INFERR-Iron infusion in haemodialysis study: INtravenous iron polymaltose for First Nations Australian patients with high FERRitin levels on haemodialysis—a protocol for a prospective open-label blinded endpoint randomised controlled trial

Abstract

Background The effectiveness of erythropoiesis-stimulating agents, which are the main stay of managing anaemia of chronic kidney disease (CKD), is largely dependent on adequate body iron stores. The iron stores are determined by the levels of serum ferritin concentration and transferrin saturation. These two surrogate markers of iron stores are used to guide iron replacement therapy. Most Aboriginal and/or Torres Islander Australians of the Northern Territory (herein respectfully referred to as First Nations Australians) with end-stage kidney disease have ferritin levels higher than current guideline recommendations for iron therapy. There is no clear evidence to guide safe and effective treatment with iron in these patients. We aim to assess the impact of intravenous iron treatment on all-cause death and hospitalisation with a principal diagnosis of all-cause infection in First Nations patients on haemodialysis with anaemia, high ferritin levels and low transferrin saturation Methods In a prospective open-label blinded endpoint randomised controlled trial, a total of 576 participants on maintenance haemodialysis with high ferritin (> 700 μg/L and ≤ 2000 μg/L) and low transferrin saturation (< 40%) from all the 7 renal units across the Northern Territory of Australia will be randomised 1:1 to receive intravenous iron polymaltose 400 mg once monthly (200 mg during 2 consecutive haemodialysis sessions) (Arm A) or no IV iron treatment (standard treatment) (Arm B). Rescue therapy will be administered when the ferritin levels fall below 700 μg/L or when clinically indicated. The primary outcome will be the differences between the two study arms in the risk of hospitalisation with all-cause infection or death. An economic analysis and several secondary and tertiary outcomes analyses will also be performed. Discussion The INFERR clinical trial will address significant uncertainty on the safety and efficacy of iron therapy in First Nations Australians with CKD with hyperferritinaemia and evidence of iron deficiency. This will hopefully lead to the development of evidence-based guidelines. It will also provide the opportunity to explore the causes of hyperferritinaemia in First Nations Australians from the Northern Territory. Trial registration This trial is registered with The Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12620000705987. Registered 29 June 2020.

Comparison of two ferritin assay platforms to assess their level of agreement in measuring serum and plasma ferritin levels in patients with chronic kidney disease

“…Immediately after implementing the change, it was noted during veri cation studies in the laboratories' external Quality Assurance (QA) program and by clinical teams that the results between the two assays were up to 40% different. This change occurred at the same time as the planning of the INtravenous iron polymaltose for First Nations Australian (Aboriginal and/or Torres Strait Islander) patients with high FERRitin levels on haemodialysis (INFERR) clinical trial [9]. The INFERR clinical trial is assessing the safety and effectiveness of administering intravenous (IV) iron to First Nations Australian patients on haemodialysis with anaemia, high ferritin, and other evidence of iron de ciency [9].…”

“…The INFERR clinical trial investigators were aware at the commencement of the trial that the change in the assay might raise questions around the cut-offs for serum ferritin levels. The protocol for the INFERR clinical trial is published elsewhere [9].…”

“…Additionally, there was a case for and need to change the cut-offs for ferritin levels in the INFERR clinical trial protocol. The INFERR clinical trial protocol inclusion criteria has serum ferritin levels of ≥ 700µg/L & ≤2000µg/L determined by the AA assay [9].…”

Comparison of two ferritin assay platforms to assess their level of agreement in measuring serum and plasma ferritin levels in patients with chronic kidney disease

“…Immediately after implementing the change, it was noted during verification studies in the laboratories’ external Quality Assurance (QA) program and by clinical teams that the results between the two assays were up to 40% different. This change occurred at the same time as the planning of the IN travenous iron polymaltose for First Nations Australian (Aboriginal and/or Torres Strait Islander) patients with high FERR itin levels on haemodialysis (INFERR) clinical trial [ 10 ]. The INFERR clinical trial is assessing the safety and effectiveness of administering intravenous (IV) iron to First Nations Australian patients on haemodialysis with anaemia, high ferritin, and other evidence of iron deficiency [ 10 ].…”

“…This change occurred at the same time as the planning of the IN travenous iron polymaltose for First Nations Australian (Aboriginal and/or Torres Strait Islander) patients with high FERR itin levels on haemodialysis (INFERR) clinical trial [ 10 ]. The INFERR clinical trial is assessing the safety and effectiveness of administering intravenous (IV) iron to First Nations Australian patients on haemodialysis with anaemia, high ferritin, and other evidence of iron deficiency [ 10 ]. The design of the trial was based on ferritin levels obtained from the AA assay.…”