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Trial registered on ANZCTR


Registration number
ACTRN12622001217796
Ethics application status
Approved
Date submitted
6/09/2022
Date registered
9/09/2022
Date last updated
25/07/2024
Date data sharing statement initially provided
9/09/2022
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 maintenance and/or reliever therapy versus standard maintenance with separate reliever therapy in children with mild, moderate and severe asthma.
Scientific title
A 52-week, open-label, randomised, multi-centre, parallel group, phase III, controlled trial in patients age 5 to 11 years with mild, moderate and severe asthma, evaluating the efficacy and safety of Budesonide-formoterol (Symbicort Turbuhaler®) maintenance and/or reliever therapy compared with standard therapy: Budesonide (Pulmicort Turbuhaler®) maintenance or Budesonide-formoterol (Symbicort Turbuhaler®) maintenance, both with Terbutaline (Bricanyl Turbuhaler®) reliever.
Secondary ID [1] 307834 0
MRINZ/22/06
Universal Trial Number (UTN)
U1111-1278-5798
Trial acronym
START CARE: STep-wise Anti-inflammatory Reliever Therapy Children’s Asthma REsearch
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Asthma 327448 0
Condition category
Condition code
Respiratory 324565 324565 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 Dry Powder Inhaler (DPI Turbuhaler). 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 and prior to exercise, for 52 weeks.
GINA step 2: 1 inhalation as needed
GINA step 3: 1 inhalation once daily, and 1 inhalation as needed
GINA step 4: 1 inhalation twice daily, and 1 inhalation as needed

GINA steps will be assessed by the investigator at study entry and the run-in period 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: following an acute severe asthma exacerbation, or following two moderate asthma exacerbations. If the escalation criteria is met, their standard treatment will be stepped up, in accordance with the START CARE stepwise treatment approach, if not already done so by their usual doctor or their treating medical team.

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] 324303 0
Treatment: Drugs
Comparator / control treatment
Inhaled Corticosteroid (ICS) or Inhaled Corticosteroid + Long-Acting Beta2-Agonist (ICS-LABA) maintenance plus separate Short-acting beta-agonist (SABA).

Budesonide 100micrograms DPI Turbuhaler maintenance or Budesonide-formoterol 100micrograms/6micrograms DPI Turbuhaler maintenance (drug and dose adjusted according to GINA step at study entry, see below), both with separate Terbutaline 500micrograms DPI Turbuhaler reliever, as needed for relief of asthma symptoms and prior to exercise, for 52 weeks.

GINA step 2: Budesonide 100mcg, 1 inhalation twice daily + Terbutaline 500mcg, 1 inhalation as needed
GINA step 3: Budesonide 100mcg, 2 inhalation twice daily + Terbutaline 500mcg, 1 inhalation as needed OR Budesonide-formoterol 100mcg/6mcg, 1 inhalation twice daily + Terbutaline 500mcg, 1 inhalation as needed
GINA step 4: Budesonide-formoterol 100mcg/6mcg, 2 inhalation twice daily + Terbutaline 500mcg, 1 inhalation as needed

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.
Control group
Active

Outcomes
Primary outcome [1] 332392 0
Asthma exacerbations (moderate and severe) as rate per participant per year.

A moderate asthma exacerbation is defined as worsening asthma leading to either:
- An urgent, unplanned medical review (e.g. primary care or ED visit) or hospital admission for less than 24 hours; not resulting in an acute prescription of systemic corticosteroids (tablets, suspension, or injection – e.g. oral prednisone); OR
- The use of systemic corticosteroids for less than 3 days, which does not meet the criteria for a severe asthma exacerbation (e.g. use of systemic corticosteroids from a non-acute prescription, such as a home supply or delayed script).

A severe asthma exacerbation is defined as worsening asthma leading to either:
- An urgent, unplanned medical review (e.g. primary care or emergency department (ED) visit) or hospital admission; resulting in an acute prescription of systemic corticosteroids (tablets, suspension, or injection); OR
- The use of systemic corticosteroids for 3 or more days.
- A hospital admission for more than or equal to 24 hours.

For a moderate asthma exacerbation to be counted as a separate event, it must be preceded by at least seven days during which no criteria for a moderate or severe asthma exacerbation are fulfilled.
For a severe asthma exacerbation to be counted as a separate event, it must be preceded by at least seven days during which no criteria for a severe asthma exacerbation are fulfilled.

Asthma exacerbations will be reported by the participant and their parent(s)/guardian(s) using study logbooks, and reviewed at study visits.
Timepoint [1] 332392 0
52 weeks from the date intervention commenced.
Secondary outcome [1] 413320 0
Severe asthma exacerbations as rate per participant per year, reported by the participant and their parent(s)/guardian(s) using study logbooks, and reviewed at study visits.
Timepoint [1] 413320 0
52 weeks from the date intervention commenced.
Secondary outcome [2] 413321 0
Composite of asthma exacerbations (moderate and severe), or step up in treatment, as rate per participant per year, reported by the participant and their parent(s)/guardian(s) using study logbooks, and/or reported and reviewed at study visits by the investigator.
Timepoint [2] 413321 0
52 weeks from the date intervention commenced.
Secondary outcome [3] 413322 0
Step up in treatment, as rate per participant per year, reported by the participant and their parent(s)/guardian(s) using study logbooks, and/or reported and reviewed at study visits by the investigator.
Timepoint [3] 413322 0
52 weeks from the date intervention commenced.
Secondary outcome [4] 413342 0
Time to first moderate or severe asthma exacerbation, reported by the participant and their parent(s)/guardian(s) using study logbooks, and reviewed at study visits.
Timepoint [4] 413342 0
Measured from the date intervention commenced, to the date the first asthma exacerbation begins.
Secondary outcome [5] 413343 0
Time to first severe asthma exacerbation, reported by the participant and their parent(s)/guardian(s) using study logbooks, and reviewed at study visits.
Timepoint [5] 413343 0
Measured from the date intervention commenced, to the date the first asthma exacerbation begins.
Secondary outcome [6] 413344 0
Time to first asthma exacerbation (moderate and severe), or step up in treatment, reported by the participant and their parent(s)/guardian(s) using study logbooks, and/or reported and reviewed at study visits by the investigator.
Timepoint [6] 413344 0
Measured from the date intervention commenced, to the date the first asthma exacerbation begins, or treatment is stepped up.
Secondary outcome [7] 413345 0
Time to first step up in treatment, reported by the participant and their parent(s)/guardian(s) using study logbooks, and/or reported and reviewed at study visits by the investigator.
Timepoint [7] 413345 0
Measured from the date intervention commenced, to the date the treatment is stepped up.
Secondary outcome [8] 413346 0
Proportion of participants with at least one asthma exacerbation (moderate and severe), reported by the participant and their parent(s)/guardian(s) using study logbooks, and reviewed at study visits.
Timepoint [8] 413346 0
52 weeks from the date intervention commenced.
Secondary outcome [9] 413347 0
Proportion of participants with at least one severe asthma exacerbation, reported by the participant and their parent(s)/guardian(s) using study logbooks, and reviewed at study visits.
Timepoint [9] 413347 0
52 weeks from the date intervention commenced.
Secondary outcome [10] 413348 0
Proportion of participants with at least one step up in treatment, reported by the participant and their parent(s)/guardian(s) using study logbooks, and/or reported and reviewed at study visits by the investigator.
Timepoint [10] 413348 0
52 weeks from the date intervention commenced.
Secondary outcome [11] 413349 0
Proportion of participants on each treatment step, reported by the participant and their parent(s)/guardian(s) using study logbooks, and/or reported and reviewed at study visits by the investigator.
Timepoint [11] 413349 0
52 weeks from the date intervention commenced.
Secondary outcome [12] 413350 0
Days in hospital.

Days in hospital will be reported by the participant and their parent(s)/guardian(s) using study logbooks, and reviewed at study visits.
Timepoint [12] 413350 0
52 weeks from the date intervention commenced.
Secondary outcome [13] 413351 0
Fractional exhaled Nitric Oxide (FeNO), measured using a NIOX VERO® device (Circassia).
Timepoint [13] 413351 0
0, 26 and 52 weeks from the date intervention commenced.
Secondary outcome [14] 413352 0
On-treatment Forced Expiratory Volume over 1 second (FEV1), measured using an NND Easy-on PC Spirometer.
Timepoint [14] 413352 0
0, 26 and 52 weeks from the date intervention commenced.
Secondary outcome [15] 413353 0
Asthma Control Questionnaire 5 (ACQ-5), a validated questionnaire for measuring asthma control.
Timepoint [15] 413353 0
0, 26 and 52 weeks from the date intervention commenced.
Secondary outcome [16] 413354 0
Days lost from school due to asthma, as recorded by the participant and their parent(s)/guardian(s) using study logbooks and reviewed at study visits.
Timepoint [16] 413354 0
52 weeks from the date intervention commenced.
Secondary outcome [17] 413355 0
Days lost from usual activities due to childcare for asthma (parent(s)/guardian(s)), as recorded by the parent(s)/guardian(s) using study logbooks and reviewed at study visits.
Timepoint [17] 413355 0
52 weeks from the date intervention commenced.
Secondary outcome [18] 413360 0
Total systemic corticosteroid dose, as reported by the participant and their parent(s)/guardian(s) using study logbooks, and reviewed at study visits.
Timepoint [18] 413360 0
52 weeks from the date intervention commenced.
Secondary outcome [19] 413363 0
Growth velocity, with height measured using a stadiometer.
Timepoint [19] 413363 0
13, 26, 39 and 52 weeks from the date intervention commenced.
Secondary outcome [20] 413364 0
Adverse Events (AEs), as a proportion of participants. Examples of known AEs include oral thrush, hoarseness, 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 [20] 413364 0
52 weeks from the date intervention commenced.
Secondary outcome [21] 413365 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 [21] 413365 0
52 weeks from the date intervention commenced.
Secondary outcome [22] 413366 0
Proportion of participants who discontinue treatment or withdraw, reported by the participant and their parent(s)/guardian(s) using study logbooks, and reviewed at study visits by the investigator.
Timepoint [22] 413366 0
52 weeks from the date intervention commenced.
Secondary outcome [23] 413370 0
The investigator and study site personnel will collect data about health care resource utilisation associated with medical encounters and medication use at each visit.
The data collected will include:
- Incidence of asthma exacerbations (from asthma exacerbation review)
- Concomitant medications used for the treatment of asthma
- Time taken off school due to asthma
- Time taken off usual activities (parent/ guardian) due to participant’s asthma
- Healthcare visits due to asthma (routine/planned and unplanned/urgent)
- Expenses incurred due to asthma
The sponsor may use the collected data to conduct economic analyses.

The incremental cost per moderate and/or severe exacerbation averted will be reported. Cost-effectiveness acceptability curves will be generated to estimate the uncertainty around this value.
The base-case analysis takes a health system perspective (asthma-related resource utilisation) in the 12-month follow-up period. Secondary analyses will include monetised time off school (participant) and time off from usual activities (caregiver).
Timepoint [23] 413370 0
52 weeks from the date intervention commenced.
Secondary outcome [24] 416742 0
The number of courses of antibiotics for respiratory tract infections, as reported by the participant and their parent(s)/guardian(s) using study logbooks, and reviewed at study visits.
Timepoint [24] 416742 0
52 weeks from the date intervention commenced.
Secondary outcome [25] 428220 0
Proportion of participants with at least one
asthma exacerbation (moderate or severe), or
step up in treatment, reported by the participant and their parent(s)/guardian(s) using study logbooks, and/or reported and reviewed at study visits by the investigator.
Timepoint [25] 428220 0
Measured from the date intervention commenced, to the date the first asthma exacerbation begins, or treatment is stepped up.
Secondary outcome [26] 437926 0
The proportion of the first 100 children who are enrolled in the START CARE study at selected sites and attempt Turbuhaler training who show satisfactory technique at all visits throughout the study, as measured by standardised inhaler technique assessment and inspiratory flow assessment in litres per minute, using the study inspiratory flow device
Timepoint [26] 437926 0
Secondary outcome [27] 437927 0
The proportion of the first 100 children who are enrolled in the START CARE study at selected sites and attempt Turbuhaler training who show satisfactory technique at all visits throughout the study, as measured by standardised inhaler technique assessment and inspiratory flow assessment in litres per minute, using the study inspiratory flow device
Timepoint [27] 437927 0
52 weeks from the date intervention commenced.
Secondary outcome [28] 437928 0
Preferences and beliefs of children and their parent(s)/guardian(s) around the use of Turbuhaler devices, as measured by a Device Preference Questionnaire
Timepoint [28] 437928 0
52 weeks from the date intervention commenced.
Secondary outcome [29] 437929 0
Preferences and beliefs of children and their parent(s)/guardian(s) around the use of Turbuhaler devices, as measured by a Device Preference Questionnaire
Timepoint [29] 437929 0
52 weeks from the date of intervention
Secondary outcome [30] 437930 0
Proportion of participants withdrawn due to inability to use the Turbuhaler device, measured through review of withdrawal logs
Timepoint [30] 437930 0
52 weeks from the date of intervention
Secondary outcome [31] 437931 0
Proportion of participants withdrawn due to inability to use the Turbuhaler device, measured through review of withdrawal logs
Timepoint [31] 437931 0
52 Weeks from the date of intervention
Secondary outcome [32] 437932 0
Number of Turbuhaler retraining events required at each study visit, as measured by the standardised Turbuhaler technique assessment.
Timepoint [32] 437932 0
52 Weeks from the date of intervention
Secondary outcome [33] 437933 0
Number of Turbuhaler retraining events required at each study visit, as measured by the standardised Turbuhaler technique assessment.
Timepoint [33] 437933 0
52 weeks from the date of intervention
Secondary outcome [34] 437934 0
Inspiratory flow rate at each study visit in litres per minute, as measured by the study inspiratory flow device
Timepoint [34] 437934 0
52 weeks from the date of intervention
Secondary outcome [35] 437935 0
Inspiratory flow rate at each study visit in litres per minute, as measured by the study inspiratory flow device
Timepoint [35] 437935 0
52 weeks from the date of intervention

Eligibility
Key inclusion criteria
1. Patients of any gender age five to 11 years (inclusive)
2. Doctor diagnosis of asthma (self-report by parent/participant or healthcare provider-reported)
3. Use of ICS or ICS-LABA maintenance plus SABA reliever therapy (corresponding to
GINA step 2, 3 or 4) in the 6 months prior to Visit 1
4. Registered with a General Practitioner
5. Satisfactory Turbuhaler technique
6. Inspiratory flow measurement of between 30 and 90 L/min
7. Provision of written informed consent (parent/guardian) and assent (participant)
8. Able and willing to switch from current treatment regimen

For randomisation at Visit 2, participants should fulfil the following criterion:

9. Satisfactory Turbuhaler technique
10. Inspiratory flow measurement of between 30 and 90 L/min
Minimum age
5 Years
Maximum age
11 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Already using ICS-formoterol or ICS-Salbutamol as a reliever
2. Any use of high dose ICS-LABA (New Zealand Child Asthma Guidelines Step 5), biologics, maintenance oral corticosteroids (i.e. GINA Step 5), or leukotriene receptor antagonists in the last 6 months
3. Any use of systemic corticosteroids in the 6 weeks prior to Visit 1
4. Use of a beta-blocker in the 6 months prior to Visit 1
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 hypersensitivity (including rash, urticaria, angioedema, bronchospasm and anaphylactic reaction) to the active substances prescribed in the study (budesonide, formoterol, terbutaline), lactose or milk protein (excipient)
7. Any intravenous therapy for the treatment of asthma, in the last year.
8. Previous Intensive Care Unit admission for asthma, or ventilation for asthma, ever
9. Participation in another clinical trial of an investigational medicinal product in the 30 days prior to Visit 1


For randomisation at Visit 2, participants are excluded from the study if the following criteria apply:

10. Any severe exacerbation, or 2 moderate exacerbations (per protocol defined criteria) and/or a change in asthma treatment other than run-in study medication from Visit 1 until Visit 2

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 to maintain allocation concealment. A participant’s treatment allocation will only be revealed to the researchers when that participant is randomised via an electronic Clinical Data Management Application (CDMA).
The study statistician will be masked while performing the primary analysis of the primary outcome variable.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Eligible participants will be randomised 1:1, with stratification according to their:
1. History of a severe asthma exacerbation in the previous 12 months (0 or equal to or greater than 1)
2. GINA Step (2 or greater than 2)

Randomisation will be performed using a computer-generated sequence to maintain allocation concealment. Block size will vary by site. The schedule will be generated by the study statistician, independent of the Investigators. 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 at the point of randomisation. Randomisation 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 variable analysis:

Analysis will be by intention-to-treat superiority analysis by a biostatistician blinded as to treatment allocation. The primary analysis is by estimation of the relative rate of total asthma exacerbations 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.

A sensitivity analysis will include the following potentially important predictors of response at baseline: age, sex, ethnicity, ACQ-5 score, GINA step (2 or greater than 2), FeNO, trial site, and the number of severe asthma exacerbations in the previous 12 months, to account for possibly different distributions of these variables in the treatment groups and to potentially increase precision of the estimates of differences. Ethnicity will be treated as: European, Maori, Pacific, Other; if there are low numbers, particularly for other, we will merge with European.

Secondary outcome variable analysis:
Secondary outcomes will be analysed using Poisson regression for rates, logistic regression for dichotomised outcomes, ANCOVA for continuous variables, and survival analyses for time to event outcomes e.g. time to first asthma exacerbation.
All estimates will be given as 95% confidence intervals, with a nominal two-sided type I error rate of 5%. We will not adjust secondary analyses for multiple analyses; the secondary analyses will be considered exploratory.

1) Poisson regression with an offset for the time of observation and a fixed effect of randomised treatment allocation:
- Severe asthma exacerbations per participant per year
- Composite of asthma exacerbations (moderate and severe), or step up in treatment, as the rate per participant per year.
- Step up in treatment, as the rate per participant per year.
- Number of days lost from school due to asthma
- Number of days lost from usual activities 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 exacerbation
- The proportion of participants with at least one severe asthma exacerbation
- The proportion of participants with at least one step up in treatment, with baseline GINA step as a covariate.
- The proportion of participants on each treatment step, with baseline GINA step as a covariate
- The proportion of participants discontinued from treatment and reason
- The proportion of participants withdrawn and reason
- Adverse events
- Serious adverse events
- The proportion of participants withdrawn due to inability to use the Turbuhaler device

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 exacerbation
- Time to first severe asthma exacerbation
- Time to first moderate or severe asthma exacerbation, or step up in treatment
- Time to first step up in treatment

4) ANCOVA with baseline (where available) 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 systemic corticosteroid dose
- The number of courses of antibiotics for respiratory tract infections
(Note: data for total corticosteroid dose may 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. 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. For composite inhaled beta2-agonist dose, Terbutaline 500mcg is considered equivalent to Formoterol 6mcg.

Tertiary/Other Endpoint(s) Analysis:
- Proportion of screen fails and participants not randomised due to unsatisfactory Turbuhaler technique, by age and reason for unsatisfactory technique.
- Number of Turbuhaler retraining events required at each study visit
- Inspiratory flow rate at each study visit

Sub-group and sensitivity analysis:
Sub-group analyses will be performed for three outcome variables: rate of asthma exacerbations, rate of severe asthma exacerbation, and ACQ-5. In these sub-group analyses the differential effect of treatment on outcome will be explored with each of the following potential moderating variables:
- Severe asthma exacerbation in the 12 months prior to enrolment
- Age at enrolment
- Sex
- Ethnicity
- Trial site
- Smoking exposure
- ACQ-5 score at randomisation (for asthma exacerbations and severe asthma exacerbations outcomes only)
- FeNO at randomisation
- FEV1 % predicted at randomisation
- Treatment step at randomisation
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.

Sensitivity Analysis:
A further sensitivity analysis will be undertaken for the primary outcome variable which will include all courses of systemic corticosteroids either prescribed, dispensed or taken, for a respiratory illness associated with increased wheezing and/or increased reliever use and/or recognition by the participant/family of “worsening asthma”. This includes courses of systemic corticosteroids prescribed by investigators to ensure the safety of participants that are unable to access timely primary care services. If the participant sees a healthcare provider for an asthma exacerbation and is given a prescription for oral corticosteroid medication to take if the exacerbation worsens or in the event of another exacerbation this event would be upgraded from a moderate to a severe exacerbation, for the purpose of the sensitivity analysis.

Other Analysis - Economic analysis:
The incremental cost per moderate and/or severe exacerbation averted will be reported. The probability that the intervention is cost-effective at various willingness-to-pay values for averting a moderate and/or severe exacerbation will be estimated by cost-effectiveness acceptability curves.
The base-case analysis will take a health system perspective (asthma-related resource utilisation) in the 12-month follow-up period. Caregivers’ self-reported healthcare resource utilisation will consist of: asthma inhalers (dispensed); antibiotics; oral corticosteroids; GP visits, after hours clinics; ED visits; paediatric outpatient visits; inpatient hospitalisations (admissions and days per admission).
Secondary analyses will monetise time off school for the participant and time off usual activities (due to asthma caregiving) for the parent(s)/guardian(s).
Subgroup analyses will stratify the sample, as defined at randomisation, by (1) mild, (2) moderate, and (3) severe asthma.

Other Analysis - Carbon footprint analysis:
Carbon footprint per participant, expressed in kilograms of carbon dioxide equivalents (kg CO2e), will be calculated based on inhaler device actuations (derived from the number of doses remaining on each returned inhaler) and healthcare encounters for asthma exacerbations.

Other Analysis - Ethnicity analysis:
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.

Other Analysis - 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.

Other Analysis - 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, SMART CARE and CARE. 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 effect 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 Novel START, PRACTICAL, SMART, PRECARE, SMART CARE, and CARE 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.

Preferences Sub-study Analysis:
Continuous variables will be described by mean and standard deviation or median and interquartile range. Categorical variables will be described by counts and proportions as percentages. Sensitivity analyses will be performed for the DPQ to check for effect modification of randomised treatment regimens.

Sample Size Determination:
Severe asthma exacerbation rates in similar age children receiving GINA Step 2 to Step 4 treatment ranges from approximately 0.3 to 1.4 per patient per year, depending on the baseline level of severity and control, and whether there was a step up or step down in treatment. In the current CARE study of children with mild asthma, the number of moderate attacks is slightly higher than the number of severe attacks, indicating that the number of moderate and severe attacks is likely to be at least double that of severe attacks. As a result, a baseline rate of moderate and severe attacks in the control regimen of 1.0 in this proposed study can be considered conservative. By simulation from appropriate Poisson distributions, we estimate 320 participants are required to
detect a difference in asthma exacerbation rates between 1.0 in the control arm and 0.67 in the Budesonide-formoterol intervention arm; rate ratio 0.67, with 90% power and two-sided alpha of 5%. Assuming a dropout rate of 20%, a total of 400 participants (200 in each arm) will be recruited.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/12/2022
Actual
5/12/2022
Date of last participant enrolment
Anticipated
30/06/2025
Actual
Date of last data collection
Anticipated
30/06/2026
Actual
Sample size
Target
400
Accrual to date
303
Final
Recruitment outside Australia
Country [1] 24984 0
New Zealand
State/province [1] 24984 0

Funding & Sponsors
Funding source category [1] 312109 0
Commercial sector/Industry
Name [1] 312109 0
AstraZeneca Ltd
Country [1] 312109 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] 313631 0
None
Name [1] 313631 0
Address [1] 313631 0
Country [1] 313631 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311511 0
Northern B Health and Disability Ethics Committee
Ethics committee address [1] 311511 0
Ministry of Health
Health and Disability Ethics Committees
133 Molesworth Street
Thorndon
Wellington 6011
Ethics committee country [1] 311511 0
New Zealand
Date submitted for ethics approval [1] 311511 0
22/08/2022
Approval date [1] 311511 0
06/10/2022
Ethics approval number [1] 311511 0
2022 FULL 13221

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

Contacts
Principal investigator
Name 121354 0
Prof Richard Beasley
Address 121354 0
Medical Research Institute of New Zealand
Level 7 CSB Building
Wellington Hospital
Riddiford Street
Newtown
Wellington 6021
Country 121354 0
New Zealand
Phone 121354 0
+64 4 805 0147
Fax 121354 0
Email 121354 0
[email protected]
Contact person for public queries
Name 121355 0
Mark Holliday
Address 121355 0
Medical Research Institute of New Zealand
Level 7 CSB Building
Wellington Hospital
Riddiford Street
Newtown
Wellington 6021
Country 121355 0
New Zealand
Phone 121355 0
+64 4 805 0240
Fax 121355 0
Email 121355 0
[email protected]
Contact person for scientific queries
Name 121356 0
Richard Beasley
Address 121356 0
Medical Research Institute of New Zealand
Level 7 CSB Building
Wellington Hospital
Riddiford Street
Newtown
Wellington 6021
Country 121356 0
New Zealand
Phone 121356 0
+64 4 805 0147
Fax 121356 0
Email 121356 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 START 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 Mr Mark Holliday via email ([email protected])


What supporting documents are/will be available?




Results publications and other study-related documents

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