Once-Monthly Continuous Erythropoietin Receptor Activator (C.E.R.A.) in Patients with Hemodialysis-Dependent Chronic Kidney Disease: Pooled Data from Phase III Trials

Abstract

Introduction: Erythropoiesis-stimulating agents and iron are commonly used in patients with chronic kidney disease with the aim of correcting anemia and maintaining stable hemoglobin levels. We analyzed pooled data from 13 studies with similar designs included in the Umbrella Continuous Erythropoietin Receptor Activator (C.E.R.A.) program to investigate the effects of continuous erythropoiesis receptor activator in clinically relevant subgroups of patients with chronic kidney disease and to determine whether the efficacy and safety outcomes demonstrated in the overall chronic kidney disease population are maintained in specific subgroups.

Methods: Data from 13 Phase III trials set up with similar design were retrospectively pooled for this analysis. Patients with chronic kidney disease who had previously been receiving epoetin or darbepoetin were switched to continuous erythropoiesis receptor activator once-monthly after a 4- to 8-week screening period. Patients entered a 16-week continuous erythropoiesis receptor activator dose-titration period followed by an 8-week evaluation period. In total, 2060 patients were included in the analysis. Subgroups were defined based on: hemoglobin target range [lower (10.0-12.0 g/dL)/upper (10.5-13.0 g/dL)], gender (female/male), age (<65/≥65), baseline N-terminal pro-B-type natriuretic peptide levels (<5000/≥5000), cardiovascular risk factors (diabetes/cardiac/vascular/none).

Results: Across all subgroups analyzed, switching from shorter-acting erythropoiesis-stimulating agents to continuous erythropoiesis receptor activator once-monthly maintained stable hemoglobin concentrations in a high proportion of patients (78%), with only moderate hemoglobin fluctuations and a low number of dose changes. The safety profile across subgroups was as expected based on pre-existing risk factors; observed increases in adverse events were attributable to underlying risk factors rather than study drug.

Conclusions: This retrospective analysis of 13 trials showed that continuous erythropoiesis receptor activator once-monthly maintained stable hemoglobin levels across a number of clinically relevant patient subgroups, including those with higher inherent cardiovascular risk. The safety profile was consistent with that previously established in the chronic kidney disease population. CLINICALTRIALS.

Gov identifiers: NCT00413894/NCT00545571/NCT00517413/NCT00560404/NCT00882713/NCT00550680/NCT00576303/NCT00660023/NCT00717821/NCT00642850/NCT00605293/NCT00661505/NCT00699348.

Funding: F. Hoffmann-La Roche Ltd, Basel, Switzerland.

Keywords: Anemia, chronic kidney disease; Continuous erythropoiesis; Efficacy; Hemodialysis; Patient subgroups; Pooled analysis; Receptor activator.

Fig. 1

Common study design. In all 13 studies, enrolled patients entered a 4- to 8-week screening period followed by a 16-week C.E.R.A. dose-titration period, and an 8-week evaluation period. C.E.R.A. continuous erythropoietin receptor activator, ESA erythropoiesis-stimulating agents

Fig. 2

Proportion of patients exhibiting hemoglobin stability. Across all studied subgroups, a large majority of patients (76–80%) exhibited hemoglobin stability (hemoglobin concentration within ±1 g/dL from screening or within the target range, evaluation period). CV cardiovascular, L lower, NT-proBNP N-terminal pro-B-type natriuretic peptide, U upper

Fig. 3

Mean Hb levels over time, by target Hb group. The error bars show 95% confidence intervals. In the upper (square symbols) and the lower (triangle symbols) Hb target groups, the achieved Hb levels were stable over time. Hb hemoglobin

Fig. 4

Percentage of patients with CV AEs per dose, Hb and CRP quintile. The proportion of patients experiencing cardiac, serious CV, thromboembolic, and vascular AEs is shown by quintiles of Hb, C.E.R.A. dose and CRP. AE adverse event, C.E.R.A. continuous erythropoietin receptor activator, CRP C-reactive protein, CV cardiovascular, Hb hemoglobin