A double blind randomized community-based trial of amoxicillin versus placebo for non-severe pneumonia in children aged 2-59 months in Pakistan

阿莫西林与安慰剂治疗巴基斯坦 2-59 个月儿童非严重肺炎的双盲随机社区试验

• 批准号: MR/L004283/1
• 负责人: Fyezah Jehan
• 金额: $ 107.02万
• 依托单位: Aga Khan University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL004283%2F1
• 关键词: double; blind; randomized; community; based

Pneumonia is a major cause of illness and death in children in low-income countries. With a view to decreasing death from pneumonia, the World Health Organization and UNICEF developed the the Integrated Management of Childhood Illness (IMCI) algorithm which simplifies management of common childhood illnesses such as pneumonia and diarrhoea into different levels of severity for determining the most appropriate case management by primary healthcare providers. Many pneumonia cases are categorized as non-severe pneumonia (defined as fast breathing above the specified age cut-off for respiratory rates). As there is incomplete information regarding the cause of this type of "pneumonia" from primary care settings, treatment guidelines by WHO are dictated by culture information from hospital pneumonia cases which are different in severity and cause. Current WHO guidelines advocate the use of oral antibiotics for non-severe pneumonia. However, it is postulated that most non severe pneumonia not requiring hospitalization is of viral aetiology, thus does not require antibiotic treatment. The cost of antibiotic treatment for all children with pneumonia is high; an estimated US$ 200 million in South Asia & sub Saharan Africa alone. Since more than 60% of pneumonia is classified as non-severe, this puts a strain on already under-sourced programmes in low-income countries. Giving antibiotics where they confer no benefit also puts the child at risk of side effects and increases the risk of antimicrobial resistance in the community. This uncertainty forms the basis of the proposed study. We propose to show in a clinical trial that the outcome of children diagnosed with WHO defined non severe pneumonia is similar regardless of whether they receive antibiotics or not. This study will be conducted in five primary health care centres located in low income communities of Karachi, Pakistan, with extensive trial experience. Children identified to have fast breathing without any danger signs will be randomized to receive either three days of the WHO recommended oral antibiotic (Amoxicillin 45mg/kg/day divided twice daily) or matching placebo (a drug that will taste and look like the amoxicillin but will not have an active ingredient) by a study physician working at the primary health centre. The assignment of the antibiotic amoxicillin or placebo to a child will be done using a computer generated randomization list in a manner that at the end of the trial, there are equal numbers of children in both arms of the trial. Based on the statistical calculations for sample size, we will need to assign 521 children to receive amoxicillin and the same number of children to receive placebo. All children will receive the antibiotic or placebo under supervision of the primary health care physician in the morning. Evening doses will be delivered by locally hired Community Health Workers (CHWs) visiting the children at their home. All children will be assessed again on day 3 by a study physician to see if the child's presenting sign of high respiratory rate has resolved or not. All children with persistently high respiratory rate and/or development of a new clinical sign indicating illness progression will be labelled a treatment failure. There will invariably be some children with treatment failure in both the treatment arms; we hypothesize that there will be equal number of treatment failures in both the groups i.e. around 7%. If we are able to show with the help of this trial that there is no added advantage of prescribing antibiotics to children with non-severe pneumonia we will develop an evidence base to revise the current WHO guidelines and thus reduce the financial burden on an already resource constrained health system and also decrease out of pocket expenses for families. In the long term this will have implications for decreasing global antimicrobial resistance to antibiotics.

肺炎是低收入国家儿童患病和死亡的主要原因。为了减少肺炎死亡，世界卫生组织和儿童基金会开发了儿童疾病综合管理(IMCI)算法，该算法将肺炎和腹泻等常见儿童疾病的管理简化为不同严重程度，以确定初级保健提供者最合适的病例管理。许多肺炎病例被归类为非严重肺炎(定义为呼吸频率超过指定年龄界限的呼吸急促)。由于初级保健机构没有关于这种“肺炎”病因的不完全信息，世卫组织的治疗指南是根据医院肺炎病例的文化信息制定的，这些病例的严重程度和病因不同。目前的世卫组织指南主张对非严重肺炎使用口服抗生素。然而，据推测，大多数不需要住院的非严重肺炎是由病毒引起的，因此不需要抗生素治疗。所有肺炎儿童的抗生素治疗费用很高；仅在南亚和撒哈拉以南非洲估计就有2亿美元。由于超过60%的肺炎被归类为非严重肺炎，这给低收入国家本已资金不足的项目带来了压力。在没有益处的地方使用抗生素也会使儿童面临副作用的风险，并增加社区中抗菌素耐药性的风险。这种不确定性构成了拟议研究的基础。我们建议在一项临床试验中表明，无论是否接受抗生素治疗，被诊断为世卫组织定义的非严重肺炎的儿童的结果是相似的。这项研究将在巴基斯坦卡拉奇低收入社区的五个初级卫生保健中心进行，具有广泛的试验经验。被确认为呼吸急促且没有任何危险迹象的儿童将被随机分为两组，一组接受世卫组织推荐的口服抗生素(阿莫西林45 mg/kg/天，每日两次)，另一组接受匹配的安慰剂(一种药物，味道和外观都像阿莫西林，但不含有效成分)，由初级卫生中心的研究医生工作。将使用计算机生成的随机列表将抗生素阿莫西林或安慰剂分配给儿童，其方式是在试验结束时，试验的两个手臂中有相同数量的儿童。根据样本量的统计计算，我们将需要分配521名儿童接受阿莫西林治疗，同样数量的儿童接受安慰剂治疗。上午，所有儿童将在初级卫生保健医生的监督下接受抗生素或安慰剂治疗。晚上的剂量将由当地雇用的社区卫生工作者(CHW)在儿童家中探望他们。所有儿童将在第三天由研究医生再次进行评估，看看儿童出现的呼吸频率高的迹象是否已经消失。所有呼吸频率持续较高和/或出现新的临床症状表明病情进展的儿童将被标记为治疗失败。在两个治疗臂中，总是会有一些儿童治疗失败；我们假设两组治疗失败的人数相等，即大约7%。如果我们能够在这项试验的帮助下证明给患有非严重肺炎的儿童开抗生素没有额外的好处，我们将建立一个证据基础来修订目前的世卫组织指南，从而减轻本已资源有限的卫生系统的财政负担，并减少家庭的自付费用。从长远来看，这将对减少全球对抗生素的抗菌素耐药性产生影响。

项目成果

A double blind community-based randomized trial of amoxicillin versus placebo for fast breathing pneumonia in children aged 2-59 months in Karachi, Pakistan (RETAPP).

• DOI: 10.1186/s12879-015-1334-9
• 发表时间: 2016-01-13
• 期刊: BMC infectious diseases
• 影响因子: 3.7
• 作者: Jehan F;Nisar MI;Kerai S;Brown N;Balouch B;Hyder Z;Ambler G;Ginsburg AS;Zaidi AK
• 通讯作者: Zaidi AK

Recurrence of WHO-defined fast breathing pneumonia among infants, its occurrence and predictors in Pakistan: a nested case-control analysis

世界卫生组织定义的巴基斯坦婴儿呼吸急促性肺炎的复发、发生率和预测因素：巢式病例对照分析

• DOI: 10.1136/bmjopen-2019-035277
• 发表时间: 2020
• 期刊: BMJ Open
• 影响因子: 2.9
• 作者: Brown N

Performance of lung ultrasound in the diagnosis of pediatric pneumonia in Mozambique and Pakistan.

• DOI: 10.1002/ppul.25176
• 发表时间: 2021-03
• 期刊: Pediatric pulmonology
• 影响因子: 3.1
• 作者: Ginsburg AS;Lenahan JL;Jehan F;Bila R;Lamorte A;Hwang J;Madrid L;Nisar MI;Vitorino P;Kanth N;Balcells R;Baloch B;May S;Valente M;Varo R;Nadeem N;Bassat Q;Volpicelli G
• 通讯作者: Volpicelli G

Serial lung ultrasounds in pediatric pneumonia in Mozambique and Pakistan.

• DOI: 10.1038/s41598-021-85485-y
• 发表时间: 2021-03-18
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Ginsburg AS;Nisar I;Madrid L;Lenahan JL;Balouch B;Vitorino P;Hwang J;Lamorte A;Kanth N;Bila R;Valente M;Varo R;May S;Bassat Q;Jehan F;Volpicelli G
• 通讯作者: Volpicelli G