Trial of Vitamin D Supplementation to Prevent TB Infection in Schoolchildren

描述(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(WHO)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病例发生在成人，原因是儿童时期获得的潜伏结核病感染(LTBI)重新激活。据估计，有23亿人患有LTBI，其中美国有1000万至1500万人。世卫组织的目标是到2050年消除结核病这一公共卫生问题，这将需要采取措施防止感染结核病。长期以来，维生素D一直被认为可以增强对结核分枝杆菌(MTB)的天然免疫力，第二阶段临床试验表明，补充维生素D可以增强对结核分枝杆菌感染的天然免疫抵抗力。我们建议进行一项第三阶段的双盲随机安慰剂对照临床试验，以确定在蒙古乌兰巴托7,350名6-15岁未感染的学龄儿童中，补充维生素D是否降低了获得LTBI的风险，那里的儿童获得LTBI的比率特别高，维生素D缺乏也是如此。研究用药将在3年内进行，72人直接观察双周口服剂量为28,000国际单位的维生素D3或安慰剂。我们将采用经过充分验证的干扰素-伽马释放试验来确定参与者在3年的随访中是否获得了长期脑损伤(主要结果)。正如《柳叶刀》[2011年；377：189-90]和《国家行动计划》[2011；108,18861-18862]最近的社论所强调的那样，专业人士一致认为，我们提议的试验需要进行。《美国国家科学院院刊》的这篇社论总结道，具有悲剧性讽刺意味的是，每天花费一便士的维生素D，可能会增强对结核病的先天和后天免疫力，却不被认为是一项值得投资的关键临床试验，这些试验可以确定补充剂是否可以预防疾病。这项试验的结果将通过确定补充维生素D是否阻止获得LTBI来为全球结核病控制政策提供信息。全世界有10多亿人缺乏维生素D，补充维生素D是安全和廉价的：间歇性推注维生素D能有效纠正缺乏，价格低廉，易于管理，副作用发生率非常低，可接受度远远高于疫苗和抗生素。我们的试验结果将很容易推广到全世界面临结核病风险的维生素D缺乏人群和已经感染LTBI的数十亿人。

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.