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Vitamin D Supplementation in TB Prevention

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ClinicalTrials.gov Identifier: NCT02276755
Recruitment Status : Completed
First Posted : October 28, 2014
Last Update Posted : July 16, 2020
Sponsor:
Information provided by (Responsible Party):
Ganmaa Davaasambuu, Harvard School of Public Health

Tracking Information
First Submitted Date  ICMJE October 23, 2014
First Posted Date  ICMJE October 28, 2014
Last Update Posted Date July 16, 2020
Actual Study Start Date  ICMJE September 2015
Actual Primary Completion Date June 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 24, 2019)
Acquisition of latent tuberculosis infection [ Time Frame: Three years ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: October 27, 2014)
The primary outcome is acquisition of latent tuberculosis (LTBI) as evidenced by conversion of the QuantiFERON-TB Gold in-tube assay test result from negative to positive. [ Time Frame: Three years ]
Differences in the proportion of children who acquire LTBI during the 3 year period who were randomized to placebo will be compared to those randomized to the Vitamin D regimen.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 24, 2019)
  • Incidence of active TB disease [ Time Frame: Three years ]
    All participants
  • Incidence of self-reported acute respiratory infection (upper, lower and both combined) [ Time Frame: Three years ]
    All participants
  • Incidence of acute respiratory infection requiring hospitalization [ Time Frame: Three years ]
    All participants
  • Incidence of acute respiratory infections requiring antibiotic treatment [ Time Frame: Three years ]
    All participants
  • Number of days off school (total number and number due to acute respiratory infection) [ Time Frame: Three years ]
    All participants
  • Incidence of acute asthma exacerbation requiring hospitalization [ Time Frame: Three years ]
    Sub-set of participants with asthma at baseline
  • Incidence of new asthma, allergic rhinitis and atopic dermatitis [ Time Frame: Three years ]
    Sub-sets of participants without asthma, allergic rhinitis or atopic dermatitis at baseline
  • Control of asthma, allergic rhinitis and atopic dermatitis [ Time Frame: Three years ]
    Sub-sets of participants identified as having asthma, allergic rhinitis or atopic dermatitis at baseline
  • Incidence of bone fracture [ Time Frame: Three years ]
    All participants
  • 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) [ Time Frame: Three years ]
    All participants
  • Body composition: impedance, impedance%, fat mass fat %, and fat-free mass [ Time Frame: Three years ]
    All participants
  • Muscle strength: grip strength and long jump distance from standing [ Time Frame: Three years ]
    All participants
  • Serum 25-hydroxyvitamin D concentration [ Time Frame: Three years ]
    All participants
  • Bone mineral density at the radius [ Time Frame: Three years ]
    Sub-set of participants
  • Physical fitness (maximal oxygen consumption estimated from 20m shuttle run) [ Time Frame: Three years ]
    Sub-set of participants
  • Attention-related behavior scores (Connors III) [ Time Frame: Three years ]
    Sub-set of participants
  • Incidence of dental caries [ Time Frame: Three years ]
    Sub-set of participants
  • Circulating and antigen-stimulated concentrations of cytokines, chemokines and other inflammatory mediators [ Time Frame: Three years ]
    Sub-set of participants
  • Exam performance [ Time Frame: Three years ]
    Sub-set of participants
  • Self-reported pubertal development [ Time Frame: Three years ]
    Sub-set of participants
  • Spirometric lung volumes (FEV1 and FVC) [ Time Frame: Three years ]
    Sub-set of participants
  • Urinary metabolome profile [ Time Frame: Three years ]
    Sub-set of participants
  • Gut microbiome profile [ Time Frame: Three years ]
    Sub-set of participants
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures
 (submitted: May 24, 2019)
  • Incidence of adverse events [ Time Frame: Three years ]
    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.
  • Heterogeneity of treatment effect among sub-groups defined by baseline vitamin D status, estimated calcium intake and vitamin D pathway genotype [ Time Frame: Three years ]
    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:
    1. An interaction term between baseline vitamin D status and allocation to vitamin D vs. placebo
    2. An interaction term between estimated calcium intake and allocation to vitamin D vs. placebo
    3. 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).
  • Cost-effectiveness of vitamin D supplementation for the prevention of LTBI and active TB [ Time Frame: Three years ]
    Health economic analysis
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Vitamin D Supplementation in TB Prevention
Official Title  ICMJE Vitamin D in TB Prevention in School Age Children
Brief Summary 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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Parallel assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE Latent Tuberculosis
Intervention  ICMJE
  • Dietary Supplement: Cholecalciferol (vitamin D3)
    14000 IU vitamin D3 weekly Experimental group will receive vitamin D supplement (Tishcon, USA).
  • Other: Placebo
    Placebo group will receive placebo (Tishcon, USA) weekly.
Study Arms  ICMJE
  • Active Comparator: Intervention: 1
    Dietary Supplement: Cholecalciferol (vitamin D3)
    Intervention: Dietary Supplement: Cholecalciferol (vitamin D3)
  • Placebo Comparator: Placebo Comparator: 2
    Dietary Supplement: Placebo
    Intervention: Other: Placebo
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 24, 2019)
8851
Original Estimated Enrollment  ICMJE
 (submitted: October 27, 2014)
8200
Actual Study Completion Date  ICMJE June 2020
Actual Primary Completion Date June 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 6 Years to 13 Years   (Child)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Mongolia
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02276755
Other Study ID Numbers  ICMJE 140513
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
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.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: Clinical Study Report (CSR)
Supporting Materials: Analytic Code
Time Frame: The items above will be shared following publication of trial reports.
Access Criteria: IPD requests should be made to the Principal Investigator: gdavaasa@hsph.harvard.edu
Responsible Party Ganmaa Davaasambuu, Harvard School of Public Health
Study Sponsor  ICMJE Harvard School of Public Health
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Davaasambuu Ganmaa, MD PhD Harvard School of Public Health
PRS Account Harvard School of Public Health
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP