Trial Review

Technical difficulties have been reported by some users of the search function and is being investigated by technical staff. Thank you for your patience and apologies for any inconvenience caused.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12623001339640
Ethics application status
Approved
Date submitted
10/11/2023
Date registered
19/12/2023
Date last updated
19/12/2023
Date data sharing statement initially provided
19/12/2023
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 as maintenance and reliever therapy versus as prescribed maintenance with salbutamol as reliever therapy in children with moderate and severe asthma.
Scientific title
A 52 week, open-label, randomised, multi-centre, parallel group, phase III, controlled trial in children aged 4 to 11 years with moderate and severe asthma, evaluating the efficacy and safety of Budesonide-formoterol (Vannair®) as single maintenance and reliever therapy versus as prescribed maintenance asthma therapy and salbutamol (Ventolin®) as reliever therapy.
Secondary ID [1] 310641 0
None
Universal Trial Number (UTN)
U1111-1291-5379
Trial acronym
SMARTCARE: Single Maintenance And Reliever Therapy - Children’s Anti-inflammatory REliever study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Asthma 331523 0
Condition category
Condition code
Respiratory 328261 328261 0 0
Asthma

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

Budesonide-formoterol (100micrograms/6micrograms) metered dose inhaler (MDI) (Vannair®) as single maintenance and reliever therapy (SMART) via spacer (Airflow Space Chamber Plus 220 ml). Regimen and dose will be adjusted according to the Global INitiative for Asthma (GINA) step at study entry, with maintenance and/or reliever use as needed for relief of asthma symptoms, for 52 weeks.

GINA step 2: 1 inhalation once daily + 1 inhalation as needed
GINA step 3: 1 inhalation once OR twice daily + 1 inhalation as needed
GINA step 4: 2 inhalations twice daily + 1 inhalation as needed

GINA steps will be assessed by the investigator at study entry and aligned to existing treatment (per the steroid equivalence table in the protocol).

During the course of the study, participant’s GINA step will be re-assessed and adjusted by the investigator based on the escalation criteria. Participants will be asked to contact investigators for urgent review (unscheduled visit) within seven days of a severe asthma exacerbation. During this review, participants will potentially have their standard treatment stepped up in accordance with the SMARTCARE stepwise treatment algorithm approach, if not already done so by their usual doctor or the medical team treating their acute asthma.

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 6 reliever inhalations in one day will be advised to go to the hospital or see their doctor today).

Adherence will not be monitored.
Intervention code [1] 327042 0
Treatment: Drugs
Comparator / control treatment
Inhaled Corticosteroid (ICS) or Combination ICS + Long-Acting Beta2-Agonist (ICS-LABA) plus separate Short-Acting Beta-Agonist (SABA).

As prescribed maintenance asthma therapy with salbutamol (100mcg) metered dose inhaler (MDI) (Ventolin®) via spacer (Airflow Space Chamber Plus 220 ml) as needed for asthma symptom relief. Regimen and dose will be adjusted according to the Global INitiative for Asthma (GINA) step at study entry, with maintenance and/or reliever use as needed for relief of asthma symptoms, for 52 weeks.

GINA step 2: Low dose ICS* + salbutamol 2 inhalations pro re nata (PRN)
GINA step 3: Medium dose ICS* OR low dose ICS-LABA* + salbutamol 2 inhalations PRN
GINA step 4: Medium dose ICS-LABA* + salbutamol 2 inhalations PRN
*ICS at trial entry

GINA steps will be assessed by the investigator at study entry and aligned to existing treatment (per the steroid equivalence table in the protocol).

During the course of the study, participant’s GINA step will be re-assessed and adjusted by the investigator based on the escalation criteria. Participants will be asked to contact Investigators for urgent review (unscheduled visit) within seven days of a severe asthma exacerbation. During this review, participants will potentially have their standard treatment stepped up in accordance with the SMARTCARE stepwise treatment algorithm approach, if not already done so by their usual doctor or the medical team treating their acute asthma.

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 reliever inhalations 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] 336133 0
Asthma exacerbations (moderate and severe) as rate per participant per year.
This will be assessed as a composite outcome.
Timepoint [1] 336133 0
52 weeks from the date intervention commenced.
Secondary outcome [1] 426963 0
Moderate asthma exacerbations as rate per participant per year.
Timepoint [1] 426963 0
52 weeks from the date intervention commenced.
Secondary outcome [2] 426964 0
Severe asthma exacerbations as rate per participant per year.
Timepoint [2] 426964 0
52 weeks from the date intervention commenced.
Secondary outcome [3] 426966 0
Composite of asthma exacerbations (moderate and severe), or step-up in treatment, as rate per participant per year.
Timepoint [3] 426966 0
52 weeks from the date intervention commenced.
Secondary outcome [4] 426967 0
Step-up in treatment, as rate per participant per year.
Timepoint [4] 426967 0
52 weeks from the date intervention commenced.
Secondary outcome [5] 426968 0
Time to first moderate or severe asthma exacerbation.
This will be assessed as a composite outcome.
Timepoint [5] 426968 0
Measured from the date intervention commenced, to the date the first asthma exacerbation begins.
Secondary outcome [6] 426969 0
Time to first severe asthma exacerbation.
Timepoint [6] 426969 0
Measured from the date intervention commenced, to the date the first severe asthma exacerbation begins.
Secondary outcome [7] 426970 0
Time to first asthma exacerbation (moderate or severe), or step-up in treatment.
This will be assessed as a composite outcome.
Timepoint [7] 426970 0
Measured from the date intervention commenced, to the date the first asthma exacerbation begins, or treatment is stepped up.
Secondary outcome [8] 426971 0
Time to first step-up in treatment.
Timepoint [8] 426971 0
Measured from the date intervention commenced, to the date the treatment is stepped up.
Secondary outcome [9] 426972 0
Proportion of participants with at least one asthma exacerbation (moderate and severe).
This will be assessed as a composite outcome.
Timepoint [9] 426972 0
52 weeks from the date intervention commenced.
Secondary outcome [10] 426973 0
Proportion of participants with at least one severe asthma exacerbation.
Timepoint [10] 426973 0
52 weeks from the date intervention commenced.
Secondary outcome [11] 426974 0
Proportion of participants with at least one asthma exacerbation (moderate and severe), or step-up in treatment.
This will be assessed as a composite outcome.
Timepoint [11] 426974 0
52 weeks from the date intervention commenced.
Secondary outcome [12] 426975 0
Proportion of participants with at least one step-up in treatment.
Timepoint [12] 426975 0
52 weeks from the date intervention commenced.
Secondary outcome [13] 426976 0
Proportion of participants on each treatment step.
Timepoint [13] 426976 0
52 weeks from the date intervention commenced.
Secondary outcome [14] 426977 0
Days lost from preschool/school due to asthma per year (participant).
Timepoint [14] 426977 0
52 weeks from the date intervention commenced.
Secondary outcome [15] 426978 0
Days lost from work due to childcare for asthma per year (parent(s)/guardian(s)).
Timepoint [15] 426978 0
52 weeks from the date intervention commenced.
Secondary outcome [16] 426979 0
Asthma control.
Timepoint [16] 426979 0
26 and 52 weeks from the date intervention commenced.
Secondary outcome [17] 426982 0
Fractional exhaled Nitric Oxide (FeNO) at 52 weeks.
Timepoint [17] 426982 0
52 weeks from the date intervention commenced.
Secondary outcome [18] 426983 0
On-treatment Forced Expiratory Volume over 1 second (FEV1) z score at 52 weeks.
Timepoint [18] 426983 0
52 weeks from the date intervention commenced.
Secondary outcome [19] 426984 0
Days in hospital due to asthma per year.
Timepoint [19] 426984 0
52 weeks from the date intervention commenced.
Secondary outcome [20] 426985 0
Hospital admissions due to asthma as a rate per participant per year.
Timepoint [20] 426985 0
52 weeks from the date intervention commenced.
Secondary outcome [21] 426987 0
Total inhaled corticosteroid dose.
Timepoint [21] 426987 0
52 weeks from the date intervention commenced.
Secondary outcome [22] 426991 0
Total systemic corticosteroid dose.
Timepoint [22] 426991 0
52 weeks from the date intervention commenced.
Secondary outcome [23] 426992 0
Total inhaled corticosteroid and systemic corticosteroid dose.
This will be assessed as a composite outcome.
Timepoint [23] 426992 0
52 weeks from the date intervention commenced.
Secondary outcome [24] 426994 0
Total composite inhaled beta2-agonist dose.
Timepoint [24] 426994 0
52 weeks from the date intervention commenced.
Secondary outcome [25] 427002 0
Growth velocity.
Timepoint [25] 427002 0
52 weeks from the date intervention commenced.
Secondary outcome [26] 427003 0
Adverse Events.
Timepoint [26] 427003 0
52 weeks from the date intervention commenced.
Secondary outcome [27] 427004 0
Serious Adverse Events.
Timepoint [27] 427004 0
52 weeks from the date intervention commenced.
Secondary outcome [28] 427005 0
Proportion of participants who discontinue treatment or withdraw.
Timepoint [28] 427005 0
52 weeks from the date intervention commenced.
Secondary outcome [29] 427006 0
Incremental cost per moderate and/or severe exacerbation averted.
This will be assessed as a composite outcome.
Timepoint [29] 427006 0
Reported by the participant and their parent(s)/guardian(s) using study logbooks, and reviewed at study visits by the study team. Participant NHI number and medical records will be used to validate data for the full 52 week study period.

Eligibility
Key inclusion criteria
1. Aged 4 to 11 years
2. Doctor or Nurse Practitioner (NP) diagnosis of asthma (self-report by parent/participant or healthcare provider-reported)
3. Use of maintenance ICS or ICS-LABA + SABA reliever therapy in the last 6 months (i.e. GINA step 2, 3 and 4)
4. Registered with a General Practitioner (GP)
5. Willing and able to switch from current treatment regimen
Minimum age
4 Years
Maximum age
11 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Significant other comorbidity including, but not limited to, cystic fibrosis and bronchiectasis or arrythmia
2. Previous life-threatening asthma (ICU admission ever or intravenous (IV) treatment in last 2 years)
3. Already using ICS-LABA as a reliever
4. GINA step 5 (few children only, brittle asthma, and potentially difficult to manage in an RCT without regular face-to-face contact); use of biologics, high dose ICS-LABA, maintenance oral corticosteroids, or leukotriene receptor antagonists in the last 6 months
5. Systemic corticosteroids in last 6 weeks prior to Visit 1
6. Any known or suspected hypersensitivity (including rash, urticaria, angioedema, bronchospasm and anaphylactic reaction) to the active substances in the study (budesonide, formoterol, salbutamol)
7. Participation in another clinical trial of an investigational medicinal product in the 30 days prior to Visit 1
8. Ex-preterm infant (born <37 weeks)

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)
Randomisation will be performed using a computer-generated sequence with a variable block size (to maintain allocation concealment), generated by a study statistician, independent of the study investigators.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
At Visit 1, participants will be randomised in a ratio of 1:1 to budesonide-formoterol SMART MDI or as prescribed maintenance asthma therapy with salbutamol MDI as-needed via spacer (with or without mask).

Randomisation will be performed using a computer-generated sequence with a variable block size (to maintain allocation concealment), generated by a study statistician, independent of the study investigators. Randomisation will be stratified by GINA step (2 or greater than 2).

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.

Allocation concealment will be by a secure database, which contains 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:

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 total (combined moderate or severe) exacerbation count. The primary analysis will be estimation of the relative rate of total exacerbations per participant per year by Poisson regression with an offset for the length of time of observation, and accounting for over-dispersion if identified.

Sensitivity analyses of the primary outcome variable and analysis will be with adjustment, accounting for potential confounding, for the following potentially important predictors of response: age, sex, ethnicity (prioritised as Maori, Pacific, non-Maori/non-Pacific), and the number of severe exacerbations in the previous year. This will account for potentially different distributions of these variables in the treatment groups and may increase precision of the estimates of differences. Analyses of whether there are different effect sizes within sub-groups i.e. effect modifiers, is specified in the sub-group analysis section.

Moderate exacerbations, and total exacerbations, as secondary outcome variables will be analysed in a similar way. A further secondary analysis will be the number of participants with at least one severe, moderate, or total exacerbation analysed by logistic regression, both with and without the potential confounding variables outlined above. Survival analysis with Kaplan-Meier plots and Cox’s proportional hazards will be used to calculate the hazard radio for time to first severe exacerbation or any exacerbation. FeNO is typically better analysed on the logarithm-transformed scale and will be analysed by a general linear model. ANCOVA, incorporating baseline FeNO and randomised treatment, to estimate the ratio of geometric mean FeNO between the two treatment arms. FEV1, height, GINA score and ACQ-5 will also be analysed by ANCOVA with the baseline measurement and randomised treatment as explanatory variables. We are uncertain of the distribution of the ‘number of days’ variables but pending exploration of this plan to treat these as Poisson count variable with a similar analysis strategy as outlined for the exacerbations.

New Zealand has a unique health identification number (NHI), as such we expect complete data for severe exacerbations, and near complete data for moderate exacerbations, even with loss to follow-up. Withdrawal will be analysed by logistic regression. Although all estimates will be given as 95% confidence intervals (CI), and so with a nominal two-sided type 1 error rate of 5%; we will not adjust secondary analyses for multiple analyses and so secondary analyses will be considered exploratory.

Secondary outcome variable analyses:

The secondary outcome analyses will be shown as point estimates with 95% Confidence Intervals, and so with a nominal two-sided type I error rate of 5%. However, we will not adjust these secondary analyses for multiplicity, and the secondary analyses will be considered exploratory.

The following methods are planned:

Poisson regression with an offset for the length of observation and a fixed effect of randomised treatment allocation:
• Moderate asthma exacerbations as relative rate per participant per year
• Severe asthma exacerbations as relative rate per participant per year
• Composite of asthma exacerbations (moderate and severe), or step-up treatment, as relative rate per participant per year
• Step-up in treatment, as relative rate per participant per year

Survival analyses with Cox regression models and illustrated by Kaplan-Meier curves with fixed effect of randomised treatment allocation:
• Time to first moderate or severe asthma exacerbation
• Time to first severe asthma exacerbation
• Time to first asthma exacerbation (moderate or severe), or step-up in treatment
• Time to step-up in treatment

t-tests for differences in mean number, although if normal distribution assumptions are strongly violated Mann-Whitney tests with Hodges-Lehmann estimate of location difference:
• Number of days lost from preschool/school due to asthma per year (participant)
• Number of days lost from work due to childcare for asthma per year (parent(s)/guardian(s))
• Number of days in hospital due to asthma per year
• Number of hospitalisations admissions due to asthma as a rate per participant per year

For these proposed analyses there may be numerous zero cell counts meaning that normal distribution assumptions may be strongly violated. This will be explored by plots and analysis of residuals and the rank-based test used if t-tests are inappropriate.

Logistic regression, both with and without potential confounding variables outlined previously:
• Proportion of participants with at least one asthma exacerbation (moderate and severe)
• Proportion of participants with at least one severe asthma exacerbation
• Proportion of participants with at least one asthma exacerbation (moderate and severe), or step-up in treatment
• Proportion of participants with at least one step-up in treatment
• Proportion of participants who discontinue or withdraw and reason
• Proportion of participants on each treatment step
• Adverse events
• Serious adverse events

ANCOVA with baseline (where taken) and randomised treatment as explanatory variables:
• Growth velocity
• ACQ-5
• FEV1
• FEV1 z-score
• FEV1 % predicted
• FEV1 prediction value (GLI values)
• FeNO (on the logarithm-transformed scale)


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

Analysis dependent on data distribution:
• Total ICS dose
• Total systemic corticosteroid dose
• Total ICS and systemic corticosteroid dose
• Total inhaled beta2-agonist dose

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

For composite systemic corticosteroid exposure per year, this will be calculated as the total inhaled corticosteroid dose per year (converted to oral prednisone equivalent dose for systemic effects on adrenal function using the conversion factor of budesonide 5,000mcg inhaled to prednisone 10mg oral, defined in a previous bioequivalence study) added to the oral corticosteroid dose per year.

Sub-group analyses:

Sub-group analyses will be performed in relation to the primary outcome variable: rate of severe asthma exacerbations per participant per year. These sub-group analyses will explore whether the nominated variable are effect modifiers: the differential effect of treatment on outcome will be explored with each of the following potential moderating variables:

• SABA use at baseline, measured as the average number of occasions per week of self-reported SABA use in the four weeks before randomisation
• Severe asthma exacerbations in the 12 months prior to randomisation
• Age at baseline
• Sex
• Ethnicity
• Household smoking status
• Baseline ACQ-5 score (for asthma attacks and severe asthma attacks outcomes only)
• Baseline FeNO
• Baseline FEV1 % predicted

For illustration on the Forest Plot, baseline ACQ-5 score, and baseline FEV1 % predicted will be dichotomised at the mean value of the control arm, and for baseline FeNO, the median value of the control arm.

Other analyses:

Missing data:
For those variables with a baseline and more than one subsequent measurement, we will use mixed linear models as a preferred approach to incorporating observed values into the final outcome assessments, which assume missing data are missing at random.

Individual patient data meta-analyses:
We plan to undertake individual patient meta-analyses combining the data from this study with:
• NZ children’s studies: PRECARE (ACTRN12623000670673), CARE (ACTRN12620001091998) and STARTCARE (ACTRN12622001217796). The primary purpose of the individual participant meta-analysis for the NZ studies recruiting children is to get more precise estimates of the effect on asthma exacerbations. Asthma exacerbations will be treated in two ways; firstly, as a rate variable (number of asthma exacerbations per unit time) and analysed by Poisson regression with time in study as an offset variable and individual study as a confounding variable for randomised treatment. As secondary analyses of this set of studies affect modification will be explored by appropriate interaction terms between treatment and potential effect modifiers such as age and GINA step.
• International SMART CARE consortium studies (Australia, NZ and UK) in which 3 different budesonide/formoterol maintenance and reliever therapy-based algorithms are to be investigated. A similar approach will be used for the international SMART CARE consortium studies with the additional predictor variable of type of Budesonide/formoterol maintenance and reliever therapy-based algorithm.
• NZ portfolio of studies including the PRECARE, CARE, Novel START, PRACTICAL, SMART, and STARTCARE providing evidence across the spectrum of asthma severity in children, adolescents and adults. For the NZ portfolio of studies, the primary aim is to more precisely estimate the effects of modification variables.

Sample size calculation:
The primary outcome variable is asthma exacerbations (moderate and severe) as rate per participant per year and we plan to estimate the relative rate of exacerbation. Exacerbation rates in similar aged cohorts to this study, but in patients with milder disease (GINA 1-3), have ranged from 0.28 to 0.84, with those at the lower end receiving step-up treatment (additional LABA) and some of those at the upper end of this range receiving step-down treatment (removal of regular ICS). Exacerbation rates in similar aged cohorts to the proposed study, but in patients with more severe disease (GINA >=3), have ranged from 1.36 to 1.44, although these are restricted to patients with IgE mediated disease. We have used the most conservative rate of 0.28 events per participant per year in the control group based on Bisgaard et al.

In adults and adolescents, ICS-formoterol reliever therapy is associated with a relative rate of severe exacerbations of 0.68; a 32% relative rate reduction. The single study of ICS-formoterol SMART in children (Bisgaard et al.) showed a relative rate of severe exacerbations of 0.28; a 72% reduction in risk. To detect a conservative relative rate of 0.55, with 90% power, two-sided alpha of 5%, needs 160 participants in each group and accounting for 15% drop-out needs 188 per group, thus 376 total participants. This is based on a Poisson regression analysis where participants can have more than one event during the study; the sample size is by simulation from two appropriate Poisson distributions. Given the prevalence of childhood asthma in NZ, 376 participants are eminently feasible to recruit within 12 months from the sites participating.

Interim statistical analyses:
There will be no interim statistical analyses.

Statistical significance:
The level of statistical significance is p<=0.05.

Procedure for accounting for missing, unused and spurious data:
Data will continue to be collected from participants if their treatment regimen is changed, or if they withdraw from the study, unless they rescind their consent/assent, in order to minimise missing data. GP/primary healthcare practitioner and self-reported data will be reviewed together; discrepancies will be arbitrated by investigators using predefined criteria. For repeated measured analyses of continuous variables, mixed linear models will be used which assume missing data are missing at random. Otherwise imputation will not be used. For the primary outcome participants with no time of observation will be given zero weight in the analysis, i.e. this will be a complete case analysis.

Economic analysis:
The annual cost of asthma (all ages) to the NZ economy is estimated to be $1,017,924,605. This is a minimum cost and does not include the direct cost of ED visits for asthma, work days lost, or the long term costs associated with time off school.

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 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.

Ethnicity analysis:
Asthma disproportionately affects Maori children compared with NZ European children (rate ratio 1.36). Health services are less accessible for Maori and there is inequity in the quality of services provided; Maori children are less likely to receive preventers (ICS), rendering them overly reliant on their SABAs. This may contribute to the much higher hospitalisation rates for asthma in Maori children. Inclusion of ICS with a beta-agonist as default (i.e. ICS-formoterol) has the potential to mitigate this risk. Evidence from adult studies shows that this approach reduces asthma exacerbations, and is at least as effective as maintenance ICS plus SABA at preventing severe asthma exacerbations in Maori adults. Additional analyses will be undertaken to explore differences in outcomes according to ethnicity, in particular looking at outcomes of participants identifying as Maori or Pacific. This analysis will be defined in an additional analysis plan.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
8/01/2024
Actual
Date of last participant enrolment
Anticipated
16/01/2026
Actual
Date of last data collection
Anticipated
15/01/2027
Actual
Sample size
Target
376
Accrual to date
Final
Recruitment outside Australia
Country [1] 25778 0
New Zealand
State/province [1] 25778 0
Auckland, Waikato, Hawkes Bay

Funding & Sponsors
Funding source category [1] 314857 0
Government body
Name [1] 314857 0
Heath Research Council of New Zealand
Country [1] 314857 0
New Zealand
Funding source category [2] 314868 0
Charities/Societies/Foundations
Name [2] 314868 0
Cure Kids
Country [2] 314868 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] 316864 0
None
Name [1] 316864 0
Address [1] 316864 0
Country [1] 316864 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313856 0
Northern B Health and Disability Ethics Committee
Ethics committee address [1] 313856 0
Private bag 92019, Auckland, 1042, New Zealand
Ethics committee country [1] 313856 0
New Zealand
Date submitted for ethics approval [1] 313856 0
16/08/2023
Approval date [1] 313856 0
09/11/2023
Ethics approval number [1] 313856 0
2023 FULL 14008

Summary
Brief summary
This randomised controlled trial aims to determine the best treatment for children between the ages of 4 and 11 years of age who have moderate to severe asthma. We will compare two asthma treatment regimens in 376 children with moderate and severe asthma to find out which is better at reducing asthma exacerbations. Eligible participants will be recruited at sites in New Zealand and randomised to either a combination inhaled corticosteroid - long acting beta2 agonist (Vannair) asthma inhaler used as single maintenance and reliever therapy (SMART therapy) OR as prescribed asthma maintenance therapy and short-acting beta2 agonist (Ventolin) asthma inhaler as reliever therapy.
Trial website
Trial related presentations / publications
Public notes
The global burden of childhood asthma is significant, and New Zealand has one of the highest prevalence rates in the world. The greatest individual burden of paediatric asthma is in those children with moderate and severe disease (GINA steps 2+).

The traditional approach to managing asthma is to prescribe a maintenance Inhaled Corticosteroid or Inhaled Corticosteroid-Long-Acting Beta2-Agonist (ICS or ICS-LABA) inhaler and/or a Short-Acting Beta2-Agonist (SABA) reliever, taken as needed for symptom relief. However, there are a number of safety concerns with this approach:

• The benefits of ICS are restricted in clinical practice by the overestimation of asthma control and, in some cases, steroid aversion. This leads to the under prescribing of ICS by clinicians, and reduced adherence to ICS by patients.
• The number of ICS inhalations patients can use each day are effectively capped, with no effective mechanism to titrate the ICS dose according to need, particularly during acute asthma exacerbations.
• SABAs can provide quick symptom relief but they lack activity against the underlying inflammatory processes in asthma. Overreliance during an acute attack can therefore lead to a delay in seeking medical assistance.
• Both ICS underuse and SABA overuse are associated with asthma mortality.

Combining an ICS with a LABA, such as formoterol, in a single inhaler offers a potential solution to protect against the dangers of beta2-agonist monotherapy and poor ICS adherence, by ensuring that an ICS dose is delivered with each “reliever” inhalation. Equally as important, the ICS dose is titrated according to need, with increased steroid being delivered during an acute worsening episode requiring increased beta2-agonist use.

ICS-formoterol, used as both Maintenance And/or Reliever Therapy (MART), is now the GINA-preferred treatment option for adolescents and adults with asthma across all treatment steps.

Further research is urgently needed to evaluate the efficacy and safety of ICS-formoterol as maintenance and/or reliever therapy, and to bring the strength of evidence and available treatment options for children on par with adults and adolescents. If comparable efficacy with ICS-formoterol maintenance and/or reliever therapy is shown in childhood asthma, then implementation of this regimen would markedly reduce the burden of asthma in all children.

We therefore propose an RCT to compare the safety and efficacy of two treatment regimens in moderate and severe childhood asthma:
1. A combination ICS-LABA as both maintenance and/or reliever therapy
2. ICS or ICS-LABA maintenence therapy with a separate SABA reliever therapy

Contacts
Principal investigator
Name 129574 0
Prof Stuart R Dalziel
Address 129574 0
Department of Paediatrics: Child and Youth Health, The University of Auckland, Room 1014, Building 507, 22-30 Park Road, Grafton, Auckland 1142
Country 129574 0
New Zealand
Phone 129574 0
+64 21869068
Fax 129574 0
Email 129574 0
s.dalziel@auckland.ac.nz
Contact person for public queries
Name 129575 0
Dr Libby Haskell
Address 129575 0
Children's Emergency Department, Starship Children's Hospital, 2 Park Road, Grafton, Auckland 1023
Country 129575 0
New Zealand
Phone 129575 0
+64 21670550
Fax 129575 0
Email 129575 0
libbyh@adhb.govt.nz
Contact person for scientific queries
Name 129576 0
Prof Stuart R Dalziel
Address 129576 0
Department of Paediatrics: Child and Youth Health, The University of Auckland, Room 1014, Building 507, 22-30 Park Road, Grafton, Auckland 1142
Country 129576 0
New Zealand
Phone 129576 0
+64 21869068
Fax 129576 0
Email 129576 0
s.dalziel@auckland.ac.nz

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 SMARTCARE 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 Professor Stuart Dalziel via email s.dalziel@auckland.ac.nz


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
20425Study protocol    This document will be made available during the st... [More Details]
20426Statistical analysis plan    This document will be made available during the st... [More Details]
20427Informed consent form    This document will be made available during the st... [More Details]
20428Ethical approval    386629-(Uploaded-18-12-2023-09-10-59)-Study-related document.pdf



Results publications and other study-related documents

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

Documents added automatically
No additional documents have been identified.