Iron Supplementation in Upper Non-variceal Gastrointestinal Bleeding

Study Overview
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Brief Summary
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Anemia is a frequent complication of gastrointestinal bleeding, affecting 61% of the patients. Currently, anemia caused by gastrointestinal bleeding can be treated with iron supplementation. However, the dose and route of the administration are still a question. The FIERCE clinical trial aims to compare the effect of intravenous iron supplementation and oral iron replacement on mortality, unplanned emergency visits, and hospital readmissions in multimorbid patients with acute nonvariceal gastrointestinal bleeding.

Detailed Description
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In gastrointestinal bleeding (GIB) iron deficiency anemia (IDA) is a common complication, affecting more than 60% of the patients. There are two pillars of the treatment of acute GIB. First, the bleeding point needs identification and endoscopic treatment. Second, the resulting hypovolemia and anemia require fluid resuscitation, transfusion, and replacement of the lost iron. There are two simple ways to manage IDA after acute GIB. Patients either have intravenous (IV) iron infusions one to six times as part of their hospital treatment or receive three months of oral iron supplementation. There is a gap in current guidelines on which approach clinicians should choose. Here the investigators plan a multicentric, two-arm, randomized controlled trial, to compare the efficacy of oral and intravenous iron supplementation in multimorbid patients with acute nonvariceal gastrointestinal bleeding. Patients will be randomly allocated in a 1:1 ratio to two groups. Group A will receive one dose of 1000 mg of IV ferric carboxymaltose on the day of randomization, while iron supplementation for group B will be performed with one ferrous sulfate tablet every day (ca. 200-300 mg) for three months. The primary outcome will be the composite outcome of all-cause mortality, unplanned emergency visit, and unplanned hospital readmission within six months after enrollment. In the first phase, the investigators plan to recruit 15 patients on each arm to assess the proportion of the primary outcome in the two groups. In the second phase, a sample size calculation for the primary outcome will be performed based on the results of the first phase.

Official Title
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Intravenous Ferric Carboxymaltose Versus Oral Ferrous Sulfate Replacement in Anaemia Due to Acute Nonvariceal Gastrointestinal Bleeding (FIERCE): Protocol of a Multicentre Randomised Controlled Trial

Conditions
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GastroIntestinal Bleeding, Anemia

Intervention / Treatment
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* Drug: Oral iron supplementation
* Drug: Intravenous iron supplementation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age ≥ 65 years; endoscopically proven acute nonvariceal GIB source; 48 hours after the endoscopic diagnosis and/or treatment; hemodynamically stable; the discharge of the patient is planned; hemoglobin level <10 g/dl on the day of randomisation; 24 hours after the last transfusion and no need for further transfusion; signed informed consent. Exclusion Criteria: known hypersensitivity to iron products (mild side effects excluded); previous diagnosis of iron overload [e.g., transferrin receptor saturation (TSAT) >50%, ferritin> 160 for women ng/ml, ferritin >270 ng/ml for men) or disorders of iron utilisation; pregnancy or breast feeding; diagnosis of iron malabsorption (at discretion of the attending clinician; e.g., severe inflammatory bowel disease, active celiac disease); chronic end stage diseases (chronic heart failure-New York Heart Association Classification class 4, chronic kidney disease (eGFR <30 mL/min/1.73 m2) with or without dialysis, liver cirrhosis with Child Pugh C score, chronic kidney disease with dialysis, chronic obstructive pulmonary disease stage 4, chronic inflammatory disease, malignancies, AIDS); active malignancies; liver cirrhosis with known varices at high risk of bleeding - endoscopic features of high risk of variceal bleeding or liver stiffness measured by transient elastography >20 kiloPascal and platelet count <150 × 10^9 cells/L; gastrointestinal tract malignancies with high risk of gastrointestinal bleeding; high risk of poor compliance or no fixed abode; myelo- or lymphoproliferative diseases; anemia not attributable to iron deficiency (sideroblastic anaemia, aplastic anaemia, haemolytic anaemia, thalassaemia, B12 vitamin or folic acid deficiency or combination of these with IDA); primary coagulation disorders (e.g. Glanzmann thrombasthenia, Von Willebrand disease, Haemophylia A, Haemophylia B); the patient will be transferred to another institute after discharge (e.g. hospital, senior care center); Eastern Cooperative Oncology Group (ECOG) Performance Status >2.

Ages Eligible for Study
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Minimum Age: 65 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
Interventional Model Description: The investigators plan to recruit 285 patients on each arm.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Oral iron supplementation<br>Patients randomized to receive oral ferrous sulfate, ca. 200-300 mg every day for 3 months. | Drug: Oral iron supplementation<br>* Ca. 200-300 mg of ferrous sulfate will be administered orally every day for 3 months.<br>|
| Active Comparator: Intravenous iron supplementation<br>Patients randomized to receive one dose of 1000 mg intravenous ferric carboxymaltose. | Drug: Intravenous iron supplementation<br>* One dose of intravenous 1000 mg ferric carboxymaltose will be administered on the day of randomization.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite outcome | The composite endpoint includes all-cause mortality, unplanned emergency visit (general practitioner or emergency outpatient clinic), and unplanned hospital admission for any reason. The investigators will calculate the proportion of the outcome in each arm. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause mortality | Death from any cause. The proportion of the outcome will be calculated in each arm and compared between the arms. The investigators will compare subgroups of patients based on the cause of mortality. | 1, and 3 months | 
| Unplanned emergency visits | Emergency visit from any cause. The proportion of the outcome will be calculated in each arm and compared between the arms. The investigators will compare subgroups of patients based on the cause of unplanned emergency visits. | 1, and 3 months | 
| Unplanned hospital admission | Hospital admission from any cause. The proportion of the outcome will be calculated in each arm and compared between the arms. The investigators will compare subgroups of patients based on the cause of unplanned admission. | 1, and 3 months | 
| Quality of life using the 36-Item Short-Form Health Survey | Changes in quality of life measured with the 36-Item Short-Form Health Survey (SF-36) questionnaire compared to baseline. | 1, and 3 months +/- 7 days | 
| Quality of life using the EuroQol five-dimensions - 5 levels questionnare | Changes in quality of life measured with the EuroQol five-dimensions - 5 levels (EQ-5D-5L) questionnaire compared to baseline. | 1, and 3 months +/- 7 days | 
| Gait speed | Changes in gait speed compared to baseline. Gait speed will be evaluated on a 4-meter flat walking path. | 1, and 3 months +/- 7 days | 
| Six-Minute Walk Test (6MWT) | Changes in Six-Minute Walk Test (6MWT) compared to baseline. | 1, and 3 months +/- 7 days | 
| Handgrip strength | Changes in handgrip strength compared to baseline. | 1, and 3 months +/- 7 days | 
| Normalization of the haemoglobin level | The percentage of participants with Hb levels of ≥12 g/dL in women and ≥13 g/d, compared to baseline. | 1, and 3 months +/- 7 days | 
| Change in Hb level | Absolute change from baseline to follow-up in Hb level. | 1, and 3 months +/- 7 days | 
| Change in haematocrit | Absolute change from baseline to follow-up in haematocrit. | 1, and 3 months +/- 7 days | 
| Change in serum iron level | Absolute change from baseline to follow-up in serum iron level. | 1, and 3 months +/- 7 days | 
| Change in serum transferrin level | Absolute change from baseline to follow-up in serum transferrin level. | 1, and 3 months +/- 7 days | 
| Change in transferrin saturation | Absolute change from baseline to follow-up in transferrin saturation. | 1, and 3 months +/- 7 days | 
| Change in soluble transferrin receptor concentration | Absolute change from baseline to follow-up in soluble transferrin receptor (sTfR) concentration. | 1, and 3 months +/- 7 days | 
| Change in ferritin level | Absolute change from baseline to follow-up in ferritin level. | 1, and 3 months +/- 7 days | 
| Change in the number of reticulocytes | Absolute change from baseline to follow-up in the number of reticulocytes. | 1, and 3 months +/- 7 days | 
| Change in the number of erythrocytes | Absolute change from baseline to follow-up in the number of erythrocytes. | 1, and 3 months +/- 7 days | 
| Change in the total iron-binding capacity | Absolute change from baseline to follow-up in the total iron-binding capacity (TIBC). | 1, and 3 months +/- 7 days | 
| Change in erythropoietin level | Absolute change from baseline to follow-up in erythropoietin level. | 1, and 3 months +/- 7 days | 
| Change in C-reactive protein level | Absolute change from baseline to follow-up in the C-reactive protein level. | 1, and 3 months +/- 7 days | 
| Change in hepcidin level | Absolute change from baseline to follow-up in hepcidin level. | 1, and 3 months +/- 7 days | 
| Change in phosphate level | Absolute change from baseline to follow-up in phosphate level. | 1, and 3 months +/- 7 days | 
| Discontinuation of the treatment due to adverse events | The percentage of discontinuation in the two arms. | 1, and 3 months +/- 7 days | 
| Cost-effectiveness | The incremental cost-effectiveness ratio (ICER): incremental costs divided by incremental effectiveness . | 1, and 3 months +/- 7 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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non-variceal upper gastrointersinal bleeding, iron supplementation, intravenous iron