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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Inflammation; Anemia; Anemia, Iron Deficiency; Intestinal Inflammation; Intestine; Complaints
• Intervention / Treatment: Dietary supplement: Ferrous sulfate; Dietary supplement: Ferrous Bisglycinate; Dietary supplement: Placebo of microcrystalline cellulose

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 480
• Phase: Phase 4

Contacts and Locations

Study Locations

• Cambodia
  • Kampong Thom, Cambodia
    • Prey Kuy, Srayov and Tboung Krapeu Health Centres

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 43 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Ferrous Sulfate; 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; 60 mg elemental iron as ferrous sulfate; Other Names: iron sulfate; ferrous sulphate; iron sulphate; Iron(II) sulfate
Experimental: Ferrous Bisglycinate; 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; 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 Comparator: Placebo; Placebo will be given orally in the form of tablets as a control made of microcrystalline cellulose.	Dietary supplement: Placebo of microcrystalline cellulose; placebo; Other Names: Control

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reported side effects	(e.g., gastrointestinal pain) as a quality of life measure.	Continuous over 12 weeks
Genetic hemoglobinopathies	Genotyping to detect the presence of the most common hemoglobinopathies	Baseline
Gut Pathogen abundance	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).	12 weeks

Collaborators and Investigators

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

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 10, 2019
• Primary Completion (Actual): May 30, 2020
• Study Completion (Anticipated): July 1, 2023

Study Registration Dates

• First Submitted: July 4, 2019
• First Submitted That Met QC Criteria: July 10, 2019
• First Posted (Actual): July 12, 2019

Study Record Updates

• Last Update Posted (Actual): April 13, 2023
• Last Update Submitted That Met QC Criteria: April 11, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: anemia; iron; iron deficiency; iron supplementation; gut inflammation
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Hematologic Diseases; Anemia, Hypochromic; Iron Metabolism Disorders; Inflammation; Anemia, Iron-Deficiency; Anemia; Physiological Effects of Drugs; Trace Elements; Micronutrients; Iron
• Other Study ID Numbers: H18-02610

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: There is not a plan to make IPD available.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No