Effects of Enhancers and Inhibitors on Absorption From Iron Supplements

Study Overview
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Brief Summary
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Iron deficiency (ID) is a major public health problem worldwide and oral iron supplementation can be an effective strategy to treat and prevent ID. To maximize iron bioavailability form oral iron supplements the simultaneous intake of the iron absorption enhancer ascorbic acid (AA) is recommended, and the simultaneous intake of coffee or tea containing the iron absorption inhibitors polyphenols should be avoided. Also, oral iron supplements are recommended to be taken on an empty stomach in the morning and without a meal to avoid any interaction with phytic acid, another iron absorption inhibitor present in many foods. However, the effects of these iron absorption enhancers and inhibitors have only been shown on iron absorption from dietary iron (up to 10mg). Also, the effect of the diurnal hepcidin increase on absorption from an iron supplement given in the afternoon without a preceding morning dose is unclear. Whether AA also increases iron bioavailability from a supplemental iron dose and whether a cup of coffee, a breakfast or iron administration in the afternoon decreases iron bioavailability from a supplemental dose is uncertain.

Official Title
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Effects of Nutritional Iron Absorption Enhancers and Inhibitors and Daytime on Absorption From Oral Iron Supplements

Conditions
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Iron-deficiency, Iron Deficiency Anemia

Intervention / Treatment
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* Other: Reference
* Other: Ascorbic acid (AA) 500 mg
* Other: Ascorbic acid (AA) 80 mg
* Other: Coffee
* Other: Breakfast
* Other: Afternoon


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female, 18 to 45 years old, SF levels <30 μg/L, Body weight < 70 kg Normal Body Mass Index (18.5-25 kg/m2), Signed informed consent. Exclusion Criteria: Anemia (Hb < 12 g/dL) Elevated CRP > 5 mg/L, Any metabolic, gastrointestinal, kidney or chronic disease such as diabetes, renal failure, hepatic dysfunction, hepatitis, hypertension, cancer or cardiovascular diseases (according to the participants own statement) affecting iron metabolism, Continuous/long-term use of medication during the whole study, which may interfere with iron absorption, gut physiology and iron metabolism, Consumption of mineral and vitamin supplements since screening and over the study period until last blood sample collection, Difficulties with blood sampling, Blood transfusion, blood donation or significant blood loss (accident, surgery) over the past 6 months, Known hypersensitivity or allergy to iron capsules in the given amount (ferrous fumarate, brilliant blue FCF (E133), titandioxide (E171) and sodium lauryl sulfate) Pregnancy, breastfeeding Women who intend to become pregnant during the course of the study, Known or suspected non-compliance, drug or alcohol (more than 2 drinks/day) abuse, Smokers (> 1 cigarette per week), Participant is likely to be absent on one the study appointments, Inability to follow the procedures of the study, e.g. due to language problems, self-reported psychological disorders, etc. of the participant.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Reference<br>Ferrum Hausmann 100 mg is consumed with 200 mL nanopure water with labelled ferrous fumarate (3 mg 54Fe). | Other: Reference<br>* Ferrum Hausmann 100 mg + 200 mL nanopure water with 3 mg 54Fe isotopes<br>|
| Experimental: Ascorbic acid (AA) 500 mg<br>Ferrum Hausmann 100 mg is consumed with 200 mL nanopure water with labelled ferrous fumarate (3 mg 57Fe) and 500 mg AA. | Other: Ascorbic acid (AA) 500 mg<br>* Ferrum Hausmann 100 mg + 200 mL nanopure water with 3 mg 57Fe isotopes + 500 mg AA<br>|
| Experimental: Ascorbic acid (AA) 80 mg<br>Ferrum Hausmann 100 mg is consumed with 200 mL nanopure water with labelled ferrous fumarate (3 mg 58Fe) and 80 mg AA. | Other: Ascorbic acid (AA) 80 mg<br>* Ferrum Hausmann 100 mg + 200 mL nanopure water with 3 mg 58Fe + 80 mg AA<br>|
| Experimental: Coffee<br>Ferrum Hausmann 100 mg is consumed with 200 mL nanopure water with labelled ferrous fumarate (3 mg 54Fe) and 150 mL coffee. | Other: Coffee<br>* Ferrum Hausmann 100 mg + 200 mL nanopure water with 3 mg 54Fe isotopes + 150 mL coffee<br>|
| Experimental: Breakfast<br>Ferrum Hausmann 100 mg is consumed with 200 mL nanopure water with labelled ferrous fumarate (3 mg 57Fe) and 1 bread roll ( 100 g) with butter and honey, 1 cup of plain yoghurt (180 mL), 1 cup of coffee (150 mL) and 1 glass of orange juice (250 mL). | Other: Breakfast<br>* Ferrum Hausmann 100 mg + 200 mL nanopure water with 3 mg 57Fe isotopes + 1 bread roll ( 100 g) with butter and honey + 1 cup of plain yoghurt (180 mL) + 1 cup of coffee (150 mL) + 1 glass of orange juice (250 mL)<br>|
| Experimental: Afternoon<br>Ferrum Hausmann 100 mg is consumed with 200 mL nanopure water with labelled ferrous fumarate (3 mg 58Fe) in the afternoon . | Other: Afternoon<br>* Ferrum Hausmann 100 mg + 200 mL nanopure water with 3 mg 58Fe isotopes administered in the afternoon<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fractional iron absorption [percent] | Fractional iron absorption will be calculated based on the shift of the iron isotope ratios in the collected blood samples after the administration of the intervention products. Fractional iron absorption will be measured as erythrocyte incorporation of the naturally occurring iron forms with different masses used to label the iron supplements. | Day 22 | 
| Fractional iron absorption [percent] | Fractional iron absorption will be calculated based on the shift of the iron isotope ratios in the collected blood samples after the administration of the intervention products. Fractional iron absorption will be measured as erythrocyte incorporation of the naturally occurring iron forms with different masses used to label the iron supplements. | Day 43 | 
| Total iron absorption [mg] | Total iron absorption will be calculated based on the shift of the iron isotope ratios in the collected blood samples after the administration of the intervention products. Total iron absorption will be measured as erythrocyte incorporation of the naturally occurring iron forms with different masses used to label the iron supplements. | Day 22 | 
| Total iron absorption [mg] | Total iron absorption will be calculated based on the shift of the iron isotope ratios in the collected blood samples after the administration of the intervention products. Total iron absorption will be measured as erythrocyte incorporation of the naturally occurring iron forms with different masses used to label the iron supplements. | Day 43 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hemoglobin (Hb) | Iron status marker | Day 1, 22, 26 and 43 | 
| Serum ferritin (SF) | Iron status marker | Day 1, 22, 26 and 43 | 
| Serum transferrin receptor (sTfR) | Iron status marker | Day 1, 22, 26 and 43 | 
| Serum iron (SFe) | Iron status marker | Day 1, 22, 26 and 43 | 
| Total iron binding capacity (TIBC) | Iron status marker | Day 1, 22, 26 and 43 | 
| Hepcidin | Iron regulatory protein | Day 1, 22 and 26 | 
| C-reactive protein (CRP) | Inflammation marker | Day 1, 22, 26 and 43 | 
| Alpha-1-acid-glycoprotein (AGP) | Inflammation marker | Day 1, 22, 26 and 43 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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iron supplementation, women of reproductive age, iron absorption enhancers, iron absorption inhibitors, ferrous fumarate, iron deficiency