| Study characteristics |
| Methods |
Study design
Study dates
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| Participants |
Study characteristics
Setting: multicentre (14 study centres) Country: USA Inclusion criteria: aged at least 18 years with CKD and CKD‐related anaemia and receiving treatment with IV epoetin alfa; HD treatment >3 times/week for > 3 months before screening and receiving IV epoetin alfa maintenance therapy for > 3 months before screening; baseline Hb concentration of 10 to 13 g/dL, based on 3 measurements taken at screening and a difference of not more than 1.0 g/dL between the first and last measurements; adequate iron status (serum ferritin > 100 ng/mL and TSAT > 20% or hypochromic red cells < 10% Exclusion criteria: nonrenal causes of anaemia; presence of >1 condition known to cause an inadequate response to ESAs (including, but not limited to, acute infection or inflammation, bleeding requiring treatment within the 3 months before screening, severe hyperparathyroidism (iPTH, > 800 pg/mL), serum aluminium > 50 µg/L, haemoglobinopathy, haemolysis, vitamin B12 or folic acid deficiency); presence of severe disease (MI, severe or unstable coronary artery disease, stroke, and/or severe hepatic disease) within 3 months before study entry; blood transfusion within 3 months before study entry; thrombocyte count >500 × 103 cells/µL; hypertension necessitating interruption of epoetin treatment in the 6 months before screening; and/or epilepsy diagnosed in the 6 months before screening; patients who did not comply with dialysis therapy; patients who had major elective surgery scheduled during the study or who had a life expectancy of < 6 months; women who were pregnant, possibly pregnant, or breastfeeding; patients with a known hypersensitivity to epoetin or polyethylene glycol; women of childbearing age were required to use an effective method of contraception throughout the study; patients with poorly controlled hypertension were not allowed to enter the extension period
Baseline characteristics
Number (analysed/randomised): overall (79/91 ‐ however, only 53/91 participants completed the extension study); intervention group 1 (not reported/46); intervention group 2 (not reported/45) ‐ however, all participants were included in the ITT analyses Mean age ± SD (years): overall (58, SD not reported) Sex (M/F): intervention group 1 (32/14); treatment group 2 (28/17) Dialysis type: HD Mean dialysis vintage ± SD (years): not reported -
Comorbidities
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| Interventions |
Intervention classification
Intervention group 1
Intervention group 2
Co‐interventions
Patients received IV iron supplementation according to normal centre practice throughout the run‐in, core, and extension treatment periods to maintain adequate iron status (TSAT at least 20% and serum ferritin at least 100 ng/mL)
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| Outcomes |
Outcomes reported
Fatigue outcome measures used: validation data available (fatigue was reported as an adverse event) Adverse events: assessed until end of treatment Serious adverse events: assessed until end of treatment Change in Hb: assessed after 6 weeks until 12 months HCT concentration: assessed until 12 months every 4 weeks Laboratory assessments of iron parameters and blood chemistry (including CRP): assessed at ‐1, 6, 12, and 19 weeks of the core treatment period and at weeks 31, 43, and 55 of the extension period Anti‐CERA antibodies: assessed at week ‐1, week4 once/week only, week 6 twice/week of the core treatment period, and week 43 of the extension period Vital signs (BP, heart rate) and weight: assessed every other week during the core treatment period and every 4 weeks during the extension period until 12 months iPTH, haptoglobin, vitamin B12, and folic acid: assessed at screening and week 43 of the extension period Adequacy of dialysis was assessed by calculating URR: assessed at 12 months Death: assessed until end of treatment MI: assessed until end of treatment
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| Notes |
Additional information
Funding: not reported Conflicts of interest/disclosures: Dr. Besarab serves as a consultant for Amgen Inc., Thousand Oaks, California; E Hoffmann‐La Roche; and the major parenteral iron companies‐‐American Regent, Inc., Shirley, New York; and Watson Pharmaceuticals, Inc., Corona, California‐‐and has received honoraria from these companies for presentations at major nephrology meetings and for presentations relating to anaemia management and the pharmacokinetic/ pharmacodynamic aspects of erythropoiesis. Dr. Salifu has received research grants from Advanced Magnetics, Inc., Cambridge, Massachusetts; E Hoffmann‐ La Roche; and Novartis Pharmaceuticals Corporation, East Hanover, New Jersey. Dr. Lunde has conducted clinical research on behalf of Abbott Laboratories Inc., Abbott Park, Illinois; E Hoffmann‐ La Roche; Bristol‐Myers Squibb Company, New York, New York; Dynavax Technologies Corp., Berkeley, California; Eli Lilly and Company, Indianapolis, Indiana; FibroGen, Inc., South San Francisco, California; Genzyme Corp., Cambridge, Massachusetts; GlaxoSmithKline, Research Triangle Park, North Carolina; Iomai Corp., Gaithersburg, Maryland; Merck & Co., Inc., Rahway, New Jersey; NICOX‐PRA Sophia Antipolis Cedex, France;Novartis; Omnicare, Inc., Covington, Kentucky; Pfizer Laboratories, Groton, Connecticut; PharmaSeek, LLC, Madison, Wisconsin; PLIVA d.d., Zagreb, Croatia; Shire Pharmaceuticals, Wayne, Pennsylvania; The Sanofi‐Aventis Group, Bridgewater, New Jersey; and Wyeth, Madison, New Jersey. Dr. Bansal has acted as a speaker/consultant for Merck, Novartis, and Pfizer; and has received research grants from Amgen, E Hoffmann‐La Roche, Merck, and Pfizer. Dr. Fishbane has received research grants from Amgen, E Hoffmann‐La Roche, and Watson; honoraria from Affymax, Inc., Palo Alto, California; Amgen; F. Hoffmann‐La Roche; and Watson; consultancies with Amgen, E Hoffmann‐La Roche, and Watson; and speakers' bureau or advisory board positions with Amgen, E Hoffmann‐La Roche, Watson, and Wyeth Trial registration identification number: not reported A priori published protocol: The protocol was approved by the local ethics committees of the institutions taking part
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| Risk of bias |
| Bias |
Authors' judgement |
Support for judgement |
| Random sequence generation (selection bias) |
Unclear risk |
Quote: "This randomised, open‐label, dose‐finding study was conducted at 14 study centres across the United States."
Comment: Sequence generation methods were not reported in sufficient detail to permit judgement |
| Allocation concealment (selection bias) |
Unclear risk |
Method of allocation concealment was not reported in sufficient detail to permit judgement |
| Blinding of participants and personnel (performance bias)
All outcomes |
High risk |
Quote: "This randomised, open‐label, dose‐finding study was conducted at 14 study centres across the United States."
Comment: An open‐label study is considered as a high risk of bias. Participants experienced side effects that participants and/or investigators could know to be specific for one of the interventions |
| Blinding of outcome assessment (detection bias)
All outcomes |
High risk |
Quote: "Adverse events (including fatigue) were recorded in the patients' case‐report forms by the investigators throughout the study."
Comment: The outcomes were assessed with an appropriate measure, without differences between groups. However, fatigue was assessed as an adverse events and it was not stated whether it was assessed without knowledge of treatment allocation, and knowledge of treatment assignment may have influenced reporting. Participant/investigators beliefs about the superiority/inferiority of either intervention could have influenced their assessment of the outcome. However, objective and subjective outcomes were assessed |
| Incomplete outcome data (attrition bias)
All outcomes |
Unclear risk |
Quote: "A total of 91 patients entered the core period (mean age, 58 years; 66% male). Fifty‐three patients continued into the extension period; 22 patients withdrew during this period (6 because of adverse e events, and 16 for other reasons). [...] Ten patients were withdrawn from the core treatment period. Four of these patients withdrew due to adverse events and 6, for other reasons (treatment refusal (2) and insufficient therapeutic response, kidney transplant, inadvertent concomitant administration of epoetin alfa, and anaemia not related to CRD (1 patient each)). All of these patients were included in the intention‐to‐treat (ITT) analysis and were also included in the per protocol (PP) analysis if they met the criteria for the latter. Twelve patients were separately excluded from the PP analysis, for a total PP population of 79 patients (28, 24, and 27 patients in groups A, B, and C, respectively). Fifty‐three patients were entered into the extension phase of the study, 27 in the QW group and 26 in the Q2W group. Six patients withdrew because of adverse events, and 16, for other reasons (kidney transplant (4), site closure or transfer (4), treatment refusal (4), insufficient therapeutic response (2), elevated parathyroid hormone concentration (1), and positive pregnancy test (1))."
Comment: Although the authors stated that the analysis were performed according to ITT and PP, Figure 2 showed that not all participants completed the study. Reasons for discontinuations were reported |
| Selective reporting (reporting bias) |
High risk |
Protocol was approved by the local ethics committees of the institutions taking part into the study (not clear if it was published). Statistical analysis plan was not available. It was unclear if the reported approach to analysing this outcome was pre‐specified or influenced by the results. Fatigue at the end of treatment was reported in a format that was not extractable per group. All outcomes that should be addressed (fatigue, cardiovascular disease, and death) were not reported |
| Other bias |
High risk |
Baseline characteristics between groups were not reported. Funding was not reported but authors had conflicts of interest |
