Randomized Controlled Trial of Subcutaneous Epoetin Alfa-epbx Versus Epoetin Alfa in End-Stage Kidney Disease.

INTRODUCTION: This double-blind, randomized controlled trial compared the safety and efficacy of subcutaneous epoetin alfa-epbx, an epoetin alfa biosimilar, with the reference product, epoetin alfa, in hemodialysis patients with end-stage kidney disease (ESKD) and anemia who were receiving epoetin alfa maintenance treatment. METHODS: Eligible patients (n = 320) were randomized (1:1) to subcutaneous epoetin alfa-epbx or epoetin alfa in a titration phase; patients who demonstrated stable subcutaneous dosing (n = 246) were re-randomized to receive subcutaneous epoetin alfa-epbx or epoetin alfa 1 to 3 times per week in a 16-week maintenance phase. Co-primary endpoints were least-squares mean difference between treatments in mean weekly hemoglobin concentration and mean weekly epoetin dose per kilogram body weight (BW) during the last 4 weeks of treatment in the maintenance phase. RESULTS: The least-squares mean difference (95% confidence interval [CI]) between treatments in weekly hemoglobin was 0.04 g/dl (-0.17 to 0.24 g/dl) and weekly epoetin dose/kg BW was -2.34 U/kg per week (-14.51 to 9.82 U/kg per week). The 95% CIs were contained within the prespecified equivalence margins of ±0.5 g/dl (weekly hemoglobin) and ±45 U/kg per week (weekly epoetin dose/kg BW). In the epoetin alfa-epbx and epoetin alfa groups, respectively, 4.0% and 4.1% of patients required blood transfusions, 69.7% and 70.5% reported adverse events, 18.9% and 27.0% reported serious adverse events, and 3 and 2 deaths were reported. Five patients were confirmed positive for anti-recombinant human erythropoietin antibody, 2 of whom tested positive at baseline. All patients tested negative for neutralizing antibodies. CONCLUSIONS: This comparative clinical trial demonstrated equivalence in efficacy and similar safety of subcutaneously administered epoetin alfa-epbx to epoetin alfa.

Intravenous Epoetin Alfa-epbx versus Epoetin Alfa for Treatment of Anemia in End-Stage Kidney Disease.

BACKGROUND AND OBJECTIVES: This study was conducted to compare the safety and efficacy of intravenous epoetin alfa-epbx, an epoetin alfa biosimilar, to epoetin alfa in patients on hemodialysis with ESKD and anemia. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this 24-week, multicenter, double-blind comparative efficacy and safety study, 612 patients on hemodialysis with ESKD and anemia who had stable hemoglobin and were receiving stable doses of intravenous epoetin alfa were randomized (1:1) to intravenous epoetin alfa or epoetin alfa-epbx. Dosing was adjusted according to the epoetin alfa prescribing information. The coprimary efficacy end points were the least squares mean difference between the two treatments in mean weekly hemoglobin level and mean weekly epoetin dose per kilogram of body weight during the last 4 weeks of treatment. RESULTS: The least squares mean difference between epoetin alfa-epbx and epoetin alfa in weekly hemoglobin was -0.12 g/dl and the 95% confidence interval (-0.25 to 0.01) was contained within the prespecified equivalence margin (-0.5 to 0.5 g/dl). The least squares mean difference between epoetin alfa-epbx and epoetin alfa in weekly epoetin dose per kilogram of body weight was 0.37 U/kg per week, and the 95% confidence interval (-10.40 to 11.13) was contained within the prespecified equivalence margin (-45 to 45 U/kg per week). Incidences of adverse events (77.1% versus 75.3%), serious adverse events (24.9% versus 27.0%), and deaths (n=5 versus 6) were similar between the epoetin alfa-epbx and epoetin alfa groups, respectively. Five patients tested positive for anti-recombinant human erythropoietin antibodies at baseline, and two additional patients (n=1 per group) developed anti-recombinant human erythropoietin antibodies while on study treatment. All patients tested negative for neutralizing antibodies, and no patient in either group experienced an event of pure red cell aplasia. CONCLUSIONS: This 24-week, comparative, clinical trial in patients on hemodialysis with ESKD and anemia demonstrated there is no clinically meaningful difference in efficacy or safety between epoetin alfa-epbx and epoetin alfa.

Pharmacokinetic and Pharmacodynamic Equivalence of Epoetin Hospira and Epogen After Single Subcutaneous Doses to Healthy Male Subjects.

PURPOSE: The purpose of this study was to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) equivalence of single 100 U/kg subcutaneous doses of Epoetin Hospira and Epogen in healthy male subjects as part of an overall program to demonstrate biosimilarity of Epoetin Hospira to the reference product Epogen. METHODS: This single-center, open-label, randomized, 2-period, crossover study was conducted in 81 healthy male subjects. Subjects were randomized to Sequence 1, in which they received 100 U/kg of Epoetin Hospira or to sequence 2, in which they received 100 U/kg Epogen subcutaneously in the first study period and the alternative treatment in the second study period. Blood was collected for determination of baseline-adjusted epoetin concentrations (BAECs) for pharmacokinetics and for determination of reticulocyte percentage of total erythrocytes for pharmacodynamics throughout both study periods. The primary PK end points were the geometric mean ratios (GMRs) of the 2 treatments for AUC0-t and Cmax based on the BAEC, and the primary PD end points were the GMRs of the 2 treatments for AUC0-t and Cmax for reticulocyte percentage. FINDINGS: The GMRs of Epoetin Hospira to Epogen for the BAEC-derived PK parameters were 1.05 for AUC0-t with a 90% CI of 1.01 to 1.11, and 1.09 for Cmax with a 90% CI of 1.01 to 1.18, with both 90% CIs contained within the prespecified equivalence margin of 0.80 to 1.25. The GMRs (Epoetin Hospira/Epogen) for the reticulocyte percentage-derived PD parameters were 1.01 for AUC0-t with a 95% CI of 0.98 to 1.05, and 1.02 for Cmax with a 95% CI of 0.98 to 1.06, with both 95% CIs contained within the prespecified equivalence margin of 0.80 to 1.25. Overall, the adverse events were of similar frequency (11.7% and 13.9% for Epoetin Hospira and Epogen, respectively) and severity between treatments. One subject had a positive anti- recombinant human erythropoietin antibody result by radioimmunoprecipitation assay before dosing and throughout the conduct of the study with negative neutralizing antibodies and with no evidence of clinical deterioration or impact on the pharmacokinetics, pharmacodynamics, or safety. IMPLICATIONS: The results of this study established the PK and PD equivalence of single 100 U/kg subcutaneous doses of the proposed biosimilar Epoetin Hospira to the reference product Epogen in healthy male subjects and support the overall demonstration of biosimilarity of Epoetin Hospira and Epogen.

A phase II/III, multicenter, safety, efficacy, and pharmacokinetic study of dexmedetomidine in preterm and term neonates.

OBJECTIVE: To investigate the safety, efficacy, and pharmacokinetic profile of dexmedetomidine in preterm and full-term neonates ≥ 28 to ≤ 44 weeks gestational age. STUDY DESIGN: Forty-two intubated, mechanically ventilated patients (n = 42) were grouped by gestational age into group I (n = 18), ≥ 28 to <36 weeks, and group II (n = 24), ≥ 36 to ≤ 44 weeks. Within each age group, there were 3 escalating dose levels, including a loading dose (LD, µg/kg) followed by a maintenance dose (MD, µg · kg(-1) · h(-1)) for 6-24 hours: level 1, 0.05 LD/MD; level 2, 0.1 LD/MD; and level 3, 0.2 LD/MD. The primary endpoint was the number of patients requiring sedation as determined by the Neonatal Pain, Agitation, Sedation Scale. RESULTS: During dexmedetomidine infusion, 5% of Neonatal Pain, Agitation, Sedation Scale scores were >3, indicating agitation/pain, with 4 patients (10%) requiring more sedation and 17 (40%) requiring more analgesia. Though there was significant variability in pharmacokinetic variables, group I appeared to have lower weight-adjusted plasma clearance (0.3 vs 0.9 L · h(-1) · kg(-1)) and increased elimination half-life (7.6 vs 3.2 hours) compared with group II. Fifty-six adverse events (AEs) were reported in 26 patients (62%); only 3 AEs (5%) were related to dexmedetomidine. There were no serious AEs and no AEs or hemodynamic changes requiring dexmedetomidine discontinuation. CONCLUSION: Dexmedetomidine is effective for sedating preterm and full-term neonates and is well-tolerated without significant AEs. Preterm neonates had decreased plasma clearance and longer elimination half-life.