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

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.

Study Overview

• Status: Recruiting
• Conditions: Inflammatory Bowel Diseases; Iron-deficiency; Iron Deficiency Anemia
• Intervention / Treatment: Drug: Intravenous iron; Drug: Ferric maltol; Drug: Ferrous fumarate

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 Type: Interventional
• Enrollment (Anticipated): 90
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: R. Loveikyte, MD; Phone Number: 00315297902; Email: patientenibd@lumc.nl

Study Locations

• Netherlands
  • Amsterdam, Netherlands
    • Recruiting
    • Amsterdam University Medical Center
    • Contact: R. Loveikyte, MD
    • Principal Investigator: R.L. Goetgebuer, MD, PhD
  • Groningen, Netherlands
    • Recruiting
    • University Medical Center Groningen
    • Principal Investigator: G. Dijkstra, MD, PhD
    • Contact: R. Loveikyte, MD
  • Leiden, Netherlands
    • Recruiting
    • Leiden University Medical Center (LUMC)
    • Principal Investigator: A.E. van der Meulen - de Jong, MD, PhD
    • Contact: R. Loveikyte, MD
  • Maastricht, Netherlands
    • Recruiting
    • Maastricht University Medical Center+
    • Contact: R. Loveikyte, MD
    • Principal Investigator: Z Mujagic, MD, PhD
  • Nijmegen, Netherlands
    • Recruiting
    • Radboud University Medical Center
    • Principal Investigator: M. Duijvestein, MD, PhD
    • Contact: R. Loveikyte, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory outcome: change in oxidative stress	Change in oxidative stress (measured by free-thiol levels) from baseline to week 6, week 14.	weeks 6, 14, and 24

Collaborators and Investigators

• Sponsor: Leiden University Medical Center
• Collaborators: Radboud University Medical Center; University Medical Center Groningen; Maastricht University Medical Center; Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Investigators: Principal Investigator: A.E. van der Meulen - de Jong, MD, PhD, LUMC

Study record dates

Study Major Dates

• Study Start (Actual): August 19, 2022
• Primary Completion (Anticipated): August 31, 2023
• Study Completion (Anticipated): August 31, 2023

Study Registration Dates

• First Submitted: May 10, 2022
• First Submitted That Met QC Criteria: July 11, 2022
• First Posted (Actual): July 13, 2022

Study Record Updates

• Last Update Posted (Actual): March 31, 2023
• Last Update Submitted That Met QC Criteria: March 29, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: Iron deficiency anemia; Inflammatory Bowel Disease; IBD; Crohn's disease; Ulcerative colitis; Iron deficiency
• Additional Relevant MeSH Terms: Digestive System Diseases; Metabolic Diseases; Hematologic Diseases; Gastrointestinal Diseases; Gastroenteritis; Anemia, Hypochromic; Anemia; Iron Metabolism Disorders; Inflammatory Bowel Diseases; Anemia, Iron-Deficiency; Intestinal Diseases; Physiological Effects of Drugs; Trace Elements; Micronutrients; Hematinics; Ferrous fumarate; Iron; Ferric maltol
• Other Study ID Numbers: NL79105.058.22; 2022-000894-16 (EudraCT Number)

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