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Trial registered on ANZCTR


Registration number
ACTRN12620001091998
Ethics application status
Approved
Date submitted
27/08/2020
Date registered
20/10/2020
Date last updated
6/07/2024
Date data sharing statement initially provided
20/10/2020
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 children with mild asthma
Scientific title
An open-label randomised controlled trial of the efficacy and safety of as-needed budesonide-formoterol vs salbutamol reliever therapy in mild childhood asthma
Secondary ID [1] 302148 0
MRINZ/20/06
Universal Trial Number (UTN)
U1111-1246-8198
Trial acronym
CARE: Children's Anti-inflammatory REliever
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Asthma 318789 0
Condition category
Condition code
Respiratory 316802 316802 0 0
Asthma

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

Budesonide-formoterol presurrised metered-dose inhaler 50micrograms/3micrograms, two puffs via spacer, as required for relief of asthma symptoms, for 52 weeks.

The intervention will be participant- and/or parent-administered.

There is no maximum daily frequency of administration of the intervention, however participants will receive a written asthma 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.
Intervention code [1] 318446 0
Treatment: Drugs
Comparator / control treatment
Short-acting beta-agonist (SABA):

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

The control will be participant- and/or parent-administered.

There is no maximum daily frequency of administration of the intervention, however participants will receive a written asthma 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.
Control group
Active

Outcomes
Primary outcome [1] 324918 0
Asthma attacks (moderate and severe) as rate per participant per year.

A moderate asthma attack is defined as worsening asthma leading to an urgent, unplanned medical review (e.g. primary care or emergency department (ED) visit) but not severe enough to warrant the prescription of systemic corticosteroids (e.g. oral prednisone) or hospital admission.

A severe asthma attack is defined as worsening asthma leading to an urgent, unplanned medical review (e.g. primary care or ED visit) or hospital admission, resulting in the prescription of systemic corticosteroids (tablets, suspension, or injection).

For an asthma attack 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 attacks will be reported by the participant and their parent(s)/guardian(s) using study logbooks and/or MyCAP (a mobile application extension of the REDCap-based CDMA), 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] 324918 0
52 weeks from the date intervention commenced.
Secondary outcome [1] 386191 0
Severe asthma attacks as rate per participant per year, reported by the participant and their parent(s)/guardian(s) using study logbooks and/or MyCAP (a mobile application extension of the REDCap-based CDMA), 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] 386191 0
52 weeks from the date intervention commenced.
Secondary outcome [2] 386192 0
Proportion of participants with at least one asthma attack (moderate and severe), reported by the participant and their parent(s)/guardian(s) using study logbooks and/or MyCAP (a mobile application extension of the REDCap-based CDMA), 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 [2] 386192 0
52 weeks from the date intervention commenced.
Secondary outcome [3] 386193 0
Proportion of participants with at least one severe asthma attack, reported by the participant and their parent(s)/guardian(s) using study logbooks and/or MyCAP (a mobile application extension of the REDCap-based CDMA), 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 [3] 386193 0
52 weeks from the date intervention commenced,
Secondary outcome [4] 386194 0
Time to first asthma attack (moderate and severe), reported by the participant and their parent(s)/guardian(s) using study logbooks and/or MyCAP (a mobile application extension of the REDCap-based CDMA), 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 [4] 386194 0
Measured from the date intervention commenced, to the date the first asthma attack begins.
Secondary outcome [5] 386195 0
Time to first severe asthma attack, reported by the participant and their parent(s)/guardian(s) using study logbooks and/or MyCAP (a mobile application extension of the REDCap-based CDMA), 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 [5] 386195 0
Measured from the date intervention commenced, to the date the first severe asthma attack begins.
Secondary outcome [6] 386196 0
Days in hospital.

Days in hospital will be reported by the participant and their parent(s)/guardian(s) using study logbooks and/or MyCAP (a mobile application extension of the REDCap-based CDMA), 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 [6] 386196 0
52 weeks from the date intervention commenced.
Secondary outcome [7] 386197 0
Fractional exhaled Nitric Oxide (FeNO), measured using a FeNObreath device.
Timepoint [7] 386197 0
52 weeks from the date intervention commenced.
Secondary outcome [8] 386198 0
On-treatment Forced Expiratory Volume over 1 second (FEV1), measured using an NND Easy-on PC Spirometer.
Timepoint [8] 386198 0
52 weeks from the date intervention commenced.
Secondary outcome [9] 386199 0
Asthma Control Questionnaire 5 (ACQ-5), a validated questionnaire for measuring asthma control.
Timepoint [9] 386199 0
26 and 52 weeks from the date intervention commenced.
Secondary outcome [10] 386200 0
Days lost from school due to asthma, as recorded by the participant and their parent(s)/guardian(s) using study logbooks and/or MyCAP (a mobile application extension of the REDCap-based CDMA), and reviewed at study visits.
Timepoint [10] 386200 0
52 weeks from the date intervention commenced.
Secondary outcome [11] 386201 0
Days lost from work due to asthma (participant), as reported by the participant and their parent(s)/guardian(s) using study logbooks and/or MyCAP (a mobile application extension of the REDCap-based CDMA), and reviewed at study visits.
Timepoint [11] 386201 0
52 weeks from the date intervention commenced.
Secondary outcome [12] 386202 0
Days lost from work due to childcare for asthma (parent(s)/guardian(s)), as reported by the participant and their parent(s)/guardian(s) using study logbooks and/or MyCAP (a mobile application extension of the REDCap-based CDMA), and reviewed at study visits.
Timepoint [12] 386202 0
52 weeks from the date intervention commenced.
Secondary outcome [13] 386203 0
Total systemic corticosteroid dose, as reported by the participant and their parent(s)/guardian(s) using study logbooks and/or MyCAP (a mobile application extension of the REDCap-based CDMA), 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 [13] 386203 0
52 weeks from the date intervention commenced.
Secondary outcome [14] 386204 0
Growth velocity, with height measured using a stadiometer.
Timepoint [14] 386204 0
52 weeks from the date intervention commenced.
Secondary outcome [15] 386205 0
Adverse Events (AEs), as a proportion of participants. Examples of known AEs include oral thrush, rapid or irregular heartbeat, tremor, and headache. These will be determined by participant/parent/guardian self-report and/or medical records, utilising Common Terminology Criteria for Adverse Events (CTCAE).
Timepoint [15] 386205 0
52 weeks from the date intervention commenced.
Secondary outcome [16] 386206 0
Serious Adverse Events (SAEs), as a proportion of participants. Examples of SAEs include severe allergic reaction and severe spasm in the airways. These will be determined by participant/parent/guardian self-report and/or medical records, utilising Common Terminology Criteria for Adverse Events (CTCAE).
Timepoint [16] 386206 0
52 weeks from the date intervention commenced.
Secondary outcome [17] 386207 0
Net cost per asthma attack prevented, measured using a health economics questionnaire (developed by the experienced study health economists)
Timepoint [17] 386207 0
52 weeks from the date intervention commenced.
Secondary outcome [18] 403467 0
Proportion of participants on each treatment step, determined by study investigator assessment at the participant's last visit.
Timepoint [18] 403467 0
52 weeks from the date intervention commenced.

Eligibility
Key inclusion criteria
1) Aged five to 15 years
2) Doctor diagnosis of asthma (parent/participant or doctor-reported) AND
a. SABA use on greater than or equal to 3 consecutive days in the last 12 months, AND/OR
b. SABA use on greater than or equal to 2 days per month, on average, in the last 12 months, AND/OR
c. Urgent medical review for worsening asthma in the last 12 months.
3. Registered with a General Practitioner
Minimum age
5 Years
Maximum age
15 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) Hospital admission (equal to or greater than 24 hours) for asthma in the last 12 months
2) Self-reported use of >6 SABA inhalers in the last 12 months (i.e. poor-control)
3) Any use of ICS, LABA, leukotriene receptor antagonist (LTRA), theophylline, anticholinergic agent or cromone in the last 6 months
4) Any use of systemic corticosteroids in the last 6 weeks
5) Any medical condition which, at the Investigator’s discretion, may present a safety risk or impact the feasibility of the study or the study results (including, but not limited to, other significant respiratory comorbidities, such as cystic fibrosis and bronchiectasis)
6) Any known or suspected contraindications to the medications prescribed in the study or their respective excipients
7) Previous life-threatening asthma (Intensive Care Unit admission)
8) Unable or unwilling to switch from current asthma treatment regimen
9) Unable or unwilling to provide written informed consent (parent(s)/guardian(s)) or assent/consent (participant)
10) Self-reported current pregnancy or breast feeding at the time of enrolment

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 case report form (eCRF).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomised in a ratio of 1:1 , with stratification according to their:

1. History of a severe asthma attack in the previous 12 months (0 or greater than or equal to 1)
2. Age group (five to 11 years; 12 to 15 years)

Randomisation was performed using a computer-generated sequence to maintain allocation concealment. Block size varied by site; sites anticipated to recruit larger numbers had random blocks sizes of two and four, to a total 192 randomisations per site (48 per four level stratification variable). Sites anticipated to recruit small numbers had a single block size of 48 per four level stratification variable, for a total of 192 randomisations per site. This was generated by the study statistician, independent of the Investigators.

If two or more participants from the same primary household are enrolled into the study, the first participant will be randomised as above; all subsequent members of the same primary household will then be allocated to receive the same treatment as the first member of the primary household. This strategy is to improve adherence to the randomised regimen.

Allocation concealment is by a secure database, which contained the randomisation sequence.
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 variable analysis:

This will be by intention-to-treat superiority analysis by a biostatistician masked as to treatment allocation. The primary analysis is by estimation of the relative rate of total asthma attacks per participant per year by Poisson regression with an offset for the time of observation and a fixed effect of randomised treatment allocation. Over-dispersion will be evaluated prior to analysis and a corrected analysis applied if necessary.

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

1) Poisson regression with an offset for the time of observation and a fixed effect of randomised treatment allocation:
• Severe asthma attacks per participant per year
• Number of days lost from school due to asthma
• Number of days lost from work due to asthma (participant)
• Number of days lost from work due to childcare for asthma (parent(s)/guardian(s))
• Number of days in hospital (note, data for the number of days in hospital is likely to be sparse. If it is not possible or appropriate to use Poisson regression, the data will be analysed descriptively).

2) Comparison of proportions by logistic regression:
• The proportion of participants with at least one asthma attack
• The proportion of participants with at least one severe asthma attack
• The proportion of participants on each treatment step (note, data for proportion of participants on each treatment step is likely to be sparse. We will consider merging data for treatment steps 2 and 3. If it is not possible or appropriate to use logistic regression, the data will be analysed descriptively).
• The proportion of participants withdrawn and reason
• Adverse events
• Serious adverse events

3) Survival analysis illustrated by Kaplan-Meier plots and use of Cox’s proportional hazards regression to estimate the hazard ratio in relation to the randomised treatment:
• Time to first asthma attack
• Time to first severe asthma attack

4) ANCOVA with baseline (where taken) as a continuous covariate
• FEV1
• FEV1 z-score
• FEV1 % predicted
• FEV1 prediction value (GLI values)
• FeNO (on the logarithm-transformed scale)
• Growth velocity

5) ANCOVA and mixed linear models for repeated measures by time:
• ACQ-5

6) Analysis dependent on data distribution:
• Total oral corticosteroid dose (note, data for oral steroid use is likely to be sparse. Methods that will be explored include: dichotomous variable “had a course of oral steroids or not”; attempt at Mann-Whitney test with Hodges-Lehmann confidence interval; and Poisson regression, treating courses of oral steroids as a count variable).

7) Descriptive data
• Total ICS dose (for inhalers with dose counters)

All estimates will be given as 95% confidence intervals, and so with a nominal two-sided type I error rate of 5%. We will not adjust secondary analyses 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 attack 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 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 attacks 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 attack) 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 is the relative rate of asthma attacks between the treatment groups.
An annualised asthma attack rate of 0.28 has been determined from studies of ICS-SABA reliever therapy (separate inhalers) in children. The relative rate of attacks for budesonide-formoterol reliever therapy versus salbutamol reliever therapy in adults with mild asthma is between 0.40 and 0.49. We have chosen the sample size to detect a more conservative relative rate than this of 0.55. By simulation from appropriate Poisson distributions we estimate this need 160 participants in each group, a total recruitment of 320 participants to achieve 90% power, two-sided alpha of 5%, to detect a difference in rates between 0.28 in the active-treatment arm and 0.51 in the SABA-only arm. Accounting for a dropout rate of 20% gives a total sample size of 380 participants (190 in each arm).

A planned sample size re-estimation took place once 228 (60%) of participants were randomised to study treatment. This determined a new sample size of 360 participants (180 in each arm, accounting for dropouts) required to achieve the above power and difference in rates between the two treatment groups.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
26/10/2020
Actual
28/01/2021
Date of last participant enrolment
Anticipated
30/06/2023
Actual
23/06/2023
Date of last data collection
Anticipated
30/06/2024
Actual
Sample size
Target
360
Accrual to date
Final
360
Recruitment outside Australia
Country [1] 22895 0
New Zealand
State/province [1] 22895 0

Funding & Sponsors
Funding source category [1] 306573 0
Government body
Name [1] 306573 0
Health Research Council of New Zealand
Country [1] 306573 0
New Zealand
Funding source category [2] 306575 0
Charities/Societies/Foundations
Name [2] 306575 0
Cure Kids
Country [2] 306575 0
New Zealand
Primary sponsor type
Other
Name
Medical Research Institute of New Zealand
Address
Level 7 CSB Building
Wellington Hospital
Riddiford Street
Newtown
Wellington 6021
Country
New Zealand
Secondary sponsor category [1] 307100 0
None
Name [1] 307100 0
Address [1] 307100 0
Country [1] 307100 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306759 0
Northern B Health and Disability Ethics Committee
Ethics committee address [1] 306759 0
Ministry of Health
Ethics Department
Freyberg Building
Reception – Ground Floor
20 Aitken Street
Wellington 6011
Ethics committee country [1] 306759 0
New Zealand
Date submitted for ethics approval [1] 306759 0
20/08/2020
Approval date [1] 306759 0
17/09/2020
Ethics approval number [1] 306759 0
20/NTB/200

Summary
Brief summary
The global burden of childhood asthma is significant, and New Zealand has one of the highest prevalence rates in the world.

Many children with asthma only use a short-acting beta-agonist (SABA) reliever inhaler, without a regular preventer (such as an inhaled corticosteroid, ICS). Whilst SABAs provide fast symptom relief, they do not treat the underlying inflammation that is commonly present, even in children with so-called “mild” asthma. Factors including the overestimation of asthma symptom control, reduced access to adequate medical treatment, and in some cases steroid aversion, all contribute to the increased asthma-related morbidity and mortality in this population.

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 of as-needed ICS-formoterol therapy in children. If comparable efficacy of this regimen is shown, then its implementation has the potential to markedly reduce asthma morbidity in children globally.

We therefore propose an RCT to compare the safety and efficacy of two treatment regimens in mild asthma:
1. A combination inhaled corticosteroid (ICS) and Long Acting Beta Agonist (LABA) as required
2. SABA as required
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 104922 0
Prof Richard Beasley
Address 104922 0
Medical Research Institute of New Zealand
Level 7 CSB Building
Wellington Hospital
Riddiford Street
Newtown
Wellington 6021
Country 104922 0
New Zealand
Phone 104922 0
+64 4 805 0147
Fax 104922 0
Email 104922 0
[email protected]
Contact person for public queries
Name 104923 0
Lee Hatter
Address 104923 0
Medical Research Institute of New Zealand
Level 7 CSB Building
Wellington Hospital
Riddiford Street
Newtown
Wellington 6021
Country 104923 0
New Zealand
Phone 104923 0
+64 4 805 0201
Fax 104923 0
Email 104923 0
[email protected]
Contact person for scientific queries
Name 104924 0
Lee Hatter
Address 104924 0
Medical Research Institute of New Zealand
Level 7 CSB Building
Wellington Hospital
Riddiford Street
Newtown
Wellington 6021
Country 104924 0
New Zealand
Phone 104924 0
+64 4 805 0201
Fax 104924 0
Email 104924 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 reported 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 a methodologically sound proposal that has been approved by the CARE steering committee.
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 Dr Lee Hatter via email ([email protected])


What supporting documents are/will be available?




Results publications and other study-related documents

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

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseThe children's anti-inflammatory reliever (CARE) study: A protocol for a randomised controlled trial of budesonideformoterol as sole reliever therapy in children with mild asthma.2021https://dx.doi.org/10.1183/23120541.00271-2021
N.B. These documents automatically identified may not have been verified by the study sponsor.