Objectives
The primary objective is to determine whether oral HIP administration (two tablets nocte per os, equivalent to 24 mg elemental iron per day) results in significantly higher transferrin saturation (TSAT) values in PD patients treated with DPO at 6 months compared with conventional oral slow-release ferrous sulphate supplementation (two tablets nocte per os, equivalent to 210 mg elemental iron per day).
The secondary objectives will be to determine whether oral HIP administration (two tablets nocte per os, equivalent to 24 mg elemental iron per day) to DPO-treated PD patients over 6 months results in
-
a)
an increase in serum ferritin concentrations;
-
b)
an increase in haemoglobin levels;
-
c)
a reduction in the prescribed dosages of DPO (Aranesp®, Amgen);
-
d)
a reduction in Key's index (DPO dosage divided by haemoglobin concentration); and,
-
e)
a reduction in significant side effects (especially gastrointestinal side effects).
Ethics approval for the HEMe iron polypeptide Against Treatment with Oral Controlled Release Iron Tablets trial (HEMATOCRIT trial) has been obtained from the local Institutional Ethics Committee in all participating centres prior to study initiation and patient enrolment. The study will be performed in accordance with the 2000 Edinburgh, Scotland Revision of the Declaration of Helsinki, the National Health and Medical Research Committee (NHMRC) Statement on Human Experimentation, Joint NHMRC/AVCC Statement and Guidelines on Research Practice, applicable ICH guidelines and the Therapeutic Goods Administration (TGA) – Note for guidance on good clinical practice (CPMP/ICH/135/95) annotated with TGA.
Participants
The study population includes adult (18 years or over) patients willing to give informed consent who have been on PD for > 1 month and receiving DPO for > 1 month. Patients will be recruited by local investigators from PD units at three Australian centres. The clinical and demographic characteristics of this population are comparable to those reported for the Australian and New Zealand PD population by the ANZDATA Registry. This, along with the multicentre nature of the trial will enhance its generalisability.
Exclusion criteria include:
-
1.
Patients with a history of psychological illness or condition which interferes with their ability to understand or comply with the requirements of the study.
-
2.
Pregnancy or breast-feeding.
-
3.
Known hypersensitivity to, or intolerance of, oral iron, HIP or DPO.
-
4.
Active peptic ulcer disease.
-
5.
Vitamin B12 or folate deficiency.
-
6.
Recent (within 1 month) acute infection.
-
7.
Parathyroid hormone level > 100 pmol/L.
-
8.
Serum aluminium > 2 μmol/L.
-
9.
Presence of systemic haematological disease (including antibody-mediated pure red cell aplasia) or known haemoglobinopathy
-
10.
Major surgery, infection, acute myocardial infarction or malignancy within the last 3 months.
-
11.
Intravenous iron therapy, vitamin C therapy, melatonin treatment, androgen therapy or blood transfusion within the previous month.
-
12.
Serum ferritin ≥ 500 μg/mL or transferrin saturation (TSAT) ≥ 50%.
-
13.
Religious or other objection to consuming product prepared from bovine blood.
Study design
The study is a prospective, open-label, randomised controlled trial. Patients will be randomised to one of two treatment groups in equal proportion (Figure 1). To ensure adequate concealment of allocation, the randomisation will be performed using sequentially numbered, opaque, sealed envelopes, stratified for the presence or absence of a TSAT ≤ 20%. The sequence of interventions was obtained from a computer-generated random number list in permuted blocks provided through the Australasian Kidney Trials (AKTN) network.
Experimental Intervention
HIP (Proferrin®ES, Colorado Biolabs, USA) is approved for use as a dietary/nutritional supplement in Canada and the United States of America. The usual dose is 1 tablet (equivalent to 12 mg elemental iron) taken twice or thrice daily, either with or without food. The side effects reported with HIP are similar to those associated with conventional oral iron preparations and include nausea, vomiting and constipation. However, trials in healthy individuals [18] and in haemodialysis patients [21] suggest that the incidence of such adverse drug reactions is relatively low, possibly due to the different absorption characteristics of heme versus non-heme iron. For example, in a study of 37 haemodialysis patients receiving HIP for 6 months, constipation occurred in 3 (8%) patients and was the only observed adverse effect of the agent. The dose of HIP used in that investigation (3 tablets per day) was 50% higher than that proposed in the present study (2 tablets per day). There are no other published data concerning the side effect profile of HIP in end-stage renal failure patients. Concern has previously been expressed about the possibility of transmission of bovine spongiform encephalopathy (BSE) through the consumption of bovine tissue [21]. Currently, HIP is manufactured from red blood cells of cows of American origin, and both the US Department of Agriculture and Food and Drug Administration (FDA) currently maintain that the United States is free of BSE. In addition, the putative infectious agents for BSE, conformationally shifted neuronal membrane copper-binding proteins called prions, usually are not found in blood [21]. Thus, the risk of BSE from taking HIP is negligible.
Control Intervention
Slow-release ferrous sulphate (Ferrogradumet®, Abbott, Sydney, Australia) is registered in Australia for use as an oral iron supplement and is one of the most common supplements prescribed in dialysis populations. The usual recommended dose is 2 to 3 tablets a day (equivalent to 210 to 315 mg of elemental iron per day). However, gastrointestinal side effects (especially constipation) usually limit the maximum dosage in end-stage renal failure patients to 2 tablets per day (the dose proposed in the current study). The side effects reported with Ferro-Gradumet are similar to those associated with other conventional oral iron preparations, although the incidence may be lower due to the controlled release nature of the formulation. They are as follows: nausea, vomiting, abdominal pain or discomfort, blackening of stools, diarrhoea and constipation. In a study of 28 PD patients at Princess Alexandra Hospital, oral Ferrogradumet® administration in a dose of 2 tablets per day for 4 months was associated with significant gastrointestinal side effects in 46% of patients (constipation 38%, nausea 19%, abdominal pain 4%). A randomised, placebo-controlled trial of oral ferrous sulphate in 32 consecutive iron-replete dialysis patients similarly revealed significant gastrointestinal side effects in 50% of subjects [22]. Ferrous sulphate absorption is significantly inhibited by concomitant food and phosphate binder medications. Consequently, subjects participating in the present trial will be instructed to take their study medications on an empty stomach and at least 2 hours apart from phosphate binder ingestion.
Concurrent Treatments
Vitamin B and folic acid supplementation are permitted. Vitamin C supplementation, melatonin and androgen therapy are prohibited during the study period.
Blinding
Blinding is not able to be performed as it is not possible to formulate identical-appearing preparations of HIP and slow-release iron. The controlled release iron tablets are too large to enclose in capsules and cannot be cut or ground. Consequently, the study will follow an open label design. An individual patient's participation in the study will cease at the end of the 6 month study period. If, before this time, the patient experiences severe anaemia (<65 g/L), symptomatic anaemia or the patient's attending physician believes that additional therapy is required (eg blood transfusion), they will be considered to have reached an end-point and will be withdrawn from study medication, but will still be followed up, with outcomes measured.
Outcome measures
The primary outcome measure will be the difference in TSAT values between the HIP and ferrous sulphate groups at the end of the 6 month study period.
The secondary outcome measures will be the differences between the 2 groups at the end of the 6 month study period with respect to serum ferritin concentration, haemoglobin level, DPO dosage, Key's index (DPO dosage divided by haemoglobin) and incidence of adverse events.
Procedures
Patients will take 2 tablets (HIP or ferrous sulphate) nocte for a period of 6 months. They will be instructed to take their study medications on an empty stomach and at least 2 hours apart from phosphate binder ingestion. At the time of inclusion in the study, demographic and clinical data will be recorded. All patients will be allowed their usual diet during the study period. DPO dosages will modified according to unit protocols, based on haemoglobin level. Full blood counts will be measured monthly, as per usual clinical practice. Iron studies will be measured every 2 months, as usual clinical practice. Patients will receive a medical review by their nephrologists every 2 months, as per usual clinical practice. No other procedure will be undertaken and all other care (including blood tests) will be provided according to standard unit protocols. Figure 2 outlines the trial schedule.
An individual patient's participation in the study will cease at the end of the 6 month study period. If, before this time, the patient experiences severe anaemia (<65 g/L), symptomatic anaemia (e.g. new onset or worsening shortness of breath or ischaemic chest pain attributable to the low haemoglobin) or the patient's attending physician believes that additional therapy is required (eg blood transfusion), they will be considered to have reached an end-point and will be withdrawn from study medication, but will still have blood counts measured monthly and followed for study outcomes. A patient's participation in the study will also cease if, during the course of the study, they complete PD therapy (eg renal transplantation or conversion to haemodialysis).
Adverse Events
The number and proportion of subjects who report treatment-emergent adverse events will be summarized for each treatment group. Treatment emergent events include events that start on or after Day 0 of the study [that is the first day of Study Drug administration], and were not present at baseline, or were present at baseline, but increased in severity after the start of the study. The Medical Dictionary for Regulatory Activities [MedDRA] Terminology will be used to classify all adverse events with rESAect to System Organ Class [SOC], high level group term (HLGT), and preferred term.
For the purposes of this study, anaemia (serum Hgb or Hct below the normal range or worsened from baseline) will not be considered an adverse event unless it reaches a severe level (<65 g/L) or is associated with significant symptoms. Similarly, iron deficiency (iron indices below the normal range or worsened from baseline) will not be considered an adverse event.
Sample size calculations
Prospective power calculations indicate that the study will have adequate statistical power (80% probability) to detect a clinically significant increase in TSAT of 7%, assuming α = 0.05 and a population standard deviation of 8%, if 44 patients were recruited in the study (22 in each group). Allowing for a 15% drop-out rate over 6 months using the adjustment formula of 1/[1 - drop-out rate] 2, we aim to recruit a total of 60 patients (30 in each group). We anticipate that a recruitment period of 18 months will be required. The assumptions for these power calculations were based on a previous randomised controlled trial of oral versus intravenous iron supplementation in PD patients [8], in which the baseline values were 107 ± 3 g/L for haemoglobin, 24.2 ± 1.7% for transferrin saturation and 323 ± 46 μg/L for serum ferritin concentration. Based on these assumptions, we estimate the power of the study for secondary outcome measures to be 77% for serum ferritin (δ 150 μg/mL, σ 180 μg/mL), 62% for haemoglobin (δ 7 g/L, σ 10 g/L), 22% for DPO divided by haemoglobin (δ 0.00075 μg.L/kg.g/week, σ 0.002 μg.L/kg.g/week) and 93% for the occurrence of gastrointestinal events (HIP 8% vs ferrous sulphate 46%).
The assumptions used for the power calculations are conservative and based on our previous study in 28 PD patients [22] and that of Nissenson et al in 37 haemodialysis patients 1. Because of power considerations and the relatively short duration of the study, no interim analysis is planned.
Statistical analysis
Primary Outcome Analyses
Differences between the intervention and control groups with respect to the primary outcome measure (TSAT level at 6 months) will be measured by comparison of the mean TSAT in each group, adjusted for baseline values (analysis of covariance). Data will be analysed on an intention to treat basis. For patients withdrawing before the end of the 6 month study, their TSAT at the time of withdrawal will be taken as their final haemoglobin.
Secondary Outcome Analyses
Secondary analysis will be performed by repeated measures analysis of covariance with and without adjustment for baseline characteristics. The analyses used for secondary outcome measures will include unpaired t-test (serum ferritin, Key's index), Mann-Whitney U-test (DPO dosage) and chi square test (adverse drug reactions).
Categorical baseline characteristics (e.g. sex, race, comorbid illnesses, etc.) will be summarized with the number and percent of subjects in each treatment group with the characteristic. Quantitative characteristics (e.g., age and weight) will be summarized by mean and standard deviation or median [interquartile range], depending on data distribution. The number and percent of subjects who are randomised, treated with randomized Study Drug, require intervention, prematurely discontinue, and complete the study will be summarized. Fisher's exact test or the Chi-square test will be used to assess treatment group differences in the proportions of subjects who require intervention and who complete the study. The number and percent of subjects will be summarised for each reason for premature discontinuation.