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Trial registered on ANZCTR


Registration number
ACTRN12616000046404
Ethics application status
Approved
Date submitted
6/01/2016
Date registered
19/01/2016
Date last updated
11/02/2021
Date data sharing statement initially provided
4/12/2018
Date results information initially provided
11/02/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
An intervention study to determine if a longer duration of antibiotics (compared to shorter duration) improves the short and long term clinical outcomes of children hospitalised for pneumonia
Scientific title
A multi-centre double-blind randomised controlled trial to determine if a longer duration of amoxicillin-clavulanic acid (compared to shorter duration) improves the short and long term clinical outcomes of children hospitalised with community-acquired pneumonia, in Indigenous children and a developing country
Secondary ID [1] 288131 0
Nil known
Universal Trial Number (UTN)
Trial acronym
HOPE Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pneumonia in children 297010 0
Condition category
Condition code
Respiratory 297257 297257 0 0
Other respiratory disorders / diseases
Infection 297306 297306 0 0
Studies of infection and infectious agents
Public Health 297446 297446 0 0
Other public health

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
All participants will have received 24-72 hours of intravenous site specific antibiotics, followed by 3 days of oral amoxicillin-clavunate acid, prescribed by site hospitals. Participants will then receive active or placebo treatment for an additional 8 days as below.

Active arm: 8 days of oral amoxcillin-clavulanate 400/57 duo formulation (70-90mg/kg/day, twice daily dosing; max 980mg per day)

Placebo arm: 8 days of oral placebo (equivalent volume as the active arm)

Treatment dose (range) is determined by local site hospital treatment protocols. Parents will keep a medication diary and/or receive phone calls to monitor adherence to intervention medication. Where possible, we will also collect empty medication bottles at the 4 week clinical review.
Intervention code [1] 293441 0
Treatment: Drugs
Comparator / control treatment
The control group receives placebo for the duration on the intervention period (8 days) whilst the active group continues on amoxicillin-clavulanic acid for the intervention period. Both medications for the study are in suspension form and the placebo has been specifically commercially manufactured which has the same taste, appearance and smell.
Control group
Placebo

Outcomes
Primary outcome [1] 296847 0
The proportion without chronic respiratory symptoms and signs or bronchiectasis. We will capture any further chronic respiratory symptoms and signs or bronchiectasis though the child’s medical records (community or hospital) and clinical review
Timepoint [1] 296847 0
We aim to review these children at 24 months, However, many children will reside in geographically isolated locations, thus a range of 23-26 months is a reasonable time frame to capture clinically important outcomes.
Secondary outcome [1] 319505 0
Adverse events (anorexia, nausea, vomiting, abdominal pain, diarrhoea, rashes)
Timepoint [1] 319505 0
We will monitor adverse effects while children are actively taking medication. Parents will keep a diary of adverse events.
Secondary outcome [2] 319506 0
Nasopharyngeal respiratory bacterial pathogens and antibiotic resistance will be assessed using nasal swabs.

This is a composite secondary outcome and can not be separated.
Timepoint [2] 319506 0
Nasopharyngeal respiratory bacterial pathogens and antibiotic resistance will be assessed using our research laboratory’s previously published methods at baseline (admission to hospital), week 4 (range 4-6 weeks) and 12 months (range 12-14 months).
Secondary outcome [3] 319507 0
Gene expression of targeted genes. This is a composite outcome, We will perform gene expression studies of the blood using micro-arrays and quantify selected gene targets as determined from the experimental group (a subset of participants where blood was collected)
Timepoint [3] 319507 0
Baseline (hospital admission) and 4-6 weeks (where possible, i.e. in a subset of children). A blood sample will be taken at baseline and again at week 4-6. At each of these time points, gene expression and target genes will be assessed.
Secondary outcome [4] 349704 0
The proportion with clinical cure (i.e. complete resolution of respiratory symptoms and signs). Children will have a standardised respiratory clinical assessment, completed by either a member of the study team (doctor, research nurse), or community health centre staff member (if required)
Timepoint [4] 349704 0
We aim to review these children at week 4, however many children will reside in geographically isolated locations, thus a range of 4-6 weeks is a reasonable time frame to capture clinically important outcomes.
Secondary outcome [5] 349705 0
Time to next respiratory-related hospitalisation assessed by chart reviews.
Timepoint [5] 349705 0
Data will be captured through chart reviews of children’s medical records (e.g. hospital and/or community health record) and/or information from parents in next 12 months.

Eligibility
Key inclusion criteria
1) Hospitalised children aged 3-mo to <6-yrs (in Darwin, children have to be Indigenous)
(2) Have features of severe pneumonia on admission (temperature >37.50C or a history of fever at home or observed at the referring clinic, age-adjusted tachypnoea [RR>50 if <12-mo; RR>40 if >12-mo] with chest wall recession and/or SpO2 <92% in air), and consolidation on CXR as diagnosed by treating clinician
(3) After 1-3 days of IV antibiotics, are afebrile, with improved respiratory symptoms and signs, SpO2 >90% in air and are ready to be switched to oral amoxicillin-clavulanate, and
(4) Have symptoms of no longer than 7 days at point of hospitalisation.
(5) Recruited within 24 hours of admission to ward
Minimum age
3 Months
Maximum age
6 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
(1) Current wheeze
(2) Underlying chronic illness other than asthma (e.g. bronchiectasis, cyanotic congenital heart disease or cardiac failure, neuromuscular disorders, immunodeficiency) that could potentially influence the current illness
(3) Severe malnutrition (weight-for-height Z-score <-3)
(4) Complicated (effusion, empyema or abscess) pneumonia, including tuberculosis
(5) Extra-pulmonary infection requiring antibiotic therapy (e.g. meningitis)
(6) Beta-lactam allergy
(7) Previously enrolled
(8) Lack a mobile phone and/or unable to return for follow-up clinic visits during the next 24 months

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Sequential allocation list with each next position concealed by opaque covering
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block design
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
An intention to treat approach will be used and per protocol used for sensitivity analysis

Primary aim: The main effects of the interventions will be determined by comparing the primary outcome: Proportion without any chronic respiratory symptoms/signs or bronchiectasis at 24 months. We will use odds and incident ratios with logistic regression and negative binomial regression models respectively as well as linear regression for determining absolute differences between proportions (with 95%CI),

Secondary aims: Proportion with clinical cure (complete resolution of respiratory symptoms and signs) at 4-weeks will be compared between groups. A Kaplan-Meier curve will be constructed for each group for time to next respiratory-related hospitalisation, and proportions will be compared using time-to-event regression models (as above). CXR abnormality and gene expression data will be compared between children with and without chronic respiratory symptoms/bronchiectasis.

Children lost to follow up will be replaced to ensure we have complete outcome data for our required sample size .

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NT
Recruitment hospital [1] 4930 0
Royal Darwin Hospital - Tiwi
Recruitment postcode(s) [1] 12438 0
0811 - Casuarina
Recruitment outside Australia
Country [1] 7407 0
Malaysia
State/province [1] 7407 0
Sarawak/Kuching
Country [2] 7408 0
Malaysia
State/province [2] 7408 0
Sabah/Kota Kinabalu
Country [3] 7409 0
Malaysia
State/province [3] 7409 0
Kuala Lumpur
Country [4] 8648 0
New Zealand
State/province [4] 8648 0
Auckland
Country [5] 9484 0
Malaysia
State/province [5] 9484 0
Klang

Funding & Sponsors
Funding source category [1] 292541 0
Government body
Name [1] 292541 0
National Health and Medical Research Council
Address [1] 292541 0
National Health and Medical Research Council
GPO Box 1421
Canberra City ACT 2601

Country [1] 292541 0
Australia
Primary sponsor type
Other
Name
Menzies School of Health Research
Address
PO Box 41096
Casuarina NT 0811
Country
Australia
Secondary sponsor category [1] 291258 0
None
Name [1] 291258 0
N/A
Address [1] 291258 0
N/A
Country [1] 291258 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294016 0
Human Research Committe of the Northern Territory Department of Health and Menzies School of Health Research
Ethics committee address [1] 294016 0
PO Box 41096
Casuarina NT 0811
Ethics committee country [1] 294016 0
Australia
Date submitted for ethics approval [1] 294016 0
20/01/2016
Approval date [1] 294016 0
25/02/2016
Ethics approval number [1] 294016 0
Ethics committee name [2] 294103 0
University of Malaya Research Ethics Committee-(UMREC)
Ethics committee address [2] 294103 0
C/o Humanities Research Cluster Office
Level 7, Research Management & Innovation Complex,
University of Malaya,
50603 Kuala Lumpur
Ethics committee country [2] 294103 0
Malaysia
Date submitted for ethics approval [2] 294103 0
29/01/2016
Approval date [2] 294103 0
Ethics approval number [2] 294103 0
Ethics committee name [3] 294104 0
Medical research and ethics committee (MREC)
Ethics committee address [3] 294104 0
Secretariat of National Institutes of Health (NIHSEC)
c/o Institute for Health Management
Jalan Rumah Sakit, Bangsar
59000 Kuala Lumpur
Ethics committee country [3] 294104 0
Malaysia
Date submitted for ethics approval [3] 294104 0
29/01/2016
Approval date [3] 294104 0
Ethics approval number [3] 294104 0

Summary
Brief summary
Indigenous Australian children have the world’s highest published rates of hospitalised pneumonia and chronic lung disease including bronchiectasis (BE). Children from developing countries are also at a similar risk. Yet, optimal treatment of pneumonia and how to prevent its long-term effects remain unclear. Trials have focused upon short-term (1-2 wk) outcomes and reduced antibiotic (AB) courses in children with non-severe (viral) pneumonia. However, in high-risk populations from Australia and Malaysia, a longer course of ABs may enhance bacteria clearance and thus reduce the risk of chronic lung disease after severe bacterial pneumonia in young children whose lungs are still developing.

Our international multicentre, double-blind RCT is designed to answer our primary question: Does a longer course of ABs (13-14 days) compared to a short course (5-6 days) improve short and long-term outcomes of young children hospitalised with chest xray-proven pneumonia? We will randomise 314 children (aged 3 months to 5 yrs) from 4 sites. Children will be seen at clinically important time points (4 wk, 12 and 24 months) and blood, nasopharyngeal swabs and chest x-rays collected, based on pilot data.

Data from this first such study worldwide will substantially advance child pneumonia treatment with implications for future lung health, especially in high-risk Indigenous children. Results would lead to changes in national and international guidelines.

As a longer AB treatment for all children may increase AB resistance and lead to ‘over-treatment’ in some, we will address these 2 issues by monitoring for AB resistance and embark on a discovery program to identify biomarkers that predict poor long-term respiratory health outcomes. Availability of novel biomarkers from host gene expression will help clinicians decide which children are at high risk, and therefore in need of more intensive follow up, and may enable targeting of longer AB treatment to those at highest risk of BE.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 62146 0
Prof Anne Chang
Address 62146 0
Menzies School of Health Research
PO Box 41096
Casuarina NT 0811
Country 62146 0
Australia
Phone 62146 0
+61 8 8946 8682
Fax 62146 0
Email 62146 0
anne.chang@menzies.edu.au
Contact person for public queries
Name 62147 0
Dr Gabrielle McCallum
Address 62147 0
Menzies School of Health Research
PO Box 41096
Casuarina NT 0811
Country 62147 0
Australia
Phone 62147 0
+61 8 89468565
Fax 62147 0
Email 62147 0
gabrielle.mccallum@menzies.edu.au
Contact person for scientific queries
Name 62148 0
Prof Anne Chang
Address 62148 0
Menzies School of Health Research
PO Box 41096
Casuarina NT 0811
Country 62148 0
Australia
Phone 62148 0
+61 8 8946 8682
Fax 62148 0
Email 62148 0
anne.chang@menzies.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Due to cultural considerations for our participant group, it is not currently planned to have de-identified data available for public access.
What supporting documents are/will be available?
Study protocol
How or where can supporting documents be obtained?
Type [1] 602 0
Study protocol
Citation [1] 602 0
Link [1] 602 0
Email [1] 602 0
Other [1] 602 0
Our study protocol has been provisionally accepted for publication.
Attachment [1] 602 0
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary