Vitamin D Supplementation in TB Prevention

Study Overview
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Brief Summary
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The goal of this clinical trial is to determine whether vitamin D supplementation reduces risk of acquiring latent tuberculosis infection (LTBI) in school age children in Mongolia. The investigators hypothesize that (1) vitamin D supplementation will reduce risk of acquisition of LTBI, (2) vitamin D supplementation will safely reduce risk of developing active TB and improve other secondary efficacy outcomes, and (3) children with the lowest vitamin D status at baseline will gain most from the intervention.

Official Title
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Vitamin D in TB Prevention in School Age Children

Conditions
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Latent Tuberculosis

Intervention / Treatment
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* Dietary Supplement: Cholecalciferol (vitamin D3)
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Boys or girls aged 6 to 13 years at enrolment Attending participating school in Ulaanbaatar at enrolment Child gives informed assent to participate in the study Child's parent/legal guardian gives informed consent for child to participate in study Exclusion Criteria: Chronic medical conditions Presence of LTBI on screening, as evidenced by a positive QFT-G Clinical signs of rickets, or diagnosis of any other condition requiring vitamin D supplementation Known primary hyperparathyroidism or sarcoidosis Taking immunosuppressant or cytotoxic therapy, or vitamin D supplement > 400IU / day Plans to move away from study area within 3 years of enrolment

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 13 Years

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: Parallel Assignment
Interventional Model Description: Parallel assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Intervention: 1<br>Dietary Supplement: Cholecalciferol (vitamin D3) | Dietary Supplement: Cholecalciferol (vitamin D3)<br>* 14000 IU vitamin D3 weekly Experimental group will receive vitamin D supplement (Tishcon, USA).<br>|
| Placebo Comparator: Placebo Comparator: 2<br>Dietary Supplement: Placebo | Other: Placebo<br>* Placebo group will receive placebo (Tishcon, USA) weekly.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acquisition of latent tuberculosis infection | The proportion of children who acquire LTBI during the 3 year period will be compared for children randomized to vitamin D3 vs. placebo using the Mantel-Haenszel risk ratio, stratified by school of attendance. The primary analysis will compare the proportion of children who are QuantiFERON-positive at the 0.35 IU/ml IFN-gamma threshold at the end of the study. Exploratory analyses will compare the proportion of children who are positive at the 4.0 IU/ml IFN-gamma threshold (denoting stable conversion) and mean / median antigen-stimulated IFN-gamma concentration analyzed as a continuous variable. | Three years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of active TB disease | All participants | Three years | 
| Incidence of self-reported acute respiratory infection (upper, lower and both combined) | All participants | Three years | 
| Incidence of acute respiratory infection requiring hospitalization | All participants | Three years | 
| Incidence of acute respiratory infections requiring antibiotic treatment | All participants | Three years | 
| Number of days off school (total number and number due to acute respiratory infection) | All participants | Three years | 
| Incidence of acute asthma exacerbation requiring hospitalization | Sub-set of participants with asthma at baseline | Three years | 
| Incidence of new asthma, allergic rhinitis and atopic dermatitis | Sub-sets of participants without asthma, allergic rhinitis or atopic dermatitis at baseline | Three years | 
| Control of asthma, allergic rhinitis and atopic dermatitis | Sub-sets of participants identified as having asthma, allergic rhinitis or atopic dermatitis at baseline | Three years | 
| Incidence of bone fracture | All participants | Three years | 
| Anthropometric outcomes (z-scores for height-for-age, weight-for-age, weight-for-height, body mass index-for-age, and waist circumference and waist-to-height ratio) | All participants | Three years | 
| Body composition: impedance, impedance%, fat mass fat %, and fat-free mass | All participants | Three years | 
| Muscle strength: grip strength and long jump distance from standing | All participants | Three years | 
| Serum 25-hydroxyvitamin D concentration | All participants | Three years | 
| Bone mineral density at the radius | Sub-set of participants | Three years | 
| Physical fitness (maximal oxygen consumption estimated from 20m shuttle run) | Sub-set of participants | Three years | 
| Attention-related behavior scores (Connors III) | Sub-set of participants | Three years | 
| Incidence of dental caries | Sub-set of participants | Three years | 
| Circulating and antigen-stimulated concentrations of cytokines, chemokines and other inflammatory mediators | Sub-set of participants | Three years | 
| Exam performance | Sub-set of participants | Three years | 
| Self-reported pubertal development | Sub-set of participants | Three years | 
| Spirometric lung volumes (FEV1 and FVC) | Sub-set of participants | Three years | 
| Urinary metabolome profile | Sub-set of participants | Three years | 
| Gut microbiome profile | Sub-set of participants | Three years |