Vitamin D Supplementation in TB Prevention

Vitamin D in TB Prevention in School Age Children

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.

Study Overview

• Status: Completed
• Conditions: Latent Tuberculosis
• Intervention / Treatment: Dietary supplement: Cholecalciferol (vitamin D3); Other: Placebo

• Study Type: Interventional
• Enrollment (Actual): 8851
• Phase: Phase 3

Contacts and Locations

Study Locations

• Mongolia
  • Ulaanbaatar, Mongolia
    • Mongolian Health Initiative

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 13 years (Child)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Boys or girls aged 6 to 13 years at enrolment
2. Attending participating school in Ulaanbaatar at enrolment
3. Child gives informed assent to participate in the study
4. Child's parent/legal guardian gives informed consent for child to participate in study

Exclusion Criteria:

1. Chronic medical conditions
2. Presence of LTBI on screening, as evidenced by a positive QFT-G
3. Clinical signs of rickets, or diagnosis of any other condition requiring vitamin D supplementation
4. Known primary hyperparathyroidism or sarcoidosis
5. Taking immunosuppressant or cytotoxic therapy, or vitamin D supplement > 400IU / day
6. Plans to move away from study area within 3 years of enrolment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse events	The proportion of participants experiencing death, one or more serious adverse events of any cause or one or more potential adverse reactions (hypercalcemia, hypercalciuria and hypervitaminosis D) will be compared between arms.	Three years
Heterogeneity of treatment effect among sub-groups defined by baseline vitamin D status, estimated calcium intake and vitamin D pathway genotype	Heterogeneity of treatment effect will be examined among sub-groups defined by baseline vitamin D status, estimated calcium intake and vitamin D pathway genotype for primary and secondary outcomes. This will be done by repeating efficacy analyses to include: An interaction term between baseline vitamin D status and allocation to vitamin D vs. placebo; An interaction term between estimated calcium intake and allocation to vitamin D vs. placebo; An interaction term between vitamin D pathway genotype and allocation to vitamin D vs. placebo. For genetic analyses, DNA will be extracted from participants' stored whole blood, and typed for a panel of candidate single nucleotide polymorphisms (SNPs) in genes influencing vitamin D metabolism (e.g. CYP2R1, CYP27B1, CYP24A1), transport (e.g. DBP) and signalling (e.g. VDR).	Three years
Cost-effectiveness of vitamin D supplementation for the prevention of LTBI and active TB	Health economic analysis	Three years

Collaborators and Investigators

• Sponsor: Harvard School of Public Health (HSPH)
• Investigators: Principal Investigator: Davaasambuu Ganmaa, MD PhD, Harvard School of Public Health (HSPH)

Publications and helpful links

General Publications

• Ganmaa D, Uyanga B, Zhou X, Gantsetseg G, Delgerekh B, Enkhmaa D, Khulan D, Ariunzaya S, Sumiya E, Bolortuya B, Yanjmaa J, Enkhtsetseg T, Munkhzaya A, Tunsag M, Khudyakov P, Seddon JA, Marais BJ, Batbayar O, Erdenetuya G, Amarsaikhan B, Spiegelman D, Tsolmon J, Martineau AR. Vitamin D Supplements for Prevention of Tuberculosis Infection and Disease. N Engl J Med. 2020 Jul 23;383(4):359-368. doi: 10.1056/NEJMoa1915176.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2015
• Primary Completion (Actual): June 1, 2019
• Study Completion (Actual): June 1, 2020

Study Registration Dates

• First Submitted: October 23, 2014
• First Submitted That Met QC Criteria: October 27, 2014
• First Posted (Estimate): October 28, 2014

Study Record Updates

• Last Update Posted (Actual): July 16, 2020
• Last Update Submitted That Met QC Criteria: July 14, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Latent Infection; Tuberculosis; Latent Tuberculosis; Physiological Effects of Drugs; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vitamin D; Cholecalciferol
• Other Study ID Numbers: 140513

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: IPD will be shared for purposes of meta-analysis, subject to approval from IRBs in Mongolia and the USA and terms of data sharing agreements.
• IPD Sharing Time Frame: The items above will be shared following publication of trial reports.
• IPD Sharing Access Criteria: IPD requests should be made to the Principal Investigator: gdavaasa@hsph.harvard.edu
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR