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NDT Advance Access originally published online on July 27, 2007
Nephrology Dialysis Transplantation 2007 22(10):3052-3054; doi:10.1093/ndt/gfm490
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org


Epoetin delta in the management of renal anaemia: results of a 6-month study

Kevin J. Martin on behalf of the Epoetin Delta 3001 Study Group

Division of Nephrology, Saint Louis University, St Louis, MO, USA

Correspondence to: Kevin J. Martin, MB, B.Ch, FACP, Division of Nephrology, Saint Louis University, 3634 Vista Avenue, St Louis, MO 63110, USA. Email: martinkj{at}slu.edu



   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Background. Epoetin delta is an epoetin that, unlike existing agents, is produced in a human cell line. The present study investigated the efficacy and tolerability of intravenous (i.v.) epoetin delta compared with i.v. epoetin alfa.

Methods. This was a 6-month, multicentre, randomized, double-blind trial in haemodialysis patients previously receiving epoetin alfa. Haematological parameters were assessed, and adverse events monitored. Equivalent efficacy was defined as a difference in mean haemoglobin between the two agents over weeks 12–24 of ≤ 1 g/dl with a 90% confidence interval (CI) within the range –1 to 1 g/dl.

Results. In total, 560 patients received epoetin delta while 192 received epoetin alfa, and 76.8% and 79.7% of patients, respectively, completed the study. Both agents showed similar efficacy in controlling anaemia: the point estimate for the difference in mean haemoglobin over weeks 12–24 was 0.01 g/dl (90% CI, –0.13, 0.15 g/dl), confirming equivalence. Adverse events were those expected in dialysis patients. Events possibly related to treatment occurred in 9.2% of patients receiving epoetin delta and 8.4% receiving epoetin alfa. Serious adverse events (SAEs) occurred in 33.0% and 26.7% of patients in the epoetin delta and epoetin alfa groups, respectively. Six patients in the epoetin delta group experienced an SAE considered possibly related to treatment (mostly access-related clotting), compared with no patient in the epoetin delta group. None of these SAEs were life threatening.

Conclusions. Epoetin delta was shown to have an equivalent efficacy and safety profile to epoetin alfa in this 6-month study.

Keywords: Clinical trial; epoetin delta; haemodialysis; randomized controlled trial; renal anaemia



   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Patients with chronic kidney disease (CKD) are at a substantially increased risk of anaemia, which in turn leads to fatigue and reduced quality of life, as well as increased morbidity and mortality [1–4]. In the 1980s, the management of anaemia was revolutionized by the introduction of the recombinant erythropoietins and there is now a considerable body of evidence supporting the efficacy and tolerability of these epoetins [5,6]. The epoetins available currently are produced using recombinant DNA technology in Chinese hamster ovary cell lines, which confer a glycosylation structure that differs from endogenous human erythropoietin [7]. An epoetin—epoetin delta (DYNEPO®, Shire plc)—has now been developed that is produced in a human cell line through gene-activation technology, resulting in an agent fully glycosylated in a human cell environment. In this article, we report a 6-month trial of intravenous (i.v.) epoetin delta injections compared with i.v. epoetin alfa in patients with CKD requiring haemodialysis.



   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 Acknowledgements
 References
 
Study design
This was a multicentre, double-blind study in which patients were randomized in a 3:1 ratio to 6 months’ treatment with i.v. epoetin delta or epoetin alfa (Epogen; Amgen Inc.) three times per week. The primary aim of the study was to demonstrate a difference in haemoglobin levels between the two groups of <1 g/dl.

The initial dose of study agents was identical to that of the last dose of epoetin alfa that each patient received before study entry, and could not be changed during the first 2 weeks of treatment. Thereafter, the dose was adjusted if dry weight changed by 5 kg, if haemoglobin dropped below 10 g/dl (dose increased by 50%), or if haemoglobin increased above 12 g/dl (dose decreased by 25%).

Patients
Patients with CKD who required haemodialysis and had previously received epoetin alfa for at least 90 days before study entry (dose not changed by more than 50% in the 30 days before giving informed consent) were eligible for the study. Patients’ baseline haemoglobin levels were required to be 9.6–12.4 g/dl, with serum ferritin ≥90 ng/ml and transferrin saturation ≥18%.

Major exclusion criteria included the following: uncontrolled hypertension; concomitant unrelated illness that could reduce life expectancy to <12 months; thrombocytopenia (platelet count <75 000/mm3); active bleeding; pregnancy, lactating or plans to become pregnant; treatment with immunosuppressive drugs (other than corticosteroids for a chronic condition) or androgen therapy within 30 days before giving informed consent; and clinically relevant systemic disease.

All patients provided written, informed consent. The study was conducted in accordance with the International Conference on Harmonization guidelines, and conformed to the principles of the Declaration of Helsinki.

Assessments
Haematological parameters were assessed at baseline and every week until week 12, and then on weeks 16, 20 and 24. The primary efficacy parameter was the average haemoglobin over weeks 12–24. Efficacy parameters were assessed on a modified intent-to-treat (mITT) population that included all randomized patients who received study medication, and had haemoglobin measured at baseline and at least once during weeks 12, 16, 20 or 24. The safety evaluable population included all randomized patients who received at least one dose of study medication.

Equivalent efficacy was defined as a difference in mean haemoglobin between the two agents over weeks 12–24 of ≤1 g/dl with a 90% confidence interval (CI) within the range –1 to 1 g/dl.



   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 Acknowledgements
 References
 
In total, 752 patients were randomized to treatment with epoetin delta (N = 560) or epoetin alfa (N = 192). Baseline characteristics of the mITT population were similar in both groups (Table 1). The 6-month study was completed by 430 patients (76.8%) in the epoetin delta group and 153 (79.7%) in the epoetin alfa group. The most common reason for withdrawal in each group was red blood cell transfusion [epoetin delta, n = 46 (8.2%); epoetin alfa: n = 11 (5.7%)]. Withdrawal as a result of an adverse event was infrequent, occurring in five patients from the epoetin alfa group (2.6%) and nine from the epoetin delta group (1.6%).


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  		Table 1. Baseline demographics (mITT population)

 
Efficacy
At baseline there was no significant difference between the epoetin delta and epoetin alfa groups in mean haemoglobin (11.16 ± 0.77 g/dl vs 11.13 ± 0.77 g/dl, respectively; P = 0.436) level. Haemoglobin parameters in the mITT population during weeks 12–24 are shown in Table 2 and Figure 1. Both agents showed similar efficacy in controlling anaemia, with similar mean doses of epoetin delta (63.5 IU/kg; 95% CI: 59.1, 67.8 IU/kg) and epoetin alfa (62.8 IU/kg; 95% CI: 56.1, 69.4) recorded during the study (equating to mean weekly doses of 190.5 and 188.4 IU/kg, respectively). The point estimate for the difference in mean haemoglobin over weeks 12–24 was 0.01 g/dl with a 90% CI of (–0.13; 0.15) g/dl, confirming the equivalent efficacy of epoetin alfa and epoetin delta. Changes in other haematological parameters were as expected in both groups.


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  		Table 2. Haemoglobin parameters during weeks 12–24 in the modified ITT population

 

Figure 1
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  		Fig. 1. Mean ± SD haemoglobin in the modified ITT population.

 
Safety
Overall, 94.4% of patients in the epoetin delta group experienced an adverse event, compared with 92.1% in the epoetin alfa group. Importantly, few of the events were considered to be possibly related to treatment; occurring in 9.2% of patients receiving epoetin delta and 8.4% receiving epoetin alfa, and most were mild to moderate in intensity. The most frequently occurring adverse events considered to be related to treatment are shown in Table 3.


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  		Table 3. The most common adverse events considered possibly related to treatment (safety evaluable population)

 
Serious adverse events occurred in 33.0% and 26.7% of patients in the epoetin delta and epoetin alfa groups, respectively. Six patients (1.1%) receiving epoetin delta experienced serious adverse events considered possibly related to treatment [thrombosis in four (all clotting related to dialysis access), hypertension in one and raised liver enzymes and ferritin levels in one] compared with none in the epoetin alfa group. None of these events in the epoetin delta group was considered to be life threatening.



   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
Acknowledgements
 References
 
This 6-month, double-blind study shows that i.v. epoetin delta is effective in the management of renal anaemia. No significant differences were demonstrated between i.v. epoetin delta and i.v. epoetin alfa with regard to haemoglobin levels, or in terms of dose, indicating that epoetin delta is as effective as epoetin alfa. Approximately 90% of patients had haemoglobin levels above 10 g/dl during weeks 12–24, showing that good control of anaemia was maintained.

In addition to showing equivalent efficacy, the safety profiles of the two agents were found to be similar. A small number of patients (1%) in the epoetin delta group experienced serious adverse events that were considered as possibly related to treatment. Most of these (four out of six) were access-related clotting, none of which were life threatening. No thromboembolism occurred. Overall, the profile of adverse events and those considered possibly related to treatment (including thrombosis) were similar in the epoetin alfa and epoetin delta groups.

In conclusion, i.v. epoetin delta has potential as a new option for nephrologists in the management of renal anaemia. Further studies are underway to assess whether the production of this agent in a human cell line leads to any clinical benefits.



   Acknowledgements
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
References
 
The Epoetin Delta 3001 Study group consisted of the following investigators:

H. Abbound, S. Acchiardo, S. Ahmad, G. Ames, M. Anger, J. Arruda, D. Batlle, A. Gupta, R. Black, K. Bolton, K. Boren, R. Brown, J. Burkart, V. Campese, T. Cavalieri, J. Cheigh, B.M. Cowley Jr, R. Delans, E. Friedman, R Goldstein, G. Groggel, L. Ham, T. Herman, J. Holley, A. Jacobs, C. Kablitz, S. Kant, K. Keener, A.J. King, K. Kleiman, E. Kowalski, T. Marbury, R. Mars, K. Martin, G. Matzke, A. Nissenson, K.A. Ntoso, M. Pahl, W. Piering, S. Popham, S.N. Rahman, R. Raja, G. Ramirez, M. Rothstein, J. Sands, J. Sigala, B. Smith, D. Spiegel, B. Spinowitz, L. Steed, J. Strom, S. Swan, M. Topiel, K. Tuttle, J. Wagner, M. Weinberg, M. Weir, W. Weise, F. Whittier, B. Wilkes, M. Williams, J. Winston, D. Wombolt. Oxford PharmaGenesis provided editorial support to the author.

Conflict of interest statement. K.J.M. has received research grants from Shire plc and is also a consultant to the company. Shire plc also provided assistance with analysis and interpretation of the data.



   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 

  1. Santoro A. Anemia in renal insufficiency. Rev Clin Exp Hematol (2002) (Suppl 1):12–20.
  2. Avram MM, Blaustein D, Fein PA, Goel N, Chattopadhyay J, Mittman N. Hemoglobin predicts long-term survival in dialysis patients: a 15-year single-center longitudinal study and a correlation trend between prealbumin and hemoglobin. Kidney Int Suppl (2003) 64:S6–S11.[CrossRef]
  3. Li S, Foley RN, Collins AJ. Anemia, hospitalization, and mortality in patients receiving peritoneal dialysis in the United States. Kidney Int (2004) 65:1864–1869.[CrossRef][Web of Science][Medline]
  4. Locatelli F, Pisoni RL, Combe C, et al. Anaemia in haemodialysis patients of five European countries: association with morbidity and mortality in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant (2004) 19:121–132.[Abstract/Free Full Text]
  5. Silverberg D. Outcomes of anaemia management in renal insufficiency and cardiac disease. Nephrol Dial Transplant (2003) 18([Suppl 2]):ii7–ii12.[Abstract/Free Full Text]
  6. Obrador GT, Pereira BJ. Anaemia of chronic kidney disease: an under-recognized and under-treated problem. Nephrol Dial Transplant (2002) 17([Suppl 11]):44–46.[Abstract]
  7. Skibeli V, Nissen-Lie G, Torjesen P. Sugar profiling proves that human serum erythropoietin differs from recombinant human erythropoietin. Blood (2001) 98:3626–3634.[Abstract/Free Full Text]
Received for publication: 22. 8.06
Accepted in revised form: 27. 6.07


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