The continous erythropoietin receptor activator (C.E.R.A.) corrects anemia at extended administration intervals in patients with chronic kidney disease not on dialysis

Results of a phase II study

Robert Provenzano, A. Besarab, I. C. Macdougall, David Ellison, A. P. Maxwell, W. Sulowicz, M. Klinger, B. Rutkowski, R. Correa-Rotter, F. C. Dougherty, P. Barre, A. Levin, A. McMahon, S. W. Tobe, A. Valdes, S. Fishbane, J. Lewis, M. Leiserowitz, R. Mehta, S. Vicks

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

Aim: This study was designed to assess the potential of the continuous erythropoietin receptor activator (C.E.R.A.) to correct anemia at extended administration intervals in erythropoiesis-stimulating agent-naïve patients with chronic kidney disease (CKD) not on dialysis and to determine its optimal starting dose. Methods: Patients were assigned to subcutaneous C.E.R.A. at 3 doses: 0.15, 0.30 and 0.60 μg/kg/wk. During the first 6 weeks, dose adjustments for efficacy were not permitted in order to assess dose response. Within each of the 3 dose groups, patients were randomized to receive C.E.R.A. QW, Q2W or Q3W; the total dose during the first 6 weeks was the same for a particular dose group across the frequency subgroups. During the next 12 weeks, dose was adjusted according to predefined hemoglobin (Hb) criteria. The primary efficacy parameter was change in Hb over 6 weeks, estimated from regression analysis between baseline and the point at which the patient received a dose change or blood transfusion. It therefore provided an estimate of Hb increase based on starting dose. Other endpoints included Hb response rate (proportion of patients with a Hb increase ≥ 1.0 g/dl on 2 consecutive occasions). A 1-year extension period investigated long term tolerability and efficacy. Results: A dose-dependent relationship was noted in the mean change in Hb from baseline over 6 weeks (p <0.0001), independent of administration schedule (p = 0.9201). There was also a significant relationship between Hb change and median serum C.E.R.A. concentration (p <0.0001). Erythropoietic responses were sustained in all groups with mean changes from baseline in Hb > 1.2 g/dl observed at doses ≥0.30 μg/kg/wk. Hb response rate increased with increasing dose: 67, 72 and 90% with C.E.R.A. 0.15, 0.30 and 0.60 μg/kg/wk, respectively. Generally, the median Hb response time was faster with increasing dose (89, 43 and 31 days, respectively). Response was unrelated to administration frequency. Stable Hb concentrations were maintained throughout the 1-year extension period. C.E.R.A. was generally well tolerated, and the most common adverse events were hypertension, urinary tract infection and renal failure. Conclusions: C.E.R.A. corrected anemia and maintained sustained and stable control of Hb over 1 year. These results suggest that 0.60 μg/kg subcutaneous C.E.R.A. given twice monthly is a suitable starting dose for further investigation in Phase III studies in patients with CKD not on dialysis.

Original languageEnglish (US)
Pages (from-to)306-317
Number of pages12
JournalClinical Nephrology
Volume67
Issue number5
StatePublished - May 2007

Fingerprint

Chronic Renal Insufficiency
Anemia
Dialysis
Hemoglobins
continuous erythropoietin receptor activator
Hematinics
Urinary Tract Infections
Blood Transfusion
Reaction Time
Renal Insufficiency
Regression Analysis
Hypertension

Keywords

  • Anemia
  • C.E.R.A.
  • Chronic kidney disease
  • Continous erythropoietin receptor activator
  • Hemoglobin

ASJC Scopus subject areas

  • Nephrology

Cite this

The continous erythropoietin receptor activator (C.E.R.A.) corrects anemia at extended administration intervals in patients with chronic kidney disease not on dialysis : Results of a phase II study. / Provenzano, Robert; Besarab, A.; Macdougall, I. C.; Ellison, David; Maxwell, A. P.; Sulowicz, W.; Klinger, M.; Rutkowski, B.; Correa-Rotter, R.; Dougherty, F. C.; Barre, P.; Levin, A.; McMahon, A.; Tobe, S. W.; Valdes, A.; Fishbane, S.; Lewis, J.; Leiserowitz, M.; Mehta, R.; Vicks, S.

In: Clinical Nephrology, Vol. 67, No. 5, 05.2007, p. 306-317.

Research output: Contribution to journalArticle

Provenzano, R, Besarab, A, Macdougall, IC, Ellison, D, Maxwell, AP, Sulowicz, W, Klinger, M, Rutkowski, B, Correa-Rotter, R, Dougherty, FC, Barre, P, Levin, A, McMahon, A, Tobe, SW, Valdes, A, Fishbane, S, Lewis, J, Leiserowitz, M, Mehta, R & Vicks, S 2007, 'The continous erythropoietin receptor activator (C.E.R.A.) corrects anemia at extended administration intervals in patients with chronic kidney disease not on dialysis: Results of a phase II study', Clinical Nephrology, vol. 67, no. 5, pp. 306-317.
Provenzano, Robert ; Besarab, A. ; Macdougall, I. C. ; Ellison, David ; Maxwell, A. P. ; Sulowicz, W. ; Klinger, M. ; Rutkowski, B. ; Correa-Rotter, R. ; Dougherty, F. C. ; Barre, P. ; Levin, A. ; McMahon, A. ; Tobe, S. W. ; Valdes, A. ; Fishbane, S. ; Lewis, J. ; Leiserowitz, M. ; Mehta, R. ; Vicks, S. / The continous erythropoietin receptor activator (C.E.R.A.) corrects anemia at extended administration intervals in patients with chronic kidney disease not on dialysis : Results of a phase II study. In: Clinical Nephrology. 2007 ; Vol. 67, No. 5. pp. 306-317.
@article{44fb7c561e0c41c2880282d99ec30c10,
title = "The continous erythropoietin receptor activator (C.E.R.A.) corrects anemia at extended administration intervals in patients with chronic kidney disease not on dialysis: Results of a phase II study",
abstract = "Aim: This study was designed to assess the potential of the continuous erythropoietin receptor activator (C.E.R.A.) to correct anemia at extended administration intervals in erythropoiesis-stimulating agent-na{\"i}ve patients with chronic kidney disease (CKD) not on dialysis and to determine its optimal starting dose. Methods: Patients were assigned to subcutaneous C.E.R.A. at 3 doses: 0.15, 0.30 and 0.60 μg/kg/wk. During the first 6 weeks, dose adjustments for efficacy were not permitted in order to assess dose response. Within each of the 3 dose groups, patients were randomized to receive C.E.R.A. QW, Q2W or Q3W; the total dose during the first 6 weeks was the same for a particular dose group across the frequency subgroups. During the next 12 weeks, dose was adjusted according to predefined hemoglobin (Hb) criteria. The primary efficacy parameter was change in Hb over 6 weeks, estimated from regression analysis between baseline and the point at which the patient received a dose change or blood transfusion. It therefore provided an estimate of Hb increase based on starting dose. Other endpoints included Hb response rate (proportion of patients with a Hb increase ≥ 1.0 g/dl on 2 consecutive occasions). A 1-year extension period investigated long term tolerability and efficacy. Results: A dose-dependent relationship was noted in the mean change in Hb from baseline over 6 weeks (p <0.0001), independent of administration schedule (p = 0.9201). There was also a significant relationship between Hb change and median serum C.E.R.A. concentration (p <0.0001). Erythropoietic responses were sustained in all groups with mean changes from baseline in Hb > 1.2 g/dl observed at doses ≥0.30 μg/kg/wk. Hb response rate increased with increasing dose: 67, 72 and 90{\%} with C.E.R.A. 0.15, 0.30 and 0.60 μg/kg/wk, respectively. Generally, the median Hb response time was faster with increasing dose (89, 43 and 31 days, respectively). Response was unrelated to administration frequency. Stable Hb concentrations were maintained throughout the 1-year extension period. C.E.R.A. was generally well tolerated, and the most common adverse events were hypertension, urinary tract infection and renal failure. Conclusions: C.E.R.A. corrected anemia and maintained sustained and stable control of Hb over 1 year. These results suggest that 0.60 μg/kg subcutaneous C.E.R.A. given twice monthly is a suitable starting dose for further investigation in Phase III studies in patients with CKD not on dialysis.",
keywords = "Anemia, C.E.R.A., Chronic kidney disease, Continous erythropoietin receptor activator, Hemoglobin",
author = "Robert Provenzano and A. Besarab and Macdougall, {I. C.} and David Ellison and Maxwell, {A. P.} and W. Sulowicz and M. Klinger and B. Rutkowski and R. Correa-Rotter and Dougherty, {F. C.} and P. Barre and A. Levin and A. McMahon and Tobe, {S. W.} and A. Valdes and S. Fishbane and J. Lewis and M. Leiserowitz and R. Mehta and S. Vicks",
year = "2007",
month = "5",
language = "English (US)",
volume = "67",
pages = "306--317",
journal = "Clinical Nephrology",
issn = "0301-0430",
publisher = "Dustri-Verlag Dr. Karl Feistle",
number = "5",

}

TY - JOUR

T1 - The continous erythropoietin receptor activator (C.E.R.A.) corrects anemia at extended administration intervals in patients with chronic kidney disease not on dialysis

T2 - Results of a phase II study

AU - Provenzano, Robert

AU - Besarab, A.

AU - Macdougall, I. C.

AU - Ellison, David

AU - Maxwell, A. P.

AU - Sulowicz, W.

AU - Klinger, M.

AU - Rutkowski, B.

AU - Correa-Rotter, R.

AU - Dougherty, F. C.

AU - Barre, P.

AU - Levin, A.

AU - McMahon, A.

AU - Tobe, S. W.

AU - Valdes, A.

AU - Fishbane, S.

AU - Lewis, J.

AU - Leiserowitz, M.

AU - Mehta, R.

AU - Vicks, S.

PY - 2007/5

Y1 - 2007/5

N2 - Aim: This study was designed to assess the potential of the continuous erythropoietin receptor activator (C.E.R.A.) to correct anemia at extended administration intervals in erythropoiesis-stimulating agent-naïve patients with chronic kidney disease (CKD) not on dialysis and to determine its optimal starting dose. Methods: Patients were assigned to subcutaneous C.E.R.A. at 3 doses: 0.15, 0.30 and 0.60 μg/kg/wk. During the first 6 weeks, dose adjustments for efficacy were not permitted in order to assess dose response. Within each of the 3 dose groups, patients were randomized to receive C.E.R.A. QW, Q2W or Q3W; the total dose during the first 6 weeks was the same for a particular dose group across the frequency subgroups. During the next 12 weeks, dose was adjusted according to predefined hemoglobin (Hb) criteria. The primary efficacy parameter was change in Hb over 6 weeks, estimated from regression analysis between baseline and the point at which the patient received a dose change or blood transfusion. It therefore provided an estimate of Hb increase based on starting dose. Other endpoints included Hb response rate (proportion of patients with a Hb increase ≥ 1.0 g/dl on 2 consecutive occasions). A 1-year extension period investigated long term tolerability and efficacy. Results: A dose-dependent relationship was noted in the mean change in Hb from baseline over 6 weeks (p <0.0001), independent of administration schedule (p = 0.9201). There was also a significant relationship between Hb change and median serum C.E.R.A. concentration (p <0.0001). Erythropoietic responses were sustained in all groups with mean changes from baseline in Hb > 1.2 g/dl observed at doses ≥0.30 μg/kg/wk. Hb response rate increased with increasing dose: 67, 72 and 90% with C.E.R.A. 0.15, 0.30 and 0.60 μg/kg/wk, respectively. Generally, the median Hb response time was faster with increasing dose (89, 43 and 31 days, respectively). Response was unrelated to administration frequency. Stable Hb concentrations were maintained throughout the 1-year extension period. C.E.R.A. was generally well tolerated, and the most common adverse events were hypertension, urinary tract infection and renal failure. Conclusions: C.E.R.A. corrected anemia and maintained sustained and stable control of Hb over 1 year. These results suggest that 0.60 μg/kg subcutaneous C.E.R.A. given twice monthly is a suitable starting dose for further investigation in Phase III studies in patients with CKD not on dialysis.

AB - Aim: This study was designed to assess the potential of the continuous erythropoietin receptor activator (C.E.R.A.) to correct anemia at extended administration intervals in erythropoiesis-stimulating agent-naïve patients with chronic kidney disease (CKD) not on dialysis and to determine its optimal starting dose. Methods: Patients were assigned to subcutaneous C.E.R.A. at 3 doses: 0.15, 0.30 and 0.60 μg/kg/wk. During the first 6 weeks, dose adjustments for efficacy were not permitted in order to assess dose response. Within each of the 3 dose groups, patients were randomized to receive C.E.R.A. QW, Q2W or Q3W; the total dose during the first 6 weeks was the same for a particular dose group across the frequency subgroups. During the next 12 weeks, dose was adjusted according to predefined hemoglobin (Hb) criteria. The primary efficacy parameter was change in Hb over 6 weeks, estimated from regression analysis between baseline and the point at which the patient received a dose change or blood transfusion. It therefore provided an estimate of Hb increase based on starting dose. Other endpoints included Hb response rate (proportion of patients with a Hb increase ≥ 1.0 g/dl on 2 consecutive occasions). A 1-year extension period investigated long term tolerability and efficacy. Results: A dose-dependent relationship was noted in the mean change in Hb from baseline over 6 weeks (p <0.0001), independent of administration schedule (p = 0.9201). There was also a significant relationship between Hb change and median serum C.E.R.A. concentration (p <0.0001). Erythropoietic responses were sustained in all groups with mean changes from baseline in Hb > 1.2 g/dl observed at doses ≥0.30 μg/kg/wk. Hb response rate increased with increasing dose: 67, 72 and 90% with C.E.R.A. 0.15, 0.30 and 0.60 μg/kg/wk, respectively. Generally, the median Hb response time was faster with increasing dose (89, 43 and 31 days, respectively). Response was unrelated to administration frequency. Stable Hb concentrations were maintained throughout the 1-year extension period. C.E.R.A. was generally well tolerated, and the most common adverse events were hypertension, urinary tract infection and renal failure. Conclusions: C.E.R.A. corrected anemia and maintained sustained and stable control of Hb over 1 year. These results suggest that 0.60 μg/kg subcutaneous C.E.R.A. given twice monthly is a suitable starting dose for further investigation in Phase III studies in patients with CKD not on dialysis.

KW - Anemia

KW - C.E.R.A.

KW - Chronic kidney disease

KW - Continous erythropoietin receptor activator

KW - Hemoglobin

UR - http://www.scopus.com/inward/record.url?scp=34248356036&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34248356036&partnerID=8YFLogxK

M3 - Article

VL - 67

SP - 306

EP - 317

JO - Clinical Nephrology

JF - Clinical Nephrology

SN - 0301-0430

IS - 5

ER -