Quadruple Fortified Salt (QFS) Trial in India

Sponsor

Cornell University (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT03853304

Collaborator

Centers for Disease Control and Prevention (U.S. Fed), Arogyavaram Medical Centre (Other)

1,000

Enrollment

Location

Arms

Anticipated Duration (Months)

52.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Anemia Folate Deficiency Vitamin B 12 Deficiency	Other: + Folic acid Other: + Vitamin B12 Other: DFS	N/A

Detailed Description

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.

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

1000 participants

Allocation:

Randomized

Intervention Model:

Factorial Assignment

Intervention 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)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 (Participant, Investigator, Outcomes Assessor)

Masking Description:

All salt formulations will be similar in taste, appearance, and texture. Salt will be packaged in bags labeled with color codes known only to the salt manufacturers and a statistician unaffiliated with the study. A statistician unaffiliated with this study will generate a random number sequence for intervention allocation. Blinding will be maintained until initial data analysis is completed.

Primary Purpose:

Prevention

Official Title:

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

Anticipated Study Start Date :

Oct 1, 2021

Anticipated Primary Completion Date :

May 1, 2023

Anticipated Study Completion Date :

May 1, 2023

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

Concentrations of erythrocyte folate and serum folate [Endline (12 months)]
Erythrocyte folate and serum folate concentrations, nmol/L
Concentrations of hemoglobin [Endline (12 months)]
Hemoglobin concentrations, g/dL
Concentrations of vitamin B12 [Endline (12 months)]
Vitamin B12 concentrations, pmol/L

Secondary Outcome Measures

Folate deficiency and insufficiency [Endline (12 months)]
Erythrocyte (RBC) folate <305.0 nmol/L; <748.0 nmol/L
Anemia [Endline (12 months)]
Hemoglobin <12.0 g/dL
Vitamin B12 deficiency and insufficiency [Endline (12 months)]
Total vitamin B12 <148.0 pmol/L; <221.0 pmol/L

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 49 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Yes

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 vitamin B12 or iron in the past 3 months