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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Inflammatory Bowel Diseases, Iron-deficiency, Iron Deficiency Anemia

Intervention / Treatment
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* Drug: Intravenous iron
* Drug: Ferric maltol
* Drug: Ferrous fumarate


Participation Criteria
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Eligibility Criteria
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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 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)

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: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intravenous iron<br>Intravenous iron therapy | Drug: Intravenous iron<br>* Included participants will receive intravenous iron therapy, the dosage will be based on national pharmaceutical formulary.<br>* Other names: i.v. iron;|
| Experimental: Ferric maltol<br>Treatment with oral ferric maltol | Drug: Ferric maltol<br>* Included participants will receive oral iron therapy with ferric maltol (twice a day 30mg for 12 weeks)<br>* Other names: Feraccru;|
| Experimental: Ferrous fumarate<br>Treatment with oral ferrous fumarate | Drug: Ferrous fumarate<br>* Included participants will receive oral iron therapy with ferrous fumarate (twice a day 100mg for 12 weeks)<br>* Other names: ferrofumaraat;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The discriminative capacity of hepcidin at baseline to differentiate between response and non-response to iron therapy with oral ferrous fumarate | 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%). | Week 14 | 
| The discriminative capacity of hepcidin at baseline to differentiate between response and non-response to iron therapy with oral ferric maltol | 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%). | Week 14 | 
| The discriminative capacity of hepcidin at baseline to differentiate between response and non-response to intravenous iron therapy | 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%). | Week 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in hepcidin | Change in hepcidin levels from baseline to weeks 6, 14, and 24 in all of the three groups | weeks 6, 14, and 24 | 
| Change in soluble Transferrin Receptor (sTfR) | Change in soluble Transferrin Receptor (sTfR) levels from baseline to weeks 6, 14, and 24 in all of the three groups. | weeks 6, 14, and 24 | 
| Change in interleukin 6 (IL-6) | Change in interleukin 6 (IL-6) levels from baseline to weeks 6, 14, and 24 in all of the three groups. | weeks 6, 14, and 24 | 
| Normalization of iron stores | 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. | weeks 6, 14, and 24 | 
| Correlation between response to iron therapy and disease activity | The correlation of disease activity (evaluated by fecal calprotectin levels) and response to iron therapy in all of the three groups. | week 14 | 
| Incidence of hypophosphatemia during iron therapy | Percentage of patients who experienced hypophosphatemia throughout iron therapy in all of the three groups | weeks 6, 14, and 24 | 
| Adverse events during iron therapy | Number of (serious) adverse events in all of the three groups. | weeks 6, 14, and 24 | 
| Change in clinical disease activity | 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. | weeks 14 and 24 | 
| Change in quality of life | 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. | weeks 14 and 24 | 
| Change in activity and productivity | 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. | weeks 14 and 24 | 
| Hematologic response during iron therapy | 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. | weeks 14 and 24 | 
| Hemoglobin increase (>0.6 mmol/L) during iron therapy | 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. | weeks 6 and 14 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IBD, Crohn's disease, Ulcerative colitis, Inflammatory Bowel Disease, Iron deficiency, Iron deficiency anemia