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

一项 III 期整群随机安慰剂对照试验，旨在评估预防性治疗对耐多药结核病儿童和青少年接触者的疗效

• 批准号: MR/M007340/1
• 负责人: Anneke Hesseling
• 金额: $ 324.16万
• 依托单位: Stellenbosch University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM007340%2F1
• 关键词: phase; III; cluster; randomised; placebo

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.

研究背景：要患上结核病（TB），必须首先接触咳嗽的人，感染，然后发病。艾滋病毒感染者和幼儿一旦感染，更有可能患上结核病。预防结核病的一种方法是找到与结核病患者同住的人，检查他们并治疗结核病感染者。这将防止他们感染结核病。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，当艾滋病毒感染者和6岁以下儿童与结核病患者接触时，应给予INH六个月。目前还不清楚我们应该给接触过耐多药结核病（MDR）患者的儿童服用什么药物，当病菌对最常用的结核病药物如异烟肼有抗药性时，耐多药结核病越来越普遍。世卫组织估计，2012年全球有超过50万例病例。据估计，全世界每年至少有100万儿童暴露于耐多药结核病。随着新的测试，以快速诊断结核病，也可以检测耐药性的常见结核病药物，成年人谁被诊断为耐多药结核病病例的数量正在增加。反过来，接触耐多药结核病的儿童数量也在增加。治疗患有耐多药结核病的儿童需要很长时间（通常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，预防儿童耐多药结核病非常重要。到目前为止，还没有设计良好的大型研究来帮助我们确定使用药物预防与耐多药结核病患者接触的儿童患病是否有效。已经进行了一些医生治疗接触过耐多药结核病的患者的研究，但是，他们每个人都有问题。我们认为药物预防耐多药结核病可能有效，但在我们确定之前，需要进行一种更好的研究，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，观察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在使用的治疗耐多药结核病的药物，称为左氧氟沙星（LFX）。我们将测试这种药物，每天服用6个月，是否可以预防儿童患结核病和/或死亡。我们将在研究中纳入与耐多药结核病患者共同生活的儿童。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24个月的随访，以确保他们不会患结核病或有任何副作用。我们还将检查药物是否容易服用，是否安全，或者结核病是否对LFX产生耐药性。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价格。一些儿童和他们的家人将被要求与诊所工作人员谈论他们对这项研究和药物的体验。潜在的应用和好处：在医生了解什么治疗方法对预防儿童耐多药结核病有效之前，很难告诉家庭该怎么做。如果我们正在测试的药物能够预防耐多药结核病，并且是安全的，并且被家庭接受，我们将能够告诉其他医生如何在世界各地减少耐多药结核病。结核病规划也将从这项研究中受益，因为更少的儿童将患上治疗费用高昂的疾病。最重要的是，如果这种药物有效，这项研究将大大有益于接触耐多药结核病的儿童。

项目成果

Outcome of culture-confirmed isoniazid-resistant rifampicin-susceptible tuberculosis in children.

• DOI: 10.5588/ijtld.16.0293
• 发表时间: 2016-11
• 期刊: The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease
• 作者: A. Garcia-Prats;L. D. Plessis;H. Draper;A.E.C. Burger;J. Seddon;K. Zimri;A. Hesseling;H. S. Schaaf

The global burden of tuberculosis mortality in children: a mathematical modelling study.

• DOI: 10.1016/s2214-109x(17)30289-9
• 发表时间: 2017-09
• 期刊: The Lancet. Global health
• 作者: Dodd PJ;Yuen CM;Sismanidis C;Seddon JA;Jenkins HE
• 通讯作者: Jenkins HE