Efficacy, tolerability and safety of darbepoetin alfa injection for the treatment of anemia associated with chronic kidney disease (CKD) undergoing dialysis: a randomized, phase-III trial

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Abstract

Background

Darbepoetin alfa (DA-α) is a long-acting erythropoiesis-stimulating glycoprotein which has half-life three-fold longer than that of Erythropoietin alfa (EPO). The objective of this study was to compare the efficacy and safety of DA-α injection versus EPO for treating renal anemia amongst Indian patients with end-stage renal disease (ESRD) undergoing dialysis.

Methods

Patients of either gender (aged 18–65 years) with ESRD undergoing dialysis who had hemoglobin (Hb) levels < 10 g/dL after receiving EPO were switched to DA-α (0.45 μg/kg) once weekly subcutaneously or EPO 50 IU/kg thrice weekly subcutaneously (centrally randomized 1:1) for 12–24 weeks (correction phase) followed by 12 weeks maintenance phase (for Hb levels ≥10 g/dL). The primary efficacy endpoint was mean change in Hb level from baseline to end of correction phase.

Results

In the intention-to-treat population ( n = 126), the between group difference in mean Hb change was − 0.01 g/dL (95% CI – 0.68 to − 0.66, p = 0.97). After adjusting for covariates, the difference was − 0.2878 g/dL (95% CI -0.936 to0.360). The lower limit of the two-sided 95% CI of primary endpoint was above the pre-specified non-inferiority margin of − 1.0 g/dL. Similar trend of non-inferiority was observed for per-protocol population. Safety profile of DA-α and EPO were observed to be similar.

Conclusion

Our study results demonstrated that for patients with ESRD undergoing dialysis, administering DA-α at lower dose frequency, is equally effective and well tolerated as EPO for treating renal anemia.

Trial registration

CTRI/2012/07/002835 [Registered on: 27/07/2012]; Trial Registered Prospectively.

Electronic supplementary material

The online version of this article (10.1186/s12882-019-1209-1) contains supplementary material, which is available to authorized users.

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Most cited references 11

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Correction of anemia with epoetin alfa in chronic kidney disease.

Ajay K. Singh, Lynda Szczech, Kezhen L Tang … (2006)

Anemia, a common complication of chronic kidney disease, usually develops as a consequence of erythropoietin deficiency. Recombinant human erythropoietin (epoetin alfa) is indicated for the correction of anemia associated with this condition. However, the optimal level of hemoglobin correction is not defined. In this open-label trial, we studied 1432 patients with chronic kidney disease, 715 of whom were randomly assigned to receive a dose of epoetin alfa targeted to achieve a hemoglobin level of 13.5 g per deciliter and 717 of whom were assigned to receive a dose targeted to achieve a level of 11.3 g per deciliter. The median study duration was 16 months. The primary end point was a composite of death, myocardial infarction, hospitalization for congestive heart failure (without renal replacement therapy), and stroke. A total of 222 composite events occurred: 125 events in the high-hemoglobin group, as compared with 97 events in the low-hemoglobin group (hazard ratio, 1.34; 95% confidence interval, 1.03 to 1.74; P=0.03). There were 65 deaths (29.3%), 101 hospitalizations for congestive heart failure (45.5%), 25 myocardial infarctions (11.3%), and 23 strokes (10.4%). Seven patients (3.2%) were hospitalized for congestive heart failure and myocardial infarction combined, and one patient (0.5%) died after having a stroke. Improvements in the quality of life were similar in the two groups. More patients in the high-hemoglobin group had at least one serious adverse event. The use of a target hemoglobin level of 13.5 g per deciliter (as compared with 11.3 g per deciliter) was associated with increased risk and no incremental improvement in the quality of life. (ClinicalTrials.gov number, NCT00211120 [ClinicalTrials.gov].). Copyright 2006 Massachusetts Medical Society.

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KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease.

, (2006)

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Predictors of early mortality among incident US hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS).

Cathy Critchlow, Jon S Anthony, Ronald L. Pisoni … (2006)

Mortality risk among hemodialysis (HD) patients may be highest soon after initiation of HD. A period of elevated mortality risk was identified among US incident HD patients, and which patient characteristics predict death during this period and throughout the first year was examined using data from the Dialysis Outcomes and Practice Patterns Study (DOPPS; 1996 through 2004). A retrospective cohort study design was used to identify mortality risk factors. All patient information was collected at enrollment. Life-table analyses and discrete logistic regression were used to identify a period of elevated mortality risk. Cox regression was used to estimate adjusted hazard ratios (HR) measuring associations between patient characteristics and mortality and to examine whether these associations changed during the first year of HD. Among 4802 incident patients, risk for death was elevated during the first 120 d compared with 121 to 365 d (27.5 versus 21.9 deaths per 100 person-years; P = 0.002). Cause-specific mortality rates were higher in the first 120 d than in the subsequent 121 to 365 d for nearly all causes, with the greatest difference being for cardiovascular-related deaths. In addition, 20% of all deaths in the first 120 d occurred subsequent to withdrawal from dialysis. Most covariates were found to have consistent effects during the first year of HD: Older age, catheter vascular access, albumin <3.5, phosphorus <3.5, cancer, and congestive heart failure all were associated with elevated mortality. Pre-ESRD nephrology care was associated with a significantly lower risk for death before 120 d (HR 0.65; 95% confidence interval 0.51 to 0.83) but not in the subsequent 121- to 365-d period (HR 1.03; 95% confidence interval 0.83 to 1.27). This care was related to approximately 50% lower rates of both cardiac deaths and withdrawal from dialysis during the first 120 d. Mortality risk was highest in the first 120 d after HD initiation. Inadequate predialysis nephrology care was strongly associated with mortality during this period, highlighting the potential benefits of contact with a nephrologist at least 1 mo before HD initiation.

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Author and article information

Contributors

Shubhadeep D. Sinha: sd.sinha@heterodrugs.com

Vamsi Krishna Bandi: vamsi.b@heterodrugs.com

Bala Reddy Bheemareddy: Balareddy.B@heterodrugs.com

Pankaj Thakur: 91-40-23704923 , Pankaj.Thakur@heterodrugs.com

Sreenivasa Chary: sreenivasa.chary@heterodrugs.com

Kalpana Mehta: kalpana.drs@gmail.com

Vikranth Reddy Pinnamareddy: vikranthreddy@yahoo.co.in

Rajendra Pandey: rajensankrityan@gmail.com

Subhramanyam Sreepada: sreepada11@gmail.com

Santosh Durugkar: sdd91@yahoo.co.in

Journal

Journal ID (nlm-ta): BMC Nephrol

Journal ID (iso-abbrev): BMC Nephrol

Title: BMC Nephrology

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2369

Publication date (Electronic): 13 March 2019

Publication date PMC-release: 13 March 2019

Publication date Collection: 2019

Volume: 20

Electronic Location Identifier: 90

Affiliations

[1 ]ISNI 0000 0004 1797 2981, GRID grid.464867.f, Clinical Development and Medical Affairs, , Hetero Group, Hetero Corporate, 7-2-A2, Industrial Estates, ; Sanath Nagar, Hyderabad, Andhra Pradesh India

[2 ]ISNI 0000 0004 1766 9130, GRID grid.413161.0, Department of Nephrology, , B.L.Y Nair Hospital, ; A.L Nair Road, Mumbai, Maharashtra India

[3 ]ISNI 0000 0004 1761 1705, GRID grid.413417.4, Care Hospitals, ; Road No. 1, Banjara Hills, Hyderabad, Andhra Pradesh India

[4 ]ISNI 0000 0004 0507 4308, GRID grid.414764.4, Department of Nephrology, , Institute of Post Graduate Medical Education and Research Kolkata, ; 244 A.J.C Bose Road, Kolkata, West Bengal India

[5 ]Sri Raghavendra Hospital, 1-7-100, Opp. Round Building, Kamala Nagar, ECIL Cross Road, ECIL, Hyderabad, Andhra Pradesh 500062 India

[6 ]Ashwini Hospital and Ramakanth Heart Care Center, Shivaji Nagar, Nanded, Maharashtra India

Article

Publisher ID: 1209

DOI: 10.1186/s12882-019-1209-1

PMC ID: 6417108

PubMed ID: 30866856

SO-VID: ace4036d-26e4-4331-9f58-e598e6ecc944

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 23 October 2018

Date accepted : 11 January 2019

Custom metadata

ScienceOpen disciplines: Nephrology

Keywords: darbepoetin alfa,erythropoietin,anemia,dialysis,end-stage renal disease

Data availability:

ScienceOpen disciplines: Nephrology

Keywords: darbepoetin alfa, erythropoietin, anemia, dialysis, end-stage renal disease

Efficacy, tolerability and safety of darbepoetin alfa injection for the treatment of anemia associated with chronic kidney disease (CKD) undergoing dialysis: a randomized, phase-III trial

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Karger: Nephrology

Most cited references 11

Correction of anemia with epoetin alfa in chronic kidney disease.

KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease.

Predictors of early mortality among incident US hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS).

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