|Year : 2015 | Volume
| Issue : 1 | Page : 78-82
|Therapeutic efficacy of a biosimilar epoetin alfa in hemodialysis patients
Amel Harzallah1, Karim Zouaghi2, Afef Dridi3, Karima Boubaker1, Soumaya Beji2, Mohamed Ayari4, Fethi El Younsi1, Fatma Ben Moussa2, Adel Kheder1
1 Department of Internal Medicine A, Charles Nicolle Hospital, Tunis, Tunisia
2 Department of Nephrology, Rabta Hospital, Tunis, Tunisia
3 Dialysis Unity of Manouba, Manouba, Tunisia
4 Dialysis Unity of Rades Foret, Ben Arous, Tunisia
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|Date of Web Publication||8-Jan-2015|
| Abstract|| |
Anemia is a frequent complication in patients with chronic kidney disease. However, human recombinant erythropoietin (rHu-EPO) has revolutionized the management of anemia in chronically dialyzed patients. Epomax ® is a new rHu-EPO alfa manufactured in Tunisia (Medis Laboratories). The aim of this study was to evaluate the efficacy and tolerance of Epomax ® in chronic hemodialysis (HD) patients in a phase-III, multicenter, clinical trial. Fiftythree HD patients (mean age 47.7 ± 13 years) who received a stable dose of rHu-EPO (Hemax ® , a rHu-EPO alfa manufactured by Biosidus Laboratories) subcutaneously were switched to Epomax ® via the same route of administration. At baseline, the mean systolic pressure was 132 ± 18 mm Hg and the mean diastolic pressure was 79 ± 8 mm Hg. The mean blood hemoglobin was 10.2 g/dL and the median ferritin level was 667 ng/mL. After a follow-up of 43 days, the mean blood hemoglobin was 10.5 g/dL under the effect of Epomax ® . There was no significant difference in the mean hemoglobin levels between the treatments with both drugs. Few adverse events were reported during the study. We conclude that Epomax ® was effective at maintaining the hemoglobin levels at target concentrations and was well tolerated in HD patients.
|How to cite this article:|
Harzallah A, Zouaghi K, Dridi A, Boubaker K, Beji S, Ayari M, El Younsi F, Moussa FB, Kheder A. Therapeutic efficacy of a biosimilar epoetin alfa in hemodialysis patients. Saudi J Kidney Dis Transpl 2015;26:78-82
|How to cite this URL:|
Harzallah A, Zouaghi K, Dridi A, Boubaker K, Beji S, Ayari M, El Younsi F, Moussa FB, Kheder A. Therapeutic efficacy of a biosimilar epoetin alfa in hemodialysis patients. Saudi J Kidney Dis Transpl [serial online] 2015 [cited 2021 Feb 25];26:78-82. Available from: https://www.sjkdt.org/text.asp?2015/26/1/78/148744
| Introduction|| |
The introduction of human recombinant erythropoietin (rHu-EPO) in the early 1990s resulted in a major progress in the management of anemia in chronic hemodialysis (HD) patients. ,,,,,,,,,,,,,,,,,
Erythropoiesis-stimulating agents (ESAs) reduce the need for blood transfusions in patients undergoing chronic HD and improve the quality of life (QoL). ,, Today, several ESAs are available including epoetin alfa and beta, darbepoetin alfa and biosimilars. 
In Tunisia, two types of biosimilar rHu-EPO alfa are available, and are produced by two foreign laboratories. In order to control the cost of this treatment, a Tunisian laboratory has developed a new biosimilar rHu-EPO alfa, called Epomax ® (Medis Laboratories, Tunisia), and this is produced locally.
The aim of this phase-III, multicenter clinical trial (Equi-Max) was to evaluate the efficacy and tolerance of this ESA administered to chronic HD patients.
| Patients and Methods|| |
We studied patients aged ≥20 years with chronic kidney disease (CKD) in four dialysis centers in Tunisia. We included in the study patients who had stable clinical condition and duration of HD ≥6 months, three HD sessions per week, treatment with rHu-EPO administered one to three times/week with a stable hemoglobin level of between 10.0 and 12.0 g/dL for at least three months at inclusion and Kt/V of >1.2 [calculated according to the formula of Barth (Kt/V = (0.031 × PRU) - 0.66 with PRU (percent reduction of urea) = (C 0 - C t )/C 0 × 100), where C 0 represents uremia before dialysis and C t uremia at the end of dialysis].
We excluded from the study patients who had neoplasia, active infectious or inflammatory diseases, a hematological disease, severe heart failure or transfusion during the three months prior to the start of the study. Patients requiring an emergency blood transfusion, receiving a renal transplant or undergoing a surgical procedure after inclusion were also excluded from the trial.
The study was conducted according to the Declaration of Helsinki, 1964 and received approval from a local ethics committee. All patients gave their informed consent to participate in the study.
The study patients were selected over a period of three weeks before inclusion, and all of them had the following investigations at baseline: Blood hemoglobin levels, hematocrit, C-reactive protein (CRP), serum albumin levels, serum iron levels and Kt/V.
Eligible patients received treatment with rHuEPO alfa (Hemax ® ) for 15 days and were then switched to Epomax ® while maintaining the same doses and the same route of administration.
The patients included in the study were followed for a period of 43 days. Visits were scheduled on Days 15, 21, 28 and 43 for periodic checks of the blood hemoglobin levels and hematocrit. The serum iron levels and CRP were measured at the end of the study, on Day 43.
| Statistical Analyses|| |
The principal evaluation criterion was the change in hemoglobin level from the start to the end of the study.
The number of patients necessary for statistical analysis was calculated to detect a difference in hemoglobinemia of 1 g/dL, at a power of 95%, with a threshold significance fixed at 5%.
Quantitative variables were described as means, standard deviations (SD), medians and ranges. Categorical variables were described by numbers and frequencies (%).
The quantitative variables were analyzed using analysis of variance (ANOVA) and the categorical variables were assessed using the chi-squared test and the MacNemar test. Concordance between the weekly doses of the two study treatments was estimated using the Kappa coefficient.
Tolerance of treatment was assessed by recording all the adverse events and by monitoring the biological parameters and the vital signs.
| Results|| |
We studied 53 patients over a period of seven months, from December 2010 to June 2011. Five patients dropped out of the study early; two stopped treatment due to abdominal pain and three withdrew their consents.
The mean age of the patients was 47.7 ± 13 years (range: 27-81) and the female to male ratio was 1.9; 25% of the patients were smokers. The causes of CKD included glomerular disease in 41.5% of the patients, vascular disease in 29.3%, interstitial kidney disease in 19.5%, diabetes in 7.3% and hereditary disease in 2.4%.
Co-morbidity was associated with CKD in 75% of the patients. Diabetes was found in 12.5% of the patients, arterial hypertension 90%, dyslipidemia in 10.5%, heart disease in in 10% and cerebrovascular accidents in 10%. Thirteen patients (32.5% of cases) had several co-morbidities.
The patients included were dialyzed for a mean of 6.4 years (range: 1−17). Mean age at the start of HD was 41 years (range: 18−74). The fistula used was humeral in 50% of the cases and radial in 45% of the patients, and 5% of patients had vascular grafts.
Low molecular-weight heparin and unfractionated heparin were used for heparinization in 49% and 24.5% of the patients, respectively. The types of dialysis membranes included synthetic polysulfone and polyamide and triacetate cellulose in 63%, 14% and 23% of patients, respectively. The mean duration of the dialysis sessions was 3 h 58 min (range: 3 h 30 min to 4 h).
The mean weight of the patients was 66.5 ± 14 kg (range: 41−97) and the mean height was 165.1 ± 10 cm, with a mean body mass index (BMI) of 24.7 ± 5 kg/m 2 . The mean inter-dialytic weight gain was 2.9 ± 0.7 kg (range: 1−4).
The mean systolic blood pressure before and after dialysis was 132 ± 18 mm Hg and 123 ± 18 mm Hg, respectively. The mean diastolic blood pressure before and after dialysis was 79 ± 12 mm Hg and 73 ± 8 mm Hg, respectively. The mean pulse rate at baseline was 73 ± 8 beats/min.
Residual diuresis was nil in 46.5% of the patients, and a mean residual diuresis of 324 ± 231 mL/24 h (range: 50−1000) was observed in 47% of the patients. All patients underwent a complete biological assessment at baseline of the study. The mean of the blood hemoglobin levels was 10.2 g/dL at baseline, the hepatitis B serology was negative in all the patients and hepatitis C serology was positive in four (7.5%) patients.
At the start of the study, all the patients received rHu-EPO alfa (Hemax ® ). The mean dose was 4113 ± 1772 IU/week on Day 15 (before the treatment switch). The weekly dose of rHu-EPO in all the patients remained unchanged, except in one patient in whom the dose was increased from 2000 IU to 4000 IU/week.
On Day 15, all the study patients were switched to treatment with Epomax ® at the same weekly dose [Figure 1]. There were few modifications to the Epomax ® dose during the study; the dose was reduced between Days 21 and 28 from 6000 to 4000 and then 2000 IU/week in one patient, and the five patients who did not complete the study received 4000 IU/week.
|Figure 1: Doses of the compared drugs and evolution of hemoglobin and blood pressure during the study.|
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Among the 53 patients in the study, 18 patients received injectable iron sucrose as a weekly infusion; the average dose of the injectable iron was 30 ± 44 mg/week.
Epomax ® and Hemax ® showed comparable mean hemoglobin levels during the follow-up of the patients [Figure 1] at no significant difference in doses of these two ESAs at the end of the study.
The safety profile of the ESAs in our study was close to that expected in HD patients. The most frequent adverse events were variations in blood pressure and headaches. No episodes of convulsions or thrombosis of the vascular access were reported. Two patients presented with abdominal pain and dropped out of the study early; the pharmaco-vigilance failed to establish any link with Epomax ® . Three other patients left the study at their own request on Day 28. All the patients had stable blood hemoglobin levels when they dropped out. No death occurred during the study.
There were no significant modifications to the biological parameters or blood pressure associated with Epomax ® [Figure 1]. The median ferritin level was 667 ng/L at baseline and 661 ng/L at the end of the study. The systolic and the diastolic blood pressures remained stable during the study.
| Discussion|| |
Our study demonstrates the bioequivalence of two ESAs related to epoetin alfa. Epomax ® molecule is produced in vitro, in rodent cells, by recombinant DNA technology. The cell line is obtained by transfection of ovary cells from the Chinese hamster with a plasmid containing the gene of interest. Epomax ® is prepared in an environmentally controlled area and respects the standarized manufacturing processes. Quality control of the primary materials and end product is carried out according to the requirements of the European pharmacopeia.
In our study, the administration of Epomax ® to HD patients was effective in maintaining the blood hemoglobin levels within the limits recommended for HD patients over the evaluation period with insignificant change in dosing of the ESA.
Epomax ® was well tolerated and its safety profile was comparable to that of Hemax ® in terms of the frequency of adverse events and the modifications of the biological parameters and vital signs.
We conclude that in this phase-III, comparative study carried out in HD adult patients with anemia secondary to CKD over a short period of time, Epomax ® was found to be equivalent to Hemax ® at maintaining stable blood hemoglobin levels and was well tolerated.
Conflict of interest: None
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Dr. Amel Harzallah
Department of Internal Medicine A, Charles Nicolle Hospital, Tunis
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