Iron Supplementation in Upper Non-variceal Gastrointestinal Bleeding (FIERCE)

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Anemia; GastroIntestinal Bleeding
• Intervention / Treatment: Drug: Oral iron supplementation; Drug: Intravenous iron supplementation

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 570
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Bálint Erőss, MD, PhD; Phone Number: +3630/887-4028; Email: eross.balint@pte.hu
• Study Contact Backup: Name: Péter Hegyi, MD, PhD, DSc, MAE; Phone Number: +3670/375-1031; Email: p.hegyi@tm-centre.org

Study Locations

• Hungary
  • Pécs, Hungary, 7624
    • Institute for Translational Medicine, University of Pécs

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years and older (Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. age ≥ 65 years;
2. endoscopically proven acute nonvariceal GIB source;
3. 48 hours after the endoscopic diagnosis and/or treatment;
4. hemodynamically stable;
5. the discharge of the patient is planned;
6. hemoglobin level <10 g/dl on the day of randomisation;
7. 24 hours after the last transfusion and no need for further transfusion;
8. signed informed consent.

Exclusion Criteria:

1. known hypersensitivity to iron products (mild side effects excluded);
2. 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;
3. pregnancy or breast feeding;
4. diagnosis of iron malabsorption (at discretion of the attending clinician; e.g., severe inflammatory bowel disease, active celiac disease);
5. 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);
6. active malignancies;
7. 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;
8. gastrointestinal tract malignancies with high risk of gastrointestinal bleeding;
9. high risk of poor compliance or no fixed abode;
10. myelo- or lymphoproliferative diseases;
11. 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);
12. primary coagulation disorders (e.g. Glanzmann thrombasthenia, Von Willebrand disease, Haemophylia A, Haemophylia B);
13. the patient will be transferred to another institute after discharge (e.g. hospital, senior care center);
14. Eastern Cooperative Oncology Group (ECOG) Performance Status >2.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Pecs

Publications and helpful links

General Publications

• Tolkien Z, Stecher L, Mander AP, Pereira DI, Powell JJ. Ferrous sulfate supplementation causes significant gastrointestinal side-effects in adults: a systematic review and meta-analysis. PLoS One. 2015 Feb 20;10(2):e0117383. doi: 10.1371/journal.pone.0117383. eCollection 2015.
• McLean E, Cogswell M, Egli I, Wojdyla D, de Benoist B. Worldwide prevalence of anaemia, WHO Vitamin and Mineral Nutrition Information System, 1993-2005. Public Health Nutr. 2009 Apr;12(4):444-54. doi: 10.1017/S1368980008002401. Epub 2008 May 23.
• Sultan P, Bampoe S, Shah R, Guo N, Estes J, Stave C, Goodnough LT, Halpern S, Butwick AJ. Oral vs intravenous iron therapy for postpartum anemia: a systematic review and meta-analysis. Am J Obstet Gynecol. 2019 Jul;221(1):19-29.e3. doi: 10.1016/j.ajog.2018.12.016. Epub 2018 Dec 19.
• McNutt MK, Bradford M, Drazen JM, Hanson B, Howard B, Jamieson KH, Kiermer V, Marcus E, Pope BK, Schekman R, Swaminathan S, Stang PJ, Verma IM. Transparency in authors' contributions and responsibilities to promote integrity in scientific publication. Proc Natl Acad Sci U S A. 2018 Mar 13;115(11):2557-2560. doi: 10.1073/pnas.1715374115. Epub 2018 Feb 27.
• Ferrer-Barcelo L, Sanchis Artero L, Sempere Garcia-Arguelles J, Canelles Gamir P, P Gisbert J, Ferrer-Arranz LM, Monzo Gallego A, Plana Campos L, Huguet Malaves JM, Lujan Sanchis M, Ruiz Sanchez L, Barcelo Cerda S, Medina Chulia E. Randomised clinical trial: intravenous vs oral iron for the treatment of anaemia after acute gastrointestinal bleeding. Aliment Pharmacol Ther. 2019 Aug;50(3):258-268. doi: 10.1111/apt.15327. Epub 2019 Jun 14.
• Bager P, Dahlerup JF. Randomised clinical trial: oral vs. intravenous iron after upper gastrointestinal haemorrhage--a placebo-controlled study. Aliment Pharmacol Ther. 2014 Jan;39(2):176-87. doi: 10.1111/apt.12556. Epub 2013 Nov 19.
• Cotter J, Baldaia C, Ferreira M, Macedo G, Pedroto I. Diagnosis and treatment of iron-deficiency anemia in gastrointestinal bleeding: A systematic review. World J Gastroenterol. 2020 Dec 7;26(45):7242-7257. doi: 10.3748/wjg.v26.i45.7242.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2025
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): February 1, 2028

Study Registration Dates

• First Submitted: September 17, 2021
• First Submitted That Met QC Criteria: September 28, 2021
• First Posted (Actual): September 29, 2021

Study Record Updates

• Last Update Posted (Actual): March 30, 2025
• Last Update Submitted That Met QC Criteria: March 25, 2025
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: intravenous iron; iron supplementation; non-variceal upper gastrointersinal bleeding
• Additional Relevant MeSH Terms: Pathologic Processes; Digestive System Diseases; Gastrointestinal Diseases; Hematologic Diseases; Anemia; Hemorrhage; Gastrointestinal Hemorrhage; Physiological Effects of Drugs; Trace Elements; Micronutrients; Iron
• Other Study ID Numbers: 46395-5/2021/EÜIG

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No