidney disease
Warady BA, Arar MY, Lerner G, Nakanishi AM, Stehman-Breen C
Pediatric Nephrology (Berlin, Germany). 2006;21((8):):1144-52.
Abstract
Darbepoetin alfa, an erythropoiesis-stimulating glycoprotein, has proved efficacious in the treatment of anemia of chronic kidney disease (CKD) in adult subjects. However, little information is available from pediatric populations. We conducted an open-label, non-inferiority, 28-week study comparing the efficacy of darbepoetin alfa with that of recombinant human erythropoietin (rHuEpo) in pediatric subjects with CKD. Subjects, aged 1-18, who were receiving stable rHuEpo treatment (n=124) were randomized (1:2) to either continue receiving rHuEpo or convert to darbepoetin alfa, with doses titrated to achieve and maintain hemoglobin (Hb) levels between 10. 0 and 12. 5 g/dl. Darbepoetin alfa was considered to be non-inferior to rHuEpo if the lower limit of the two-sided 95% confidence interval (CI) for the difference in the mean change in Hb between the two treatment groups was above -1. 0 g/dl. The adjusted mean change in Hb between the baseline and the evaluation period for the rHuEpo and darbepoetin alfa groups was -0. 16 g/dl and 0. 15 g/dl, respectively, with a difference of 0. 31 g/dl (95% CI: -0. 45, 1. 07) between the means. These results, and the comparable safety profiles, demonstrate that darbepoetin alfa is non-inferior to rHuEpo in the treatment of anemia in pediatric patients with CKD.
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9.
Sodium ferric gluconate complex therapy in anemic children on hemodialysis
Warady BA, Zobrist RH, Wu J, Finan E, Ferrlecit Pediatric Study Group
Pediatric Nephrology (Berlin, Germany). 2005;20((9):):1320-7.
Abstract
Pediatric patients with end-stage renal disease undergoing hemodialysis (HD) frequently develop anemia. Administration of recombinant human erythropoietin (rHuEPO) is effective in managing this anemia, although the additional demand for iron often results in iron deficiency. In adult patients undergoing HD, intravenous (IV) iron administration is known to replenish iron stores more effectively than oral iron administration. Nevertheless, IV iron supplementation is underutilized in pediatric patients, possibly because of unproved safety in this population. This international, multicenter study investigated the safety and efficacy of two dosing regimens (1. 5 mg kg(-1) and 3. 0 mg kg(-1)) of sodium ferric gluconate complex (SFGC) therapy, during eight consecutive HD sessions, in iron-deficient pediatric HD patients receiving concomitant rHuEPO therapy. Safety was evaluated in 66 patients and efficacy was evaluated in 56 patients. Significant increases from baseline were observed in both treatment groups 2 and 4 weeks after cessation of SFGC dosing for mean hemoglobin, hematocrit, transferrin saturation, serum ferritin, and reticulocyte hemoglobin content. Efficacy and safety profiles were comparable for 1. 5 mg kg(-1) and 3. 0 mg kg(-1) SFGC with no unexpected adverse events with either dose. Administration of SFGC was safe and efficacious in the pediatric HD population. Given the equivalent efficacy of the two doses, an initial dosing regimen of 1. 5 mg kg(-1) is recommended for pediatric HD patients.
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10.
Intermittent versus maintenance iron therapy in children on hemodialysis: a randomized study
Ruiz-Jaramillo Mde L, Guízar-Mendoza JM, Gutiérrez-Navarro Mde J, Dubey-Ortega LA, Amador-Licona N
Pediatric Nephrology (Berlin, Germany). 2004;19((1):):77-81.
Abstract
In patients with renal anemia, iron therapy can be administered intermittently or regularly at a low dose. We performed a randomized clinical trial in pediatric patients with end-stage renal failure on hemodialysis and absolute or functional iron deficiency. The study group received maintenance iron therapy according to the ferritin serum levels and the control group received intermittent 10-weekly doses. Success was defined as stabilization of ferritin levels between 100 and 800 microg/l and transferrin saturation (TSAT) between 20% and 50%, in addition to an increase in the hemoglobin level. The major reason for exclusion was iron overload. The study group received 6 mg/kg per month of parenteral iron [95% confidence interval (CI) 3. 3-8. 8] and the control group 14. 4 mg/kg per month (95% CI 12-16. 8) ( P<0. 001). After 4 months of treatment, ferritin levels increased to 66 microg/l (95% CI 69-200) in the study group and to 334 microg/l (95% CI 145-522) in the control group ( P=0. 009). Maintenance therapy and intermittent weekly doses were successful in 73% and 38%, respectively. After 3 months of treatment, hemoglobin levels increased to 10 g/dl, with no difference between the groups. However, in the control group the increase in hemoglobin levels was unsustained, and 3 patients needed transfusion. Patients in the control group had a higher risk of iron overload than patients in the study group (70% vs. 19%). Thus, the regimen based on assessment of serum ferritin levels was more efficient than the intermittent regimen because it increased and maintained the hemoglobin levels with lower iron doses and a lower risk of iron overload.