Potential Harms of Untargeted Iron Supplementation in Cambodia Where Iron Deficiency is Not the Cause of Anemia

Study Overview
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Brief Summary
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In 2016, the World Health Organization (WHO) set a global policy recommending daily oral iron supplementation (60 mg iron) for 12 weeks for all women living in countries where anemia prevalence is >40%, such as in Cambodia. However, recent studies have shown the prevalence of iron deficiency to be low in Cambodian women and that supplementation would likely only benefit  10% of women. Iron supplementation may be harmful in women with genetic blood disorders (e.g. thalassemia), which are common in Cambodia, as these individuals are already at an increased risk of iron overload. The risks are made greater by the fact that iron absorption from most common form of supplementation, ferrous sulfate, is low. Typically less than 20% is absorbed in the gut; the remaining 80% passes unabsorbed into the colon where it can increase the risk of pathogen growth and gut inflammation. Alternatively, ferrous bisglycinate is a newer supplemental form of iron. This amino acid chelate has 2-4x higher bioavailability than ferrous sulfate and is associated with fewer GI side-effects. In view of WHO policy and risks of supplementation, there is a need to determine the potential for harm, and if novel forms of iron supplements are safer.

Detailed Description
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The World Health Organization (WHO) set a Global Nutrition Target to reduce anemia in women of reproductive age by 50% by 2025. In 2016, the WHO implemented a global policy recommending oral iron supplementation (60 mg daily for 12 weeks) for all women where anemia prevalence is more than 40%, such as in Cambodia. However, recent studies have shown the prevalence of iron deficiency to be low in Cambodian women. If iron deficiency is not the cause of anemia, then iron supplementation will not be effective at treating it. Further, iron supplementation may be harmful in some individuals, especially those with anemia caused by genetic blood disorders (which are common in Cambodia), as these individuals are already at an increased risk of iron overload. The risks are made greater by the fact that the type of iron that is commonly used in supplements (ferrous sulfate) is poorly absorbed. Typically, less than 20% is absorbed in the gut; the remaining 80% is unabsorbed in the colon where it can increase the risk of pathogen growth and gut inflammation. To investigate the safety of untargeted iron supplementation, we will undertake a new study in Cambodia, where we will evaluate a newer type of iron supplement that may be absorbed better, and thus, safer than the conventional type. We will recruit non-pregnant women (18-45 years) and ask them to take one of the two forms of iron (ferrous sulfate or ferrous bisglycinate) or a placebo for 12 weeks (in line with the WHO global policy). We will measure hemoglobin and ferritin levels, which are markers of anemia and iron status, and markers of gut inflammation and gut pathogen abundance, before and after the intervention. This study will contribute to the evidence for safe and effective iron supplementation for women worldwide.

Official Title
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Is Iron Supplementation Harmful in Populations Where Iron Deficiency is Not the Cause of Anemia? A 12 Week Randomized Controlled Trial in Cambodia

Conditions
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Anemia, Anemia, Iron Deficiency, Intestinal Inflammation, Inflammation, Intestine; Complaints

Intervention / Treatment
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* Dietary Supplement: Ferrous sulfate
* Dietary Supplement: Ferrous Bisglycinate
* Dietary Supplement: Placebo of microcrystalline cellulose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: apparently healthy consent to participate in the study and provide blood, flocked rectal swab and stool samples expected to reside in the study location for the study period. Exclusion Criteria: any known illness or disease pregnant taking antibiotics, non-steroidal anti-inflammatory drugs, dietary supplements, or vitamin and mineral supplements in the previous 12 weeks.

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: Parallel Assignment
Interventional Model Description: 12-week double-blind, three-arm, placebo-controlled randomized controlled trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Ferrous Sulfate<br>Iron will be given orally in the form of tablets. A supplement of 60 mg will be taken daily for 12 weeks. World Health Organization standard dose and commonly used form of iron. | Dietary Supplement: Ferrous sulfate<br>* 60 mg elemental iron as ferrous sulfate<br>* Other names: Iron(II) sulfate;|
| Experimental: Ferrous Bisglycinate<br>Iron will be given orally in the form of tablets. A supplement of 18 mg will be taken daily for 12 weeks. Ferrous bisglycinate has a bioavailability 2-4x greater than ferrous sulfate. | Dietary Supplement: Ferrous Bisglycinate<br>* 18 mg elemental iron as ferrous bisglycinate<br>* Other names: Ferrous Bis-glycinate;|
| Placebo Comparator: Placebo<br>Placebo will be given orally in the form of tablets as a control made of microcrystalline cellulose. | Dietary Supplement: Placebo of microcrystalline cellulose<br>* placebo<br>* Other names: Control;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum Ferritin | Serum ferritin concentration (µg/l) at 12 weeks | 12 weeks | 
| Fecal calprotectin | Fecal calprotectin concentration (mg/kg stool) at 12 weeks as a measure of gut inflammation. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gut pathogen abundance | Real-time PCR nucleic acid amplification assay with an enteric bacterial panel. | 12 weeks | 
| Gut parasite abundance | Real-time PCR nucleic acid amplification assay with an enteric parasite panel. | 12 weeks | 
| DNA damage | DNA damage will be assessed by measuring DNA single-strand breaks, indicated by olive tail movement with use of alkali single-cell gel electrophoresis (Comet assay). | 12 weeks | 
| Alpha-1 acid glycoprotein (AGP, g/l) |  | 12 weeks | 
| C-reactive protein (CRP, mg/l) |  | 12 weeks | 
| Hemoglobin (g/L) |  | 12 weeks | 
| Folate (ng/ml) |  | 12 weeks | 
| Vitamin B12 (pmol/l) |  | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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anemia, gut inflammation, iron deficiency, iron, iron supplementation