Trial Comparing Ferric(III)Carboxymaltose Infusion With Oral Iron Suppletion as Treatment of Anaemia

Study Overview
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Brief Summary
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The aim of this multicenter trial is to determine the efficacy of preoperative intravenous iron suppletion in comparison with the standard preoperative oral substitution in anaemic patients with colorectal cancer in curing the anemia and the assess the effect of preoperative iron on morbidity, postoperative recovery and quality of life. Hypothesis: It is our hypothesis that a more profound approach of preoperative anaemia with intravenous iron will lead to a higher percentage of patients with normalization of Hb-level (> 12 g/dl (7.5 mmol/l) for women and > 13 g/dl (8 mmol/l) for men), which potentially reduces morbidity, length of stay, improves quality of live, decreases fatigue and could be more cost effective compared to current practice with oral substitution of iron.

Detailed Description
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This multicenter randomized clinical trial aims to optimize postoperative outcome in anaemic patients who undergo curative surgery for colorectal carcinoma. The aim of this trial is to investigate which route of administration is superior in the treatment of iron deficiency anaemia in these patients. In addition, an economic evaluation of intravenous iron versus oral iron will be done. The evaluation will be performed from a societal perspective as (i) a cost-effectiveness analysis with the costs per responder to iron suppletion therapy as primary outcome and (ii) a cost-utility analysis with the costs per quality adjusted life-year (QALY) as primary outcome. The cost effectiveness analysis closely relates to clinical efficacy measure and allows for setting priorities in treatment of anaemia in colorectal cancer patients. The cost-utility analysis allows for a comparison of the societal impact of intravenous iron suppletion on post-operative recovery, such as shorter length of stay and earlier return to daily activities, with the impact of other interventions and of interventions in other areas of health care. The primary aim of this trial is: To compare the percentage of patients with normalization of Hb-level (> 12 g/dl (7.5 mmol/l) for women and > 13 g/dl (8 mmol/l) for men after intravenous versus oral iron therapy in patients undergoing curative surgery for colorectal carcinoma. Secondary aims of the FIT trial are: To analyse the effect of preoperative iron therapy (intravenous versus oral) on postoperative morbidity, length of stay, amount of blood transfusions needed and quality of life and fatigue scores. To determine the cost effectiveness of preoperative intravenous iron substitution in comparison with oral substitution. Sample size: The principal analysis will consist of an intention-to-treat comparison of the proportions of patients with iron deficiency anaemia between the two study groups. The trial is designed as a superiority trial, hypothesizing a greater percentage of patients achieving normalization of Hb-level (called 'responder') in favour of infusion of ferric(III)carboxymaltose compared to oral iron suppletion. Our power calculation is based on the study of Seid et al(19), which compared ferric(III)carboxymaltose with oral ferrous sulphate in a population of post-partum women with an iron deficiency anaemia. The proportion achieving a normalization of Hb after two weeks of treatment was 55% in the intravenous iron group and 35% in the oral iron group. We expect that the efficacy of the iron therapy is lower in patients with a colorectal carcinoma. Therefore, the expected percentage of patients who achieve normalization of Hb-level (Hb >7.5 mmol/l (12 g/dl) for women and Hb >8.o mmol/l (13 g/dl) for men) is 45% in the intravenous iron group and 25% in the oral iron group. Based on these proportions, a sample size of 89 patients per group is needed for a Chi square test to achieve 80% power at a two sided alpha of 0.05. With an estimated loss to follow up of 10%, a sample size of 198 is calculated. We used nQuery advisor version 7.0 to calculate the sample size.

Official Title
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Multicenter Randomized Controlled Trial Comparing Ferric(III)Carboxymaltose Infusion With Oral Iron Suppletion in the Treatment of Preoperative Anaemia in Colorectal Cancer Patients

Conditions
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Anemia, Colorectal Carcinoma, Surgery

Intervention / Treatment
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* Drug: Ferrous fumarate
* Drug: ferric(III)carboxymaltose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: M0-stage Colorectal carcinoma Laparoscopic or open segmental colonic resection or (low) anterior resection Iron deficiency anaemia: Hb <7,5 mmol/l (12 g/dl) for women and Hb < 8 mmol/l (13 g/dl) for men and TSAT<20% Age 18 or older Written informed consent for study participation Exclusion Criteria: Palliative surgery / metastasized disease Received blood transfusion within one month before screening Serum ferritin ≥ 800 µg/L Pregnancy Preoperative chemoradiation (Short course radiotherapy (5x5 Gy) = no exclusion) Contraindication for the use of ferric(III)carboxymaltose or ferrofumarate ASA classification > 3 Use of erythropoietin stimulating agents within three months before screening Chronic kidney disease (GFR < 30ml/min/m) Myelodysplastic syndrome Severe anaemia with indication for blood transfusion Elevated liver enzymes (more than three times normal value) Hereditary Hemochromatosis Thalassemia Haemolytic anaemia/ chronic haemolysis

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Ferrous fumarate<br>Patients randomized to standard care with ferrous fumarate will receive three tablets of 200 mg daily from randomisation until day before surgery | Drug: Ferrous fumarate<br>* Patients randomized to standard care with ferrous fumarate will receive three tablets of 200 mg daily from randomisation until day before surgery<br>* Other names: ferrofumarate;|
| Active Comparator: ferric(III)carboxymaltose<br>Patients randomized to intravenous iron (ferric(III)carboxymaltose) will be dosed according to Summary of Product Characteristics (SPC) depending on body weight and Hb value and administered in one or two infusions with one week in between. A maximum dose of 1000mg or 15mg/kg per week will be administered | Drug: ferric(III)carboxymaltose<br>* Patients randomized to intravenous iron (ferric(III)carboxymaltose) will be dosed according to Summary of Product Characteristics (SPC) depending on body weight and Hb value and administered in one or two infusions with one week in between. A maximum dose of 1000mg or 15mg/kg per week will be administered<br>* Other names: Ferinject;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Normalization of Hb-level. | Percentage of patients with normalization of Hb-level from start treatment until day of admission for surgery. (Hb >12g/dl (7.5mmol/L) for women and Hb >13 g/dl (8.0mmol/L) for men). Patient will be randomised after they visit the surgery outpatient clinic to discuss the treatment option for their colorectal carcinoma. Average time between this visit and surgery in the Netherlands is maximally 5 weeks. Patients on oral iron suppletion will start with the iron therapy on the day of the randomisation. For the patients that will receive intravenous iron an appointment will be made on the short-care unit to facilitate the infusion of the iron. The period between infusion and surgery should be longer than two weeks. Our primary endpoint: Percentage of patients with normalization of Hb-level. Will be measured at the day of admission before surgery. Which is one day prior to surgery. The Hb-level will be followed-up after surgery on postoperative day 1, day 7 and after 4,8 and 12 weeks. | From Baseline (date of randomisation) untill day of admission for surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in Morbidity score | The difference in morbidity score will be assessed using the Comprehensive Complication index, between both study groups | postoperative at week 1, week 4, week 8 and week 12 |