Predicting Response to Iron Supplementation in Patients With Active Inflammatory Bowel Disease

Phase 4

Recruiting

• Conditions: Inflammatory Bowel Diseases; Iron Deficiency Anemia; Iron-deficiency
• Interventions: Drug: Ferric maltol; Drug: Intravenous iron; Drug: Ferrous fumarate

• Registration Number: NCT05456932
• Lead Sponsor: Leiden University Medical Center

Brief Summary

Iron deficiency anemia is the most common systemic manifestation of Inflammatory Bowel Diseases (IBD)-Crohn's disease and ulcerative colitis. Iron deficiency with or without anemia poses a diagnostic and therapeutic challenge due to chronic gastrointestinal blood loss and the inflammatory nature of IBD. Recent illumination of iron metabolism has brought attention to the systemic iron regulator-hepcidin, a peptide hormone that regulates intestinal iron absorption and systemic iron availability. Elevated hepcidin is associated with oral iron malabsorption in IBD. This study aims to evaluate whether hepcidin concentration at baseline can predict response to oral and intravenous iron therapy in patients with IBD and concomitant iron deficiency with or without anemia.

Detailed Description

The PRIme is a multicenter and randomized study that aims to evaluate the capacity of hepcidin at baseline to predict response to oral or intravenous iron therapy in patients with active IBD. Study participants will be randomized and allocated (open-label) to one of the three study arms: intravenous iron therapy, therapy with oral ferrous fumarate, or therapy with oral ferric maltol.

During the study, biochemical indices such as hemoglobin, iron status, hepcidin and related cytokines will be measured at week 6, 14, and 24 after the start of the therapy. In addition, the study will evaluate changes in oxidative stress, quality of live, and productivity.

Study Timeline

• Study First Submitted: 2022-05-10
• Study First Submitted QC: 2022-07-11
• Study First Posted: 2022-07-13
• Study Start: 2022-08-19
• Status Verified: 2023-03
• Last Update Submitted: 2023-03-29
• Last Update Posted: 2023-03-31
• Primary Completion: 2023-08-31
• Study Completion: 2023-08-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 90

Inclusion Criteria

• Established IBD diagnosis (Crohn's disease, ulcerative colitis, IBD-unclassified)
• Adults (≥18 years of age)
• Active IBD (defined as any endoscopic, radiologic or biochemical disease activity [fecal calprotectin >150 mg/kg or C-reactive protein >5 mg/l])
• Iron deficiency anemia (defined as ferritin <100 ug/l and hemoglobin <7.5 mmol/l for females or <8.5 mmol/l for males) or iron deficiency (defined as ferritin <100 ug/l and transferrin saturation <20%)
• Documented informed consent

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Exclusion Criteria

• Blood transfusion or therapy with oral and/or intravenous iron in the past eight weeks
• Documented intolerance to oral or intravenous iron
• Severe anemia (defined as hemoglobin <6.2 mmol/l for females and males)
• Documented history of liver cirrhosis, heart failure, hemoglobinopathies, autoimmune hemolytic anemia, myelodysplastic syndrome, or chronic obstructive pulmonary disease
• Documented history of recent treatment for a malignancy (excluding dermatological malignancies such as basal cell carcinoma or squamous cell carcinoma). Patients can be included if the treatment for malignancy has been finalized ≥6 months before the inclusion date.
• Documented history of bariatric surgery or gastric/duodenal resections due to benign or malignant pathologies
• End-stage renal disease (impaired renal function, defined as estimated Glomerular Filtration Rate (eGFR) <30 ml/min/1.73m2)
• Folic acid deficiency
• Vitamin B12 deficiency
• Documented pregnancy or breastfeeding at the time of inclusion
• Documented major operation (e.g., laparotomy) less than six weeks before inclusion
• Unable to give informed consent due to inability to understand Dutch language or incapacitation (e.g., due to cognitive/psychological conditions or hospitalization in Intensive Care)

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Ferric maltol	Ferric maltol	Treatment with oral ferric maltol
Intravenous iron	Intravenous iron	Intravenous iron therapy
Ferrous fumarate	Ferrous fumarate	Treatment with oral ferrous fumarate

Primary Outcome Measures

Name	Time	Method
The discriminative capacity of hepcidin at baseline to differentiate between response and non-response to iron therapy with oral ferrous fumarate	Week 14	Hepcidin concentration will be measured in blood at baseline. Receiver Operating Characteristic (ROC) curve with associated Area Under the Curve (AUC) will be used to evaluate the discriminative ability of hepcidin concentration at baseline to differentiate between response and non-response to iron therapy with ferrous fumarate. Response to iron therapy will be evaluated at week 14 and will be defined as hemoglobin normalization (or \>1.2 mmol/L increase) for patients with iron-deficiency anemia; for patients with non-anemic iron deficiency the response will be defined as normalization of iron stores (i.e., ferritin \>100 ug/L and transferrin saturation \>20%).
The discriminative capacity of hepcidin at baseline to differentiate between response and non-response to iron therapy with oral ferric maltol	Week 14	Hepcidin concentration will be measured in blood at baseline. Receiver Operating Characteristic (ROC) curve with associated Area Under the Curve (AUC) will be used to evaluate the discriminative ability of hepcidin concentration at baseline to differentiate between response and non-response to iron therapy with ferric maltol. Response to iron therapy will be evaluated at week 14 and will be defined as hemoglobin normalization (or \>1.2 mmol/L increase) for patients with iron-deficiency anemia; for patients with non-anemic iron deficiency the response will be defined as normalization of iron stores (i.e., ferritin \>100 ug/L and transferrin saturation \>20%).
The discriminative capacity of hepcidin at baseline to differentiate between response and non-response to intravenous iron therapy	Week 14	Hepcidin concentration will be measured in blood at baseline. Receiver Operating Characteristic (ROC) curve with associated Area Under the Curve (AUC) will be used to evaluate the discriminative ability of hepcidin concentration at baseline to differentiate between response and non-response to intravenous iron therapy. Response to iron therapy will be evaluated at week 14 and will be defined as hemoglobin normalization (or \>1.2 mmol/L increase) for patients with iron-deficiency anemia; for patients with non-anemic iron deficiency the response will be defined as normalization of iron stores (i.e., ferritin \>100 ug/L and transferrin saturation \>20%).

Secondary Outcome Measures

Name	Time	Method
Adverse events during iron therapy	weeks 6, 14, and 24	Number of (serious) adverse events in all of the three groups.
Change in hepcidin	weeks 6, 14, and 24	Change in hepcidin levels from baseline to weeks 6, 14, and 24 in all of the three groups
Change in soluble Transferrin Receptor (sTfR)	weeks 6, 14, and 24	Change in soluble Transferrin Receptor (sTfR) levels from baseline to weeks 6, 14, and 24 in all of the three groups.
Change in interleukin 6 (IL-6)	weeks 6, 14, and 24	Change in interleukin 6 (IL-6) levels from baseline to weeks 6, 14, and 24 in all of the three groups.
Normalization of iron stores	weeks 6, 14, and 24	Percentage of patients who achieve normalization of iron stores (an increase in transferrin saturation (transferrin saturation \>20%) and an increase in ferritin above 100 ug/l) at weeks 6, 14, and 24 in all of the three groups.
Correlation between response to iron therapy and disease activity	week 14	The correlation of disease activity (evaluated by fecal calprotectin levels) and response to iron therapy in all of the three groups.
Incidence of hypophosphatemia during iron therapy	weeks 6, 14, and 24	Percentage of patients who experienced hypophosphatemia throughout iron therapy in all of the three groups
Change in clinical disease activity	weeks 14 and 24	Change in clinical disease activity (measured by mobile Health Index (mHI) 0-24 for patients with Crohn's disease and 0-34 for patients with ulcerative colitis; higher scores indicate a more active disease) from baseline to week 14, and week 24 in all of the three groups.
Change in quality of life	weeks 14 and 24	Change in quality of life (measured by 36-item Short Form Survey (SF-36) expressed on a scale 0-100 where higher scores indicate less disability and better quality of life) from baseline to week 14, and week 24 in all of the three groups.
Change in activity and productivity	weeks 14 and 24	Change in activity and productivity (measured by Work Productivity and Activity Impairment: Inflammatory Bowel Disease (WPAI:IBD) expressed as 0-100% where higher percentages indicate greater impairment) from baseline to week 14, and week 24 in all of the three groups.
Hematologic response during iron therapy	weeks 14 and 24	Percentage of patients who achieved an adequate hematologic response (defined by hemoglobin increase \>1.2 mmol/L or hemoglobin normalization) at weeks 14 and 24 in all of the three groups.
Hemoglobin increase (>0.6 mmol/L) during iron therapy	weeks 6 and 14	Percentage of patients who experienced a ≥0.6 mmol/l change in hemoglobin from baseline to weeks 6 and 14 in all of the three groups.

Trial Locations

Locations (5)

Radboud University Medical Center; 🇳🇱 Nijmegen, Netherlands

University Medical Center Groningen; 🇳🇱 Groningen, Netherlands

Maastricht University Medical Center+; 🇳🇱 Maastricht, Netherlands

Amsterdam University Medical Center; 🇳🇱 Amsterdam, Netherlands

Leiden University Medical Center (LUMC); 🇳🇱 Leiden, Netherlands