Darbepoetin alfa effectively maintains haemoglobin concentrations at extended dose intervals relative to intravenous or subcutaneous recombinant human erythropoietin in dialysis patients
Reinhard Brunkhorst1,
Jürgen Bommer2,
Johann Braun3,
Marianne Haag-Weber4 for the German Aranesp® Study Group,
Caroline Gill5,
Jürgen Wagner6 and
Thomas Wagener6
1Klinikum Hannover Oststadt, Hannover, 2Department of Nephrology, University of Heidelberg, 3KfH Centers for Dialysis, Nürnberg and 4Straubing, 6Amgen, Munich, Germany and 5Amgen, Cambridge, UK
Correspondence and offprint requests to: Professor Reinhard Brunkhorst, Krankenhaus Oststadt, Podbielskistrasse 380, D-30659 Hannover, Germany. Email: sekretariat.brunkhorst.oststadt{at}klinikum-hannover.de
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Abstract
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Background. Darbepoetin alfa is a unique molecule that stimulates erythropoiesis by the same mechanism as endogenous erythropoietin. Due to its
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 (10150 µg) were titrated to maintain haemoglobin concentrations of 1013 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 2124) 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 µg/week (95% CI 19.02±20.87) and 21.6 µg/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.
Keywords: darbepoetin alfa; dialysis; haemoglobin; renal anaemia; route of administration; safety
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Introduction
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Darbepoetin alfa is a unique erythropoietic protein that, by virtue of its longer elimination half-life [1] and greater in vivo biological activity [2], can be administered less frequently than recombinant human erythropoietin (rHuEpo). Indeed, several studies have confirmed that darbepoetin alfa can be administered less frequently than rHuEpo to correct and maintain haemoglobin in subjects with kidney disease, both on dialysis and not on dialysis [312]. Darbepoetin alfa has also been shown to maintain haemoglobin concentrations effectively when administered as infrequently as once every 3 or 4 weeks [6,9]. Previous studies have demonstrated that darbepoetin alfa intravenous (i.v.) and subcutaneous (s.c.) dose requirements are comparable [7,13]. The implication of this finding is clinically relevant, as it enables clinicians to base their decision on the most suitable route of administration of erythropoietic therapy on clinical and not economic reasons. Moreover, it has been shown recently that i.v. darbepoetin alfa administered at extended dose intervals is as effective as i.v. rHuEpo in achieving and maintaining haemoglobin concentrations [5,8,14]. This study was performed in order to confirm further the efficacy and safety of unit doses of darbepoetin alfa given at extended dose intervals for maintaining haemoglobin concentrations in dialysis subjects.
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Subjects and methods
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This multicentre, prospective, open-label, single-arm study in 1502 chronic kidney disease (CKD) subjects on dialysis evaluated the efficacy and safety of unit doses of darbepoetin alfa administered either i.v. or s.c. for the treatment of renal anaemia. Clinically stable subjects (
18 years of age) with mean haemoglobin concentrations of 1013 g/dl, based on three haemoglobin measurements during the 2-week screening/baseline period, who were receiving haemodialysis (HD) or peritoneal dialysis (PD) for at least 6 months were recruited from 167 dialysis units in Germany. Subjects were required to be receiving stable rHuEpo (epoetin alfa or beta) therapy one, two or three times a week i.v. or s.c., for at least 8 weeks prior to study entry [stable is defined as
25% change (up or down) in weekly dose over 8 weeks]. To ensure adequate iron stores to support erythropoiesis, serum ferritin was required to be
100 µg/l, or transferrin saturation
20%.
Subjects were excluded if they had: New York Heart Association (NYHA) class III or IV congestive heart failure; uncontrolled hypertension (defined as pre-dialysis diastolic blood pressure
110 mmHg during the screening period); evidence of uncontrolled hyperparathyroidism (defined as parathyroid hormone level > 1500 pg/ml during the 12 months prior to baseline); treatment for grand mal epilepsy; haematological, inflammatory or infectious conditions that might interfere with the erythropoietic response; or received red blood cell transfusions within 12 weeks before screening or during the screening/baseline period. Although no specific laboratory criteria for inflammatory or infectious disease were defined in the study protocol, clinicians were requested to exercise clinical judgement regarding subject exclusion based on underlying disease. Pregnant or lactating females were also excluded.
The study was conducted in accordance with the revised Declaration of Helsinki, and the study protocol was approved by each participating institution's independent Research Ethics Committee. Subjects were requested to give written informed consent before participation.
After a 2-week screening and baseline period, subjects were switched from rHuEpo to darbepoetin alfa at an extended dose interval, but using the same route of administration. Subjects who were receiving rHuEpo two or three times a week were switched to darbepoetin alfa once a week, and subjects who were receiving rHuEpo once a week were switched to darbepoetin alfa once every 2 weeks. For these European nephrology patients, a 200 IU epoetin:1 µg darbepoetin alfa ratio was used to determine the starting dose when patients were switched from epoetin to darbepoetin alfa [15]. Darbepoetin alfa was available for administration at the following unit doses: 10, 15, 20, 30, 40, 50, 60, 80, 100, 130 or 150 µg. If a dose of rHuEpo did not equate exactly to a unit dose of darbepoetin alfa at switching, then the nearest available unit dose of darbepoetin alfa was used. Subsequent darbepoetin alfa doses were titrated based on haemoglobin response. The period after the first dose of darbepoetin alfa (weeks 120) was used for dose titration and maintenance of haemoglobin, followed by a 4-week evaluation period (weeks 2124) during which the primary efficacy end point was assessed. Due to the half-life of circulating red blood cells (
60 days in dialysis patients), it was anticipated that the equilibrium of haemoglobin concentrations after switching from rHuEpo to darbepoetin alfa would occur within 2024 weeks [16].
Blood samples were drawn at baseline and at bi-weekly intervals during the dose titration period, and at weekly intervals during the evaluation period to measure haemoglobin. Iron status (serum ferritin or transferrin saturation) was assessed at baseline, week 8, week 16 and week 24. Subjects were also tested for the presence of antibodies to darbepoetin alfa, if requested by the investigator.
The primary efficacy end point was the change in haemoglobin concentration between baseline and the evaluation period. Secondary end points included the dosage of darbepoetin alfa throughout the study. Safety variables assessed the nature, frequency, severity, relationship to treatment, and outcome of all adverse events. Laboratory parameters were also monitored.
The dose of darbepoetin alfa was titrated to maintain the haemoglobin concentration within a target range of 1013 g/dl throughout the 24-week study period. If the subject's haemoglobin concentration increased above the target range on two consecutive assessments, the dose of darbepoetin alfa was decreased to the next lower unit dose. Conversely, if a subject's haemoglobin concentration fell below the target range on two consecutive assessments, then the dose of darbepoetin alfa was increased to the next higher unit dose. Any change in dose was one step up or down the unit doses (pre-filled syringes). When subjects were treated at the lowest or highest dose level, the frequency of administration was adjusted as the dose could not be decreased or increased, respectively. To maintain serum ferritin
100 µg/l or transferrin saturation
20%, i.v. iron supplementation was administered according to individual dialysis unit policy.
Statistical analysis
The primary efficacy analysis compared the mean change in haemoglobin concentration between the baseline (mean of three values) and evaluation periods (mean of four values). Based on a previous darbepoetin alfa study [7], where an SD of 0.8 g/dl was observed for change in haemoglobin, it was estimated that with 90% power and a 5% significance level, a sample size of 1500 subjects would allow detection of a change in haemoglobin concentration of ±0.07 g/dl or greater between baseline and the evaluation period (weeks 2124). This sample size would also allow investigation of change in haemoglobin within subgroups, e.g. based on baseline haemoglobin concentration and route of administration.
Summary statistics (mean or geometric mean, median, SD and range for continuous variables, and number and percentage of subjects in each category for categorical variables) are presented for baseline, efficacy and safety end points. Change in haemoglobin and dose is summarized with means (geometric means for dose) and two-sided 95% confidence intervals (CIs).
An intent-to-treat (ITT) analysis, including all subjects assigned a study number (1502 subjects), was performed for the primary analysis of efficacy. Dose and frequency of administration during the evaluation period and the change in dose between baseline and evaluation periods were analysed for those subjects who received at least one dose of study drug during the evaluation period. Safety was analysed in all subjects in the ITT population who received at least one dose of darbepoetin alfa (1499 subjects). All statistical analyses were performed with the SAS System Version 8.2.
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Results
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A total of 1502 subjects were recruited into the study and 1499 subjects received at least one dose of darbepoetin alfa. Subject demographics (Table 1) and baseline characteristics (Table 2) for the study population were similar regardless of the route of administration, and were representative of a dialysis population. Most subjects were on HD (n = 1491; 99%), with only 11 (1%) receiving PD. The mean age was 58.9 years (range 2191 years). The most common causes of CKD were glomerulonephritis (29%) and diabetes mellitus (18%). The mean haemoglobin concentration at baseline was 11.46 g/dl (range 9.913.0 g/dl). A total of 1049 (70%) subjects had a baseline haemoglobin concentration
11 g/dl.
The majority of subjects completed both the 20-week dose titration period (1393 subjects; 93%) and the subsequent 4-week evaluation period (1369 subjects; 91%). Over the 24-week study period, 133 (9%) subjects discontinued the study. Three (< 1%) subjects did not receive study drug, 106 (7%) subjects discontinued during the dose titration period, and 24 (1.6%) during the evaluation period. The most frequent reasons for discontinuation were kidney transplantation (n = 37) and death (n = 34).
The overall mean change in haemoglobin concentration from baseline to the evaluation period was an increase of 0.10 g/dl (95% CI 0.04±0.17). Regardless of route of administration, darbepoetin alfa effectively maintained mean haemoglobin concentrations above 11 g/dl throughout the entire study period (Figure 1). Mean haemoglobin concentrations increased most markedly over the first 12 weeks of darbepoetin alfa treatment (Figure 1). Darbepoetin alfa administered by both the i.v. and s.c. routes resulted in stable mean haemoglobin concentrations during the evaluation period (Figure 2). Following i.v. administration, the mean haemoglobin concentration during the evaluation period increased by 0.19 g/dl (95% CI 0.11±0.27) compared with baseline. The mean change in haemoglobin concentration from baseline to the evaluation period following s.c. administration was 0.02 g/dl (95% CI 0.12 to +0.07). With regard to frequency of administration, the mean change in haemoglobin concentration from baseline to the evaluation period was +0.14 g/dl (95% CI 0.08±0.21) in subjects receiving darbepoetin alfa once a week, and 0.13 g/dl (95% CI 0.29 to 0.04) in subjects receiving darbepoetin alfa once every 2 weeks.

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Fig. 2. Mean change (95% CI) in haemoglobin concentration between baseline and the evaluation period by route of administration.
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In the overall study population, the mean weekly darbepoetin alfa dose requirement during the evaluation period was 20.58 µg (95% CI 19.84±21.35). Investigation of the mean weekly darbepoetin alfa dose requirement by route of administration revealed that the mean weekly i.v. dose requirement decreased from 23.23 µg (95% CI 22.34±24.17) at baseline to 19.92 µg (95% CI 19.02±20.87) during the evaluation period. Similarly, the mean weekly s.c. dose requirement decreased from 22.95 µg (95% CI 21.90±24.06) at baseline to 21.61 µg (95% CI 20.36±22.94) during the evaluation period (Figure 3).
Subjects with a baseline haemoglobin concentration < 11 g/dl (n = 453) experienced a clinically significant mean increase in haemoglobin concentration of 0.67 g/dl (95% CI 0.56±0.77) at evaluation. Subjects with a baseline haemoglobin concentration
11 g/dl (n = 1049) experienced a mean decrease of 0.14 g/dl (95% CI 0.21 to 0.07).
Subjects with baseline haemoglobin concentrations <11 g/dl experienced significant mean increases in haemoglobin concentration from baseline to the evaluation period, which were more pronounced following i.v. than s.c. administration (0.81 vs 0.48 g/dl, respectively) (Table 3). These increases, not surprisingly, were associated with increases in mean weekly dose requirements of darbepoetin alfa s.c. and i.v. (Table 4).
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Table 3. Mean (95% CI) change in haemoglobin from baseline to evaluation (weeks 2124) by route of administration and baseline haemoglobin concentration
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Table 4. Mean (95% CI) weekly darbepoetin alfa dose requirements at baseline and evaluation (weeks 2124) by route of administration and baseline haemoglobin concentration
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The frequency of darbepoetin alfa administration during the evaluation period was also investigated. In total, 97% (192/198) of subjects assigned to once every 2 weeks dosing received darbepoetin alfa once every 2 weeks during the evaluation period, and 95% (1129/1190) of those assigned to once a week dosing achieved the same frequency during the evaluation period.
Safety
Darbepoetin alfa was well tolerated in this study. Adverse events were consistent with those typically observed in the dialysis population, and were not attributable to treatment with darbepoetin alfa in the vast majority of cases. Overall, 68% of subjects reported at least one adverse event. The most commonly occurring adverse events were upper respiratory tract infection (16%), diarrhoea (7%) and hypertension (7%). One hundred and sixty-one subjects (11%) experienced at least one adverse event that was considered by the investigator to be treatment related. These adverse events included mild and transient injection site pain (4%), hypertension (2%), and thrombosis of vascular access (1%). Analyses of the adverse event profile by age, sex, dialysis modality, baseline haemoglobin concentration and administration route revealed no notable differences in the incidence rates for any of these subgroups. There were no cases of antibody-mediated pure red cell aplasia (PRCA) associated with darbepoetin alfa treatment. Seventeen subjects (1%) withdrew from the study due to adverse events, and there were 34 deaths (2%) over the study duration. All but one of the deaths was attributed to co-morbid conditions, and were reported by the study investigators as unrelated to darbepoetin alfa treatment. One death, due to cardiac arrest in a 75-year-old female with a history of chronic heart disease, hypertension, diabetes mellitus and hyperlipidaemia, was considered by the investigator to be possibly related to darbepoetin alfa.
Over the 24-week study period, no relevant changes were observed in the mean systolic and diastolic blood pressure values, and there was no clinically relevant change in the use of anti-hypertensive medications throughout the study. In total, 1022 subjects (68%) were receiving anti-hypertensive medication at baseline, and 1165 subjects (78%) received anti-hypertensive medication at any time during the study. During the study, similar proportions of subjects had doses of anti-hypertensive medications added (25%) or increased (12%) vs those with anti-hypertensive medications stopped (20%) or decreased (10%). There were no changes in laboratory or biochemical variables associated with darbepoetin alfa treatment. Subjects iron status was stable throughout the study. Mean serum ferritin concentration was 523.8 µg/l at baseline and was maintained above 100 µg/l throughout the study (527.9 µg/l at evaluation). Mean transferrin saturation was 32.5% at baseline and 31.7% at evaluation, remaining above 20% throughout the study.
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Discussion
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Previous studies have shown that darbepoetin alfa can effectively maintain haemoglobin concentrations when given at extended dose intervals relative to rHuEpo in dialysis subjects [59]. The results of this study further confirm the results of these earlier trials, and indicate that unit dosing with darbepoetin alfa can effectively and safely maintain haemoglobin concentrations within a target range after switching from rHuEpo at extended dose intervals.
Despite reducing the frequency of administration, there was no change in mean haemoglobin concentration from baseline to the evaluation period in the overall study population. Indeed, mean haemoglobin concentrations were maintained above the European Best Practice Guidelines recommendation of 11 g/dl throughout the entire study period [17]. There was a marked increase in haemoglobin concentrations over the initial 12-week period of the study, which was accompanied by a stabilization period over weeks 1224. The slight decline in haemoglobin concentrations after week 12 is probably reflective of subjects achieving the target haemoglobin concentration of > 13 g/dl. Indeed, during the study, 32% of subjects met the threshold of two consecutive haemoglobin concentrations > 13 g/dl, and were therefore required by the study protocol to have a dose reduction (data not shown). Of these subjects who met the threshold of > 13 g/dl, 64% did so during weeks 112, and the remaining 36% met the threshold during weeks 1324. Consequently, these subjects revealed with some latency a slight decline in haemoglobin concentration, which was still apparent during the evaluation period. This effect may in part disguise the steady-state haemoglobin levels observed during the evaluation period among subjects who had a mean haemoglobin concentration below the threshold level and were, therefore, maintained on a steady dose of darbepoetin alfa. Notably, doses of darbepoetin alfa did not increase during the study, irrespective of route of administration.
Approximately 30% of subjects (453/1502) had a baseline haemoglobin concentration < 11 g/dl, suggesting that they were suboptimally treated with rHuEpo. In keeping with the observations of a previous study [8], these subjects experienced a significant mean increase in haemoglobin of almost 0.7 g/dl after switching to darbepoetin alfa. The increase in this study population was even more pronounced in the subgroup receiving i.v. darbepoetin alfa, and was also clinically significant (+0.48 g/dl) in subjects who received s.c. darbepoetin alfa. These data suggest that patients will be able to maintain target haemoglobin concentrations recommended for European patients with renal anaemia [17] when switched from rHuEpo to darbepoetin alfa at extended dose intervals. Current treatment guidelines recommend that, given its pharmacokinetic profile, rHuEpo should be administered two or three times weekly for the treatment of anaemia in dialysis patients [17,18]. Although rHuEpo has been evaluated using a once-weekly schedule for maintaining haemoglobin concentrations [19,20], this was undertaken in a limited number of stable and highly selected HD subjects. As a result of the greater elimination half-life of darbepoetin alfa relative to rHuEpo [1], extended dose intervals, such as once every 2 weeks [5,7,8,10], and even once every 3 or 4 weeks [7,9,12], are possible with darbepoetin alfa for both correcting and maintaining haemoglobin concentrations.
The safety profile of darbepoetin alfa was comparable with that reported for rHuEpo. The adverse events were generally consistent with those expected for a patient population on dialysis, and few events were considered to be related to darbepoetin alfa treatment. In addition, previous randomized, controlled trials have reported similar incidence rates of adverse events among subjects receiving darbepoetin alfa and rHuEpo [5,6]. There were no cases of antibody-mediated PRCA associated with darbepoetin alfa treatment.
Anaemia has long been recognized as one of the most debilitating features of kidney disease [21], and correction of anaemia may therefore be accompanied by an increase in patient productivity, improved patient health-related quality of life and reduced health care costs. This may confer economic benefits for individuals, as well as for society as a whole. Additional benefits of treatment with darbepoetin alfa may include improved patient compliance, not only because fewer clinic visits are required for those receiving i.v. treatment, but also because fewer injections are needed.
In conclusion, the results of this 6-month study in 1502 CKD subjects on dialysis demonstrate that treatment of renal anaemia with darbepoetin alfa can effectively and safely maintain haemoglobin concentrations at extended dose intervals relative to rHuEpo. Such findings suggest that darbepoetin alfa has the potential to simplify anaemia management for patients and health care providers. Ongoing studies will determine whether monthly dosing will confer additional advantages in this patient population, particularly for patients not on dialysis.
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Acknowledgments
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This study was supported by Amgen.
Conflict of interest statement. R. Brunkhorst and J. Braun are consultants for Amgen. J. Bommer is conducting research for this company. C. Gill holds stock in Amgen, the makers of darbepoetin alfa, and works as a statistician for the company. J. Wagner and T. Wagener are employees of Amgen.
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Received for publication: 10. 6.03
Accepted in revised form: 11.12.03