ceiving intravenous epoetin alfa or beta or darbepoetin alfa. Eligible patients entered the CERA dose titration phase (DTP), followed by an efficacy evaluation ...
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ORIGINAL ARTICLE
DOI: 10.5301/jn.5000251
Efficacy and safety of once-monthly continuous erythropoietin receptor activator in patients with chronic renal anemia Francesco Locatelli 1, Salvatore Mandolfo 2, Massimo Menegato Adorati 3, Giuseppe Villa 4, Renzo Tarchini 5, Francesco Pizzarelli 6, Ferruccio Conte 7, Carlo Guastoni 8, Biagio Ricciardi 9, Alessandro Crotta 10
Abstract Background: In the management of anemia in patients with chronic kidney disease stage 5 undergoing dialysis (CKD-5D), maintaining hemoglobin (Hb) within the range recommended by the guidelines is challenging. Methods: The CARISMA study aim was to evaluate the efficacy, safety and tolerability of a once-monthly continuous erythropoietin receptor activator (CERA) for the treatment of anemia in CKD-5D patients. In this single-arm, multicenter, open-label, phase IIIb study, we screened adult patients from 66 centers in Italy receiving intravenous epoetin alfa or beta or darbepoetin alfa. Eligible patients entered the CERA dose titration phase (DTP), followed by an efficacy evaluation period (EEP) and a long-term safety period (LTSP). Patients were analyzed by intention-to-treat (ITT), per protocol (PP) and safety populations. Results: The rate of patients maintaining Hb within the range 10.0-12.0 g/dL throughout the EEP was 63.22% (220/348), and concentration from baseline to any postbaseline time point. CERA may thus offer a convenient and effective treatment 73.94% (122/165) in the ITT and PP population, respectively, periods in both populations. The rate of patients requiring a dose change was higher during the DTP (69.2%) and the LTSP (73.0%) than during the EEP (54.5%), as expected. CERA treatment was generally well tolerated.
Department of Nephrology, Dialysis and Renal Transplant, Alessandro Manzoni Hospital, Lecco - Italy 2 Lodi Hospital, Lodi - Italy 3 S. Antonio Hospital, San Daniele Del Friuli - Italy 4 Salvatore Maugeri Foundation, Pavia - Italy 5 Carlo Poma Hospital, Mantova - Italy 6 St. Maria Annunziata Hospital, Firenze - Italy 7 Uboldo Hospital, Cernusco sul Naviglio - Italy 8 Legnano Hospital, Legnano - Italy 9 Fogliani Hospital, Milazzo - Italy 10 Roche SpA, Monza - Italy 1
Conclusions: Once-monthly CERA administered to CKD-5D patients was associated with negligible changes in mean Hb option for these patients. Key words: Anemia, CERA, Chronic renal anemia, Hemodialysis, Hemoglobin
Introduction Chronic kidney disease (CKD) patients commonly have a deficiency in the production of endogenous erythropoietin, causing anemia in over 90% of patients with CKD stage 5 undergoing dialysis (CKD-5D). Severe anemia is associated with higher morbidity and mortality and reduced quality of life (1-7). Erythropoiesis-stimulating agents (ESAs) are commonly used to correct renal anemia, as maintenance of hemoglobin (Hb) within a desired range can have a major impact on patient outcomes (8, 9). The issue remains, however, controversial, and a recent European study failed to identify Hb variation as a predictor of mortality in hemodialysis patients (10). The therapeutic goals in the management of anemia in CKD patients are the partial correction of anemia, the maintenance of stable Hb levels, reduced frequency of ESA administration and a stable, lowest possible ESA dose (11, 12).
© 2013 Società Italiana di Nefrologia - ISSN 1121-8428
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Locatelli et al: Once-monthly CERA in chronic renal anemia
A continuous erythropoietin receptor activator (CERA) differs from epoetin beta through the integration of a methoxy polyethylene glycol molecule, determining a longer half-life (approximately 130 hours) (13). The primary objective of the CARISMA study was to assess the long-term maintenance of Hb levels with once-monthly intravenous CERA therapy in hemodialysis patients previously treated with other ESAs, in a real-life clinical setting. The secondary objectives included the evaluation of safety and tolerability.
Subjects and methods Patients The study (NCT00699348) was conducted at 66 sites in Italy. Table I shows patient inclusion and exclusion criteria. The study was conducted under the provisions of the Declaration of Helsinki and in accordance with the International Conference on Harmonization (ICH) consolidated guideline on good clinical practice (GCP) (14). The local ethics committees of each center participating in the study gave their approval. Each patient provided written informed consent.
Study design This study was a single-arm open-label multicenter study. The study duration was 56 weeks, comprising 4 main phases (Fig. 1). Patients were screened for eligibility during a 4-week period (stability verification period [SVP]) during which patients continued to receive prestudy treatment, including ESA. A dose titration period (weeks 0 to 16; DTP) was used for CERA dose titration and stabilization of Hb. This was followed by an efficacy evaluation period (weeks 17 to 24; EEP) to assess the primary efficacy end point. A long-term safety period (LTSP) was started after the EEP to capture adverse events and to assess stability of Hb. The initial dose of CERA was established based on the last dose of the previous ESA, as recommended by the manufacturer in the summary of product characteristics (SmPC) (15): for a previous weekly dose of 80 µg darbepoetin alfa, the CERA dose was 360 µg. Throughout the study, the dose of CERA was adjusted to maintain the individual patient’s Hb within a range of ±1.0 g/ dL of the reference Hb concentration and between 10.0 and 2
12.0 g/dL. The reference Hb was taken as the mean of all Hb assessments during the SVP. Dose adjustments were scheduled for once every month, unless safety concerns dictated otherwise. Dose adjustment ±50% had to be made if Hb ≥13 g/dL or ≤9 g/dL, or the difference between 2 consecutive Hb levels was ≥2 g/dL. Dose adjustment of ±25% should have been made when the values of the scheduled Hb assessments on the day of administration of CERA and on the previous visit were both out of the range 10.5-11.5 g/dL and the difference between the reference and the most recent value was >1 g/dL, or both were out of the range 10-12 g/dL. Loss of treatment effect was defined as decline in Hb of at least 2.8 g/dL in a 4-week period, or transfusion of ≥1 blood unit per week for a minimum of 2 consecutive weeks in the absence of overt bleeding and uninterrupted treatment with study drug according to protocol guidance. Patients transfused were withdrawn from the study. In the event of loss of treatment effect of unknown etiology, an anti-epoetin antibody test was performed. Use of iron supplementation was also reported.
Study drug CERA (Mircera; Roche Pharma AG, Grenzach-Wyhlen, Germany) was available in prefilled syringes containing 30, 40, 50, 60, 75, 100, 120, 150, 200 or 250 μg each in a 0.3mL solution, or 360 or 400 μg in a 0.6-mL solution (15).
Assessment Patients were assessed at each visit, for Hb levels, blood pressure, heart rate and adverse events, and concomitant treatments were recorded.
Statistical analysis A 400-subject sample was considered necessary based on previous studies. The primary end point was the proportion of patients maintaining their mean Hb concentration within ±1 g/dL of the reference range and between 10.0 and 12.0 g/dL during the EEP. Analyses were done on both the intention-to-treat (ITT; patients who received at least 1 dose of CERA and had at least 1 postdose follow-up) and per protocol (PP) populations (patients with all protocol data available). The 2-sided 95% confidence interval of this proportion was calculated using the Pearson-Clopper method. Secondary efficacy variables were the change in Hb between the EEP and SVP phases, proportion of patients and
© 2013 Società Italiana di Nefrologia - ISSN 1121-8428
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TABLE I MAIN PATIENT INCLUSION AND EXCLUSION CRITERIA Inclusion criteria
Exclusion criteria
Adult hemodialysis patients ≥18 years of age, with chronic renal disease
Transfusion of red blood cells during the previous 2 months
Written formal consent Hb concentration between 10.0 and 12.0 g/dL Adequate iron status (serum ferritin >100 ng/mL and TSAT >20% or hypochromic red cells 170/100 mm Hg despite medication, on average of 2 values measured at least 2 hours apart before dialysis Significant acute or chronic bleeding such as overt gastrointestinal bleeding
Active malignant disease (except nonmelanoma skin cancer) Continuous intravenous maintenance epoetin alfa or beta, or darbepoetin alfa therapy with the same Hemolysis: haptoglobin 500×109/L or
