Short enhanced anti-tuberculosis and anti-thrombosis treatment for children with tuberculous meningitis

小儿结核性脑膜炎短期强化抗结核抗血栓治疗

• 批准号: MR/R006113/1
• 负责人: Diana Gibb
• 金额: $ 547.43万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR006113%2F1
• 关键词: Short; enhanced; anti; tuberculosis; thrombosis

Children who come into contact with an adult who has tuberculosis (TB) are at a high risk of getting TB themselves. Globally, nearly a million children get TB each year. As well as being at high risk of getting TB, young children are especially prone to getting severe TB, which affects the brain. This is called TB meningitis (or TBM). About one in five children who get TBM die of the disease. Of the children who survive, half will have some kind of disability. As well as this tragedy for the child, there is a large personal and financial cost to families who look after these children, often for many years. Health systems and societies are also affected. The World Health Organization currently advises 12 months of treatment for children with TBM. They recommend that children with other sorts of TB have 6 months of treatment. This advice is not based on good quality evidence. Experts have been calling for a study to be done to try to find out if it is safe and effective to treat children with TBM for six months. Halving the treatment time would probably have large benefits for families and health systems. Researchers in South Africa have investigated treating children for six months, by giving them slightly different drugs and at higher doses. This means higher drug concentrations are achieved in the brain. The outcomes for these children seem at least as good as the outcomes in other places where 12 months of treatment are given. However, we cannot be sure if it is safe and effective because it has never been tested in a randomised trial. The drug aspirin has been used for many years for fever and pain. It is also known to make the blood clot less readily. It is used widely as a treatment for adults who have had heart attacks or strokes to prevent blood clots. Much of the damage in children with TBM is caused by stroke. Aspirin (in addition to TBM treatment) may help to reduce this damage. Two studies have looked at this issue in children. One study showed that aspirin was beneficial and one showed that it was not. Both studies were quite small and doctors remain unsure whether to use aspirin.We plan to carry out a randomised trial to answer two questions. 1) Is it safe and effective to treat children with TBM for 6 months as opposed to 12 months? We plan to see if children treated for 6 months have outcomes that are as good as children treated for 12 months. The children treated for 12 months will receive the currently advised treatment. The children treated for 6 months will receive higher dosages of the drugs and one drug that is different. 2) Does aspirin reduce the risk of disability in children with TBM? We plan to give half the children aspirin and the other half a placebo (sugar pill) so that neither they nor the study team knows which child is receiving which treatment.We will monitor all children for side effects. We will also investigate whether these two approaches are acceptable to families and what the financial implications are for both families and for health systems.We will need about 400 children in the trial to answer these questions. We will carry out the trial in Uganda, Vietnam, Zambia and Zimbabwe. By doing the trial in many different places, we can be confident that any results that we find will be relevant for children all over the world. If either shortening treatment or adding aspirin is safe and effective, the results of this trial could improve how doctors treat children with TBM across the world.

与患有结核病(TB)的成年人接触的儿童本身也有感染结核病的高风险。在全球范围内，每年有近100万儿童感染结核病。除了感染结核病的高风险外，幼儿尤其容易患上严重的结核病，这会影响大脑。这被称为TB脑膜炎(或称TBM)。大约五分之一患有TBM的儿童死于这种疾病。在幸存的儿童中，有一半会有某种残疾。除了孩子的这场悲剧之外，照顾这些孩子的家庭还面临着巨大的个人和经济成本，通常是多年。卫生系统和社会也受到影响。世界卫生组织目前建议对患有TBM的儿童进行12个月的治疗。他们建议患有其他类型结核病的儿童接受6个月的治疗。这一建议不是基于高质量的证据。专家们一直在呼吁进行一项研究，试图找出治疗患有TBM的儿童六个月是否安全有效。将治疗时间减半可能会给家庭和医疗系统带来很大好处。南非的研究人员对治疗儿童进行了为期六个月的调查，给他们服用的药物略有不同，剂量更高。这意味着在大脑中实现了更高的药物浓度。这些儿童的结果似乎至少与其他接受12个月治疗的地方的结果一样好。然而，我们不能确定它是否安全有效，因为它从未在随机试验中进行过测试。阿司匹林多年来一直用于治疗发烧和疼痛。众所周知，它还会使血液凝块不那么容易形成。它被广泛用于治疗心脏病发作或中风的成年人，以防止血栓形成。TBM儿童的大部分损伤是由中风引起的。阿司匹林(在TBM治疗的基础上)可能有助于减轻这种损害。两项研究对儿童的这一问题进行了研究。一项研究表明阿司匹林是有益的，而另一项研究表明它没有好处。这两项研究的规模都很小，医生们仍然不确定是否使用阿司匹林。我们计划进行一项随机试验，以回答两个问题。1)治疗儿童TBM 6个月而不是12个月是否安全有效？我们计划看看接受6个月治疗的儿童是否有与接受12个月治疗的儿童一样好的结果。接受治疗12个月的儿童将接受目前建议的治疗。治疗6个月的儿童将获得更高剂量的药物和一种不同的药物。2)阿司匹林是否能降低TBM儿童的残疾风险？我们计划给一半的儿童服用阿司匹林，给另一半儿童服用安慰剂(糖丸)，这样他们和研究小组都不知道哪个孩子正在接受哪种治疗。我们将监测所有儿童的副作用。我们还将调查这两种方法是否为家庭所接受，以及这两种方法对家庭和医疗系统的财政影响。我们将需要大约400名儿童在试验中回答这些问题。我们将在乌干达、越南、赞比亚和津巴布韦进行试验。通过在许多不同的地方进行试验，我们可以相信，我们发现的任何结果都将与世界各地的儿童相关。如果缩短治疗或增加阿司匹林是安全有效的，这项试验的结果可能会改善世界各地医生治疗TBM儿童的方式。

项目成果

Defeating Paediatric Tuberculous Meningitis: Applying the WHO "Defeating Meningitis by 2030: Global Roadmap".

• DOI: 10.3390/microorganisms9040857
• 发表时间: 2021-04-16
• 期刊: Microorganisms
• 影响因子: 4.5
• 作者: Basu Roy R;Bakeera-Kitaka S;Chabala C;Gibb DM;Huynh J;Mujuru H;Sankhyan N;Seddon JA;Sharma S;Singh V;Wobudeya E;Anderson ST
• 通讯作者: Anderson ST

Evaluating pediatric tuberculosis dosing guidelines: A model-based individual data pooled analysis.

• DOI: 10.1371/journal.pmed.1004303
• 发表时间: 2023-11
• 期刊: PLoS medicine
• 影响因子: 15.8

Treating young children co-infected with tuberculosis and HIV

治疗同时感染结核病和艾滋病毒的幼儿

• DOI: 10.1016/s2352-3018(18)30326-6
• 发表时间: 2019
• 期刊: The Lancet HIV
• 作者: Turkova A

Inadequate Lopinavir Concentrations With Modified 8-Hourly Lopinavir/Ritonavir 4:1 Dosing During Rifampicin-based Tuberculosis Treatment in Children Living With HIV.

• DOI: 10.1097/inf.0000000000004047
• 发表时间: 2023-10-01
• 期刊: The Pediatric infectious disease journal

Global Estimates and Determinants of Antituberculosis Drug Pharmacokinetics in Children and Adolescents: A Systematic Review and Individual Patient Data Meta-Analysis

儿童和青少年抗结核药物药代动力学的全球估计和决定因素：系统评价和个体患者数据荟萃分析

• DOI: 10.2139/ssrn.4161712
• 发表时间: 2022
• 期刊: SSRN Electronic Journal
• 作者: Gafar F