Trial of Vitamin D Supplementation to Prevent TB Infection in Schoolchildren

描述（由申请人提供）：结核病（TB）是一种传染病，是全球发病率和死亡率的主要原因：世界卫生组织（世卫组织）估计，2011年全球有870万病例导致140万人死亡。大多数活动性结核病例发生于成人，是儿童期获得的潜伏性结核感染（LTBI）重新激活的结果。估计有23亿人患有LTBI，其中包括美国的1000万至1500万人。世卫组织的目标是到2050年消除作为公共卫生问题的结核病，这将需要采取措施防止获得长期结核病。人们早就知道维生素D可以增强对结核分枝杆菌（MTB）的先天免疫，2期临床试验表明，补充维生素D可以增强对结核分枝杆菌感染的先天免疫抵抗力。我们建议进行一项3期双盲随机安慰剂对照临床试验，以确定补充维生素D是否能降低蒙古乌兰巴托7350名6-15岁未感染的学童获得LTBI的风险，蒙古儿童获得LTBI的比率特别高，维生素D缺乏症也很高。研究药物将在3年内进行72次直接观察，每两周口服28,000 IU维生素D3或安慰剂。我们将采用一种经过良好验证的干扰素- γ释放试验来确定参与者是否在3年随访中获得LTBI（主要结局）。正如《柳叶刀》（Lancet）杂志最近的社论所强调的那样，这是一个专业共识[2011；中国科学院院刊[2011]；[108,18861 -18862]，我们建议的试验需要进行。《美国国家科学院院刊》的社论总结道：“这是一个悲剧性的讽刺，维生素D每天花费一分钱，可以增强对结核病的先天和获得性免疫力，但却不被认为是值得投资的关键临床试验，以确定补充维生素D是否可以预防疾病。”该试验的结果将通过确定补充维生素D是否能预防LTBI的获得，为全球结核病控制政策提供信息。全世界有10亿多人缺乏维生素D，补充维生素D既安全又便宜：间歇性大剂量维生素D可有效纠正缺乏症，价格低廉，易于管理，不良反应发生率极低，可接受程度比疫苗和抗生素高得多。我们的试验结果将很容易推广到全球有结核病风险的维生素D缺乏人群和数十亿已经感染LTBI的人群。

DESCRIPTION (provided by applicant): 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.