A phase III cluster randomised placebo-controlled trial to assess the efficacy of preventive therapy in child and adolescent contacts of MDR-TB

研究背景：要患上结核病，某人必须首先接触到咳嗽的人，受到感染，然后发展成这种疾病。艾滋病毒携带者和幼儿一旦感染，就更有可能患上结核病。预防结核病的一种方法是找到与患有结核病的人住在一起的人，对他们进行检查，并对感染结核病的人进行治疗。这将防止他们患上结核病。许多研究表明，一种名为异烟肼(INH)的药物在咳嗽后服用可降低患结核病的风险，因此世界卫生组织(WHO)建议艾滋病毒感染者和6岁以下儿童在与结核病患者接触时给予异烟肼6个月。目前还不清楚，当细菌对最常用的结核病药物如异烟肼耐药时，我们应该给接触过耐多药结核病(MDR)结核病的儿童开什么药。耐多药结核病正变得越来越普遍。世卫组织估计，2012年全球有50多万病例。在世界范围内，据估计，每年至少有100万儿童接触耐多药结核病。随着快速诊断结核病的新测试也可以检测对常见结核病药物的耐药性，被诊断为耐多药结核病病例的成年人数量正在增加。反过来，接触耐多药结核病的儿童人数也在增加。治疗耐多药结核病儿童需要很长时间(通常为18个月)，通常需要住院，药物可能有许多副作用，而且价格昂贵。因此，在儿童中预防耐多药结核病是非常重要的。到目前为止，还没有任何大型和精心设计的研究来帮助我们决定使用药物来防止与耐多药结核病患者接触的儿童是否有效。已经进行了一些研究，其中医生治疗了接触过耐多药结核病的患者，但每一项研究都有问题。我们认为预防耐多药结核病的药物可能有效，但在我们确定之前，需要进行一项更好的研究，即随机对照试验，以证明它有效。目的和目标：我们想在南非进行一项研究，研究居住在耐多药结核病患者家中的人。我们将使用一种医生已经用来治疗耐多药结核病的药物，名为左氧氟沙星(LFX)。我们将测试这种在6个月内每天服用的药物是否可以防止儿童感染结核病和/或死亡。我们将把与耐多药结核病患者一起生活的儿童包括在研究中。服用这种药物的儿童将与服用糖丸或安慰剂的儿童进行比较。这种糖丸看起来像LFX，但没有活性药物。儿童将接受为期24个月的跟踪调查，以确保他们不会感染结核病或产生任何副作用。我们还将检查这种药物是否易于服用，是否安全，或者结核病是否对LFX产生了抗药性。我们还将检查以我们认为应该给予的方式给予这种药物的费用有多高。一些孩子和他们的家人将被要求与诊所工作人员谈论他们的研究经验和药物。潜在的应用和好处：在医生了解到预防儿童耐多药结核病的有效方法之前，很难告诉家人该怎么做。如果我们正在测试的药物对预防耐多药结核病有效，并且是安全的，并且为家庭所接受，我们将能够告诉世界各地的其他医生如何减少耐多药结核病。结核病规划也将从这项研究中受益，因为较少的儿童会患上一种治疗费用高昂的疾病。最重要的是，如果这种药物奏效，这项研究可能会极大地造福于接触耐多药结核病的儿童。

Context of research: To become sick with tuberculosis (TB), someone must first be exposed to someone who is coughing, become infected and then develop the disease. People with HIV and young children are more likely to develop TB disease once they are infected. One way to prevent TB is to find the people who live in a home with someone who has TB, check them and treat those with TB infection. This will prevent them from getting sick with TB disease. Many studies have shown that a drug called isoniazid (INH) reduces the risk of developing TB when given after being coughed on, so World Health Organization (WHO) advises giving INH to HIV-infected people and children under age 6 for six months when they have contact with someone with TB.Right now it is unclear what medicine we should give a child who has been exposed to someone with multidrug-resistant (MDR)-TB, when the germ is resistant to the most commonly used TB medicines, like INH. MDR-TB is becoming more common. The WHO estimated that there were more than half a million cases worldwide in 2012. Worldwide, it is estimated that at least a million children are exposed to MDR-TB every year. With new tests to diagnose TB quickly that can also detect resistance to the common TB medicines, the number of adults who are diagnosed with MDR-TB cases is increasing. In turn, the number of children exposed to MDR-TB is also increasing. Treating children who become sick with MDR-TB takes a long time (usually 18 months), usually needs a hospital stay, has medicines that may have many side effects, and is expensive. For these reasons, preventing MDR-TB in children is therefore very important.Until now, there have been no big and well designed studies to help us decide if using medicine to prevent a child with contact with someone with MDR-TB from becoming sick works. A few studies where doctors treated patients who have been in contact with MDR-TB have been done, but, each of them had problems. We think medicine to prevent MDR-TB might work, but a better type of study, a randomised control trial, needs to be done to prove that it works before we can be sure.Aims and objectives: We want to do a study in South Africa that looks at people living in the homes of someone with MDR TB disease. We will use a drug that doctors already use to treat MDR-TB called levofloxacin (LFX). We will test whether this medicine, given every day for 6 months, can prevent children from getting TB and/or dying. We will include children who live with someone with MDR-TB in the study. Children who get the medicine will be compared to those who get a sugar pill or placebo. This sugar pill looks like LFX but has no active medicine. Children will be followed for 24 months to make sure they do not get TB or have any side effects. We will also check if the medicine was easy to take, if it was safe, or if the TB became resistant to the LFX. We will also check how expensive it is to give this kind of medicine in the way that we think it should be given. Some children and their families will be asked to talk about their experience of the study and the medicine with the clinic staff.Potential applications and benefits: Until doctors learn what treatments work for preventing MDR-TB in children, it will hard to tell families what to do. If the medicine we are testing works to prevent MDR-TB, and is safe, and acceptable to families, we will be able to tell other doctors how to decrease MDR-TB all over the world. TB programmes will also benefit from this research because fewer children will get a disease which is costly to treat. Most importantly, if this medicine works, this study could greatly benefit children exposed to MDR-TB.