Iron Supplementation in Upper Non-variceal Gastrointestinal Bleeding

Anemia Clinical Trial

— FIERCE  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05060731
• Other study ID #: 46395-5/2021/EÜIG
• Status: Not yet recruiting
• Phase: Phase 4
• Start date: September 1, 2024
• Est. completion date: February 1, 2027

Study information

• Verified date: November 2023
• Source: University of Pecs
• Contact: Bálint Eross, MD, PhD
• Phone: +3630/887-4028
• Email: eross.balint[@]pte.hu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 570
• Est. completion date: February 1, 2027
• Est. primary completion date: December 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 65 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Anemia
• GastroIntestinal Bleeding
• Gastrointestinal Hemorrhage
• Hemorrhage

Intervention

Drug:
• Oral iron supplementation
Ca. 200-300 mg of ferrous sulfate will be administered orally every day for 3 months.
• Intravenous iron supplementation
One dose of intravenous 1000 mg ferric carboxymaltose will be administered on the day of randomization.

Locations

Country	Name	City	State
Hungary	Institute for Translational Medicine, University of Pécs	Pécs

Sponsors (1)

Lead Sponsor	Collaborator
University of Pecs

Country where clinical trial is conducted

Hungary, 

References & Publications (7)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Six-Minute Walk Test (6MWT)	Changes in Six-Minute Walk Test (6MWT) compared to baseline.	1, and 3 months +/- 7 days
Secondary	Handgrip strength	Changes in handgrip strength compared to baseline.	1, and 3 months +/- 7 days
Secondary	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
Secondary	Change in Hb level	Absolute change from baseline to follow-up in Hb level.	1, and 3 months +/- 7 days
Secondary	Change in haematocrit	Absolute change from baseline to follow-up in haematocrit.	1, and 3 months +/- 7 days
Secondary	Change in serum iron level	Absolute change from baseline to follow-up in serum iron level.	1, and 3 months +/- 7 days
Secondary	Change in serum transferrin level	Absolute change from baseline to follow-up in serum transferrin level.	1, and 3 months +/- 7 days
Secondary	Change in transferrin saturation	Absolute change from baseline to follow-up in transferrin saturation.	1, and 3 months +/- 7 days
Secondary	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
Secondary	Change in ferritin level	Absolute change from baseline to follow-up in ferritin level.	1, and 3 months +/- 7 days
Secondary	Change in the number of reticulocytes	Absolute change from baseline to follow-up in the number of reticulocytes.	1, and 3 months +/- 7 days
Secondary	Change in the number of erythrocytes	Absolute change from baseline to follow-up in the number of erythrocytes.	1, and 3 months +/- 7 days
Secondary	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
Secondary	Change in erythropoietin level	Absolute change from baseline to follow-up in erythropoietin level.	1, and 3 months +/- 7 days
Secondary	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
Secondary	Change in hepcidin level	Absolute change from baseline to follow-up in hepcidin level.	1, and 3 months +/- 7 days
Secondary	Change in phosphate level	Absolute change from baseline to follow-up in phosphate level.	1, and 3 months +/- 7 days
Secondary	Discontinuation of the treatment due to adverse events	The percentage of discontinuation in the two arms.	1, and 3 months +/- 7 days
Secondary	Cost-effectiveness	The incremental cost-effectiveness ratio (ICER): incremental costs divided by incremental effectiveness .	1, and 3 months +/- 7 days

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