- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02481375
Is Iron Deficiency the Cause of Anemia Among Women in Cambodia?
Is Iron Deficiency the Cause of Anemia Among Women of Reproductive Age in Cambodia? A 2 x 2 Factorial Double Blind Randomized Controlled Trial of Oral Iron and Multiple Micronutrient Supplementation
Globally, the most common cause of anemia is thought to be iron deficiency anemia (IDA). This was assumed to be the major cause of anemia in Cambodia, because Cambodian diets, which consist mainly of rice, lack iron-rich animal food sources. However, our findings from a previous study in Cambodia (a Canadian government funded study investigating multiple interventions to improve food and nutrition security) showed that IDA is almost non-existent and challenges this assumption. In a cross-sectional survey of 450 women from rural Cambodia, only 1.0% had Hb and ferritin levels indicative of IDA (Hb <120 g/L and ferritin <15 μg/L). A national survey conducted by UNICEF in 2014 found similarly low rates of IDA (Dr. Arnaud Laillou, UNICEF Cambodia). Further, other micronutrients known to be associated with anemia were also low (<3%) including folate and vitamins B12 and B6.
In addition, 54% of the Prey Veng women had a genetic Hb disorder (e.g., α-thalassemias), which are inherited diseases that can result in a defective Hb structure and/or impair Hb production, either of which can reduce Hb concentration and increase the risk of anemia. Further, genetic Hb disorders cause ferritin and soluble transferrin receptor (sTfR) concentrations to increase, which reduce the diagnostic sensitivity of these biomarkers to identify IDA.
In 2011, the Cambodian Ministry of Health (MOH) recommended weekly iron and folic acid (IFA) supplementation for all women of reproductive age, consistent with WHO guidelines. However, if iron deficiency is not a major cause of anemia, then at best supplementation is a waste of valuable resources and at worst could cause harm. Further, the justification for provision of multiple micronutrients among this population has not yet been proven, despite the push from some organizations such as the WHO. There is an urgent need to conduct a trial to clarify whether iron or other micronutrient deficiencies are a major cause of anemia in Cambodia.
Research Objectives:
- To compare Hb concentration (g/L) after 12-weeks of supplementation in women to determine if iron significantly improves Hb concentration, compared to a placebo;
- To compare Hb concentration (g/L) across the four groups (multiple micronutrients with iron, multiple micronutrients without iron, iron alone, and placebo) after 12-weeks; and
- To determine which of the hematological indicators (ferritin, sTfR, reticulocyte count and hepcidin) have the strongest diagnostic ability to predict responsiveness to iron therapy after 12-weeks using receiver operating characteristic (ROC) analyses.
Methods: A 2 x 2 factorial randomized controlled trial will be conducted over 12 weeks. A total of ~800 women (18-45 y) with mild or moderate anemia will be recruited and randomized to 1 of 4 groups: multiple micronutrients with iron, multiple micronutrients without iron, iron alone or placebo. Blood will be collected at baseline and at 1 and 12 weeks after the intervention and assessed for Hb, hematological biomarkers, inflammation and genetic Hb disorders. The investigators will use a general linear model to measure differences in Hb concentration across the four groups after the intervention. Receiver operating characteristic curves will be used to determine the diagnostic ability of the multiple hematological indicators to predict responsiveness to iron therapy.
Study Overview
Status
Intervention / Treatment
Detailed Description
Background:
Anemia is a severe public health problem in Cambodia, affecting ~44% of women of reproductive age. Defined as a hemoglobin (Hb) concentration below 120 g/L, anemia can increase the risk of adverse pregnancy outcomes and impair work capacity and productivity. The potential causes of anemia are poor nutrition (e.g. micronutrient deficiencies), genetic Hb disorders (e.g. thalassemia), and inflammation and disease.
Globally, the most common cause of anemia is thought to be iron deficiency anemia (IDA). This was assumed to be the major cause of anemia in Cambodia, because Cambodian diets, which consist mainly of rice, lack iron-rich animal food sources. However, our findings from a previous study in Cambodia (a Canadian government funded study investigating multiple interventions to improve food and nutrition security) showed that IDA is almost non-existent and challenges this assumption. In a cross-sectional survey of 450 women from rural Cambodia, only 1.0% had Hb and ferritin levels indicative of IDA (Hb <120 g/L and ferritin <15 μg/L). A national survey conducted by UNICEF in 2014 found similarly low rates of IDA (Dr. Arnaud Laillou, UNICEF Cambodia). Further, other micronutrients known to be associated with anemia were also low (<3%) including folate and vitamins B12 and B6. On the other hand, other nutrients known to be associated with anemia such as zinc and riboflavin deficiencies were prevalent (30% and 82%, respectively). In addition, 54% of the Prey Veng women had a genetic Hb disorder (e.g., α-thalassemias), which are inherited diseases that can result in a defective Hb structure and/or impair Hb production, either of which can reduce Hb concentration and increase the risk of anemia. Further, genetic Hb disorders cause ferritin and soluble transferrin receptor (sTfR) concentrations to increase, which reduce the diagnostic sensitivity of these biomarkers to identify IDA.
In 2011, the Cambodian Ministry of Health (MOH) recommended weekly iron and folic acid (IFA) supplementation for all women of reproductive age, consistent with WHO guidelines. However, if iron deficiency is not a major cause of anemia, then at best supplementation is a waste of valuable resources and at worst could cause harm. Further, the justification for provision of multiple micronutrients among this population has not yet been proven, despite the push from some organizations such as the WHO. There is an urgent need to conduct a trial to clarify whether iron or other micronutrient deficiencies are a major cause of anemia in Cambodia.
Research Hypotheses:
The iron-supplemented group will have a significantly higher mean Hb concentration than the placebo group after 12-weeks, indicating a higher prevalence of iron deficiency than suggested by ferritin and sTfR biomarkers at baseline. The multiple micronutrients with iron group will have a significantly higher mean Hb concentration than the iron alone-supplemented group, indicating that the addition of other micronutrients confer a benefit in reducing anemia. Reticulocyte count is the most sensitive biomarker to predict the responsiveness to iron therapy.
Research Goals and Objectives:
Goal 1. To determine if iron deficiency exists among women in Cambodia, where genetic Hb disorders and inflammation are prevalent, by conducting a randomized controlled trial of iron supplementation.
Objective 1: To compare Hb concentration (g/L) after 12-weeks of supplementation in women to determine if iron significantly improves Hb concentration, compared to a placebo.
Goal 2: To determine if the addition of other micronutrients confers any additional benefit to iron supplementation, by conducting a 2 x 2 factorial study design.
Objective 2: To compare Hb concentration (g/L) across the four groups (multiple micronutrients with iron, multiple micronutrients without iron, iron alone, and placebo) after 12-weeks.
Goal 3. To investigate multiple biomarkers of iron deficiency to determine which is most sensitive and specific to predict the response to iron or multiple micronutrient with iron supplementation.
Objective 3: To determine which of the hematological indicators (baseline values for ferritin, sTfR, reticulocyte count and hepcidin) have the strongest diagnostic ability to predict responsiveness to iron therapy after 12-weeks using receiver operating characteristic (ROC) analyses.
Study Design:
A 2 x 2 factorial double blind randomized controlled trial will be conducted over 12 weeks. A total of ~800 women (18-45 y) with anemia will be recruited and randomized to 1 of 4 groups: multiple micronutrients with iron, multiple micronutrients without iron, iron alone or placebo.
Population and Setting: Cambodian women will be recruited to local health centers using convenience sampling from 4 randomly selected villages in a peri-urban area of Kampong Chhnang province. This province is ~1.5 hours outside of the capital city of Phnom Penh.
Randomization: Women will be randomized 1:1 by a computer-generated random list to one of four interventions (n=200 each group). Randomization to either a treatment or control group will reduce bias and confounding factors, which may affect the Hb response (outcome). The manufacturers of the gel capsules will be responsible for blinding the four interventions at time of capsule packaging and will retain confidentiality of capsule contents until the time of study completion.
Methods:
Blood will be collected at baseline, and at 1 and 12 weeks after the intervention and assessed for Hb, hematological biomarkers (reticulocyte count, MCV, RDW, hepcidin), micronutrients and iron biomarkers (vitamin B12, folate, zinc, riboflavin, ferritin, sTfR, RBP) inflammation (AGP and CRP) and genetic Hb disorders. We will use a general linear model to measure differences in Hb concentration across the four groups after the intervention. Receiver operating characteristic curves will be used to determine the diagnostic ability of the multiple hematological indicators to predict responsiveness to iron therapy.
Implications: This translational research is urgently required in Cambodia to build the evidence needed to inform the Ministry of Health on strategies, policy and programs to reduce, prevent and treat anemia among women in Southeast Asia (~300,000,000) and among Southeast Asian immigrants in Canada (who will number ~450,000 by 2031).
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
-
-
Kampong Chhnang Province
-
Kampong Chhnang, Kampong Chhnang Province, Cambodia
- Kampong Chhnang province
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- women between 18-45 years
- healthy except for Hb = or <117 g/L
- consent to participate in the study.
Exclusion Criteria:
- women with Hb >117 g/L
- women who are currently pregnant
- women who are taking medications, including any dietary supplements.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Diagnostic
- Allocation: Randomized
- Interventional Model: Factorial Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Multiple micronutrients with iron
Multiple micronutrient formulations were based on the UNICEF/WHO/UNU standard formulation for pregnant and lactating women (UNIMMAP) with increased iron (from 30 mg to 60 mg elemental iron) for comparability to the iron only group (60 mg). This formulation has 15 micronutrients including iron. Women will receive the multiple micronutrient with iron for 12 weeks. |
12-wk supplementation of vitamin A, B1, B2, B6 ,B12, D, E, niacin, folic acid, zinc, copper, selenium, iodine
12-wk supplementation of iron
Other Names:
|
Active Comparator: Multiple micronutrients without iron
This formulation has the 14 micronutrients included in the UNIMMAP formulation, but does not include iron. Women will receive the multiple micronutrient without iron for 12 weeks. |
12-wk supplementation of vitamin A, B1, B2, B6 ,B12, D, E, niacin, folic acid, zinc, copper, selenium, iodine
|
Active Comparator: Iron only
This formulation only has 60 mg elemental iron. Women will receive iron for 12 weeks. |
12-wk supplementation of iron
Other Names:
|
Placebo Comparator: Placebo
This formulation is a placebo. Women will receive a placebo for 12 weeks. |
12-wk supplementation of placebo
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Hemoglobin Levels at 12-weeks. Marginal Means (95% CI).
Time Frame: 12-weeks of intervention
|
Marginal means (95% CI) at 12-weeks using a generalized mixed-effects model with adjustments for baseline values and village clusters.
Multiple imputation was used to impute n=49 missing values for hemoglobin at endline.
|
12-weeks of intervention
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Study Chair: Kroeun Hou, MPH, Helen Keller International, Cambodia
- Study Chair: Sophonneary Prak, MPH, National Maternal and Child Health Center, Ministry of Health, Cambodia
- Study Chair: Crystal Karakochuk, MSc, PhD(c), University of British Columbia
Publications and helpful links
General Publications
- Williams BA, Cochrane KM, Fischer JAJ, Aljaadi AM, McAnena L, Ward M, McNulty H, Kroeun H, Green TJ, Whitfield KC, Karakochuk CD. The Homozygous Hemoglobin EE Variant Is Associated with Poorer Riboflavin Status in Cambodian Women of Reproductive Age. J Nutr. 2020 Jul 1;150(7):1943-1950. doi: 10.1093/jn/nxaa119.
- Holmes JB, Kroeun H, Houghton LA, Gibson RS, Harding KB, De-Regil LM, Kraemer K, Barr SI, Karakochuk CD. Including 60 mg Elemental Iron in a Multiple Micronutrient Supplement Blunts the Increase in Serum Zinc after 12 Weeks of Daily Supplementation in Predominantly Anemic, Nonpregnant Cambodian Women of Reproductive Age. J Nutr. 2019 Sep 1;149(9):1503-1510. doi: 10.1093/jn/nxz097.
- Karakochuk CD, Barker MK, Whitfield KC, Barr SI, Vercauteren SM, Devlin AM, Hutcheon JA, Houghton LA, Prak S, Hou K, Chai TL, Stormer A, Ly S, Devenish R, Oberkanins C, Puhringer H, Harding KB, De-Regil LM, Kraemer K, Green TJ. The effect of oral iron with or without multiple micronutrients on hemoglobin concentration and hemoglobin response among nonpregnant Cambodian women of reproductive age: a 2 x 2 factorial, double-blind, randomized controlled supplementation trial. Am J Clin Nutr. 2017 Jul;106(1):233-244. doi: 10.3945/ajcn.116.140996. Epub 2017 May 10.
- Rappaport AI, Barr SI, Green TJ, Karakochuk CD. Variation in haemoglobin measurement across different HemoCue devices and device operators in rural Cambodia. J Clin Pathol. 2017 Jul;70(7):615-618. doi: 10.1136/jclinpath-2017-204351. Epub 2017 Mar 8.
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- H15-00933
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Inflammation
-
University of EdinburghUmeå UniversityCompletedSystemic Inflammation | Respiratory InflammationSweden
-
University of AarhusAarhus University Hospital; University of CopenhagenCompletedSystemic Inflammation | Airway InflammationDenmark
-
Sykehuset TelemarkRikshospitalet University Hospital; Helse Sor-OstCompletedAirway Inflammation | Peripheral Blood Inflammation Markers | Cement Dust ExposureNorway
-
Assistance Publique - Hôpitaux de ParisCompletedDigestive InflammationFrance
-
Pamukkale UniversityCompletedPeriodontal InflammationTurkey
-
Universidade Federal do ParaCompleted
-
KLE Society's Institute of Dental SciencesCompletedRegenerative InflammationIndia
-
Fondation Ophtalmologique Adolphe de RothschildCompleted
-
Singapore National Eye CentreCompletedIntraocular Inflammation in ChildrenSingapore
Clinical Trials on Multiple micronutrients
-
Makerere UniversityThe Norwegian Programme for Development, Research and Higher EducationCompleted
-
Universiti Putra MalaysiaCompletedAnemia | Wasting | Underweight | Stunted GrowthMalaysia
-
Galapagos NVCompleted
-
Ege UniversityCompleted
-
Galapagos NVCompleted
-
Dr Cipto Mangunkusumo General HospitalRecruitingMaternal-Fetal Relations | Nutrition, Healthy | Nutritional Deficiency | Maternal Care Patterns | Perinatal Outcome | Maternal OutcomeIndonesia
-
University of OxfordZogenix International Limited, Inc., a subsidiary of Zogenix, Inc.WithdrawnDepression | Anxiety | Dravet Syndrome
-
George Washington UniversityColumbia University; Harvard School of Public Health (HSPH); Ifakara Health Institute and other collaboratorsNot yet recruiting
-
George Washington UniversityColumbia University; Harvard School of Public Health (HSPH); Ifakara Health Institute and other collaboratorsNot yet recruiting
-
Enterprise Therapeutics LtdCompleted