Inflammatory Bowel Diseases, Iron-deficiency, Iron Deficiency Anemia
Conditions
Keywords
IBD, Crohn's disease, Ulcerative colitis, Inflammatory Bowel Disease, Iron deficiency, Iron deficiency anemia
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.
Interventions
DRUGIntravenous iron
Included participants will receive intravenous iron therapy, the dosage will be based on national pharmaceutical formulary.
DRUGFerric maltol
Included participants will receive oral iron therapy with ferric maltol (twice a day 30mg for 12 weeks)
DRUGFerrous fumarate
Included participants will receive oral iron therapy with ferrous fumarate (twice a day 100mg for 12 weeks)
Sponsors
University Medical Center Groningen
Radboud University Medical Center
Maastricht University Medical Center
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Leiden University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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%). |
| 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%). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| Adverse events during iron therapy | weeks 6, 14, and 24 | Number of (serious) adverse events 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. |
| 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. |
| 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 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Exploratory outcome: change in oxidative stress | weeks 6, 14, and 24 | Change in oxidative stress (measured by free-thiol levels) from baseline to week 6, week 14. |
Countries
Netherlands
Contacts
Primary ContactR. Loveikyte, MD
Outcome results
None listed