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Trial registered on ANZCTR


Registration number
ACTRN12623000098639
Ethics application status
Approved
Date submitted
17/01/2023
Date registered
27/01/2023
Date last updated
21/07/2024
Date data sharing statement initially provided
27/01/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Long-term treatment with azithromycin to prevent bronchiectasis and recurrent cough (LEAP-Cough)
Scientific title
The effectiveness of long-term treatment with azithromycin to prevent bronchiectasis and recurrent cough (LEAP-Cough) and developing individualised approaches for children with chronic wet cough
Secondary ID [1] 308757 0
None
Universal Trial Number (UTN)
Trial acronym
LEAP-Cough
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic wet cough 328703 0
Condition category
Condition code
Respiratory 325714 325714 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Azithromycin: Oral 10mg/kg/dose (max 500 mg/dose), 3x weekly for 9 months or 30mg/kg/dose weekly. Supplied as powder for suspension or tablet.

The type (powder or tablet) and frequency (x3/week or weekly) will be determined based on the child's age, preference and setting. Adherence will be monitored by diary monitoring and collection of medication from the pharmacy.
Intervention code [1] 325213 0
Treatment: Drugs
Comparator / control treatment
Control group will not receive anything and adviced to continue with normal activities
Control group
Active

Outcomes
Primary outcome [1] 333562 0
Proportion of children with recurrent protracted bacterial bronchitis (PBB) >3 episodes PBB/year or bronchiectasis. These will be collected by participant reports and medical records.
Timepoint [1] 333562 0
Within 12 months for PBB recurrence
Within 24 months of enrolment for bronchiectasis
Secondary outcome [1] 417526 0
Adverse events, including non-pulmonary infections requiring antibiotics (e.g. vomiting, nausea, use of additional antibiotics for non-respiratory conditions)
These will be collected by participant reports and medical records.
Timepoint [1] 417526 0
9 months post-enrolment,
Secondary outcome [2] 417527 0
Parent Cough Specific Quality of Life.
These will be collected by participant reports.
Timepoint [2] 417527 0
12 months, 24 months post-enrolment,
Secondary outcome [3] 417528 0
Time to next exacerbation of wet cough requiring treatment with antibiotics.
These will be collected by participant reports and medical records.
Timepoint [3] 417528 0
in weeks from time of randomisation up to 24 months
Secondary outcome [4] 417529 0
Spirometry and any lung function tests completed
These will be collected by medical records.
Timepoint [4] 417529 0
24 months post-enrolment
Secondary outcome [5] 417530 0
Cost-effectiveness of treatment (incremental cost per recurrent PBB or bronchiectasis prevented) by calculating difference between resource use and costs from hospital medical records. These will be collected by participant reports and medical records. Participant reports will be collected by a combintaion of on-line surveys, telephone calls and face-to-face reviews,
Timepoint [5] 417530 0
24 months post-enrolment,
Secondary outcome [6] 417531 0
Time off work and school in days. These will be collected by participant reports. articipant reports will be collected by a combintaion of on-line surveys, telephone calls and face-to-face reviews,
Timepoint [6] 417531 0
24 months post-enrolment,

Eligibility
Key inclusion criteria
1. Children aged 2 months-19 years
2. Suspected of having PBB i.e current or past history of chronic wet cough
3. Plan to remain in contact with one of the study sites for 24 months
4. Have one or more ‘high-risk traits’
• Cough duration >6-months
• Recurrent antibiotics use [>3 episodes to treat chronic wet cough in preceding 12-mo]
or
• Airway Haemophilus influenzae infection.
Minimum age
2 Months
Maximum age
19 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Presence of chronic cough pointers suggesting other causes of CWC- based on treating clinicians’ evaluation. (eg. bronchiectasis);
2. Known chronic lung disease eg. CT confirmed bronchiectasis (asthma not excluded as many children with PBB are misdiagnosed) or
3. Previously enrolled.
4. Contraindication to azithromycin (known liver dysfunction, known hypersensitivity to Azithromycin) or
5. Enrolled in another current RCT.

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomisation by computer, done through REDCap.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted blocks (2-8 blocks). Treatment allocation of individual participants will be by groups stratified by (i) site (Brisbane [2 sites], Melbourne, Sydney, Darwin, Perth), (ii) age group (6 year and less, over 6 years) and (iii) presence of current wet cough at the point of randomisation (yes/no).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3 / Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
Detailed Statistical Analyses Plan (SAP) will be prepared prior to unblinding and analyses. Data will be audited, cleaned and locked before final analysis is undertaken. The investigators will only see analyses of pooled data until statistical analysis code has been written (on pooled data) and agreed, and the trial has terminated.

For the primary aim (RCT): We will use a generalised linear model with binomial family and identity link to determine the relative difference in the proportion of children with PBB-bronchiectasis between the two intervention groups. The main effect in the model will be the treatment groups of azithromycin vs controls.

Secondary: For QoL (main secondary endpoint), the QoL change from baseline for each person ([12-mo minus baseline] and [24-mo minus baseline]) and the intervention effect of between-group difference in means, we will use a linear-mixed model (checking assumptions).

For (i) lung function values [% predicted values of FEV1 and forced expiratory volume (FVC)], and (ii) time off school/work; between treatment arms will be analysed using ANCOVA and presented as the mean difference (95%CI). (iii) A Kaplan-Meier curve will be constructed for each group (azithromycin vs control) for time-to-first exacerbation, and we will perform a log-rank test and report a hazard ratio (Cox regression model). (iv) Chi2 tests will be used to compare the proportion of children with ‘medication attributable adverse events’ between groups.

Cost-effectiveness will be reported in a secondary paper.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
4/07/2023
Actual
3/07/2023
Date of last participant enrolment
Anticipated
31/12/2027
Actual
Date of last data collection
Anticipated
31/12/2029
Actual
Sample size
Target
274
Accrual to date
61
Final
Recruitment in Australia
Recruitment state(s)
NSW,NT,QLD,WA,VIC
Recruitment hospital [1] 23830 0
Queensland Children's Hospital - South Brisbane
Recruitment hospital [2] 23831 0
Royal Darwin Hospital - Tiwi
Recruitment hospital [3] 23832 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [4] 23833 0
Perth Children's Hospital - Nedlands
Recruitment hospital [5] 23834 0
The Royal Childrens Hospital - Parkville
Recruitment postcode(s) [1] 39285 0
4101 - South Brisbane
Recruitment postcode(s) [2] 39286 0
0810 - Tiwi
Recruitment postcode(s) [3] 39287 0
2145 - Westmead
Recruitment postcode(s) [4] 39288 0
6009 - Nedlands
Recruitment postcode(s) [5] 39289 0
3052 - Parkville
Recruitment outside Australia
Country [1] 26436 0
Malaysia
State/province [1] 26436 0
Kuala Lumpur
Country [2] 26437 0
Philippines
State/province [2] 26437 0
Quezon City, Manila
Country [3] 26438 0
Guatemala
State/province [3] 26438 0
Guatemala City

Funding & Sponsors
Funding source category [1] 312980 0
Government body
Name [1] 312980 0
National Health and Medical Research Council - MRFF
Country [1] 312980 0
Australia
Funding source category [2] 317001 0
Charities/Societies/Foundations
Name [2] 317001 0
Thrasher Research Fund
Country [2] 317001 0
United States of America
Primary sponsor type
University
Name
Queensland University of Technology
Address
2 George St, Brisbane City QLD 4000
Country
Australia
Secondary sponsor category [1] 314666 0
None
Name [1] 314666 0
Address [1] 314666 0
Country [1] 314666 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312245 0
Children’s Health Queensland Human Research Ethics Committee
Ethics committee address [1] 312245 0
Level 7, Centre for Children’s Health Research 62 Graham St
South Brisbane, Queensland 4101
Ethics committee country [1] 312245 0
Australia
Date submitted for ethics approval [1] 312245 0
16/01/2023
Approval date [1] 312245 0
22/02/2023
Ethics approval number [1] 312245 0
HREC Reference number: HREC/23/QCHQ/85258

Summary
Brief summary
Chronic wet cough (CWC) is among the commonest symptoms of chronic lung disease. In children, it is associated with bronchiectasis (BE), recurrent doctor visits and impaired quality-of-life (QoL). Early diagnosis/treatment leads to decreased cost and, improved QoL and clinical outcomes. Yet, there is currently there are no published data on treatable traits in children with child CWC or intervention that prevents BE.

Our primary question is: In children with CWC and with ‘high-risk traits’ (recurrent antibiotics for CWC, airway H. influenzae infection or cough duration >6-mo), does 9-mo of azithromycin (vs controls) reduce the risk of future recurrent protracted bacterial bronchitis (recPBB) and BE?

Our secondary aims are to determine if 9-mo of regular azithromycin (vs. controls) improve other clinical outcomes (lung function, time-to-next exacerbation, recurrence rate, and time off work/school) and its cost-effectiveness, in children with CWC and with ‘high-risk traits’.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 123974 0
Prof Anne Chang
Address 123974 0
Queensland Children's Hospital
Stanley Street, South Brisbane, Qld 4101
Country 123974 0
Australia
Phone 123974 0
+61 7 30697283
Fax 123974 0
Email 123974 0
[email protected]
Contact person for public queries
Name 123975 0
Anne Cook
Address 123975 0
Children's Centre for Health Research
Graham Street,
South Brisbane
Qld 4101
Country 123975 0
Australia
Phone 123975 0
+61 7 30697283
Fax 123975 0
Email 123975 0
[email protected]
Contact person for scientific queries
Name 123976 0
Anne Chang
Address 123976 0
Queensland Children's Hospital
Stanley Street, South Brisbane, Qld 4101
Country 123976 0
Australia
Phone 123976 0
+61 7 30697283
Fax 123976 0
Email 123976 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
As data include sensitive information from First Nations children and minors, no data will be shared.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
Dimensions AIDevelopments and priorities in bronchiectasis research2023https://doi.org/10.1016/s2213-2600(23)00258-8
N.B. These documents automatically identified may not have been verified by the study sponsor.