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Radiotherapy and Oncology : Journal of... Apr 2018To evaluate if correction of low hemoglobin (Hb) levels by means of darbepoetin alfa improves the outcomes of radiotherapy in patients with squamous cell carcinoma of... (Randomized Controlled Trial)
Randomized Controlled Trial
DAHANCA 10 - Effect of darbepoetin alfa and radiotherapy in the treatment of squamous cell carcinoma of the head and neck. A multicenter, open-label, randomized, phase 3 trial by the Danish head and neck cancer group.
PURPOSE
To evaluate if correction of low hemoglobin (Hb) levels by means of darbepoetin alfa improves the outcomes of radiotherapy in patients with squamous cell carcinoma of the head and neck (HNSCC).
PATIENTS AND METHODS
Patients eligible for primary radiotherapy and who had Hb values below 14.0 g/dl were randomized to receive accelerated fractionated radiotherapy with or without darbepoetin alfa. Patients also received the hypoxic radiosensitizer nimorazole. Darbepoetin alfa was given weekly during radiotherapy or until the Hb value exceeded 15.5 g/dl.
RESULTS
Following a planned interim analysis which showed inferiority of the experimental treatment the trial was stopped after inclusion of 522 patients (of a planned intake of 600). Of these, 513 were eligible for analysis (254 patients treated with darbepoetin alfa and 259 patients in the control group). Overall, the patients were distributed according to the stratification parameters (gender, T and N staging, tumor site). Treatment with darbepoetin alfa increased the Hb level to the planned value in 81% of the patients. The compliance was good without excess serious adverse events. The results showed a poorer outcome with a 5-year cumulative loco-regional failure rate of 47% vs. 34%, Hazard Ratio (HR): 1.53 [1.16-2.02], for the darbepoetin alfa vs. control arm, respectively. This was also seen for the endpoints of event-free survival (HR: 1.36 [1.09-1.69]), disease-specific death (HR: 1.43 [1.08-1.90]), and overall survival (HR: 1.30 [1.02-1.64]). There was no enhanced risk of cardio-vascular events observed in the experimental arm or any significant differences in acute or late radiation related morbidity. All univariate analyses were confirmed in a multivariate setting.
CONCLUSION
Correction of the Hb level with darbepoetin alfa during radiotherapy of patients with HNSCC resulted in a significantly poorer tumor control and survival.
Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Squamous Cell; Darbepoetin alfa; Disease-Free Survival; Dose Fractionation, Radiation; Female; Head and Neck Neoplasms; Hemoglobins; Humans; Male; Middle Aged; Nimorazole; Oxygen; Patient Compliance; Radiation-Sensitizing Agents; Squamous Cell Carcinoma of Head and Neck
PubMed: 29523409
DOI: 10.1016/j.radonc.2018.02.018 -
Journal of the American Society of... Feb 2021Exposure to high doses or a high cumulative dose of erythropoiesis-stimulating agents (ESAs) may contribute to cardiovascular events in patients with CKD and anemia.... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Exposure 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.
METHODS
In 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 g/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.
RESULTS
There 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 g) compared with the titration-dose group (53. 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) g and 53.6 (31.1, 89.9) g, respectively; the median of the difference between treatment groups was -22.1 (95% CI, -26.1 to -18.1) g.
CONCLUSIONS
These 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.
Topics: Aged; Aged, 80 and over; Algorithms; Anemia; Darbepoetin alfa; Drug Administration Schedule; Erythrocyte Transfusion; Female; Hematinics; Hemoglobins; Humans; Male; Middle Aged; Renal Insufficiency, Chronic
PubMed: 33288629
DOI: 10.1681/ASN.2020050556 -
Pharmacotherapy Apr 2007To compare the effectiveness of darbepoetin alfa with epoetin alfa (recombinant human erythropoietin [rHuEPO]) for achieving transfusion independence and increasing... (Clinical Trial)
Clinical Trial Comparative Study
STUDY OBJECTIVE
To compare the effectiveness of darbepoetin alfa with epoetin alfa (recombinant human erythropoietin [rHuEPO]) for achieving transfusion independence and increasing hemoglobin concentrations in critically ill patients.
DESIGN
Retrospective, descriptive study.
SETTING
Level I trauma center intensive care units.
PATIENTS
Seventy-two patients who spent at least 3 days in the cardio-thoracic, medical, or surgery-trauma intensive care units and received at least one weekly dose of rHuEPO 40,000 units (33 patients) or darbepoetin alfa 100 microg (39 patients).
MEASUREMENTS AND MAIN RESULTS
Number of rHuEPO and darbepoetin alfa doses, hemoglobin concentrations, and cumulative number of transfusions were recorded for up to 28 days after the first dose was given, and the data were statistically analyzed. Beginning a median of 10 days after the patients were admitted to the intensive care unit, they received a median of 3.5 doses of darbepoetin alfa or 4 doses of rHuEPO. Mean hemoglobin concentrations at which treatment with darbepoetin alfa and rHuEPO were started were 8 and 8.2 g/dl, respectively (p=0.41). Transfusion independence was achieved in 44% of patients in the darbepoetin alfa group compared with 36% of patients in the rHuEPO group (p=0.63). Patients in both groups received a mean of 2.7 units of packed red blood cells during the 28-day study period. The mean change in hemoglobin levels from baseline over time did not significantly differ between groups (p=0.75).
CONCLUSIONS
Patients receiving darbepoetin alfa 100 microg/week and those receiving rHuEPO 40,000 units/week for anemia of critical illness achieved similar rates of transfusion independence and increases in hemoglobin concentrations from baseline at 28 days. Compared with previously published studies, erythropoietic agents were administered late in the course of critical illness in response to low hemoglobin concentrations.
Topics: Adult; Aged; Anemia; Blood Transfusion; Critical Care; Critical Illness; Darbepoetin alfa; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Intensive Care Units; Iron Compounds; Male; Middle Aged; Recombinant Proteins; Retrospective Studies; Time Factors; Trauma Centers; Treatment Outcome
PubMed: 17381380
DOI: 10.1592/phco.27.4.535 -
Pediatric Nephrology (Berlin, Germany) Nov 2002Darbepoetin alfa is a novel erythropoiesis-stimulating protein with a two- to threefold longer half-life than recombinant human erythropoietin (epoetin) in adult... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Darbepoetin alfa is a novel erythropoiesis-stimulating protein with a two- to threefold longer half-life than recombinant human erythropoietin (epoetin) in adult patients with chronic kidney disease (CKD). This randomized, open-label, crossover study was conducted to determine the pharmacokinetic profile of darbepoetin alfa in pediatric patients with CKD. Twelve patients 3-16 years of age with CKD were randomized and received a single 0.5 micro g/kg dose of darbepoetin alfa administered intravenously (IV) or subcutaneously (SC). After a 14- to 16-day washout period, patients received an identical dose of darbepoetin alfa by the alternate route. After IV administration, the mean clearance of darbepoetin alfa was 2.3 ml/h per kg, with a mean terminal half-life of 22.1 h. After SC administration, absorption was rate limiting, with a mean terminal half-life of 42.8 h and a mean bioavailability of 54%. Comparison of these results with those from a previous study of darbepoetin alfa in adult patients indicated that the disposition of darbepoetin alfa administered IV or SC is similar in adult and pediatric patients, although absorption may be slightly more rapid in pediatric patients after SC dosing. The mean terminal half-life of darbepoetin alfa in this study was approximately two- to fourfold longer than that previously reported for epoetin in pediatric patients.
Topics: Adolescent; Adult; Area Under Curve; Biological Availability; Child; Child, Preschool; Cross-Over Studies; Darbepoetin alfa; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Half-Life; Humans; Infant; Injections, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Renal Dialysis
PubMed: 12432437
DOI: 10.1007/s00467-002-0932-0 -
British Journal of Haematology Jul 2011
Clinical Trial
Topics: Adolescent; Adult; Anemia; Darbepoetin alfa; Erythropoietin; Female; Hematinics; Humans; Male; Young Adult; beta-Thalassemia
PubMed: 21496003
DOI: 10.1111/j.1365-2141.2011.08617.x -
PloS One 2020Renal anemia is predominantly caused by a relative deficiency in erythropoietin (EPO). Conventional treatment for renal anemia includes the use of recombinant human EPO...
Renal anemia is predominantly caused by a relative deficiency in erythropoietin (EPO). Conventional treatment for renal anemia includes the use of recombinant human EPO (rhEPO) or a long-acting erythropoiesis-activating agent named darbepoetin alfa, which is a modified rhEPO with a carbohydrate chain structure that differs from native hEPO. We have developed a biosimilar to darbepoetin alfa designated JR-131. Here, we comprehensively compare the physicochemical and biological characteristics of JR-131 to darbepoetin alfa. JR-131 demonstrated similar protein structure to the originator, darbepoetin alfa, by peptide mapping and circular dichroism spectroscopy. Additionally, mass spectroscopic analyses and capillary zone electrophoresis revealed similar glycosylation patterns between the two products. Human bone marrow-derived erythroblasts differentiated and proliferated to form colonies with JR-131 to a similar degree as darbepoetin alfa. Finally, JR-131 stimulated erythropoiesis and improved anemia in rats similarly to darbepoetin alfa. Our data show the similarity in physicochemical and biological properties of JR-131 to those of darbepoetin alfa, and JR-131 therefore represents a biosimilar for use in the treatment of renal anemia.
Topics: Anemia; Animals; Biosimilar Pharmaceuticals; CHO Cells; Cricetinae; Cricetulus; Darbepoetin alfa; Disease Models, Animal; Electrophoresis, Capillary; Erythropoiesis; Glycosylation; Kidney; Male; Molecular Weight; Nephrectomy; Peptide Mapping; Protein Structure, Secondary; Rats, Sprague-Dawley; Sugars; Treatment Outcome
PubMed: 32302352
DOI: 10.1371/journal.pone.0231830 -
Advances in Therapy 2007It is well known that epoetin alfa increases serum endothelin (ET)-1 and blood pressure. No data are available, however, on the effects of darbepoetin alfa on serum ET-1... (Clinical Trial)
Clinical Trial Comparative Study
It is well known that epoetin alfa increases serum endothelin (ET)-1 and blood pressure. No data are available, however, on the effects of darbepoetin alfa on serum ET-1 and blood pressure. This study was conducted to compare the effects of darbepoetin alfa and epoetin alfa on serum ET-1 and blood pressure in patients on hemodialysis (HD). A total of 42 patients on HD were included in the study. Serum samples for measuring levels of ET-1 were taken 30 min after administration of epoetin alfa. After blood samples had been taken from all patients, epoetin alfa was changed to darbepoetin alfa. Three months after the start of darbepoetin alfa treatment, blood samples were taken to measure the same parameters. Mean arterial blood pressure was measured before recombinant human erythropoietin (EPO) administration and 30 min after EPO administration while patients were taking epoetin alfa or darbepoetin alfa. Injection of epoetin alfa or darbepoetin alfa significantly increased serum ET-1 levels compared with levels in those patients who were not on EPO therapy (P<.05). When the effects of epoetin alfa on serum ET-1 level were compared with those of darbepoetin alfa, the 2 types of EPO were found to increase serum ET-1 levels similarly (P>.05). Administration of epoetin alfa or darbepoetin alfa increased systolic and diastolic blood pressures significantly over values in the control group (P<.05). Serum systolic and diastolic blood pressures increased similarly after injection of epoetin alfa or darbepoetin alfa. Administration of darbepoetin alfa increased blood pressure in patients on HD in a way that was positively correlated with enhanced ET-1 release; a similar correlation was noted with epoetin alfa.
Topics: Blood Pressure; Darbepoetin alfa; Endothelin-1; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Recombinant Proteins; Renal Dialysis
PubMed: 17565925
DOI: 10.1007/BF02849903 -
Clinical Journal of the American... Apr 2011Quality of life (QOL) is markedly impaired in patients with anemia, diabetes mellitus, and chronic kidney disease. Limited data exist regarding the effect of anemia... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND OBJECTIVES
Quality of life (QOL) is markedly impaired in patients with anemia, diabetes mellitus, and chronic kidney disease. Limited data exist regarding the effect of anemia treatment on patient perceptions. The objectives were to determine the longitudinal impact of anemia treatment on quality of life in patients with diabetes and chronic kidney disease and to determine the predictors of baseline and change in QOL.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
In a large, double blind study, patients with type 2 diabetes mellitus, nondialysis chronic kidney disease (estimated GFR, 20 to 60 ml/min per 1.73 m(2)), and anemia (hemoglobin 10.4 g/dl) were randomized to darbepoetin alfa or placebo. QOL was measured with Functional Assessment of Cancer Therapy-Fatigue, Short Form-36, and EuroQol scores over 97 weeks.
RESULTS
Patients randomized to darbepoetin alfa reported significant improvements compared with placebo patients in Functional Assessment of Cancer Therapy-Fatigue, and EuroQol scores visual analog scores, persisting through 97 weeks. No consistent differences in Short Form-36 were noted. Consistent predictors of worse change scores include lower activity level, older age, pulmonary disease, and duration of diabetes. Interim stroke had a substantial negative impact on fatigue and physical function.
CONCLUSION
Darbepoetin alfa confers a consistent, but small, improvement in fatigue and overall quality of life but not in other domains. These modest QOL benefits must be considered in the context of neutral overall effect and increased risk of stroke in a small proportion of patients. Patient's QOL and potential treatment risk should be considered in any treatment decision.
Topics: Aged; Anemia; Darbepoetin alfa; Diabetes Complications; Double-Blind Method; Erythropoietin; Female; Health Status; Humans; Kidney Diseases; Male; Middle Aged; Quality of Life
PubMed: 21212421
DOI: 10.2215/CJN.06450710 -
The New England Journal of Medicine Feb 2010
Topics: Adult; Anemia; Child; Darbepoetin alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Male; Renal Insufficiency, Chronic; Risk; Sex Factors; Stroke
PubMed: 20164489
DOI: 10.1056/NEJMc0912452 -
The effect of darbepoetin alfa on renal fibrosis in rats with acute unilateral ureteral obstruction.Archivos Espanoles de Urologia Mar 2018The most important treatment strategy for obstructive nephropathy is to protect renal tissue from the deleterious effects of fibrosis. Therefore, we sought to...
OBJECTIVES
The most important treatment strategy for obstructive nephropathy is to protect renal tissue from the deleterious effects of fibrosis. Therefore, we sought to investigate the renoprotective effects of darbepoetin alfa on unilateral ureteral obstructions.
METHODS
We used 12 female and 12 male 3-monthold Wistar rats weighing between 250 and 350 g. The rats were divided equally into sham, darbepoetin and control groups. With the exception of the sham group, left unilateral obstructions were applied to all of the rats. The darbepoetin group received perioperative darbepoetin alfa at a dose of 10 mg/kg. The rats were sacrificed on postoperative day 7, and 3-cc blood samples and bilateral renal specimens were collected from each rat.
RESULTS
Renal ectasia was observed significantly less frequently in the darbepoetin group than the obstruction group (p<0.001). Additionally, the uptake rates of cortical TNF and medullary SMA in the darbepoetin group were comparable to those in the sham group but lower than those in the ureteral obstruction group (p<0.001 and p<0.008, respectively). When biomarkers of renal injury, including cystatin-C, malondialdehyde, and B2 microglobulin, were evaluated in combination, B2 microglobulin was found at higher levels in the ureteral obstruction group (p<0.004).
CONCLUSION
As we know pelvicalyceal ectasia reflects intrapelvic pressure into renal tubular system via renal reflux. Therefore pelvicalyceal ectasia can be used as an indicator of renal tubular pressure. Although as a limitation of our study, renal tubular pressure was not quantitatively evaluated, parallelism between levels of renal ectasia detected in the rats of the sham, and DPO groups can predict that this drug (darbepoetin-a) can decrease renal tubular pressure in acute ureteral obstruction. Moreover, B2 microglobulin levels in the sham, and DPO groups differed from those of ureteral obstruction group, which suggested that DPO does not impair renal perfusion in addition to its decreasing effects on renal tubular pressure. We think that in countries with higher incidence rates of stone disease similar to our country, DPO may be used among medical treatment alternatives, which aim to preserve renal reserve.
Topics: Acute Disease; Animals; Darbepoetin alfa; Female; Fibrosis; Kidney; Male; Rats; Rats, Wistar; Ureteral Obstruction
PubMed: 29521269
DOI: No ID Found