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

Primary Purpose

Inflammatory Bowel Diseases, Iron-deficiency, Iron Deficiency Anemia

Status

Recruiting

Phase

Phase 4

Locations

Netherlands

Study Type

Interventional

Intervention

Intravenous iron

Ferric maltol

Ferrous fumarate

About this trial

This is an interventional diagnostic trial for Inflammatory Bowel Diseases focused on measuring IBD, Crohn's disease, Ulcerative colitis, Inflammatory Bowel Disease, Iron deficiency, Iron deficiency anemia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Established IBD diagnosis (Crohn's disease, ulcerative colitis, IBD-unclassified)
Adults (≥18 years of age)
Scheduled induction therapy (any induction therapy; e.g., infliximab, adalimumab, golimumab, vedolizumab, ustekinumab, tofacitinib, filgotinib, tacrolimus, etc.)
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)
Proton-pump inhibitor use

Sites / Locations

Amsterdam University Medical CenterRecruiting
University Medical Center GroningenRecruiting
Leiden University Medical Center (LUMC)Recruiting
Maastricht University Medical Center+Recruiting
Radboud University Medical CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

Intravenous iron

Ferric maltol

Ferrous fumarate

Arm Description

Intravenous iron therapy

Treatment with oral ferric maltol

Treatment with oral ferrous fumarate

Outcomes

Primary Outcome Measures

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%).

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%).

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%).

Secondary Outcome Measures

Change in hepcidin

Change in hepcidin levels from baseline to weeks 6, 14, and 24 in all of the three groups

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.

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.

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.

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.

Incidence of hypophosphatemia during iron therapy

Percentage of patients who experienced hypophosphatemia throughout iron therapy in all of the three groups

Adverse events during iron therapy

Number of (serious) adverse events in all of the three groups.

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.

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.

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.

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.

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.

Full Information

NCT ID

NCT05456932

First Posted

May 10, 2022

Last Updated

March 29, 2023

Sponsor

Leiden University Medical Center

Collaborators

University Medical Center Groningen, Radboud University Medical Center, Maastricht University Medical Center, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

1. Study Identification

Unique Protocol Identification Number

NCT05456932

Brief Title

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

Acronym

PRIme

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

March 2023

Overall Recruitment Status

Recruiting

Study Start Date

August 19, 2022 (Actual)

Primary Completion Date

August 31, 2023 (Anticipated)

Study Completion Date

August 31, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Leiden University Medical Center

Collaborators

University Medical Center Groningen, Radboud University Medical Center, Maastricht University Medical Center, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Inflammatory Bowel Diseases, Iron-deficiency, Iron Deficiency Anemia

Keywords

IBD, Crohn's disease, Ulcerative colitis, Inflammatory Bowel Disease, Iron deficiency, Iron deficiency anemia

7. Study Design

Primary Purpose

Diagnostic

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

90 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Intravenous iron

Arm Type

Experimental

Arm Description

Intravenous iron therapy

Arm Title

Ferric maltol

Arm Type

Experimental

Arm Description

Treatment with oral ferric maltol

Arm Title

Ferrous fumarate

Arm Type

Experimental

Arm Description

Treatment with oral ferrous fumarate

Intervention Type

Drug

Intervention Name(s)

Intravenous iron

Other Intervention Name(s)

i.v. iron

Intervention Description

Included participants will receive intravenous iron therapy, the dosage will be based on national pharmaceutical formulary.

Intervention Type

Drug

Intervention Name(s)

Ferric maltol

Other Intervention Name(s)

Feraccru

Intervention Description

Included participants will receive oral iron therapy with ferric maltol (twice a day 30mg for 12 weeks)

Intervention Type

Drug

Intervention Name(s)

Ferrous fumarate

Other Intervention Name(s)

ferrofumaraat

Intervention Description

Included participants will receive oral iron therapy with ferrous fumarate (twice a day 100mg for 12 weeks)

Primary Outcome Measure Information:

Title

The discriminative capacity of hepcidin at baseline to differentiate between response and non-response to iron therapy with oral ferrous fumarate

Description

Time Frame

Week 14

Title

The discriminative capacity of hepcidin at baseline to differentiate between response and non-response to iron therapy with oral ferric maltol

Description

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%).

Time Frame

Week 14

Title

The discriminative capacity of hepcidin at baseline to differentiate between response and non-response to intravenous iron therapy

Description

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%).

Time Frame

Week 14

Secondary Outcome Measure Information:

Title

Change in hepcidin

Description

Change in hepcidin levels from baseline to weeks 6, 14, and 24 in all of the three groups

Time Frame

weeks 6, 14, and 24

Title

Change in soluble Transferrin Receptor (sTfR)

Description

Change in soluble Transferrin Receptor (sTfR) levels from baseline to weeks 6, 14, and 24 in all of the three groups.

Time Frame

weeks 6, 14, and 24

Title

Change in interleukin 6 (IL-6)

Description

Change in interleukin 6 (IL-6) levels from baseline to weeks 6, 14, and 24 in all of the three groups.

Time Frame

weeks 6, 14, and 24

Title

Normalization of iron stores

Description

Time Frame

weeks 6, 14, and 24

Title

Correlation between response to iron therapy and disease activity

Description

The correlation of disease activity (evaluated by fecal calprotectin levels) and response to iron therapy in all of the three groups.

Time Frame

week 14

Title

Incidence of hypophosphatemia during iron therapy

Description

Percentage of patients who experienced hypophosphatemia throughout iron therapy in all of the three groups

Time Frame

weeks 6, 14, and 24

Title

Adverse events during iron therapy

Description

Number of (serious) adverse events in all of the three groups.

Time Frame

weeks 6, 14, and 24

Title

Change in clinical disease activity

Description

Time Frame

weeks 14 and 24

Title

Change in quality of life

Description

Time Frame

weeks 14 and 24

Title

Change in activity and productivity

Description

Time Frame

weeks 14 and 24

Title

Hematologic response during iron therapy

Description

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.

Time Frame

weeks 14 and 24

Title

Hemoglobin increase (>0.6 mmol/L) during iron therapy

Description

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.

Time Frame

weeks 6 and 14

Other Pre-specified Outcome Measures:

Title

Exploratory outcome: change in oxidative stress

Description

Change in oxidative stress (measured by free-thiol levels) from baseline to week 6, week 14.

Time Frame

weeks 6, 14, and 24

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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)

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

R. Loveikyte, MD

Phone

00315297902

patientenibd@lumc.nl

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

A.E. van der Meulen - de Jong, MD, PhD

Organizational Affiliation

LUMC

Official's Role

Principal Investigator

Facility Information:

Facility Name

Amsterdam University Medical Center

City

Amsterdam

Country

Netherlands

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

R. Loveikyte, MD

First Name & Middle Initial & Last Name & Degree

R.L. Goetgebuer, MD, PhD

Facility Name

University Medical Center Groningen

City

Groningen

Country

Netherlands

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

R. Loveikyte, MD

First Name & Middle Initial & Last Name & Degree

G. Dijkstra, MD, PhD

Facility Name

Leiden University Medical Center (LUMC)

City

Leiden

Country

Netherlands

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

R. Loveikyte, MD

First Name & Middle Initial & Last Name & Degree

A.E. van der Meulen - de Jong, MD, PhD

Facility Name

Maastricht University Medical Center+

City

Maastricht

Country

Netherlands

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

R. Loveikyte, MD

First Name & Middle Initial & Last Name & Degree

Z Mujagic, MD, PhD

Facility Name

Radboud University Medical Center

City

Nijmegen

Country

Netherlands

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

R. Loveikyte, MD

First Name & Middle Initial & Last Name & Degree

M. Duijvestein, MD, PhD

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

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

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