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Trial registered on ANZCTR


Registration number
ACTRN12623000670673
Ethics application status
Approved
Date submitted
29/03/2023
Date registered
21/06/2023
Date last updated
24/11/2024
Date data sharing statement initially provided
21/06/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
A Randomised Controlled Trial of the efficacy and safety of an Inhaled Corticosteroid and Long Acting Beta Agonist reliever therapy regimen in preschool children with mild asthma/recurrent wheeze.
Scientific title
An open-label randomised controlled trial of as-needed budesonide-formoterol vs. salbutamol reliever therapy in preschool children with mild asthma/recurrent wheeze.
Secondary ID [1] 308779 0
None.
Universal Trial Number (UTN)
U1111-1282-1375.
Trial acronym
PRECARE: PREschool Children's Anti-inflammatory REliever.
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Asthma. 328720 0
Condition category
Condition code
Respiratory 325731 325731 0 0
Asthma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Inhaled Corticosteroid with Long-Acting-Beta2-Agonist (ICS-LABA):

Budesonide-formoterol pressurised metered-dose inhaler 100micrograms/6micrograms, one puff via spacer, as required for relief of asthma/wheeze symptoms, for 52 weeks.

The intervention will be parent/guardian administered.

There is no maximum daily frequency of administration of the intervention, however participants will receive a personalised written action plan detailing when to seek medical help (participant's using more than 6 puffs in one day will be advised to go to the hospital or see their doctor today).

Adherence will not be monitored.

Children and their parent/guardian will attend a face-to-face appointment at a clinic space (Visit 1 - approximately 60-90 minutes) with a member of the research team. This is to ascertain their eligibility for the study, and then to randomise to a treatment arm. Children aged 4 years will be assessed as to the suitability of using a spacer with no mask versus with a mask when administering the medication. Any child under 3 years of age or who can't demonstrate adequate spacer use will be educated to use a mask attached to the spacer for all treatments. Education will be given on correct inhaler use (children will be instructed to take six breaths from the spacer for each puff of medication) and a written action plan will be completed and discussed with the child and their parent/guardian. Inhaler use, spacer technique and asthma action plan will be reassessed at Visits 2, 3 and 4 and re-education provided as necessary.
Intervention code [1] 325232 0
Treatment: Drugs
Comparator / control treatment
Short-Acting-Beta-Agonist (SABA):

Salbutamol pressurised metered-dose inhaler 100micrograms, two puffs via spacer, as required for asthma/wheeze symptoms, for 52 weeks.

The control will be parent/guardian administered.

There is no maximum daily frequency of administration of the intervention, however participants will receive a personalised written action plan detailing when to seek medical help (participant's using more than 12 puffs in one day will be advised to go to the hospital or see their doctor today).

Adherence will not be monitored.

Children and their parent/guardian will attend a face-to-face appointment at a clinic space (Visit 1 - approximately 60-90 minutes) with a member of the research team. This is to ascertain their eligibility for the study, and then to randomise to a treatment arm. Children aged 4 years will be assessed as to the suitability of using a spacer with no mask versus with a mask when administering the medication. Any child under 3 years of age or who can't demonstrate adequate spacer use will be educated to use a mask attached to the spacer for all treatments. Education will be given on correct inhaler use (children will be instructed to take six breaths from the spacer for each puff of medication) and a written action plan will be completed and discussed with the child and their parent/guardian. Inhaler use, spacer technique and asthma action plan will be reassessed at Visits 2, 3 and 4 and re-education provided as necessary.
Control group
Active

Outcomes
Primary outcome [1] 333580 0
Moderate and severe asthma/wheeze exacerbations as rate per participant per year.
This will be assessed as a composite outcome.

A moderate asthma/wheeze exacerbation is defined as:
- Worsening asthma/wheeze leading to an urgent, unplanned medical review (e.g. primary care or emergency department (ED) visits) or hospital admission <24 hours; NOT resulting in the prescription of systemic corticosteroids (tablets, suspension, or injection - e.g. oral prednisone) OR
- The use of systemic corticosteroids, which does not meet the criteria for a severe asthma/wheeze exacerbation (e.g. use of systemic corticosteroids from a non-acute prescription, such as a home supply or delayed prescription).

A severe asthma/wheeze exacerbation is defined as:
- Worsening asthma/wheeze leading to an urgent, unplanned medical review (e.g. primary care or ED visit) or hospital admission and resulting in the prescription of systemic corticosteroids (tablets, suspension, or injection - e.g. oral prednisone); OR
- A hospital admission for >=24 hours.

An "asthma/wheeze exacerbation" encompasses both moderate and severe asthma/wheeze exacerbations. Note, for an exacerbation to be counted as a separate event, it must be preceded by at least 7 days during which none of the above criteria are fulfilled.

Asthma/wheeze exacerbations will be reported by the parent(s)/guardian(s) using study logbooks, and reviewed at study visits. Participant National Health Index (NHI) number and medical records will be used to validate data for the full 52 week study period.
Timepoint [1] 333580 0
52 weeks from the date intervention commenced.
Secondary outcome [1] 417624 0
Severe asthma/wheeze exacerbations as rate per participant per year, reported by the parent(s)/guardian(s) using study logbooks, and reviewed at study visits.
Participant NHI number and medical records will be used to validate data for the full 52 week study period.
Timepoint [1] 417624 0
52 weeks from date intervention commenced.
Secondary outcome [2] 417625 0
Moderate asthma/wheeze exacerbations as rate per participant per year, reported by the parent(s)/guardian(s) using study logbooks, and reviewed at study visits.
Participant NHI number and medical records will be used to validate data for the full 52 week study period.
Timepoint [2] 417625 0
52 weeks from the date intervention commenced.
Secondary outcome [3] 417627 0
Proportion of participants with at least one severe asthma/wheeze exacerbation, reported by the parent(s)/guardian(s) using study logbooks, and reviewed at study visits.
Participant NHI number and medical records will be used to validate data for the full 52 week study period.
Timepoint [3] 417627 0
52 weeks from the date intervention commenced.
Secondary outcome [4] 417628 0
Proportion of participants with at least one moderate or severe asthma/wheeze exacerbation, reported by the parent(s)/guardian(s) using study logbooks, and reviewed at study visits.
Participant NHI number and medical records will be used to validate data for the full 52 week study period.
Timepoint [4] 417628 0
52 weeks from the date intervention commenced.
Secondary outcome [5] 417629 0
Time to first moderate or severe asthma/wheeze exacerbation, reported by the parent(s)/guardian(s) using study logbooks, and reviewed at study visits.
Participant NHI number and medical records will be used to validate data for the full 52 week study period.
Timepoint [5] 417629 0
Measured from the date intervention commenced, to the date the first moderate or severe asthma/wheeze exacerbation begins, up to a maximum of 52 weeks post commencement of intervention.
Secondary outcome [6] 417630 0
Time to first severe asthma/wheeze exacerbation, reported by the parent(s)/guardian(s) using study logbooks, and reviewed at study visits.
Participant NHI number and medical records will be used to validate data for the full 52 week study period.
Timepoint [6] 417630 0
Measured from the date intervention commenced, to the date the first severe asthma/wheeze exacerbation begins, up to a maximum of 52 weeks post commencement of intervention.
Secondary outcome [7] 417631 0
Days in hospital due to asthma/wheeze per year, reported by the parent(s)/guardian(s) using study logbooks, and reviewed at study visits.
Participant NHI number and medical records will be used to validate data for the full 52 week study period.
Timepoint [7] 417631 0
52 weeks from the date the intervention commenced.
Secondary outcome [8] 417632 0
Hospital admissions due to asthma/wheeze as a rate per participant per year, reported by the parent(s)/guardian(s) using study logbooks, and reviewed at study visits.
Participant NHI number and medical records will be used to validate data for the full 52 week study period.
Timepoint [8] 417632 0
52 weeks from the date intervention commenced.
Secondary outcome [9] 417633 0
Days lost from preschool/school due to asthma/wheeze per year (participant), reported by the parent(s)/guardian(s) using study logbooks, and reviewed at study visits.
Timepoint [9] 417633 0
52 weeks from the date intervention commenced.
Secondary outcome [10] 417634 0
Days lost from work due to childcare for asthma/wheeze per year (parent/guardian), reported by the parent(s)/guardian(s) using study logbooks, and reviewed at study visits.
Timepoint [10] 417634 0
52 weeks from the date intervention commenced.
Secondary outcome [11] 417635 0
Global Initiative for Asthma (GINA) Assessment of Asthma Symptom control, as reported by parent(s)/guardian(s).
Timepoint [11] 417635 0
13, 26, 39 and 52 weeks from the date intervention commenced.
Secondary outcome [12] 417636 0
Track for Respiratory and Asthma Control in Kids (TRACK) assessment of asthma control, as reported by parent(s)/guardian(s).
Timepoint [12] 417636 0
13, 26, 39 and 52 weeks from the date intervention commenced.
Secondary outcome [13] 417637 0
Treatment failure (an increase in, step-up or change from randomised treatment), as reported by the parent(s)/guardian(s) using study log books, study data and reviewed at study visits. Participant NHI and medical records will be used to validate data for the full 52 week period.
Timepoint [13] 417637 0
52 weeks from the date intervention commenced.
Secondary outcome [14] 417638 0
Proportion of participants on each treatment step, as reported by the parent(s)/guardian(s) using study log books, study data and reviewed at study visits. Participant NHI and medical records will be used to validate data for the full 52 week period.
Timepoint [14] 417638 0
52 weeks from the date intervention commenced.
Secondary outcome [15] 417639 0
Average reliever (inhaled beta-against) inhalations per participant per day as reported by the parent(s)/guardian(s) using study log books and reviewed at study visits.
Timepoint [15] 417639 0
52 weeks from the date intervention commenced.
Secondary outcome [16] 420162 0
Total inhaled corticosteroid dose, as reported by the parent(s)/guardian(s) using study log books and reviewed at study visits. Participants NHI and medical records will be used to validate data for the full 52 week period.
Timepoint [16] 420162 0
52 weeks from the date intervention commenced.
Secondary outcome [17] 420163 0
Total systemic corticosteroid dose, as reported by the parent(s)/guardian(s) using study log books and reviewed at study visits. Participants NHI and medical records will be used to validate data for the full 52 week period.
Timepoint [17] 420163 0
52 weeks from the date intervention commenced.
Secondary outcome [18] 420164 0
Total inhaled corticosteroid dose and systemic corticosteroid dose, as reported by the parent(s)/guardian(s) using study log books and reviewed at study visits. Participant NHI and medical records will be used to validate data for the full 52 week period.
Timepoint [18] 420164 0
52 weeks from the date intervention commenced.
Secondary outcome [19] 420165 0
Growth velocity, with height measured using a stadiometer.
Timepoint [19] 420165 0
52 weeks from the date intervention commenced.
Secondary outcome [20] 420166 0
Adverse events (AE), as a proportion of participants. Example of AEs include oral thrush, rapid irregular heartbeat, tremor, and headache. These will be determined by the by the parent(s)/guardian(s) report and/or medical records utilising Common Terminology Criteria for Adverse Events (CTCAE).
Timepoint [20] 420166 0
52 weeks form the date intervention commenced.
Secondary outcome [21] 420168 0
Serious Adverse Events (SAEs), as a proportion of participants. Example of SAEs include severe allergic reaction and severe spasm in the airways. These will be determined by the by the parent(s)/guardian(s) report and/or medical records utilising Common Terminology Criteria for Adverse Events (CTCAE).
Timepoint [21] 420168 0
52 weeks from the date intervention commenced.
Secondary outcome [22] 420169 0
Net cost per asthma/wheeze exacerbation prevented, measured using a health economics questionnaire (specifically designed by experienced health economists for Children Anti-inflammatory REliever (CARE) studies).
Timepoint [22] 420169 0
52 weeks from the date the participant commenced intervention.

Eligibility
Key inclusion criteria
1. Aged 24 to 59 months; AND
2. >=3 wheezing episodes in the last 12 months (at least one doctor or nurse prescriber diagnosed); AND
3. Prescription of SABA in the last 12 months.
Minimum age
24 Months
Maximum age
59 Months
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Previous life-threatening asthma/wheeze (intensive care unit admission or intravenous treatment); OR
2. Self-reported use of more than six SABA MDIs in the last 12 months (i.e. poorly controlled); OR
3. Use of asthma medications other than SABA (ICS, LABA, leukotriene receptor antagonist, theophylline, anticholinergic agent or cromone) in last 3 months; OR
4. Significant other comorbidity including, but not limited to, cystic fibrosis and bronchiectasis or arrhythmia; OR
5. Unable or unwilling to switch from current treatment regimen; OR
6. Ex-preterm infant (born <37 weeks' gestation); OR
7. Children living outside urban areas (i.e. significant distance from ambulance or hospital).

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)
Allocation concealment will be by a secure database, which contains the randomisation sequence. A participant's treatment allocation will only be revealed to the researchers when that participant is randomised via the electronic randomisation form.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be performed using a computer-generated sequence with a variable block size (two to four) per site (to maintain allocation concealment), generated by the study statistician, independent of the study investigators. Participants will be randomised in a ratio of 1:1, with stratification according to a positive or negative Asthma Predictive Index score.

When a participant is randomised they will be given a randomisation number (sequential number at that site prefaced with the letter R and the designated site number). Randomisation codes will be sequentially assigned as soon as participants are confirmed as eligible for randomisation. Randomisation codes cannot be re-used.

Where two or more participants in the same primary household are enrolled into the study, the first participant will be randomised as above; all subsequent participants in the same primary household will be allocated to receive the same treatment as the first participant. This is to ensure compliance with the treatment regimens. When a participant is allocated to a treatment they will be given an allocation number (sequential number at that site prefaced with the letter A and the designated site number). Allocation codes will be sequentially assigned as soon as participants are confirmed as eligible. Allocation codes cannot be re-used.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Primary outcome variance analysis:

Analysis will be by intention-to-treat, meaning analyses will be with respect to randomised treatment allocation and not by treatment received, by a biostatistician blinded to allocation. Complete case analyses will be performed; all participants with data available for a particular outcome variable will be analysed and imputation procedures for missing data will not be used.

The primary outcome is the count of exacerbations in relation to the length of time of observation and the primary analysis will be by estimation of the relative rate of total exacerbations per participant per year by Poisson regression, with an offset for the length of observation, and accounting for over-dispersion if identified.

For secondary outcome analyses, the following methods will be used:

1. Poisson regression with an offset for the length of observation and a fixed effect of randomised treatment allocation:
- Severe asthma/wheeze exacerbations as rate per participant year
- Moderate asthma/wheeze exacerbations as rate per participant year
- Number of days lost from preschool/school due to asthma/wheeze
- Number of days lost from work due to asthma/wheeze (parent(s)/guardian(s))
- Number of days in hospital due to asthma/wheeze
- Number of hospitalisations due to asthma/wheeze
- Average reliever (inhaled beta-agonist) inhalations per participant per day.

Data for the number of days in hospital is like to be sparse. If it is not possible or appropriate to use Poisson regression, the data will be analysed descriptively.

2. Analysis using logistic regression, both with and without potential confounding variables:
- Proportion of participants with at least one severe asthma/wheeze exacerbation
- Proportion of participants with at least one moderate or severe asthma/wheeze exacerbation
- Total asthma/wheeze exacerbations
- The proportion of participants withdrawn and reason
- Proportion of participants on each treatment step
- Adverse events
- Serious adverse events.

3. Survival analysis illustrated with Kaplan-Meier plots and use of Cox's proportional hazards to calculate the hazard ratio in relation to the randomised treatment:
- Time to first asthma/wheeze exacerbation
- Time to first moderate or severe asthma/wheeze exacerbation.

4. ANCOVA with baseline (where taken) and randomised treatment as explanatory variables:
- Growth velocity
- GINA Assessment of Asthma Symptom Control
- TRACK Assessment of Asthma Control.

5. Analysis dependent on data distribution:
- Total inhaled corticosteroid (ICS) dose
- Total systemic corticosteroid dose
- Total ICS/systemic corticosteroid dose.

Data for oral steroid use is likely to be sparse. Methods that will be explored include: dichotomous variable "had course of oral steroid or not"; Mann-Whitney test with Hodges-Lehmann CI; and Poisson regression, treating courses of oral steroids as a count variable.

All estimates will be given as 95% CIs, and so with a nominal two-sided type 1 error rate of 5%. We will not adjust secondary anaylses for multiple analyses and so the secondary analyses will be considered exploratory.

A baseline cost-effectiveness analysis will be undertaken that, for each treatment, calculates the net cost per exacerbation event that is prevented. Net costs will include direct treatment costs (e.g. medication, staff time, and time costs for self-administered medication) as well as cost averted (e.g. fewer days off preschool/school, and savings in childcare costs for sick children). An extension of the cost-effectiveness analysis is to add consideration of benefits such as reduced distress from exacerbations and reduced anxiety (for the child and parent(s)/guardian(s)) as severe events are reduced. The addition of factors such as savings in distress will be used to transform the analysis into a full cost-benefit (or cost-utility) analysis, which forms a more appropriate guide for public policy decision-making. To undertake this extension, consideration will be given to the addition of specific questions (e.g. the negative affect consequences of an exacerbation) to our pre- and post-treatment questionnaires for families. This extension may prove valuable beyond the current study by demonstrating how factors such as distress can be incorporated into an evaluation of treatment options.

Sample size calculation:
The primary outcome variable is moderate and severe asthma/wheeze exacerbations as rate per participant per year and we plan to estimate the relative rate of exacerbation. Past research reports that the annual rate of moderate and severe exacerbations in preschool children, similar to those planned to be recruited for this study, is between 1.6 and 2.4 events per year; we have used the conservative rate of 1.6 events per year in the control group. Our past research in adults found that budesonide-formoterol reliever therapy is associated with a relative rate of moderate and severe exacerbations of 0.49; a 51% relative rate reduction. To detect a conservative relative rate of 0.70, with 90% power, two-sided alpha of 5%, needs 125 participants in each group and accounting for 10% drop-out needs 140 per group, and thus 280 total participants. This is based on a Poisson regression analysis where participants can have more than one event during the course of the study; the sample size is by simulation from two appropriate Poisson distributions. Given the prevalence of preschool wheeze/asthma in NZ (1,070 presentations in children aged 24 to 59 months to Starship Hospital alone in 2019) 280 participants is eminently feasible to recruit within 12 months from the research sites participating, including Starship Hospital.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
3/07/2023
Actual
24/07/2023
Date of last participant enrolment
Anticipated
7/07/2025
Actual
Date of last data collection
Anticipated
13/07/2026
Actual
Sample size
Target
280
Accrual to date
88
Final
Recruitment outside Australia
Country [1] 25222 0
New Zealand
State/province [1] 25222 0
Auckland, Waikato, Hawkes Bay

Funding & Sponsors
Funding source category [1] 312996 0
Government body
Name [1] 312996 0
Health Research Council of New Zealand
Country [1] 312996 0
New Zealand
Funding source category [2] 313039 0
Charities/Societies/Foundations
Name [2] 313039 0
Cure Kids
Country [2] 313039 0
New Zealand
Primary sponsor type
University
Name
The University of Auckland
Address
Building 507,
22-30 Park Road,
Grafton,
Auckland 1142
Country
New Zealand
Secondary sponsor category [1] 314725 0
None
Name [1] 314725 0
Address [1] 314725 0
Country [1] 314725 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312260 0
Northern A Health and Disability Ethics Committee
Ethics committee address [1] 312260 0
Ministry of Health
133 Molesworth Street
Wellington 6011
Ethics committee country [1] 312260 0
New Zealand
Date submitted for ethics approval [1] 312260 0
02/10/2022
Approval date [1] 312260 0
02/11/2022
Ethics approval number [1] 312260 0
2022 FULL 12742

Summary
Brief summary
Asthma is the most common chronic disease of childhood. In New Zealand (NZ), prevalence rates for paediatric asthma, and for severe asthma, are amongst the highest in the world.

Asthma is a chronic inflammatory disease of the small airways. Swelling of the airway lining, and constriction of the surrounding muscle causes them to narrow. Many children only use a short-acting beta-agonist (SABA) reliever inhaler, such as Salbutamol. These inhalers provide fast symptom relief, but do not treat the underlying inflammation. Inhaled corticosteroids (ICS) are required for this and are the mainstay of asthma maintenance therapy. Despite best efforts, ICS are under-described by clinicians and underutilised by patients. This leaves the airway swelling unchecked, which increases the risk of poor control and asthma attacks.

Inclusion of ICS with a beta-agonist reliever as default, in a 2 in 1 combination inhaler (i.e. budesonide-formoterol), has the potential to mitigate the risk of harm. Two recent studies in adults with mild asthma (SYMGA1 and Novel-START) found that budesonide-formoterol taken as needed reduced asthma attacks by more than 50% compared to salbutamol taken as needed. These findings led to a fundamental change in the way mild asthma in adults and adolescents is managed; the Global Initiative for Asthma (GINA) no longer recommends the use of beta-agonist monotherapy in this age group, instead promoting ICS-formoterol as the preferred option. Whether these findings translate to childhood asthma is unknown as there have been no randomised controlled trials (RCTs) in children. If comparable efficacy of this regimen is shown, then its implantation has the potential to markedly reduce asthma morbidity in children globally.

This study aims to determine the efficacy and safety of as-needed budesonide-formoterol (ICS-LABA) reliever therapy compared with salbutamol (SABA) reliever therapy (current standard treatment) in children 24 to 59 months with mild asthma/recurrent wheeze. We plan an open-label randomised controlled trial to compare these two treatment options in 280 children. Eligible participants will be recruited at sites in NZ and randomised (1:1) to receive either budesonide-formoterol as needed or salbutamol as needed.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 124022 0
Prof Stuart R Dalziel
Address 124022 0
Department of Paediatrics: Child and Youth Health, The University of Auckland,
Room 1014,
Building 507,
22-30 Park Road,
Grafton,
Auckland 1142
Country 124022 0
New Zealand
Phone 124022 0
+64 21869068
Fax 124022 0
Email 124022 0
[email protected]
Contact person for public queries
Name 124023 0
Libby Haskell
Address 124023 0
Children's Emergency Department,
Starship Children's Hospital,
2 Park Road,
Grafton,
Auckland 1023
Country 124023 0
New Zealand
Phone 124023 0
+64 21670550
Fax 124023 0
Email 124023 0
[email protected]
Contact person for scientific queries
Name 124024 0
Stuart R Dalziel
Address 124024 0
Department of Paediatrics: Child and Youth Health, The University of Auckland,
Room 1014,
Building 507,
22-30 Park Road,
Grafton,
Auckland 1142
Country 124024 0
New Zealand
Phone 124024 0
+64 21869068
Fax 124024 0
Email 124024 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual participant data that underlie the results in this article, after de-identification (text, tables, figures, and appendices).
When will data be available (start and end dates)?
One year after publication until a minimum of 5 years after publication.
Available to whom?
Researchers who provide methodologically sound proposal that has been approved by the PRECARE steering committee, subject to appropriate ethics approval.
Available for what types of analyses?
To achieve the aims outlined in the approved proposal.
How or where can data be obtained?
Proposals should be directed to Prof Stuart Dalziel via email ([email protected])


What supporting documents are/will be available?




Results publications and other study-related documents

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