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

NCT04017598 | Completed Phase 4 DMC

• 1 other identifier: H18-02610
• Study Type: interventional
• Target: 480
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

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

Keywords

anemia; gut inflammation; iron deficiency; iron; iron supplementation

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (8)

• Gut pathogen abundance

  12 weeks

• Gut parasite abundance

  12 weeks

• DNA damage

  12 weeks

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

  12 weeks

• C-reactive protein (CRP, mg/l)

  12 weeks

Other Outcomes (3)

• Reported side effects

  Continuous over 12 weeks

• Genetic hemoglobinopathies

  Baseline

• Gut Pathogen abundance

  12 weeks

Study Arms (3)

Ferrous Sulfate

ACTIVE COMPARATOR

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

Ferrous Bisglycinate

EXPERIMENTAL

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

Placebo

PLACEBO COMPARATOR

Placebo will be given orally in the form of tablets as a control made of microcrystalline cellulose.

Dietary Supplement: Placebo of microcrystalline cellulose

Interventions

Ferrous sulfate DIETARY_SUPPLEMENT

60 mg elemental iron as ferrous sulfate

Also known as: iron sulfate, ferrous sulphate, iron sulphate, Iron(II) sulfate

Ferrous Sulfate

Ferrous Bisglycinate DIETARY_SUPPLEMENT

18 mg elemental iron as ferrous bisglycinate

Also known as: iron amino acid chelate, Iron glycinate, Bisglycine iron(II) salt, Iron(II) bisglycinate, Ferrous Bis-glycinate

Ferrous Bisglycinate

Placebo of microcrystalline cellulose DIETARY_SUPPLEMENT

placebo

Also known as: Control

Placebo

Eligibility Criteria

• Age: 18 Years - 45 Years
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

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

Study Sites (1)

Prey Kuy, Srayov and Tboung Krapeu Health Centres

Kampong Thom, Cambodia

Location

Related Publications (4)

• Cirigliano E, Saint A, Pei LX, Wong CW, Wang S, Fischer JA, Kroeun H, Karakochuk CD. Iron Supplementation with Ferrous Sulfate or Ferrous Bisglycinate for 12 Weeks Does Not Influence Group B Streptococcus Colonization in Cambodian Women: A Secondary Analysis of a Randomized Controlled Trial. J Nutr. 2025 Dec;155(12):4264-4270. doi: 10.1016/j.tjnut.2025.10.014. Epub 2025 Oct 11.

  PMID: 41082982 DERIVED

• Fischer JAJ, Pei LX, Elango R, Hou K, Goldfarb DM, Karakochuk CD. Is a Lower Dose of More Bioavailable Iron (18-mg Ferrous Bisglycinate) Noninferior to 60-mg Ferrous Sulfate in Increasing Ferritin Concentrations While Reducing Gut Inflammation and Enteropathogen Detection in Cambodian Women? A Randomized Controlled Noninferiority Trial. J Nutr. 2023 Aug;153(8):2453-2462. doi: 10.1016/j.tjnut.2023.05.029. Epub 2023 Jun 2.

  PMID: 37271416 DERIVED

• Finlayson-Trick E, Nearing J, Fischer JA, Ma Y, Wang S, Krouen H, Goldfarb DM, Karakochuk CD. The Effect of Oral Iron Supplementation on Gut Microbial Composition: a Secondary Analysis of a Double-Blind, Randomized Controlled Trial among Cambodian Women of Reproductive Age. Microbiol Spectr. 2023 Jun 15;11(3):e0527322. doi: 10.1128/spectrum.05273-22. Epub 2023 May 18.

  PMID: 37199608 DERIVED

• Fischer JA, Pei LX, Goldfarb DM, Albert A, Elango R, Kroeun H, Karakochuk CD. Is untargeted iron supplementation harmful when iron deficiency is not the major cause of anaemia? Study protocol for a double-blind, randomised controlled trial among non-pregnant Cambodian women. BMJ Open. 2020 Aug 16;10(8):e037232. doi: 10.1136/bmjopen-2020-037232.

  PMID: 32801202 DERIVED

MeSH Terms

Conditions

Anemia, Iron-Deficiency; Anemia; Inflammation; Iron Deficiencies

Interventions

ferrous sulfate; Iron-Dextran Complex; ferrous bisglycinate; iron(III) N,N'-bis((5-bromo-2-hydroxyphenyl)glycinate); Salts

Condition Hierarchy (Ancestors)

Anemia, Hypochromic; Hematologic Diseases; Hemic and Lymphatic Diseases; Iron Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Coordination Complexes; Organic Chemicals; Dextrans; Glucans; Polysaccharides; Carbohydrates; Inorganic Chemicals

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The manufacturers of the tablets (Dr. Simon Wood, Natural Factors) will be responsible for allocation concealment of the three tablet formulations at time of packaging. All tablets will be non-distinguishable in size, colour, and packaging. Trial investigators, research staff, and participants will all be blinded to the assigned interventions
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principle Investigator

Model Details: 12-week double-blind, three-arm, placebo-controlled randomized controlled trial

Study Record Dates

• First Submitted: July 4, 2019
• First Posted: July 12, 2019
• Study Start: December 10, 2019
• Primary Completion: May 30, 2020
• Study Completion: December 1, 2023
• Last Updated: May 8, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)