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

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ClinicalTrials.gov Identifier: NCT04017598
Recruitment Status : Not yet recruiting
First Posted : July 12, 2019
Last Update Posted : January 18, 2020
Sponsor:
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
Information provided by (Responsible Party):
Crystal Karakochuk, University of British Columbia

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.


Condition or disease Intervention/treatment Phase
Anemia, Iron Deficiency Anemia Intestinal Inflammation Inflammation Intestine; Complaints Dietary Supplement: Ferrous sulfate Dietary Supplement: Ferrous Bisglycinate Dietary Supplement: Placebo of microcrystalline cellulose Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 480 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: 12-week double-blind, three-arm, placebo-controlled randomized controlled trial
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: 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
Primary Purpose: Treatment
Official Title: Is Iron Supplementation Harmful in Populations Where Iron Deficiency is Not the Cause of Anemia? A 12 Week Randomized Controlled Trial in Cambodia
Estimated Study Start Date : January 2020
Estimated Primary Completion Date : June 2020
Estimated Study Completion Date : June 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Anemia Iron

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 Name: Control




Primary Outcome Measures :
  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 Outcome Measures :
  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 Outcome Measures:
  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).



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Accepts Healthy Volunteers:   Yes
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04017598


Contacts
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Contact: Crystal Karakochuk, PhD 1 604 822 0421 crystal.karakochuk@ubc.ca

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

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Responsible Party: Crystal Karakochuk, Principle Investigator, University of British Columbia
ClinicalTrials.gov Identifier: NCT04017598    
Other Study ID Numbers: H18-02610
First Posted: July 12, 2019    Key Record Dates
Last Update Posted: January 18, 2020
Last Verified: January 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: There is not a plan to make IPD available.

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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
Keywords provided by Crystal Karakochuk, University of British Columbia:
anemia
gut inflammation
iron deficiency
iron
iron supplementation
Additional relevant MeSH terms:
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Anemia
Anemia, Iron-Deficiency
Inflammation
Pathologic Processes
Hematologic Diseases
Anemia, Hypochromic
Iron Metabolism Disorders
Metabolic Diseases
Iron
Glycine
Trace Elements
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs
Glycine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action