Participants
The study was conducted at the London Health Sciences Centre, a University-affiliated academic center in London, Ontario Canada. We included adult (18 years of age or older (outpatients with iron deficiency anemia eligible to receive intravenous iron as a part of their clinical management. Iron deficiency anemia was defined as hemoglobin less than 130 g/L and a ferritin of less than 50 μg/L. This hemoglobin level was chosen because our perioperative blood conservation program identifies potential surgical patients with hemoglobin values between 100 and 130 g/L for possible intravenous iron to reduce the exposure to allogeneic blood products. Patients were excluded if they were on hemodialysis, had previous exposure to any form of intravenous iron or were unable to provide written informed consent.
Study design and sample size
The primary objective of this study was to assess the feasibility and to inform details for the design of a future randomized controlled trial to be conducted at our centre comparing the safety of equal doses of intravenous iron dextran or iron sucrose in non-hemodialysis adult patients. Based on the results of our previous retrospective study of adverse reactions to intravenous iron [16], we calculated that we would need to enrol 213 patients per group to demonstrate a 5 % difference between groups for the main outcome at the 95 % level of significance with a power of 80 %. In order for such a trial to be considered feasible we would need to enrol approximately 100 patients per year. Based on our clinical volumes we anticipated that we could identify 120 potential patients per year. If 90 % agreed to participate, then we would be able to complete accrual for the full trial within 4 years.
The study was designed as a double-blinded randomized controlled trial comparing equal doses of intravenous iron dextran with intravenous iron sucrose. Randomization sequences were computer-generated via a third party (IBM, San Jose, California, USA) and stratified by site (2 sites), in blocks of 8. Randomization tables were only accessible by our central pharmacy requiring this information for concealment of iron products. Participants could choose to stop the study any point during the study or be unblinded at the discretion of the treating physician if it was felt that continuing would harm the patient. Subsequently, cross-over to the other agent could be done at the discretion of the treating physician. The study complied with the Declaration of Helsinki, Health Canada and the international conference on harmonization – good clinical practice (ICH-GCP) guidelines. The study protocol was approved by the Research Ethics Board of the University of Western Ontario (HSREB 13767). Written informed consent was obtained from all participants. This study was registered at ClinicalTrials.gov with number NCT00593619 January 8, 2008.
Interventions
Patients were randomized to receive either intravenous iron dextran with an estimated molecular weight of 200 kDa (Infufer®, Sandoz Canada Inc., Montreal, Canada) or iron sucrose (Venofer®, Luitpold Pharmaceuticals Inc., Shirley, New York, USA) at a dose of 300 mg given in 250 mL of normal saline and administered over 2 h with the first 25 mg over 10 min as a test dose. Each study drug was concealed and had a unique study label. No pre-medications were permitted. Before and after iron infusion, samples were obtained for complete blood count and serum ferritin.
Study outcomes
The primary feasibility outcome of the study was enrollment of at least 100 patients per year. The primary clinical outcome of the study was the occurrence of immediate severe adverse reactions (ADRs). Secondary outcomes were the occurrence of: immediate and delayed serious ADRs; immediate anaphylactic/anaphylactoid ADRs, immediate combined mild and moderate ADRs, delayed ADRs, all-cause mortality; mean time physicians spent managing ADRs; mean time nurses spent managing ADRs; and absolute difference in hemoglobin, platelet and ferritin. We also planned to collect costing data for a cost effectiveness analysis. ADRs were recorded including the onset (in minutes from initial administration), duration and description of symptoms/signs, intervention(s) applied, and any additional nursing time required to manage the reaction. ADRs were considered immediate if they occurred during the infusion time or delayed if occurred within the first 24 h post-infusion (Fig. 1). All patients were contacted at home via telephone after 24 h by a member of the research team for assessment of delayed reactions. The severity of ADRs was classified according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events v3 · 0 guidelines: (Table 2). Three blinded assessors (2 Hematologists and 1 Cardiologist), blinded to patient allocation, reviewed the ADRs and independently adjudicated the type and severity of ADRs. Discrepancies were resolved by consensus with a fourth investigator.
Statistical analysis
All statistical analyses were performed on an intention-to-treat basis. Baseline characteristics of participants, primary and secondary outcomes were analyzed by means of descriptive statistics. For comparison between groups we used Fisher’s exact test for categorical variables and unpaired t-test for continuous variables. We calculated relative risk (RR) and 95 % confidence intervals (95 % CI) for primary and secondary outcomes, using the iron sucrose group as reference. P-values <0.05 were considered statistically significant.