Tuberculosis (TB) is an infectious disease that is a major global cause of morbidity and mortality: the World Health Organization (WHO) estimates that 8.7 million cases resulted in 1.4 million deaths worldwide in 2011. Most active TB cases arise in adults as a consequence of reactivation of a latent TB infection (LTBI) acquired in childhood. An estimated 2.3 billion people have LTBI, including 10-15 million people in the US.
WHO aims to eliminate TB as a public health problem by 2050, and this will require measures to prevent acquisition of LTBI. Vitamin D has long been known to enhance innate immunity to Mycobacterium tuberculosis (MTB), and Phase 2 clinical trials show that vitamin D supplementation enhances innate immune resistance to MTB infection. We propose to conduct a Phase 3 double-blind randomized placebo-controlled clinical trial to determine whether vitamin D supplementation reduces risk of acquisition of LTBI in 7,350 uninfected schoolchildren aged 6-15 years in Ulaanbaatar, Mongolia, where rates of LTBI acquisition in children are particularly high as is vitamin D deficiency. Study medication will be administered over 3 years as 72 directly observed bi-weekly oral doses of 28,000 IU Vitamin D3 or placebo. We will employ a well-validated interferon-gamma release assay to determine whether participants have acquired LTBI at 3 years of follow-up (primary outcome). There is professional consensus, as highlighted in recent editorials in the Lancet [2011;377:189-90] and PNAS [2011;108, 18861-18862], that the trial we propose needs to be conducted. The PNAS editorial concludes that "It is a tragic irony that vitamin D, which costs a penny a day and may enhance innate and acquired immunity to TB, is not considered a worthy investment for critical clinical trials that could determine whether supplementation can prevent disease." The results of this trial will inform global TB control policy by determining whether vitamin D supplementation prevents acquisition of LTBI. More than one billion people worldwide are Vitamin D deficient, and supplementation is safe and inexpensive: intermittent bolus doses of vitamin D are effective in correcting deficiency, are inexpensive, easy to administer, have a very low incidence of adverse effects and much higher degree of acceptability than vaccines and antibiotics. The results of our trial will be readily generalizable to the vitamin D deficient populations at risk of TB worldwide and to the billions already infected with LTBI.

Public Health Relevance

Tuberculosis is posing a global emergency;an astonishing one-third of the global population, including 10-15 million people in the United States, are afflicted with a latent TB infection from Mycobacterium tuberculosis. The WHO's Stop TB strategy aims to eliminate TB as a public health problem (i.e. to reduce incidence to <1 per million per year) by 2050. The results of this trial will inform global TB control policy by determining whether vitamin D supplementation protects against TB infection.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL122624-01
Application #
8673990
Study Section
Clinical Research and Field Studies of Infectious Diseases Study Section (CRFS)
Program Officer
Blaisdell, Carol J
Project Start
2014-09-18
Project End
2019-06-30
Budget Start
2014-09-18
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
$659,269
Indirect Cost
$141,729
Name
Harvard University
Department
Nutrition
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115