Study Title

A study to compare different injectable antibiotic treatments and different modes of fluid treatment for children with severe pneumonia.

What is the problem?

Pneumonia, an infection of the lungs, is one of the leading causes of death among young children. World Health Organization (WHO) has recommendations for the diagnosis and treatment of pneumonia in low- and middle-income countries using simple clinical features and low cost, widely available antibiotics. The recommend treatment for children at the highest risk of death (severe pneumonia) is injectable benzyl penicillin or ampicillin and gentamicin. Following the introduction of vaccines against the main causes of pneumonia to national immunisation programmes in many low-income countries, there has been growing debate over the appropriateness of the currently recommended treatments. Many clinicians already believe that the recommended treatment is ineffective and frequently opt to use other antibiotics such as amoxicillin-clavulanic acid and ceftriaxone instead. We need a study to determine which antibiotics are best.

Children with severe pneumonia are typically not able to eat food and so standard practice is to try and continue some form of fluid and energy intake during the serious illness. Some authorities advise against feeding through a tube inserted into the stomach through the nose in severely ill children. The main reason for this is are the potential for affecting the ability to breath in a patient already experiencing difficulty breathing and an increased risk of choking on feeds given through the tube. However, the alternative, providing fluids through an intravenous drip, requires careful monitoring by a nurse to ensure the fluid is given at a safe rate over the desired duration. If fluids drip in too fast this may itself cause breathing problems. This a common challenge in many low resource settings where a limited number of nursing staff are required to attend to several duties. Fluids provided through a drip also lack the necessary nutrients to match the increased demands of the body during a serious illness. We plan to carry out a study comparing the different antibiotics and approaches to feeding/fluid management described above.

What questions are we trying to answer?

Current data suggest that more than 10% of children with severe pneumonia die and we are trying to find better ways of treating them to reduce this. We want to find out (1) which antibiotics are the most effective for the treatment of children admitted to hospital with severe pneumonia, and (2) whether feeding through a tube inserted into the stomach through the nose is more effective than providing fluids through a drip inserted in a vein for the management of children with severe pneumonia.

Where is the study taking place, how many people does it involve and how are they selected?

The study will take place at up to 10 hospitals in Kenya, one in Uganda and one in Tanzania. A total of 4392 children aged 2 – 59 months will be allocated to the study treatment groups through a balanced process that ensures each child has a fair chance of receiving any given study treatments. Each of the two questions will be studied in the same set of patients. Thus, a child recruited in the study will receive any one of the three antibiotic treatments and either an intravenous drip for fluids or tube feeding into the stomach. For each of the study questions, we will compare the percentage of children who die within the first five days of recruitment in the alternative treatment groups. We will also compare the length of hospitalisation, time taken to be able to drink, any adverse effects that may be related to the antibiotic treatments, and the percentage of children who die within 30 days of recruitment in the different treatment groups. In a smaller group of children at selected sites, we will also study the causes of pneumonia by performing chest X-rays and studying samples collected from the nose, and the long-term outcomes of the illness by assessing the same group of children 3 months after recruitment.

What does the study involve for those who are in it?

A member of the study team will seek initial permission from the caregiver to include their child in the study. This initial permission will allow children to be provisionally enrolled into the study without delaying the initiation of emergency treatment. The study clinician will interview the caregiver and examine each child after which he/she will prescribe one of the three antibiotic treatments and either an intravenous fluid drip or tube feeding, allocated through a random process. Children will be reviewed daily by the study team, working together with the hospital staff to provide the best care available in the hospital. Further detailed written permission will be sought by the study clinician once the child has stabilised during which additional information on the study will be provided. Children will be followed up during the hospital stay and for 30 days after enrolment through a phone call or a face-to-face visit at the hospital, depending on the alternative that is more convenient and feasible for the caregiver. We will perform a chest X-ray and collect a sample from the nose in a small group of patients who will be followed up for three months after enrolment to better understand the causes and long-term effects of severe pneumonia.

What are the benefits and risks/costs of the study for those involved? 

How will the study benefit society? 

Since pneumonia is the leading cause of hospitalisation in Kenya, Uganda, Tanzania, and other countries in the region, the findings from this research will directly inform policy on the appropriate care of a substantial number of sick children with the hope of reducing child mortality.

When does the study start and finish?

Pneumonia is the leading infectious cause of death among children. Inpatient mortality among children with severe pneumonia often exceeds 10%. For more than 30 years, World Health Organization (WHO) guidelines have recommended empirical treatment with a combination of injectable benzylpenicillin or ampicillin plus gentamicin for children at the highest risk of mortality (severe pneumonia). There is growing debate over the appropriateness of the current recommendations for empirical treatment. The first key question this trial seeks to address is whether either injectable amoxicillin-clavulanic acid or ceftriaxone is superior to benzylpenicillin or ampicillin plus gentamicin (standard care) for the treatment of children hospitalised with severe pneumonia.

Some authorities advise against enteral nutrition in severely ill patients, citing concerns of compromised respiratory status and increased risk of aspiration with nasogastric feeding. Evidence to support these concerns is lacking. Further, administration of intravenous fluids demands careful monitoring - a common challenge in many low resource settings. Intravenous fluids are also deficient in nutritive value to match the raised metabolic demands associated with acute illness. The second key question is therefore whether nasogastric feeding is superior to intravenous fluid therapy for supportive management of children with severe pneumonia.

This 3x2 factorial pragmatic randomised controlled trial will aim to recruit 4392 children aged 2-59 months at up to ten hospitals in Kenya, two in Tanzania, and one in Uganda by competitive enrolment. The primary endpoint will be mortality at Day 5 post-enrolment. Secondary outcomes will be length of hospitalisation, time taken to be able to drink, adverse effects related to the antibiotic treatments, and mortality at Day 30.

A more detailed analysis of aetiology and outcomes will be performed on a sub-population of 500 children randomly selected from sites in Kenya representing high and low malaria transmission regions. This sub-study will involve obtaining chest radiographs, collection of nasopharyngeal samples to test for viral pathogens (Respiratory syncytial virus subtypes A and B and Adenovirus), and clinical assessment three months after recruitment.

The study questions being tackled have been identified as research priorities by policy makers at the Ministry of Health in Kenya, WHO and UNICEF. We therefore anticipate the rapid translation of the findings to policy and clinical practice in settings where the burden of pneumonia is highest.