Prospective multicenter study of HX575 (biosimilar epoetin-α) in patients with chronic kidney disease applying a target hemoglobin of 10--12 g/dl.

HX575 was approved in the European Union in August 2007 as the first-ever biosimilar epoetin-α product. The present study extended the safety database on HX575 by monitoring adverse events (AEs) in clinical practice. Hemoglobin (Hb) levels and HX575 doses were recorded for the assessment of efficacy. This open, 6-month single-arm study was conducted in 10 European countries with a target enrollment of 1,500 patients with anemia due to chronic kidney disease (CKD). HX575 was intravenously (i.v.) administered aiming at an Hb target of 10 - 12 g/dl. Most patients (92.3%) had already received erythropoiesis stimulating agents (ESAs) treatment before enrolment into this study; the recorded treatments mainly comprised i.v. or subcutaneous (s.c.) administration of epoetin-α, epoetin-ß or darbepoetin. The study period covered 770 patient years. The observed AE profile was in line with expectations for this patient population. Thrombotic vascular events (TVEs) were reported in 11.9% of patients (0.2612 per patient year). Tumor incidence was 1.4% (0.0299 per patient year). No subject developed anti-epoetin antibodies. Mean Hb levels were effectively maintained between 11.2 and 11.3 g/dl following the conversion from a broad spectrum of pre-study ESA treatments with stable overall mean i.v. HX575 doses. The proportion of patients within the Hb target range increased from 57.5% at baseline to 66.8% at study end.

Safety, immunogenicity and efficacy of subcutaneous biosimilar epoetin-α (HX575) in non-dialysis patients with renal anemia: a multi-center, randomized, double-blind study.

BACKGROUND: HX575 is a biosimilar version of epoetin-α that is approved for the treatment of anemia associated with chronic kidney disease (CKD) using the intravenous route of administration. Here we report data from a study of anemic pre-dialysis patients to assess the safety, immunogenicity and efficacy of subcutaneous (s.c.) administration of HX575 vs. Erypo®/Eprex® (Ortho Biotech, Neuss, Germany). METHODS: This was a randomized, double-blind study in adult patients (n = 337) with Stage III - V CKD and a hemoglobin (Hb) level of 7.5 - 11.0 g/dl. Eligible patients were randomized to 52 weeks of treatment with HX575 or Erypo®/Eprex® at a starting dose of 25 IU/kg body weight 3 times weekly or 75 IU/kg body weight once weekly during Weeks 1 - 5. This could be adjusted after 5 weeks to maintain Hb levels between 10 and 12 g/dl. The primary objective was to assess the safety and immunogenicity of HX575 compared with Erypo®/Eprex®. Efficacy endpoints were mean absolute change in Hb from baseline to end of Week 13 and mean weekly epoetin dosage in Weeks 11 - 13. RESULTS: HX575 was equivalent to Erypo®/Eprex® in terms of maintaining Hb levels and epoetin dose requirements. Two patients in the HX575 group developed neutralizing antibodies (NAbs) to erythropoietin, which resulted in the study being terminated prematurely. Aside from these two events, reported adverse events were as expected for patients with Stage III - V CKD and similar in both treatment groups. CONCLUSIONS: This study demonstrated the efficacy and therapeutic equivalence of s.c. HX575 compared with the reference epoetin-α, but 2 patients developed NAbs during treatment with s.c. HX575 in this study. Results of a thorough root-cause analysis reported elsewhere indicate that increased tungsten exposure in pre-filled syringes precipitated immunogenic reactions.

Low-GDP fluid (Gambrosol trio) attenuates decline of residual renal function in PD patients: a prospective randomized study.

BACKGROUND: Residual renal function (RRF) impacts outcome of peritoneal dialysis (PD) patients. Some PD fluids contain glucose degradation products (GDPs) which have been shown to affect cell systems and tissues. They may also act as precursors of advanced glycosylation endproducts (AGEs) both locally and systemically, potentially inflicting damage to the kidney as the major organ for AGE elimination. We conducted a clinical study in PD patients to see if the content of GDP in the PD fluid has any influence on the decline of the residual renal function. METHODS: In a multicentre approach, 80 patients (GFF > or = 3 mL/min/1.732 or creatinine clearance > or =3 mL/min/1.73 m(2)) were randomized to treatment with a PD fluid containing low levels of GDP or standard PD fluid for 18 months. RRF was assessed every 4-6 weeks. Fluid balance, mesothelial cell mass marker CA125, peritoneal membrane characteristics, C-reactive protein (CRP), total protein, albumin, electrolytes and phosphate were measured repeatedly. RESULTS: Data from 69 patients revealed a significant difference in monthly RRF change: -1.5% (95% CI = -3.07% to +0.03%) with low GDP (43 patients) vs -4.3% (95% CI = -6.8% to -2.06%) with standard fluids (26 patients) (P = 0.0437), independent of angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker medication. Twenty-four-hour urine volume declined more slowly with low-GDP fluid compared to standard fluids (12 vs 38 mL/month, P = 0.0241), and monthly change of phosphate level was smaller (+0.013 vs +0.061 mg/dL, P = 0.0381). CONCLUSIONS: Our prospective study demonstrates for the first time a significant benefit concerning preservation of RRF and urine volume of using a PD fluid with low GDP levels. These findings suggest that GDPs might affect patient outcome related to RRF.

[Influence of new dialysis solutions on clinical results in patients treated with peritoneal dialysis]. / Einfluss neuer Dialysatlösungen auf klinische Ergebnisse bei Peritonealdialyse-Patienten.

Long-term peritoneal dialysis is associated with changes in the peritoneal membrane. Conventional dialysate solutions are bioincompatible because of their low pH, high glucose content, hyperosmolality and increased concentration of glucose degradation products. The development of double-compartment systems has made it possible to separate glucose from the buffer during heat sterilization, resulting in a higher or even physiologic pH of the solution with reduced concentration of glucose degradation products. These new solutions are less toxic for several cell groups and are better than conventional solutions in preserving membrane function, as demonstrated by experiments in rats. Glucose degradation products promote formation of advanced glycation end-products, and plasma levels of these are markedly reduced when double-compartment systems are used. Clinical studies with these more physiologic dialysis solutions have demonstrated better correction of acidosis, less inflow pain, significantly elevated CA-125 dialysate levels and lower concentrations of markers for inflammation and fibrosis in the effluent. In a retrospective study, a lower rate of mortality was observed in patients who were treated using a double-compartment system than in those treated with standard dialysis solution. Amino acids (in the low-molecular-weight range) and icodextrin (in the high-molecular-weight range) are newer osmotic agents that have been developed as alternatives to glucose. Several clinical studies have shown that amino-acid solution improves various nutritional parameters in patients with malnutrition and is more biocompatible than standard glucose solution. Icodextrin is an iso-osmolar dialysis solution. Ultrafiltration takes place via colloid osmotic pressure and is sufficient in all types of peritoneal transport. Clinical studies using icodextrin have shown better fluid control, especially in high transporters, reduced carbohydrate load and fewer patients with ultrafiltration failure compared with those treated with conventional dialysis solutions. However, allergic skin reactions have been observed in up to 10% of patients treated with icodextrin. Icodextrin may induce a fall of sodium plasma levels. Because of cross-reaction with elevated plasma levels of maltose, serum amylase is determined falsely low and glucose (using the glucose-dehydrogenase method) is measured falsely high, but high plasma levels of maltose do not affect measurement of lipase or measurement of glucose using the glucose-oxidase method. New dialysate solutions will have a positive influence on both survival and technical drop-out rates in patients receiving peritoneal dialysis treatment.

Darbepoetin alfa effectively maintains haemoglobin concentrations at extended dose intervals relative to intravenous or subcutaneous recombinant human erythropoietin in dialysis patients.

BACKGROUND: Darbepoetin alfa is a unique molecule that stimulates erythropoiesis by the same mechanism as endogenous erythropoietin. Due to its approximately 3-fold longer half-life and greater biological activity than recombinant human erythropoietin (rHuEpo), darbepoetin alfa maintains effective haemoglobin control at extended dose intervals compared with rHuEpo. This study assessed the efficacy and safety of unit doses of darbepoetin alfa for the treatment of renal anaemia. METHODS: In this multicentre, prospective, open-label study, 1502 dialysis subjects maintained on stable rHuEpo treatment were switched to darbepoetin alfa at extended dose intervals by the same route of administration as previous rHuEpo therapy [intravenous (i.v.), n = 900 or subcutaneous (s.c.), n = 602]. Subjects receiving rHuEpo two (n = 408, 27%) or three times (n = 884, 59%) a week were switched to darbepoetin alfa once a week, and those receiving rHuEpo once a week (n = 210, 14%) were switched to darbepoetin alfa once every 2 weeks. The unit doses of darbepoetin alfa (10-150 microg) were titrated to maintain haemoglobin concentrations of 10-13 g/dl for 24 weeks. RESULTS: Haemoglobin concentrations were maintained effectively in subjects regardless of whether they received darbepoetin alfa once a week or once every 2 weeks. The overall mean change in haemoglobin from baseline to the evaluation period (weeks 21-24) was +0.10 g/dl [95% confidence interval (CI) 0.04+/- 0.17]. The mean haemoglobin concentration increased by 0.19 g/dl (95% CI 0.11+/-0.27) in subjects receiving i.v. darbepoetin alfa, and was unchanged (-0.02 g/dl; 95% CI -0.12 to 0.07) in patients treated with s.c. darbepoetin alfa. Subjects with baseline haemoglobin < 11 g/dl experienced a clinically relevant increase in mean haemoglobin concentration of 0.67 g/dl (95% CI 0.56+/-0.77) from baseline to the evaluation period. The mean weekly i.v. and s.c. darbepoetin alfa dosage requirements during the evaluation period were 19.9 microg/week (95% CI 19.02+/-20.87) and 21.6 microg/week (95% CI 20.36+/- 22.94), respectively. Darbepoetin alfa was well tolerated and the safety profile was consistent with previous trials with darbepoetin alfa in dialysis subjects. CONCLUSIONS: Treating renal anaemia with darbepoetin alfa administered at extended dose intervals is both effective and well tolerated. Moreover, administration of darbepoetin alfa by both the i.v. and s.c. route is associated with stable haemoglobin concentrations.

Personal dialysis capacity (PDC(TM)) test: a multicentre clinical study.

BACKGROUND: The assessment of the peritoneal membrane capacity and physiology of the individual patient is becoming increasingly important. It allows the prescription of an individualized peritoneal dialysis (PD)-regimen, and the monitoring of peritoneal membrane function over time. The PDC(TM) program offers the possibility to evaluate the peritoneal membrane characteristics and to predict solute and water removal by simulation of different treatment regimens. METHODS: This study evaluates the relevance of the PDC(TM) program when routinely used. The PDC(TM) data of 336 patients from nine different centres in Europe were evaluated. RESULTS: The area parameter was 20 985+/-7578 cm/1.73 m(2) (mean+/-SD). The reabsorption of fluid after dissipation of glucose, Jv(AR), was 1.97+/-1.00 ml/min/1.73 m(2). The large pore fluid flux, Jv(L), was 0.11+/-0.07 ml/min/1.73 m(2). A multivariate model for prediction of serum albumin included dialysate protein loss, Jv(L), Jv(AR), nPCR, A(0)/deltaX, BMI and gender (R(2)=0.81, P<0.001). Total clearance fell with increasing PD duration (P<0.001). A negative relation between A(0)/deltaX and ultrafiltration (rho=-0.26, P<0.05), a positive relation between A(0)/deltaX and peritoneal creatinine clearance (rho=0.52, P<0.05) and urea clearance (rho=0.36, P<0.05), and a positive relation between measured peritoneal creatinine and urea clearance (rho=0.64, P<0.01) was observed. CONCLUSIONS: In summary, the present study shows that the PDC(TM) program is a robust, accurate method to describe the peritoneal membrane transport characteristics. Analysis of PDC(TM) data of large groups of patients, especially if followed up over time, can give interesting information on the physiology of the peritoneal membrane and the impact of different parameters on it.