Anemia, Iron DeficiencyPhase 4NCT04017598
Potential Harms of Untargeted Iron Supplementation in Cambodia Where Iron Deficiency is Not the Cause of Anemia
A Phase 4 study testing Ferrous sulfate and Ferrous Bisglycinate in people with Anemia, Iron Deficiency and Anemia, run by University of British Columbia at 1 site in Cambodia.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 45 years, women onlyHealthy volunteers can take part
- Conditions the study is for
- Anemia, Iron Deficiency, Anemia, Intestinal Inflammation
- What is being tested?
- Ferrous sulfate and Ferrous Bisglycinate
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 480 participants
- Where
- 1 siteCambodia
- Study dates
- 10 Dec 2019to 1 Dec 2023
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 45 years
- Women only
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
Cambodia1 site
Prey Kuy, Srayov and Tboung Krapeu Health Centres
Kampong Thom
About this study
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
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.
Read the 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.
- Conditions
- Anemia, Iron Deficiency, Anemia, Intestinal Inflammation, Inflammation, Intestine; Complaints
- Being tested
- Ferrous sulfate, Ferrous Bisglycinate, Placebo of microcrystalline cellulose
- Keywords
- anemia, gut inflammation, iron deficiency, iron, iron supplementation
- Medical subject headings
- Anemia, Iron-Deficiency, Anemia, Inflammation, Iron Deficiencies
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Ferrous sulfateDietary supplement
Also called iron sulfate, ferrous sulphate, iron sulphate, Iron(II) sulfate
60 mg elemental iron as ferrous sulfate
Ferrous BisglycinateDietary supplement
Also called iron amino acid chelate, Iron glycinate, Bisglycine iron(II) salt, Iron(II) bisglycinate
18 mg elemental iron as ferrous bisglycinate
Placebo of microcrystalline celluloseDietary supplement
Also called Control
placebo
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Dietary Supplement: Ferrous Bisglycinate |
| Placebo | Placebo comparator | Placebo will be given orally in the form of tablets as a control made of microcrystalline cellulose. Receives: Dietary Supplement: Placebo of microcrystalline cellulose |
What is being measured
The primary outcome is the main question the study is designed to answer.
Serum Ferritin
Serum ferritin concentration (µg/l) at 12 weeks
Measured: 12 weeks
Fecal calprotectin
Fecal calprotectin concentration (mg/kg stool) at 12 weeks as a measure of gut inflammation.
Measured: 12 weeks
Secondary outcomes (8)
Gut pathogen abundance
Real-time PCR nucleic acid amplification assay with an enteric bacterial panel.
Measured: 12 weeks
Gut parasite abundance
Real-time PCR nucleic acid amplification assay with an enteric parasite panel.
Measured: 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).
Measured: 12 weeks
Alpha-1 acid glycoprotein (AGP, g/l)
Measured: 12 weeks
C-reactive protein (CRP, mg/l)
Measured: 12 weeks
Hemoglobin (g/L)
Measured: 12 weeks
Folate (ng/ml)
Measured: 12 weeks
Vitamin B12 (pmol/l)
Measured: 12 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Jul 2019
- Study start10 Dec 2019
- Primary completion30 May 2020
- Study completion1 Dec 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Anemia, Iron DeficiencyStudies of the same condition, open and under way.
- More trials run by University of British ColumbiaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- 12-week double-blind, three-arm, placebo-controlled randomized controlled trial
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 480 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of British Columbia
- Sponsor type
- University, hospital or other
- 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
- Responsible party
- Principal investigator, Crystal Karakochuk, University of British Columbia
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04017598
- Sponsor's protocol ID
- H18-02610
- Status last verified
- May 2024
- First submitted
- 4 Jul 2019
- Last updated
- 8 May 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: There is not a plan to make IPD available.
Publications
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.
PubMed 41082982Fischer 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.
PubMed 37271416Finlayson-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.
PubMed 37199608Fischer 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.
PubMed 32801202
Study at a glance
From the registry record, last updated by the sponsor on 8 May 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT04017598
- Acronym / sponsor ID
- H18-02610
- Conditions
- Anemia, Iron Deficiency, Anemia, Intestinal Inflammation, Inflammation, Intestine; Complaints
- Keywords
- anemia, gut inflammation, iron deficiency, iron, iron supplementation
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 480 participants (actual)
- Lead sponsor
- University of British ColumbiaUniversity, hospital or other
- 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
- Study start
- 10 Dec 2019 (actual)
- Primary completion
- 30 May 2020 (actual)
- Study completion
- 1 Dec 2023 (actual)
- First posted
- 12 Jul 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 3
- Model description
- 12-week double-blind, three-arm, placebo-controlled randomized controlled trial
| Arm | Type | Receives |
|---|---|---|
| Ferrous Sulfate | Active comparator | Dietary Supplement: Ferrous sulfateIron 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. |
| Ferrous Bisglycinate | Experimental | Dietary Supplement: Ferrous BisglycinateIron 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. |
| Placebo | Placebo comparator | Dietary Supplement: Placebo of microcrystalline cellulosePlacebo will be given orally in the form of tablets as a control made of microcrystalline cellulose. |
Who may qualify
- Ages
- 18 to 45 years
- Sex
- Female only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (3 listed)
- 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.
Key exclusion criteria (3 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Ferrous sulfateAlso: iron sulfate, ferrous sulphate, iron sulphate, Iron(II) sulfate60 mg elemental iron as ferrous sulfate | Dietary supplement | Ferrous Sulfate |
| Ferrous BisglycinateAlso: iron amino acid chelate, Iron glycinate, Bisglycine iron(II) salt, Iron(II) bisglycinate18 mg elemental iron as ferrous bisglycinate | Dietary supplement | Ferrous Bisglycinate |
| Placebo of microcrystalline celluloseAlso: Controlplacebo | Dietary supplement | Placebo |
Primary outcome
Serum Ferritin
Time frame: 12 weeks
Serum ferritin concentration (µg/l) at 12 weeks
Fecal calprotectin
Time frame: 12 weeks
Fecal calprotectin concentration (mg/kg stool) at 12 weeks as a measure of gut inflammation.
8 secondary outcomes
Gut pathogen abundance
Time frame: 12 weeks
Gut parasite abundance
Time frame: 12 weeks
DNA damage
Time frame: 12 weeks
Alpha-1 acid glycoprotein (AGP, g/l)
Time frame: 12 weeks
C-reactive protein (CRP, mg/l)
Time frame: 12 weeks
Hemoglobin (g/L)
Time frame: 12 weeks
Folate (ng/ml)
Time frame: 12 weeks
Vitamin B12 (pmol/l)
Time frame: 12 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 May 2024.
- Derived from this study: PubMed 41082982Cirigliano 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.
- Derived from this study: PubMed 37271416Fischer 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.
- Derived from this study: PubMed 37199608Finlayson-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.
- Derived from this study: PubMed 32801202Fischer 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.
- Individual participant dataSharing planned: No. There is not a plan to make IPD available.
Related trials for Anemia, Iron Deficiency
RecruitingPhase 4
The Effects of Ferric Derisomaltose in Patients With Acute Heart Failure and Iron Deficiency on Exercise Capacity and Quality of Life(COREVIVE-HFrEF)
Heart Failure With Reduced Ejection Fraction, Iron Deficiency
RecruitingPhase 4
The Effects of Ferric Derisomaltose in Patients With Acute Heart Failure and Iron Deficiency on Exercise Capacity and Quality of Life
Heart Failure With Preserved Ejection Fraction, Iron Deficiencies
Recruiting
The Effects of Iron Treatment on Vaccine Immunogenicity in Kenyan Infants With Iron Deficiency
Iron Deficiencies
RecruitingPhase 4
The Effects of Low-Dose Versus High-Dose Intravenous IRON Therapy With Ferric DerisomaltOSE in Patients With Chronic Heart Failure and Iron Deficiency
Heart Failure, Iron Deficiency
Enrolling by invitationObservational study
Long-term Impacts of Psychosocial Stimulation and Iron Supplementation
Iron Deficiency Anemia, Parenting Intervention
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Ferrous sulfate and Ferrous Bisglycinate in people with Anemia, Iron Deficiency and Anemia, run by University of British Columbia at 1 site in Cambodia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 8 May 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Cambodia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Serum Ferritin (time frame: 12 weeks). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04017598, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 May 2024.