Folic Acid and Vitamin B12 in Young Indian Children

Study Overview
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Brief Summary
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Hypothesis: Supplementation of two recommended daily allowances (RDA) of folic acid with or without simultaneous administration of vitamin B12 reduces the rates of acute lower respiratory tract infections (ALRI), clinical pneumonia and diarrhea. Design/Methods We will conduct a preventive randomized placebo controlled clinical trial of folic acid and vitamin B12 supplementation in 1000 children aged 6 to 30 months living in a low to middle-income socioeconomic setting in New Delhi, India. Children aged 6-30 months will be identified through a survey. Eligible and willing Children aged 6-30 months will be randomized to 4 treatment groups. Trial to enrollment informed consent will be obtained by the Study Physician/Supervisor. At enrollment a baseline form will be filled and the child weight and length taken. The baseline blood samples will be collected. The supplements will be given daily for 6 months. Morbidity will be ascertained through biweekly home visits by field workers.

Detailed Description
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Pneumonia and diarrhea are among the leading causes of poor health and death in young children of developing countries. Many of these children have inadequate intakes of several vitamins and minerals. Folate and vitamin B12 are important for normal function of the immune system. Deficiencies of these vitamins are often part of general malnutrition and might be responsible for the excess morbidity and mortality seen in malnourished children. In a recent cohort study in almost 2,500 Indian children we demonstrated that those with poor folate status had higher rates of diarrhea and pneumonia. This study also showed that children that were not breastfed had poor folate status and our analyses suggested that the effect of breastfeeding in preventing respiratory and gastrointestinal infections could be explained by the folate content of breast milk. The finding that poor folate status is related to increased susceptibility to childhood infections needs to be confirmed in well conducted clinical trials in populations where folate deficiency is prevalent. This trial aims to examine whether daily supplementation of 2 recommended doses of folate or vitamin B12 or both will lessen the incidence of acute lower respiratory tract infections and diarrhea. We will also measure if the supplementation improves the weight and length of supplemented children.

Official Title
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Routine Administration of Folic Acid and Vitamin B12 to Prevent Childhood Infections in Young Indian Children

Conditions
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Diarrhea, Pneumonia

Intervention / Treatment
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* Dietary Supplement: Folic Acid
* Dietary Supplement: Vitamin B12
* Dietary Supplement: Placebo
* Dietary Supplement: Folic acid and vitamin B12


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: 6 to 30 months Either sex Likely to reside in area for next 6 months Exclusion Criteria: Severe systemic illness requiring hospitalization Severe malnutrition, i.e. weight for height < -3 z of the WHO standard for this age group. For ethical reasons these children require micronutrient supplementation and adequate medical care. Non consent Consuming vitamin supplements that include folic acid and vitamin B12. Severe anemia (Hb < 7 g/dL).

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 30 Months

Sexes Eligible for Study
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All

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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: A<br>Placebo dietary supplement | Dietary Supplement: Placebo<br>* Placebo with no active ingredients<br>|
| Experimental: B<br>Folic acid | Dietary Supplement: Folic Acid<br>* 150µgm/day for 6 months in children older than 11 months and 80µgm in 6 to 11 months.<br>* Other names: Folate;|
| Experimental: C<br>Vitamin B12 | Dietary Supplement: Vitamin B12<br>* 1.8µgm/day for 6 months in children older than 11 months and 0.5µgm in 6 to 11 months.<br>* Other names: Cobalamin;|
| Experimental: D<br>Folic acid and Vitamin B12 | Dietary Supplement: Folic acid and vitamin B12<br>* Folic acid 150µgm/day for 6 months in children older than 11 months and 80µgm in 6 to 11 months vitamin B12 1.8µgm/day for 6 months in children older than 11 months and 0.5µgm in 6 to 11 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of episodes diarrhea (all, severe, prolonged) and pneumonia (ALRI, Clinical pneumonia) |  | 6 months | 
| Prevalence of diarrhea |  | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Growth (length for age, weight for age, and length for weight) |  | 6 month | 
| Adverse events (vomiting and gastric discomfort) |  | 6 months | 
| Changes in folate, vitamin B12, methyl malonic acid, and homocysteine concentration |  | 6 months | 
| Developmental Milestones | Developmental milestones. The developmental milestones will be measured using the ASQ-3. ASQ-3 is an easily administered and comprehensive checklist consisting of 30 items measuring skills in 5 different domains; Communication, Gross Motor, Fine Motor, Personal-Social and Problem-Solving. The questionnaires are divided into two-month intervals for use with children 4-60 months of age, and scores are normed to indicate whether children are developing age-appropriately. | End study, i.e. after 6 months of vitamin B12 and/or folic acid administration | 
| Measure the association between pneumonia incidence and the plasma mannose binding lectin (MBL) concentration |  | Baseline blood samples | 
| Measure the exposure to Cryptosporidium spp | We will measure the exposure to Cryptosporidium spp. in Indian children aged 6-30 months by measurement of antibodies to recombinant gp15, a conserved surface protein in plasma samples taken at baseline. | Baseline blood samples | 
| Measure the association between the antibody response to Cryptosporidium and plasma MBL |  | Baseline blood samples | 
| Compare the change in plasma MBL between the intervention groups | We will compare the change in plasma MBL between those who have been given 2 RDA of vitamin B12 and/or folic acid with those who were given placebo in a subsample of 256 children. | 6 months | 
| Vitamin D status | We will measure vitamin D (25-hydroxy vitamin D) in all children at baseline to describe the vitamin D status and the proportion with vitamin D deficiency. | Baseline blood samples | 
| Vitamin D status and the risk for respiratory infections | We will measure the vitamin D status at baseline and assess to what extent it predicts the risk of subsequent respiratory tract infections over the next 6 months. | Baseline samples and 6 months follow up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Nutrition, Children, Folate, Vitamin B12, India, Homocysteine, Methyl Malonic Acid