Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000315819
Ethics application status
Approved
Date submitted
16/02/2021
Date registered
22/03/2021
Date last updated
15/09/2024
Date data sharing statement initially provided
22/03/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
BronchiEctasis Trial Testing ERdosteine (BETTER)
Scientific title
Evaluating the effect of erdosteine on respiratory exacerbation rate of children and adults with bronchiectasis - a double-blind, randomised controlled trial
Secondary ID [1] 303719 0
None
Universal Trial Number (UTN)
None
Trial acronym
BETTER
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Bronchiectasis 320241 0
Condition category
Condition code
Respiratory 318174 318174 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Erdosteine: Oral twice daily doses for 12 months [<15 kg = 2.5mls/dose; 15-19 kg = 5mls/dose; 20-30 kg = 7.5ml/dose (or one capsule in children who can take capsules); >30 kg = 10ml/dose (or one capsule in participants who can take capsules)]. The formulation for liquid is powder for suspension.

Adherence will be monitored by return of bottles or capsule packaging.

In a subset of participants, we will also evaluate if inflammatory and/or microbial biomarkers will identify pathways and/or predict those at greater risk of recurrent respiratory exacerbations. These outcomes will not be reported in the RCT. Participants for this component will be based on whether they consent to these additional procedures (sputum and blood). Where possible, bloods and sputum will be taken at baseline and at commencement of an exacerbation.
Intervention code [1] 319432 0
Treatment: Drugs
Comparator / control treatment
Placebo = equivalent volume of oral suspension of excipients or matching placebo microcellulose capsule.
Control group
Placebo

Outcomes
Primary outcome [1] 326159 0
Respiratory exacerbation rate. An acute respiratory episode is defined by an acute respiratory event (RE) that: (a) is treated with antibiotics AND (b) an increase in sputum volume or purulence, for 3 or more days of change in cough (at least 20% increase in cough score or type [dry to wet/productive]) or physician confirmed acute change in respiratory rate, work of breathing or chest signs or hospitalisation.

In adults, RE will be defined as an acute respiratory episode that:
(a) is treated with antibiotics AND
(b) deterioration in three or more of the following key symptoms for at least 48-hours: cough; sputum volume and/or consistency; sputum purulence; breathlessness and/or exercise tolerance; fatigue and/or malaise or haemoptysis.

These will be collected by participant reports and medical records.
Timepoint [1] 326159 0
12 months post-commencement of intervention
Secondary outcome [1] 390280 0
Quality of Life [QoL]. In children Parent-proxy quality of life (PC-QoL) will be used; in adults bronchiectasis QoL will be used.
Timepoint [1] 390280 0
6 and 12 months post-commencement of intervention
Secondary outcome [2] 390281 0
Spirometry values (FVC and FEV1 % predicted)
(change from best values at baseline to best value at last visit)
Timepoint [2] 390281 0
12 months post-commencement of intervention
Secondary outcome [3] 390282 0
Total duration of respiratory exacerbations (in days). This will be collected by active surveillance through participant reports and medical records.
Timepoint [3] 390282 0
12 months post-commencement of intervention
Secondary outcome [4] 390283 0
Time to next acute respiratory exacerbation through surveillance of exacerbations using telephone, emails, web-based contact and review of medical records
Timepoint [4] 390283 0
Variable dependent on first exacerbation
Secondary outcome [5] 390284 0
A trial-based incremental incremental cost-effectiveness ratio (ICER) will estimate the incremental cost per exacerbation avoided. ICER=[(CostErdoteine) minus (CostPlacebo)]/[(EffectErdosteine minus EffectPlacebo)]
Timepoint [5] 390284 0
12 months post-commencement of intervention
Secondary outcome [6] 390285 0
Adverse events (e.g. nausea, vomiting, flare-ups not requiring antibiotics during 12 months treatment period) through surveillance of AEs using at least monthly telephone, emails, web-based contact and review of medical records
Timepoint [6] 390285 0
12 months post-commencement of intervention (total number through continuous recording)
Secondary outcome [7] 407658 0
Biomarkers (gene expression markers of blood) and airway microbia (airway specimens e.g. sputum). In a subset of participants, we will also evaluate if inflammatory and/or microbial biomarkers can identify pathways and/or predict those at greater risk of recurrent respiratory exacerbations, as an exploratory outcomes. As technology changes with time, these will be stored and processed after the clinical components of the study has been completed.
Timepoint [7] 407658 0
Baseline compared to first exacerbation within 12 months of study period post enrolment

Eligibility
Key inclusion criteria
1. Participants aged 2 to 49 years
2. Bronchiectasis with at least 2 acute respiratory exacerbations in the last 18 months AND
3. Able to be contacted for the 15 month follow up period.
Minimum age
2 Years
Maximum age
49 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Cystic fibrosis
2. Contraindication to erdosteine use (e.g. liver dysfunction, hypersensitivity, renal failure, deficiency of the cystathionine-synthetase enzyme, phenylketonuria, active peptic ulcer)
3. Pregnant, pregnancy planned (in next 12 months) or nursing mothers
4. Previously randomised
5. Hospitalised in the last 4 weeks for respiratory instability
6. Participation in another intervention concurrent RCT.

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)
Individual participants will be allocated to next number of on the stratified list. The list does not contain the allocation of the 2 study groups. The code for each unique number is held and kept by the local hospital's pharmacist and is not known to anyone else.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A computer-generated permuted block (4-8 block sizes) randomisation sequence is planned (stratified by sites; n=8). Sequence will be generated by an independent statistician.
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 3 / Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
Intention-to-treat analyses will be used where possible and per protocol (PP) undertaken as a sensitivity analysis. For exacerbation rate (primary outcome), we will use a negative binomial regression model (including treatment group, stratifying factors as independent factors and number of months in the study included as an offset) to determine between-group differences (with 95%CI).

For QoL (secondary outcome), the QoL change from baseline for each person [(6-mo minus baseline) and (12-mo minus baseline)] and the intervention effect is a difference in means between the erdosteine and placebo groups. After standardising the children’s and adults’ change in QoL measures using the SDs of their respective baseline QoL (as per Cochrane meta-analysis for combining different scales), we will use a linear-mixed model (checking assumptions).

Duration of exacerbations between treatment arms will be analysed using ANCOVA and presented as the mean difference (95%CI).

To compare the groups for time to next exacerbation, we will use Cox proportional hazard modelling to calculate hazard ratios. Time to next exacerbation will be compared using a log rank test.

Cost-effectiveness data: Incremental cost-effectiveness ratio on the potential benefits (in terms of savings in hospitalisations and other associated costs to health services and patients) of erdosteine compared to placebo and compared to the additional cost of administering the medication

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/04/2021
Actual
27/05/2021
Date of last participant enrolment
Anticipated
13/09/2024
Actual
Date of last data collection
Anticipated
13/08/2025
Actual
Sample size
Target
205
Accrual to date
205
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 18382 0
Queensland Children's Hospital - South Brisbane
Recruitment hospital [2] 18383 0
Gold Coast University Hospital - Southport
Recruitment hospital [3] 21993 0
Royal Darwin Hospital - Tiwi
Recruitment hospital [4] 21995 0
Mater Adult Hospital - South Brisbane
Recruitment hospital [5] 21996 0
Concord Repatriation Hospital - Concord
Recruitment hospital [6] 24123 0
Royal Perth Hospital - Perth
Recruitment postcode(s) [1] 32469 0
4101 - South Brisbane
Recruitment postcode(s) [2] 32470 0
4215 - Southport
Recruitment postcode(s) [3] 37094 0
0810 - Tiwi
Recruitment postcode(s) [4] 37096 0
4101 - South Brisbane
Recruitment postcode(s) [5] 37097 0
2139 - Concord
Recruitment postcode(s) [6] 39631 0
6000 - Perth
Recruitment outside Australia
Country [1] 24676 0
Malaysia
State/province [1] 24676 0
Kuala Lumpur
Country [2] 24677 0
Philippines
State/province [2] 24677 0
Quezon City

Funding & Sponsors
Funding source category [1] 307538 0
Charities/Societies/Foundations
Name [1] 307538 0
Queensland Children's Hospital Foundation
Country [1] 307538 0
Australia
Funding source category [2] 311051 0
Charities/Societies/Foundations
Name [2] 311051 0
Thrasher Research Fund - EW "Al" Thrasher Award
Country [2] 311051 0
United States of America
Funding source category [3] 311052 0
Government body
Name [3] 311052 0
Medical Research Future Fund/National Health and Medical Research Council
Country [3] 311052 0
Australia
Primary sponsor type
University
Name
Queensland University of Technology
Address
CCHR
Graham Street,
South Brisbane
Qld 4101
Country
Australia
Secondary sponsor category [1] 308222 0
None
Name [1] 308222 0
Address [1] 308222 0
Country [1] 308222 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307604 0
Children’s Health Queensland Human Research Ethics Committee
Ethics committee address [1] 307604 0
Ethics committee country [1] 307604 0
Australia
Date submitted for ethics approval [1] 307604 0
26/04/2020
Approval date [1] 307604 0
22/07/2020
Ethics approval number [1] 307604 0
HREC/20/QCHQ/64068

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 107830 0
Prof Anne Chang
Address 107830 0
Queensland Children's Hospital
Stanley Street, South Brisbane, Qld 4101
Country 107830 0
Australia
Phone 107830 0
+61 730681111
Fax 107830 0
Email 107830 0
[email protected]
Contact person for public queries
Name 107831 0
Alena Gadoury
Address 107831 0
Children's Centre for Health Research Graham Street, South Brisbane Qld 4101
Country 107831 0
Australia
Phone 107831 0
+61 7 30697283
Fax 107831 0
Email 107831 0
[email protected]
Contact person for scientific queries
Name 107832 0
Anne Chang
Address 107832 0
Queensland Children's Hospital
Stanley Street, South Brisbane, Qld 4101
Country 107832 0
Australia
Phone 107832 0
+61 7 30681111
Fax 107832 0
Email 107832 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
Children's data and thus not shared in accordance to ethical requirements in our institution


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
EmbaseDevelopments and priorities in bronchiectasis research.2023https://dx.doi.org/10.1016/S2213-2600%2823%2900258-8
N.B. These documents automatically identified may not have been verified by the study sponsor.