Quadruple Fortified Salt (QFS) Trial in India

Study Overview
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Brief Summary
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Neural tube closure defects (NTDs) are a common adverse pregnancy outcome and among the most severe birth defects in the United States and globally. Women of reproductive age are a high-risk population for anemia and micronutrient deficiencies, and there is increasing evidence of the role of periconceptional nutritional status in the risk of birth defects and other common pregnancy complications. However, there is little representative population-level data from Southern India, where the burden of micronutrient deficiencies and birth defects is estimated to be among the highest in the world. Salt fortification is a promising strategy to prevent anemia and multiple micronutrient deficiencies, as it utilizes a widely consumed and affordable food and existing production and distribution systems. The objectives of this randomized controlled trial are to determine the efficacy of quadruple-fortified salt (QFS) - i.e., iron, iodine, folic acid, and vitamin B12 - on 1) erythrocyte folate and serum folate concentrations, 2) hemoglobin concentrations, and 3) vitamin B12 concentrations, among women of reproductive age in Southern India. If proven to be efficacious, QFS could represent a low-cost and sustainable strategy to prevent anemia and micronutrient deficiencies and improve the health of vulnerable populations, including women and young children.

Detailed Description
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Neural tube closure defects (NTDs) are a common adverse pregnancy outcome, and one of the most debilitating birth defects in the United States and globally. NTDs comprise a cluster of neurodevelopmental conditions associated with the failure of neural tube closure during embryonic development. There are over 260,000 cases of NTDs each year globally, ranging from 1 to 80 per 10,000 births. Despite prevention efforts, NTDs remain a leading cause of neonatal morbidity and mortality worldwide, incurring medical costs of over $500,000 per person. Randomized trials have established that periconceptional folic acid supplementation prevents the occurrence and recurrence of NTDs by up to 70%. This led to the development of dietary recommendations for women of childbearing age in the U.S. and folic acid fortification of wheat and maize flour in over 80 countries. Fortification of food staples is a sustainable intervention to improve micronutrient status in populations, and fortification of flour with folic acid is considered one of the most efficacious and cost-effective public health interventions to date. However, current folic acid fortification programs have not eliminated NTDs, and are constrained by suboptimal coverage and lack of consumption of targeted staple foods by at-risk populations. Fortification efforts to date have mainly targeted wheat and maize flour, which are not primary staples in some settings with the highest NTD burden, such as Southern India. It is estimated that India alone accounts for over one-third of all NTDs globally. In Southern India, the site of this randomized trial, rice is the primary staple, and the persistent burden of micronutrient deficiencies underscores the need to innovate additional strategies to deliver folic acid to at-risk populations. Salt fortification is a promising strategy to prevent multiple micronutrient deficiencies, as it utilizes a widely consumed and affordable food and has existing production and distribution systems. In India, salt is one of the most widely consumed fortifiable staples. Previous studies demonstrated that double-fortified salt (DFS) with iron and iodine significantly improved iron status in women of reproductive age and schoolchildren. However, the high baseline prevalence of anemia and micronutrient deficiencies of folate and vitamin B12 persisted, highlighting a need for additional interventions to target multiple micronutrient deficiencies. Recent technological advances have informed the development of a low-cost formulation of quadruple-fortified salt (QFS) - i.e., iron, iodine, folic acid, and vitamin B12 (Diosady, Mannar). This QFS is formulated to prevent chemical interactions of micronutrients and maintain stability in tropical conditions, and is ready for use in randomized efficacy trials in human populations. The objectives of this randomized controlled trial are to determine the efficacy of quadruple-fortified salt (QFS) - i.e., iron, iodine, folic acid, and vitamin B12 - on 1) erythrocyte folate and serum folate concentrations, 2) hemoglobin concentrations, and 3) vitamin B12 concentrations, among women of reproductive age in Southern India. If proven to be efficacious, QFS could represent a low-cost and sustainable strategy to prevent anemia and micronutrient deficiencies and improve the the health of vulnerable populations, including women and young children.

Official Title
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A Randomized Trial of Quadruple Fortified Salt for Anemia and Birth Defects Prevention in Southern India

Conditions
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Anemia, Folate Deficiency, Vitamin B 12 Deficiency

Intervention / Treatment
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* Other: + Folic acid
* Other: + Vitamin B12
* Other: DFS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women between 18 and 49 years of age Healthy Not pregnant or lactating Plan to reside in the catchment area of our periconceptional surveillance program for at least two years Exclusion Criteria: Severe anemia (Hemoglobin <8.0 g/dL) HIV, active tuberculosis disease, or malaria infection Malabsorption disorders (medical condition that may affect vitamin B12 absorption or metabolism) Severe hypertension (SBP≥140 mm Hg or DBP≥90 mm Hg) Other serious preexisting medical condition (i.e., defined as the need for regular medication use) Daily micronutrient supplements (i.e., tablets, capsules, dispersible tablets; ≥4 times in the past week) Intramuscular or intravenous interventions containing micronutrients (e.g., iron, vitamin B12, folic acid) in the past 3 months.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 49 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: After confirming eligibility and informed consent/assent, women will be randomly assigned to one of the 4 intervention arms, using a 2 X 2 factorial design: Quadruple-fortified salt (QFS; i.e., iron, iodine, folic acid, and vitamin B12) DFS + folic acid DFS + vitamin B12; and Double-fortified salt (DFS; i.e., iron and iodine)
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Quadruple-Fortified Salt (QFS)<br>Salt fortified with iron, iodine, folic acid, and vitamin B12 | Other: + Folic acid<br>* Salt fortified with folic acid<br>Other: + Vitamin B12<br>* Salt fortified with vitamin B12<br>Other: DFS<br>* Salt fortified with iron and iodine<br>|
| Experimental: DFS + Folic acid<br>Salt fortified with iron, iodine, and folic acid | Other: + Folic acid<br>* Salt fortified with folic acid<br>Other: DFS<br>* Salt fortified with iron and iodine<br>|
| Experimental: DFS + Vitamin B12<br>Salt fortified with iron, iodine, and vitamin B12 | Other: + Vitamin B12<br>* Salt fortified with vitamin B12<br>Other: DFS<br>* Salt fortified with iron and iodine<br>|
| Active Comparator: Double-fortified salt (DFS)<br>Salt fortified with iron and iodine | Other: DFS<br>* Salt fortified with iron and iodine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentrations of erythrocyte folate and serum folate | Erythrocyte folate and serum folate concentrations, nmol/L | Endline (12 months) | 
| Concentrations of hemoglobin | Hemoglobin concentrations, g/dL | Endline (12 months) | 
| Concentrations of vitamin B12 | Vitamin B12 concentrations, pmol/L | Endline (12 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Folate deficiency and insufficiency | Erythrocyte (RBC) folate <305.0 nmol/L; <748.0 nmol/L | Endline (12 months) | 
| Anemia | Hemoglobin <12.0 g/dL | Endline (12 months) | 
| Vitamin B12 deficiency and insufficiency | Total vitamin B12 <148.0 pmol/L; <221.0 pmol/L | Endline (12 months) |