Intravenous methoxy polyethylene glycol-epoetin beta for haemoglobin control in patients with chronic kidney disease who are on dialysis: a randomised non-inferiority trial (MAXIMA)

Summary

Background

Conventional treatment with epoetin to manage anaemia in chronic kidney disease needs frequent administrations, changes of dose, and close monitoring of haemoglobin concentrations. We aimed to compare the effectiveness of methoxy polyethylene glycol-epoetin beta, given intravenously at 2-week or 4-week intervals, with epoetin treatment one to three times per week for haemoglobin control in haemodialysis patients.

Methods

We screened 1115 adult patients from 96 centres who had stable chronic renal anaemia and were on dialysis treatment and intravenous maintenance epoetin. We did an open-label, parallel-group, non-inferiority trial to compare two dosing intervals of methoxy polyethylene glycol-epoetin beta with standard epoetin treatment. We established baseline haemoglobin concentration and eligibility over a 4-week run-in period. 223 patients were randomly assigned to receive methoxy polyethylene glycol-epoetin beta every 2 weeks, and 224 to receive it every 4 weeks. The initial dose was based on the average epoetin dose given during the week before the switch. The primary endpoint was change in haemoglobin concentration between baseline and the assessment period. We analysed patients both by intention to treat and per protocol. This study is registered with ClinicalTrials.gov, number NCT00077610.

Findings

We excluded 133 of the 673 randomised patients from the per-protocol analysis because they had inadequate iron status or fewer than five haemoglobin measurements during the assessment period or needed red blood cell transfusions. The mean change from baseline haemoglobin for patients who had switched to intravenous methoxy polyethylene glycol-epoetin beta every 2 weeks (−0·71 g/L, 95% CI −2·20 to 0·77) or every 4 weeks (−0·25 g/L, −1·79 to 1·29) was non-inferior to the mean change for patients who continued treatment with epoetin (−0·75 g/L, −2·26 to 0·75) (p<0·0001 for both comparisons). Of the 666 patients who received at least one dose of study drug, the incidence of adverse events or serious adverse events did not differ between groups (p=0·30 and p=0·40, respectively).

Interpretation

This long-acting erythropoiesis-stimulating agent is as safe as conventional epoetin treatment, and can maintain anaemia management in haemodialysis patients when given intravenously at 4-week dosing intervals.

Introduction

Anaemia is a common complication of chronic kidney disease, and is prevalent in patients who start dialysis.1, 2 In patients with chronic kidney disease, treatment of anaemia with erythropoiesis-stimulating agents enhances quality of life.³ With erythropoiesis-stimulating agents, many patients fail to achieve minimum haemoglobin concentrations recommended by current treatment guidelines.4, 5

Conventional erythropoiesis-stimulating agents such as epoetin have short half-lives which necessitate frequent administration to maintain stable haemoglobin concentrations. Frequent administration, dose changes, and close monitoring of haemoglobin concentrations complicate management of anaemia. Any prolongation of dosing intervals with erythropoiesis-stimulating agents must not sacrifice stable maintenance of haemoglobin.

In Phase I and Phase II studies, methoxy polyethylene glycol-epoetin beta (also known as C.E.R.A.), has been shown to have a half-life of about 130 h with intravenous and subcutaneous administration, which allows dosing intervals to be prolonged.6, 7, 8, 9, 10, 11 The MAXIMA (Maintenance of Haemoglobin Excels with IV Administration of C.E.R.A.) trial aimed to examine the efficacy of this drug, given intravenously once every 2 or 4 weeks, compared with conventional epoetin treatment, for the maintenance of haemoglobin concentrations in patients with chronic kidney disease who were on dialysis and who converted directly from treatment with epoetin alfa or beta.