Efficacy and tolerability of intravenous continuous erythropoietin receptor activator: a 19-week, phase II, multicenter, randomized, open-label, dose-finding study with a 12-month extension phase in patients with chronic renal disease.

BACKGROUND: A continuous erythropoietin receptor activator (C.E.R.A.) is currently in development for the treatment of anemia in patients with chronic renal disease (CRD) receiving or not receiving dialysis treatment.

OBJECTIVES: The objectives of this study were to determine the optimal dose and administration schedule for IV C.E.R.A. in patients with CRD previously treated with IV epoetin alfa TIW, and to assess its tolerability profile in these patients. In addition, a 12-month extension phase was used to assess the long-term efficacy and tolerability of C.E.R.A.

METHODS: This randomized, open-label, dose-finding study was conducted at 14 study centers across the United States. Male and female patients aged >/=18 years with CRD and CRD-related anemia and receiving treatment with IV epoetin alfa were enrolled. After a 2-week run-in period in which all patients continued to receive their previous epoetin treatment TIW, patients were switched to C.E.R.A. at 1 of 3 doses, determined by multiplying the previous weekly epoetin dose by 1 of 3 ratios (0.25 pg/150 IU, 0.4 pg/150 IU, or 0.6 pg/150 IU). Within each dose group, patients were randomized to 1 of 2 frequency subgroups: QW or Q2W Dose adjustments were not permitted during the first 6 weeks; the total dose during this period was the same for a particular dose group across the frequency subgroups. The primary efficacy parameter was change in hemoglobin (Hb) standardized to a 6-week period between baseline and the point when the patient had a dose change or blood transfusion, thus providing an estimate of Hb change based on starting dose. Following completion of a 19-week core period, patients could enter the 12-month extension period, aiming to maintain Hb concentrations between 11 and 12 g/dL. Adverse events (AEs) were recorded in the patients' case-report forms by the investigators throughout the study.

RESULTS: A total of 91 patients entered the core period (mean age, 58 years; 66% male); 10 patients withdrew prematurely during this period (4 owing to AEs and 6 for other reasons). Fifty-three patients continued into the extension period; 22 patients withdrew during this period (6 because of AEs, and 16 for other reasons). There was a significant dose-response effect (P < 0.001) and a significant effect of schedule (P < 0.002) for the primary efficacy end point. Stable Hb concentrations were maintained throughout the study (11-12 g/dL, with a narrow 95% CI). No significant difference between schedules was observed during the extension period, and few dose changes were required (mean, 4 and 2 per patient per year in the QW and Q2W groups, respectively). Nineteen and 22 patients experienced serious AEs during the core and extension periods, respectively, but only 1 event was considered related to study treatment. The most frequent AEs were headache and vomiting during the core study period and dizziness, fatigue, chest pain, and pyrexia during the extension period.

CONCLUSIONS: In this study, N C.E.R.A. provided effective maintenance of Hb concentrations in patients receiving dialysis treatment who were switched directly from N epoetin alfa TIW to N C.E.R.A. QW or Q2W C.E.R.A. was generally well tolerated.