HOspitalised Pneumonia Extended (HOPE) Study to reduce the long-term effects of childhood pneumonia: protocol for a multicentre, double-blind, parallel, superiority randomised controlled trial

Abstract

IntroductionEarly childhood pneumonia is a common problem globally with long-term complications that include bronchiectasis and chronic obstructive pulmonary disease. It is biologically plausible that these long-term effects may be minimised in young children at increased risk of such sequelae if any residual lower airway infection and inflammation in their developing lungs can be treated successfully by longer antibiotic courses. In contrast, shortened antibiotic treatments are being promoted because of concerns over inducing antimicrobial resistance. Nevertheless, the optimal treatment duration remains unknown. Outcomes from randomised controlled trials (RCTs) on paediatric pneumonia have focused on short-term (usually <2 weeks) results. Indeed, no long-term RCT-generated outcome data are available currently. We hypothesise that a longer antibiotic course, compared with the standard treatment course, reduces the risk of chronic respiratory symptoms/signs or bronchiectasis 24 months after the original pneumonia episode.Methods and analysisThis multicentre, parallel, double-blind, placebo-controlled randomised trial involving seven hospitals in six cities from three different countries commenced in May 2016. Three-hundred-and-fourteen eligible Australian Indigenous, New Zealand Māori/Pacific and Malaysian children (aged 0.25 to 5 years) hospitalised for community-acquired, chest X-ray (CXR)-proven pneumonia are being recruited. Following intravenous antibiotics and 3 days of amoxicillin-clavulanate, they are randomised (stratified by site and age group, allocation-concealed) to receive either: (i) amoxicillin-clavulanate (80 mg/kg/day (maximum 980 mg of amoxicillin) in two-divided doses or (ii) placebo (equal volume and dosing frequency) for 8 days. Clinical data, nasopharyngeal swab, bloods and CXR are collected. The primary outcome is the proportion of children without chronic respiratory symptom/signs of bronchiectasis at 24 months. The main secondary outcomes are ‘clinical cure’ at 4 weeks, time-to-next respiratory-related hospitalisation and antibiotic resistance of nasopharyngeal respiratory bacteria.Ethics and disseminationThe Human Research Ethics Committees of all the recruiting institutions (Darwin: Northern Territory Department of Health and Menzies School of Health Research; Auckland: Starship Children’s and KidsFirst Hospitals; East Malaysia: Likas Hospital and Sarawak General Hospital; Kuala Lumpur: University of Malaya Research Ethics Committee; and Klang: Malaysian Department of Health) have approved the research protocol version 7 (13 August 2018). The RCT and other results will be submitted for publication.Trial registrationACTRN12616000046404.

Extended Versus Standard Antibiotic Course Duration in Children <5 Years of Age Hospitalized With Community-acquired Pneumonia in High-risk Settings: Four-week Outcomes of a Multicenter, Double-blind, Parallel, Superiority Randomized Controlled Trial

“…This is of relevance to our target population, who from early life have high-density nasopharyngeal colonization by bacterial pathogens ( Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis 37 ) associated with lower airway disease. 22…”

“…Those randomized to the extended course arm had an additional 8 days of amoxicillin-clavulanate, while those in the standard arm received 8 days of oral placebo. 22 Randomization was stratified by age (<1 or 1–5 years) and site (n = 5). Treatment allocation was concealed from all investigators, hospital staff and caregivers throughout the trial.…”

“…This will determine whether an extended antibiotic course, compared with a standard course of antibiotics, reduces the risk of developing chronic respiratory symptoms/signs or bronchiectasis over the following 24 months. 22 Here, as initial findings from the main study, we report the 4 week clinical endpoints, which will contribute to the current, limited clinical data for antibiotic course duration for children hospitalized with uncomplicated pneumonia. We determined whether an extended antibiotic course (13–14 days) is superior to a standard course (5–6 days) for achieving clinical cure at 4 weeks when treating children hospitalized with pneumonia.…”

Study Protocol for Preventing Early-Onset Pneumonia in Young Children Through Maternal Immunisation: A Multi-Centre Randomised Controlled Trial (PneuMatters)

“…Secondly, at this site, there is relatively high mortality and morbidity from ALRIs, including pneumonia ( 65 ), and chronic suppurative lung disease is a recognised health problem ( 66 ). Finally, the senior researchers have established successful collaborations ( 47 ).…”

“…Infants' data are obtained from parents/carers and the medical notes at every visit (birth details, breast feeding, growth, respiratory symptoms/signs and ALRIs co-morbidities). We have established robust methods for capturing ALRI episodes from our previous RCTs ( 44 , 45 , 47 ). Hospital records will be reviewed for identifying hospitalisations.…”