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Trial registered on ANZCTR


Registration number
ACTRN12622001304729
Ethics application status
Approved
Date submitted
28/09/2022
Date registered
7/10/2022
Date last updated
15/10/2023
Date data sharing statement initially provided
7/10/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
A randomIsed controlled trial of budesonide-formoterol vs terbutaline for symptom relief in adults with mild-moderate asthma on inhaled corticosteroid maintenance therapy
Scientific title
An open-label randomised controlled trial investigating the effect of as-needed budesonide-formoterol vs terbutaline reliever therapy on airways inflammation in adults with mild-moderate asthma on inhaled corticosteroid maintenance therapy
Secondary ID [1] 307830 0
MRINZ/22/04
Universal Trial Number (UTN)
U1111-1277-9274
Trial acronym
INFORM ASTHMA Trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Asthma 327436 0
Condition category
Condition code
Respiratory 324559 324559 0 0
Asthma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Budesonide-formoterol (200/6mcg per actuation) dry powder inhaler (Symbicort Turbuhaler) one actuation as needed (no maximum daily dose limits) for relief of asthma symptoms plus maintenance budesonide 200mcg dry powder inhaler (Pulmicort Turbuhaler), for 26 weeks.

Pulmicort Turbuhaler will be taken daily for 26 weeks as maintenance inhaled corticosteroid (ICS) treatment at a fixed dose (one actuation once daily (200mcg/day), one actuation twice daily (400mcg/day), or two actuations twice daily (800mcg/day)), determined at the start of the study based on their current prescribed treatment regimen prior to entering the study.

Participants will return all study inhalers to the study site at each clinic visit. Intervention accountability will be determined by investigators manually counting the number of actuations remaining in the returned inhaler. New inhalers will be dispensed to participants at each clinic visit.
Intervention code [1] 324297 0
Treatment: Drugs
Comparator / control treatment
Terbutaline 200mcg dry powder inhaler (Bricanyl Turbuhaler - corresponding to 250mcg metered dose) two actuations as needed (no maximum daily dose limits) for relief of asthma symptoms plus maintenance budesonide 200 mcg dry powder inhaler (Pulmicort Turbuhaler), for 26 weeks

Pulmicort Turbuhaler will be taken daily for 26 weeks as maintenance ICS treatment at a fixed dose (one actuation once daily (200mcg/day), one actuation twice daily (400mcg/day), or two actuations twice daily (800mcg/day)), determined at the start of the study based on their current prescribed treatment regimen prior to entering the study.

Participants will return all study inhalers to the study site at each clinic visit. Intervention accountability will be determined by investigators manually counting the number of actuations remaining in the returned inhaler. New inhalers will be dispensed to participants at each clinic visit.
Control group
Active

Outcomes
Primary outcome [1] 332385 0
Fraction of exhaled Nitric Oxide (FeNO) measured using the Vivatmo me (Bosch) FeNO analyser
Timepoint [1] 332385 0
Week 26 from the date intervention commenced
Secondary outcome [1] 413269 0
FeNO time course measured using the Vivatmo me (Bosch) FeNO analyser
Timepoint [1] 413269 0
Weeks 1-13 and week 26 from the date intervention commenced
Secondary outcome [2] 413270 0
Asthma control measured using the Asthma Control Questionnaire-5 (ACQ-5)
Timepoint [2] 413270 0
Weeks 13 and 26 from the date intervention commenced
Secondary outcome [3] 413271 0
On-treatment Forced Expiratory Volume over 1 second (FEV1) measured using the Easy On-PC (NDD) Spirometer
Timepoint [3] 413271 0
Weeks 13 and 26 from the date intervention commenced
Secondary outcome [4] 413272 0
Time to first severe asthma attack, reported by the participant using study logbooks, and reviewed at study visits
Timepoint [4] 413272 0
Week 26 from the date intervention commenced
Secondary outcome [5] 413273 0
Rate of severe asthma attacks per participant per year, reported by the participant using study logbooks, and reviewed at study visits
Timepoint [5] 413273 0
Week 26 from the date intervention commenced
Secondary outcome [6] 413274 0
Rate of moderate asthma attacks per participant per year, reported by the participant using study logbooks, and reviewed at study visits
Timepoint [6] 413274 0
Week 26 from the date intervention commenced
Secondary outcome [7] 413275 0
Rate of composite asthma attacks (combined moderate and severe) per participant per year, reported by the participant using study logbooks, and reviewed at study visits
Timepoint [7] 413275 0
Week 26 from the date intervention commenced
Secondary outcome [8] 413276 0
Number of self-reported composite admissions (combined ED and hospital) for asthma, reported by the participant using study logbooks, and reviewed at study visits.
Timepoint [8] 413276 0
Week 26 from the date intervention commenced
Secondary outcome [9] 413277 0
Total composite corticosteroid dose (combined total inhaled and systemic dose for asthma), reported by the participant using study logbooks, and reviewed at study visits (systemic corticoisteroid dose), and determined through counting of remaining doses in returned inhalers (inhaled corticosteroid dose).
Timepoint [9] 413277 0
Week 26 from the date intervention commenced
Secondary outcome [10] 413278 0
Total inhaled corticosteroid dose, determined through counting of remaining doses in returned inhalers
Timepoint [10] 413278 0
Week 26 from the date intervention commenced
Secondary outcome [11] 413279 0
Total beta2-agonist dose, determined through counting of remaining doses in returned inhalers
Timepoint [11] 413279 0
Week 26 from the date intervention commenced
Secondary outcome [12] 413280 0
Number of Adverse Events. Examples of known AEs include oral thrush, hoarseness, rapid or irregular heartbeat, tremor, and headache. These will be determined by participant and/or medical records, utilising Common Terminology Criteria for Adverse Events (CTCAE).
Timepoint [12] 413280 0
Week 26 from the date intervention commenced
Secondary outcome [13] 413281 0
Number of Serious Adverse Events. Examples of SAEs include severe allergic reaction and severe spasm in the airways. These will be determined by participant and/or medical records, utilising Common Terminology Criteria for Adverse Events (CTCAE).
Timepoint [13] 413281 0
Week 26 from the date intervention commenced
Secondary outcome [14] 414168 0
Total systemic corticosteroid dose for asthma assessed by intervention, reported by the participant using study logbooks, and reviewed at study visits
Timepoint [14] 414168 0
Week 26 from the date intervention commenced
Secondary outcome [15] 414169 0
Peripheral blood eosinophil count
Timepoint [15] 414169 0
Week 26 from the date intervention commenced

Eligibility
Key inclusion criteria
- Aged 16 to 75 years
- Self-reported doctor’s diagnosis of asthma for >/= 6 months prior to visit 1
- Current use (within the last 3 months) of either:
Inhaled corticosteroid (ICS) maintenance (any dose) plus a short-acting beta-agonist (SABA) reliever inhaler OR
SABA reliever inhaler only OR
ICS/LABA combination reliever inhaler only
- Average use of SABA reliever on >/= 2 episodes per week, over the last 12 weeks
- FeNO >/= 25 ppb at screening
- Ability to perform FeNO measurements at home on a regular basis
- Ability to use the turbuhaler device
- Self-reported registered with a General Practitioner
Minimum age
16 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Current use (within the last 3 months) of other asthma medications including: ICS/long-acting beta-agonist (LABA) combination inhalers, leukotriene receptor antagonists, theophylline, regular oral corticosteroids, sodium cromoglycate or anticholinergic agents
- Average use of ICS/LABA combination reliever inhaler on = 8 episodes per week, over the last 12 weeks
- Any use of systemic corticosteroids in the last 6 weeks
- Self-reported diagnosis of COPD, bronchiectasis, vocal cord dysfunction or interstitial lung disease
- Self-reported current smokers, defined as someone who has smoked more than 100 cigarettes (including hand rolled cigarettes, cigars, cigarillos, etc), or has used an e-cigarette on more than 100 occasions in their lifetime, and has smoked or vaped in the last 28 days
- Self-reported greater than 20 pack year smoking history, or asthma diagnosis after the age of 40 years in current or ex-smokers with >/=10 pack year history
- Self-reported congestive heart failure, atrial fibrillation, unstable coronary artery disease, or other clinically significant cardiac disease
- 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
- Any known or suspected contraindications to the medications prescribed in the study or their respective excipients
- Previous life-threatening asthma (Intensive Care Unit admission for asthma ever)
- Unable or unwilling to switch from current asthma treatment regimen
- Unable or unwilling to provide written informed consent
- Self-reported current or planned pregnancy or breast feeding at the time of enrolment
- Self-report of participation in another research trial involving an unapproved investigational medicinal product, in the past 12 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 created by the study statistician, independent of the investigators undertaking recruitment. The eCRF system will conceal the allocations and will release a participant’s randomisation outcome at the time of randomisation. Study staff will not have access to the randomisation schedule.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomised in a ratio of 1:1 to either as-needed budesonide-formoterol or as-needed terbutaline, with maintenance budesonide. Randomisation will be stratified according to severe exacerbations in the previous 12 months and their baseline ICS dose:
• None
• Very low and Low dose (less than/equal to 400mcg budesonide equivalent)
• Medium or high dose (greater than 400mcg budesonide equivalent)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
All participants who are enrolled will be included in the analysis which will be by intention to treat. There will be no formal adjustment for multiplicity and secondary outcomes will be treated as exploratory.

Primary outcome analysis:
Comparison of FeNO at week 26 will be by ANCOVA, adjusted for baseline FeNO. The FeNO data will be logarithm transformed and differences reported by both differences in logarithm FeNO and the exponent of this, the latter of which is interpreted as the ratio of geometric means.

Secondary outcome analysis:
For the time course of the FeNO over 26 weeks, comparisons of treatments at each time point will be made by t-tests, as a simple comparison, and by mixed linear models, with the baseline value as a baseline covariate, and each participant as a random effect, to account for repeated measurements. The pattern of change with time will be explored with a time-by treatment interaction in a mixed linear model. For ACQ, peripheral blood eosinophil count, and FEV1 at 26 weeks, comparison will be by ANCOVA, adjusted for baseline. Ordinal scale variables will be analysed by ordinal regression. Pre-specified subgroup analyses will be performed to evaluate if specific characteristics influence treatment response.
Comparison of the rate of severe, moderate, and moderate and severe exacerbations per patient per year will be undertaken by Poisson regression with an offset for the time of observation and a fixed effect for the baseline Global Initiative for Asthma (GINA) step treatment category and number of prior severe exacerbations before recruitment. Over-dispersion will be evaluated prior to analysis and a corrected analysis applied as necessary. Survival analysis with Kaplan-Meier plots and Cox’s proportional hazards will be used to calculate the hazard ratio for time to first severe exacerbation.

Sample size calculation:
Based on the 'Novel START'(1) and 'PRACTICAL' (2) studies, the change from baseline logarithm FeNO SD was about 0.6. A difference in logarithm FeNO of 0.30; corresponding to a geometric mean ratio of 0.74, at 90% power, needs 172 total. Accounting for a drop-out rate of 5%, 90 participants are needed per arm (180 in total). If the geometric mean FeNO at baseline is 40 then this corresponds to a geometric mean FeNO to detect in the treatment group of 30. As a result, the study is adequately powered to detect a clinically important difference in FeNO, based on the ATS recommendation that a reduction in FeNO of at least 20% indicates a significant fall following an intervention.

(1) Beasley, Richard, et al. "Controlled trial of budesonide–formoterol as needed for mild asthma." New England Journal of Medicine 380.21 (2019): 2020-2030.
(2) Hardy, Jo, et al. "Budesonide-formoterol reliever therapy versus maintenance budesonide plus terbutaline reliever therapy in adults with mild to moderate asthma (PRACTICAL): a 52-week, open-label, multicentre, superiority, randomised controlled trial." The Lancet 394.10202 (2019): 919-928.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
29/03/2023
Actual
28/03/2023
Date of last participant enrolment
Anticipated
30/09/2024
Actual
Date of last data collection
Anticipated
30/03/2025
Actual
Sample size
Target
180
Accrual to date
69
Final
Recruitment outside Australia
Country [1] 24976 0
New Zealand
State/province [1] 24976 0

Funding & Sponsors
Funding source category [1] 312104 0
Other Collaborative groups
Name [1] 312104 0
Medical Research Institute of New Zealand
Country [1] 312104 0
New Zealand
Primary sponsor type
Other Collaborative groups
Name
Medical Research Institute of New Zealand
Address
Level 7, CSB Building
Wellington Hospital
Riddiford St, Newtown
Wellington 6021
Country
New Zealand
Secondary sponsor category [1] 313630 0
None
Name [1] 313630 0
Address [1] 313630 0
Country [1] 313630 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311507 0
Northern A Health and Disability Ethics Committee
Ethics committee address [1] 311507 0
Ministry of Health
Health and Disability Ethics Committees
133 Molesworth Street
Thorndon
Wellington 6011
Ethics committee country [1] 311507 0
New Zealand
Date submitted for ethics approval [1] 311507 0
05/10/2022
Approval date [1] 311507 0
03/11/2022
Ethics approval number [1] 311507 0
2022 FULL 13331

Summary
Brief summary
People who have mild-moderate asthma are traditionally treated with a short-acting beta-agonist (SABA) for symptom relief, with or without daily low dose inhaled corticosteroids (ICS). However, even when ICS are prescribed, most patients have poor compliance, despite education. One potential approach which addresses this problem inherent in ICS-based maintenance treatment is to combine an ICS in the beta2-agonist reliever inhaler, thereby ensuring that the patient receives a dose of ICS whenever they use their bronchodilator.

Switching the relief inhaler from a SABA to a combined ICS-formoterol inhaler so that patients receive ICS each time they use their relief inhaler could potentially reduce airways inflammation, improve asthma control and reduce the risk of asthma attacks.
We therefore plan to determine the clinical benefit of replacing a SABA with an ICS-formoterol inhaler in patients with mild-moderate asthma, who also receive a low or medium dose ICS as maintenance treatment. This proposed RCT should provide the evidence on which this approach can be considered for use in clinical practice. If confirmed to be effective, this simple change to asthma management could markedly improve overall asthma control and reduce exacerbations and potentially reduce deaths from asthma.

The FeNO has been chosen as the primary outcome measure as it is a validated biological marker of airways inflammation in asthma.

We hypothesise that In adults aged 16 to 75 with mild-moderate asthma, as-needed budesonide-formoterol (Symbicort Turbuhaler) for symptom relief will lead to reduced airways inflammation compared with terbutaline (Bricanyl Turbuhaler) reliever therapy, on a background of maintenance ICS therapy.
Trial website
https://www.mrinz.ac.nz/currently-recruiting/inform
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 121342 0
Dr Jonathan Noble
Address 121342 0
Medical Research Institute of New Zealand
Level 7, CSB Building
Wellington Hospital
Riddiford St, Newtown
Wellington 6021
Country 121342 0
New Zealand
Phone 121342 0
+64 4 8050147
Fax 121342 0
Email 121342 0
jon.noble@mrinz.ac.nz
Contact person for public queries
Name 121343 0
Dr Jonathan Noble
Address 121343 0
Medical Research Institute of New Zealand
Level 7, CSB Building
Wellington Hospital
Riddiford St, Newtown
Wellington 6021
Country 121343 0
New Zealand
Phone 121343 0
+64 4 8050147
Fax 121343 0
Email 121343 0
jon.noble@mrinz.ac.nz
Contact person for scientific queries
Name 121344 0
Dr Jonathan Noble
Address 121344 0
Medical Research Institute of New Zealand
Level 7, CSB Building
Wellington Hospital
Riddiford St, Newtown
Wellington 6021
Country 121344 0
New Zealand
Phone 121344 0
+64 4 8050147
Fax 121344 0
Email 121344 0
jon.noble@mrinz.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?
De-identifed data underlying published results only.
When will data be available (start and end dates)?
Data will be available immediately following publication; no end date determined
Available to whom?
Researchers who provide a methodologically sound proposal, assessed on a case-by-case basis at the discretion of the Sponsor.
Available for what types of analyses?
To achieve the aims of the approved proposal.
How or where can data be obtained?
Access subject to approvals by Sponsor.

Contact details:
Professor Richard Beasley
Medical Research Institute of New Zealand

Postal Address:
Private Bag 7902, Wellington 6242

Physical Address:
Level 7, CSB Building
Wellington Hospital
Riddiford St, Newtown
Wellington 6021
New Zealand

Telephone: +64 4 805 0238


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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

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