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NCT Number: NCT04017598

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

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.

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Key information

Conditions

Anemia, Iron Deficiency Anemia Anemia, Hypochromic Anemia, Iron-Deficiency Hematologic Diseases Hemic and Lymphatic Diseases Inflammation Intestinal Inflammation Intestine; Complaints Iron Deficiencies Iron Metabolism Disorders Metabolic Diseases Nutritional and Metabolic Diseases Pathologic Processes Pathological Conditions, Signs and Symptoms

Age range

18 year–45 year

Sex eligibility

Female

Study type

Interventional

Phase

Phase 4

Primary location

Prey Kuy, Srayov and Tboung Krapeu Health Centres

Kampong Thom, Cambodia

About this study

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.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Ferrous Sulfate

Dietary Supplement

60 mg elemental iron as ferrous sulfate

Other names: iron sulfate, ferrous sulphate, iron sulphate, Iron(II) sulfate

Ferrous Bisglycinate

Dietary Supplement

18 mg elemental iron as ferrous bisglycinate

Other names: iron amino acid chelate, Iron glycinate, Bisglycine iron(II) salt, Iron(II) bisglycinate, Ferrous Bis-glycinate

Placebo of microcrystalline cellulose

Dietary Supplement

placebo

Other names: Control

Primary outcomes

  1. Serum Ferritin

    Time frame: 12 weeks

    Serum ferritin concentration (µg/l) at 12 weeks

  2. Fecal calprotectin

    Time frame: 12 weeks

    Fecal calprotectin concentration (mg/kg stool) at 12 weeks as a measure of gut inflammation.

Secondary outcomes

  1. Gut pathogen abundance

    Time frame: 12 weeks

    Real-time PCR nucleic acid amplification assay with an enteric bacterial panel.

  2. Gut parasite abundance

    Time frame: 12 weeks

    Real-time PCR nucleic acid amplification assay with an enteric parasite panel.

  3. DNA damage

    Time frame: 12 weeks

    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).

  4. Alpha-1 acid glycoprotein (AGP, g/l)

    Time frame: 12 weeks

  5. C-reactive protein (CRP, mg/l)

    Time frame: 12 weeks

  6. Hemoglobin (g/L)

    Time frame: 12 weeks

  7. Folate (ng/ml)

    Time frame: 12 weeks

  8. Vitamin B12 (pmol/l)

    Time frame: 12 weeks

Other outcomes

  1. Reported side effects

    Time frame: Continuous over 12 weeks

    (e.g., gastrointestinal pain) as a quality of life measure.

  2. Genetic hemoglobinopathies

    Time frame: Baseline

    Genotyping to detect the presence of the most common hemoglobinopathies

  3. Gut Pathogen abundance

    Time frame: 12 weeks

    Whole metagenome shotgun 16S ribosomal RNA sequencing will be conducted on fecal samples, in order to validate the method against the established BD MAX panel in a subset of 150 women from our trial (50 from each study arm).

Sponsors and collaborators

Lead sponsor

University of British Columbia

Other

Collaborators

  • BC Children's Hospital Research Institute
  • Helen Keller International
  • NCHADS - Ministry of Health of Cambodia
  • The National Institute of Public Health Laboratory, Phnom Penh

Registry information

Official study title

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

Important dates

Study start
2019
Primary completion
2020
Study completion
2023
First posted
Jul 12, 2019
Registry last updated
May 8, 2024

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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