IHAT Absorption Kinetics

Study Overview
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Brief Summary
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At MRC Human Nutrition Research, the investigators have developed an engineered analogue of the ferritin-core for safe and effective iron supplementation. Iron hydroxide adipate tartrate (IHAT) is a tartrate-modified, nano-disperse Fe(III) oxo-hydroxide, formed in an adipate buffer, with similar functional properties and small primary particle size ( 2 nm) as the iron found in the ferritin core; it better mimics iron absorption from food than the non-physiological bolus doses of ferrous sulphate currently used. This exploratory study will test the hypothesis that IHAT has equivalent bioavailability to ferrous sulphate but produces a less harmful post-ingestion rise in transferrin saturation. The design is a 3-arm (IDA, non-IDA and IDA-IHAT new manufacture), crossover, randomised, single-dose study. Primary endpoint: Relative bioavailability value of IHAT versus ferrous sulphate. This will be determined from the red blood cell incorporation of isotope-labelled iron 14 days following a single oral dose. Secondary endpoints: Serum iron at 0, 2, 4, 6 hours following a single dose of each iron compound. Transferrin saturation at 0, 2, 4, 6 hours following a single dose of each iron compound. Plasma 58Fe and 57Fe at 0, 2, 4, 6 hours. Pathogen growth using ex vivo assays in serum collected from each subject at 0, 2, 4 and 6 hours following a single dose.

Detailed Description
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The study's main hypothesis is that IHAT will be bioavailable in pre-menopausal anaemic Gambian women and will lead to a lower serum iron and transferrin saturation increase than an equivalent dose of ferrous sulphate. Furthermore, the investigators hypothesize that IHAT will produce a less harmful post-ingestion rise in transferrin saturation, i.e. the serum collected from subjects following a single dose of IHAT will promote less pathogen growth in ex vivo assays than that collected following an equivalent dose of ferrous sulphate. Finally, based on previous animal data [5], the investigators hypothesize that IHAT absorption will be significantly higher in anaemic women compared to non-anaemic women, and that this will not be the case with ferrous sulphate. This study is a cross-over, single-dose comparison against ferrous sulphate (standard of care) in anaemic and non-anaemic women. The iron single dosage for both compounds will be 60mg elemental iron equivalent and each compound will be labelled with a stable iron isotope. Outcomes will be: red blood cell incorporation of labelled iron, serum iron, transferrin saturation and pathogen growth in ex vivo serum assays. Primary objective: To determine iron bioavailability (i.e. red blood cell incorporation) from a single dose of IHAT versus ferrous sulphate in pre-menopausal Gambian women. Secondary objective: To determine serum iron absorption following a single dose of IHAT versus ferrous sulphate in pre-menopausal Gambian women. To evaluate if a single-dose of IHAT produces a less harmful post-ingestion rise in transferrin saturation and serum iron than ferrous sulphate. Each compound is labelled with a stable isotope of Fe so that its absorption can be determined from the red blood cell incorporation of the stable isotope 14 days after the single dose. This study is effectively a Phase 0 study (pharmacokinetics) with small numbers and because iron absorption varies from individual to individual, depending on their body iron needs and gastrointestinal digestion issues, it is more accurate to use each study subject as her own control. Therefore, each subject will ingest IHAT on one study day and the active treatment comparator on a separate day. The 2 study visits need to be 14 days apart to allow for red blood cell incorporation of the stable iron isotopes used to label the iron materials. This method is the gold standard to determine relative bioavailability values (RBV) of novel iron compounds (i.e. in relation to ferrous sulphate absorption) and allows an accurate determination of RBV of IHAT that otherwise would not be possible if we used a parallel study design with small numbers.

Official Title
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An Exploratory Study to Determine Bioavailability and Transferrin Saturation Following a Single Dose of a Novel Iron Supplement (IHAT) in Gambian Women.

Conditions
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Iron-deficiency Anemia

Intervention / Treatment
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* Dietary Supplement: IHAT
* Dietary Supplement: Ferrous sulphate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pre-menopausal women apparently healthy (as judged by a study nurse at the screening day) with normal CRP (measured at screening). Non-pregnant (will be tested with a rapid pregnancy test) and non-lactating women. IDA arm: 9≤Hb≤11 g/dL and ferritin≤ 15 ng/ml Non-IDA arm: Hb>11 g/dL and ferritin> 15 ng/ml. Exclusion Criteria: Malaria and other infections Severe anaemia (Hb<9 g/dL) CRP> 5 mg/L Chronic disease Currently participating in other iron intervention studies.

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: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Iron deficient anaemic: IDA<br>Iron deficient anaemic women. Interventions: two iron supplements will be used: IHAT- iron hydroxide adipate tartrate: an analogue of natural food iron. Ferrous sulphate- the gold standard for iron supplementation. For both the iron single-dose will be 60mg elemental iron equivalent. Each compound will be labelled with a stable isotope of iron: IHAT with 2 mg 58Fe and ferrous sulphate with 10 mg 57Fe. 1 capsule of each compound will be ingested with a full glass of water in two separate occasions, 14 days apart. | Dietary Supplement: IHAT<br>* Iron hydroxide adipate tartrate (IHAT): Single dose capsule containing IHAT equivalent to 60mg iron with 2 mg isotopically enriched with 58Fe.<br>Dietary Supplement: Ferrous sulphate<br>* Ferrous sulphate: Single dose capsule containing ferrous sulphate heptahydrate equivalent to 60 mg iron with 10 mg isotopically enriched with 57Fe.<br>|
| Experimental: Iron sufficient: non-IDA<br>Women that are not anaemic or iron deficient. Interventions: two iron supplements will be used: IHAT- iron hydroxide adipate tartrate: an analogue of natural food iron. Ferrous sulphate- the gold standard for iron supplementation. For both the iron single-dose will be 60mg elemental iron equivalent. Each compound will be labelled with a stable isotope of iron: IHAT with 2 mg 58Fe and ferrous sulphate with 10 mg 57Fe. 1 capsule of each compound will be ingested with a full glass of water in two separate occasions, 14 days apart. | Dietary Supplement: IHAT<br>* Iron hydroxide adipate tartrate (IHAT): Single dose capsule containing IHAT equivalent to 60mg iron with 2 mg isotopically enriched with 58Fe.<br>Dietary Supplement: Ferrous sulphate<br>* Ferrous sulphate: Single dose capsule containing ferrous sulphate heptahydrate equivalent to 60 mg iron with 10 mg isotopically enriched with 57Fe.<br>|
| Experimental: Iron deficient anaemic (IDA): IHAT new manufacture<br>Iron deficient anaemic women. Interventions: two iron supplements will be used: IHAT new manufacture- iron hydroxide adipate tartrate: an analogue of natural food iron. Ferrous sulphate- the gold standard for iron supplementation. For both the iron single-dose will be 60mg elemental iron equivalent. Each compound will be labelled with a stable isotope of iron: IHAT with 2 mg 58Fe and ferrous sulphate with 10 mg 57Fe. 1 capsule of each compound will be ingested with a full glass of water in two separate occasions, 14 days apart. | Dietary Supplement: IHAT<br>* Iron hydroxide adipate tartrate (IHAT): Single dose capsule containing IHAT equivalent to 60mg iron with 2 mg isotopically enriched with 58Fe.<br>Dietary Supplement: Ferrous sulphate<br>* Ferrous sulphate: Single dose capsule containing ferrous sulphate heptahydrate equivalent to 60 mg iron with 10 mg isotopically enriched with 57Fe.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative bioavailability value of IHAT versus ferrous sulphate | This will be determined from the red blood cell incorporation of isotope-labelled iron 14 days following a single oral dose. | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum iron | Serum iron will be determined at 0, 2, 4, 6 hours following a single dose of each iron compounds (i.e. on days 1 and 14). | 6 hours | 
| Transferrin saturation | Tsat will be determined at 0, 2, 4, 6 hours following a single dose of each iron compounds (i.e. on days 1 and 14). | 6 hours | 
| Pathogen Growth | Pathogen growth will be determined using ex vivo assays in serum collected from each subject at 0, 2, 4 and 6 hours following a single dose of each compound (days 1 and 14). | 6 hours | 
| Plasma iron | Plasma 58Fe and 57Fe will be determined at 0, 2, 4, 6 hours (on days 1 and 14). | 6 hours |