title: The continuous 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: OBJECTIVE
  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-naīve 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 microg/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 > or = 0.30 microg/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 microg/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 microg/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.
authors.affiliation: Division of Nephrology, St. John Hospital, 22201 Moross Road, Suite 150, Detroit, MI 48236, USA. robert.provenzano@stjohn.org
authors.forename: R
authors.initials: R
authors.lastname: Provenzano
authors.forename: A
authors.initials: A
authors.lastname: Besarab
authors.forename: I C
authors.initials: IC
authors.lastname: Macdougall
authors.forename: D H
authors.initials: DH
authors.lastname: Ellison
authors.forename: A P
authors.initials: AP
authors.lastname: Maxwell
authors.forename: W
authors.initials: W
authors.lastname: Sulowicz
authors.forename: M
authors.initials: M
authors.lastname: Klinger
authors.forename: B
authors.initials: B
authors.lastname: Rutkowski
authors.forename: R
authors.initials: R
authors.lastname: Correa-Rotter
authors.forename: F C
authors.initials: FC
authors.lastname: Dougherty
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D000740:Anemia / Q000188:drug therapy* / Q000209:etiology*; D019540:Area Under Curve; D015415:Biomarkers / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004920:Erythropoiesis / Q000187:drug effects; D004921:Erythropoietin / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D005260:Female; D005293:Ferritins / Q000097:blood / Q000187:drug effects; D005500:Follow-Up Studies; D006454:Hemoglobins / Q000187:drug effects; D006801:Humans; D007676:Kidney Failure, Chronic / Q000150:complications*; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000009:adverse effects; D011994:Recombinant Proteins; D012044:Regression Analysis; D006435:Renal Dialysis; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D006454:Hemoglobins; D011994:Recombinant Proteins; C508420:continuous erythropoietin receptor activator; D004921:Erythropoietin; D011092:Polyethylene Glycols; D005293:Ferritins