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Trial registered on ANZCTR


Registration number
ACTRN12624001488594
Ethics application status
Approved
Date submitted
20/11/2024
Date registered
20/12/2024
Date last updated
20/12/2024
Date data sharing statement initially provided
20/12/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
A study comparing two step-wise treatment tracks for adults with asthma: inhaled corticosteroid with formoterol reliever therapy versus short-acting beta-agonist reliever therapy.
Scientific title
A randomised, parallel group trial comparing two stepwise treatment tracks for the pharmacological management of adult asthma: ICS/formoterol reliever vs SABA reliever-based therapy
Secondary ID [1] 313152 0
None
Universal Trial Number (UTN)
U1111-1314-2955
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Asthma 335425 0
Condition category
Condition code
Respiratory 332255 332255 0 0
Asthma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a randomised, parallel group, single centre, open label study comparing two algorithmic stepwise approaches to the pharmacological management of adult and adolescent asthma. 152 eligible patients diagnosed with asthma aged 16-75 years who in the 3 months prior to enrollment have been prescribed short acting beta-agoinst (SABA) reliever therapy alone, maintenance inhaled corticosteroids (ICS) plus SABA reliever therapy, or maintenance ICS/long acting beta agonist (LABA) plus SABA reliever therapy, will be enrolled and randomised in a 1:1 ratio to the two study arms; Algorithm 1 and Algorithm 2 at Visit 1 (week 1). The algorithm step at randomisation is based on the participants Global Initiative for Asthma (GINA) treatment step at enrollment.

Visit one will last approximately two hours. Participants will be followed up at four follow up visits (visits 2,3,4 and 5) every 13 weeks lasting approximately one hour.

At follow up visits participants transition between treatment step according to the GINA criteria for asthma control and if they have had a severe exacerbation in the prior 6 months. Patients step up a treatment level at clinic visits in response to a severe exacerbation or uncontrolled asthma (GINA criteria of 3-4/4). Patients step down a treatment level at clinic visits if there has been no severe exacerbation in the last 6 months, and if they have well controlled asthma (GINA criteria 0/4) at the clinic visit.

Inventions:
Arm 1:
• Step 1: lCS/formoterol 200/6µg one actuation as required for the relief of symptoms.
• Step 2: Maintenance low dose lCS/formoterol 200/6µg one actuation twice daily plus lCS/formoterol 200/6µg one actuation as required for the relief of symptoms.
• Step 3: Maintenance medium dose lCS/formoterol 200/6µg two actuations twice daily plus lCS/formoterol 200/6µg one actuation as required for the relief of symptoms.

The cumulative ICS dose will be assessed by inhaler dose counters for Accuhaler, Ellipta and Spiromax devices returned by the participant at each clinic visit. Diary cards and e-monitoring will not be performed.
Intervention code [1] 329916 0
Treatment: Drugs
Comparator / control treatment
Arm 2:
Step 1: Salbutamol 100ug delivered by pressurized metered dose inhaler (pMDI) (Ventolin pMDI), 2 actuations as required, and Fluticasone Propionate 100µg/actuation dry powder inhaler (DPI) (Flixotide Accuhaler), 1 actuation taken at the same time as the salbutamol.
Step 2: Fluticasone Propionate 100µg/actuation DPI (Flixotide Accuhaler) 1 actuation twice daily and Salbutamol 100ug delivered by pMDI (Ventolin pMDI), 2 actuations as required.
Step 3: Fluticasone propionate/Salmeterol 100/50µg/actuation DPI (Seretide Accuhaler) 1 actuation twice daily and salbutamol 100ug delivered by pMDI (Ventolin pMDI), 2 actuations as required
Step 4a: Fluticasone propionate/Salmeterol 250/50µg DPI (Seretide Accuhaler) 1 actuation twice daily and salbutamol 100ug delivered by pMDI (Ventolin pMDI), 2 actuations as required.
Step 4b: Fluticasone furoate/vilanterol 200/25ug DPI (Breo Ellipta) 1 actuation once daily and salbutamol 100µg delivered by pMDI (Ventolin pMDI), 2 actuations as required.

The algorithm step at randomisation is based on the participants Global Initiative for Asthma (GINA) treatment step at enrollment. At randomisation participants will be recruited at step 1,2,3 and step 4a. At follow up visits participants transition between treatment step according to the GINA criteria for asthma control and if they have had a severe exacerbation in the prior 6 months. Patients step up a treatment level at clinic visits in response to a severe exacerbation or uncontrolled asthma (GINA criteria of 3-4/4). Patients step down a treatment level at clinic visits if there has been no severe exacerbation in the last 6 months, and if they have well controlled asthma (GINA criteria 0/4) at the clinic visit.

Participants who meet the criteria to step up who are allocated to step 3 will step up to step 4a. Participants who meet the criteria to step up who are allocated to step 4a will step up to step 4b. Participants allocated to these steps who meet the criteria to step down will step down from 4b to 4a, and 4a to step 3.


Control group
Active

Outcomes
Primary outcome [1] 339827 0
Mean inhaled budesonide equivalent corticosteroid dose per day (budesonide µg/day)
Timepoint [1] 339827 0
Week 52 post enrollment
Secondary outcome [1] 441530 0
Fractional exhaled nitric oxide (FeNO)
Timepoint [1] 441530 0
Baseline, week 52 post enrollment
Secondary outcome [2] 441531 0
Peripheral blood eosinophils
Timepoint [2] 441531 0
Baseline, week 52 post enrollment
Secondary outcome [3] 441532 0
Total IgE
Timepoint [3] 441532 0
Baseline, week 52 post enrollment
Secondary outcome [4] 441533 0
Participant satisfaction with medication
Timepoint [4] 441533 0
Baseline, week 52 post enrollment
Secondary outcome [5] 441535 0
Asthma control
Timepoint [5] 441535 0
Baseline, week 13, 26,39,52 post enrollment
Secondary outcome [6] 441536 0
Quality of life
Timepoint [6] 441536 0
Baseline, 52 post enrollment
Secondary outcome [7] 441537 0
Participant beliefs about medications
Timepoint [7] 441537 0
Baseline, week 52 post enrollment
Secondary outcome [8] 441539 0
Rate of severe and moderate exacerbations per patient per year
Timepoint [8] 441539 0
Week 52 post enrollment
Secondary outcome [9] 441540 0
Corticosteroid exposure
Timepoint [9] 441540 0
Week 52 post enrollment
Secondary outcome [10] 441541 0
HbA1c
Timepoint [10] 441541 0
Baseline, week 52 post enrollment
Secondary outcome [11] 441542 0
Treatment step
Timepoint [11] 441542 0
Week 13, 26, 39, 52 post enrollment
Secondary outcome [12] 441543 0
Other asthma related medications taken
Timepoint [12] 441543 0
Week 13,26,29,52 post enrollment
Secondary outcome [13] 442392 0
Proportion of participants that step-up treatment step
Timepoint [13] 442392 0
Baseline, week 13,26,39.52 post enrollment
Secondary outcome [14] 442393 0
Proportion of participants that step-down treatment step
Timepoint [14] 442393 0
Baseline, week 13,26,39.52 post enrollment
Secondary outcome [15] 442394 0
Proportion of participants withdrawn and reason
Timepoint [15] 442394 0
Week 13,26,39,52 post enrollment
Secondary outcome [16] 442395 0
Number of adverse events of special interest
Timepoint [16] 442395 0
Week 52 post enrollment
Secondary outcome [17] 442396 0
Number of serious adverse events of special interest
Timepoint [17] 442396 0
Week 52 post enrollment post enrollment
Secondary outcome [18] 442525 0
Time to first severe exacerbation
Timepoint [18] 442525 0
Week 52 post enrollment
Secondary outcome [19] 442526 0
Time to first moderate or severe exacerbation
Timepoint [19] 442526 0
Week 52 post enrollment
Secondary outcome [20] 442527 0
Proportion with ICS exposure >400µg/day budesonide equivalent in last 3 months
Timepoint [20] 442527 0
Baseline and week 13,26,39,52 post enrollment
Secondary outcome [21] 442528 0
Proportion with ICS exposure >800µg/day budesonide equivalent in last 3 months 3., determined using study records and calculating inhaled corticosteroid exposure using dose counters on study inhaler devices returned by participants at study visits
Timepoint [21] 442528 0
Baseline, week 13, 26, 39, 52 post enrollment
Secondary outcome [22] 442529 0
Individual scores for each domain of the TSQM (effectiveness, convenience, side effects, global satisfaction)
Timepoint [22] 442529 0
Baseline, week 52 post enrollment
Secondary outcome [23] 442530 0
Asthma control
Timepoint [23] 442530 0
Baseline, week 13, 26,39,52 post enrollment
Secondary outcome [24] 442531 0
Participant beliefs about medications
Timepoint [24] 442531 0
Baseline, week 52 post enrollment
Secondary outcome [25] 442889 0
Asthma control
Timepoint [25] 442889 0
Baseline, week 52 post enrolment

Eligibility
Key inclusion criteria
• Self-reported doctor’s diagnosis of asthma for greater than 12 months
• Age 16 to 75 years
• Current use (within the last 3 months) of either:
o SABA reliever monotherapy and the self-reported use of a SABA on greater than or equal to 2 occasions for the relief of asthma symptoms in the previous 4 weeks, excluding before exercise
o ICS maintenance plus SABA reliever therapy
o ICS/LABA maintenance plus SABA reliever therapy
• Participant is willing and able to give informed consent for participation in the trial.
• In the Investigator’s opinion, participant is able and willing to comply with all trial requirements.
• In the Investigator’s opinion, participant is able and willing to use all inhaler devices used in study.
• Self-reported registration 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 last 3 months) of the following medications:
o Budesonide/Formoterol anti-inflammatory reliever therapy (AIR)
o Budesonide/Formoterol Single Maintenance and Reliever Therapy (MART)
o ICS/LABA maintenance inhaler greater than 500µg Fluticasone Propionate equivalent per day
o Leukotriene receptor antagonists
o Long-acting muscarinic antagonists
o Theophylline
o Regular oral corticosteroids
o Sodium cromoglycate or nedocromil sodium
o Monoclonal antibody therapy
• Self-reported urgent medical review for asthma, or treatment with systemic corticosteroids such as oral prednisone, in the four weeks before potential study entry.
• ICU admission for asthma (ever).
• Self-reported diagnosis of COPD, bronchiectasis, vocal cord dysfunction or interstitial lung disease.
• Self-reported greater than 20 pack year smoking history, or onset of respiratory symptoms after the age of 40 years in current or ex-smokers with greater than10 pack year history.
• Self-reported current pregnancy or breast feeding at the time of enrolment or planned pregnancy within the study period.
• Self-reported congestive heart failure, atrial fibrillation, unstable coronary artery disease, or other clinically significant cardiac disease.
• Participant is unwilling or unable to switch from current asthma treatment regimen.
• Self-report of participation in another research trial involving an investigational product, in the past 3 months.
• A Body Mass Index of greater than 40
• Any known or suspected contraindications to the medications prescribed for the study or their respective excipients, including severe milk protein allergy
• Any other condition which, at the Investigator’s discretion, is believed may present a safety risk or impact the feasibility of the study or the study results

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 (1,2,3,4)

Randomisation will be performed using a computer-generated sequence to maintain allocation concealment. 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 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
For the primary outcome variable of mean inhaled budesonide equivalent corticosteroid dose per day, it is uncertain if normality assumptions will be met for ANCOVA approaches. These will be tested by graphical plots of residuals as well as formal tests for normality of residuals. If normality assumptions are reasonably well met then ANCOVA will be used with the categorical predictor of interest the randomised therapy. Co-variates will be the baseline ICS dose, GINA step at baseline, baseline ACQ and severe exacerbation in the 12 months prior to baseline . If normality assumptions are not well met for the primary outcome a rank-based test, the Mann-Whitney, with the Hodges-Lehmann estimator of the central tendency and an appropriate confidence interval, will be used.

Composite ICS and OCS exposure, treatment step, TSQM V.II global satisfaction and domain scores, BMQ, ACQ-5, AQLQ-S, FEV1, logarithm FeNO, blood eosinophils, total IgE, and blood HbA1c will be analysed by ANCOVA with baseline measurement (where taken), ICS dose at baseline, baseline GINA treatment step, and severe exacerbation last 12 months as co-variates and randomised treatment as the variable of interest.
The proportion of participants with ICS exposure >400µg/day and >800µg/day, proportion of participants on each GINA step, proportion of participants on each treatment step, stepping up, or stepping down, adverse events of special interest and serious adverse events of special interest will be analysed by logistic regression.
Severe and moderate-and-severe exacerbations will be analysed by Poisson regression with an offset for number of days in the study.
Time to first severe exacerbation and time to first moderate or severe exacerbation will be by 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.

Minimising ICS exposure is a target of treatment as increasing level of ICS exposure is associated with increased risk of systemic adverse events, with substantive risk evident for medium to high doses fluticasone propionate (>250-500µg) or equivalent. We propose that a mean difference in ICS exposure of 100 µg per day of fluticasone propionate (equivalent to 160µg budesonide) is clinically meaningful, due to the close to linear relationship between ICS dose and risk of systemic adverse events up to a Fluticasone Propionate dose of 1000µg/day (3). A 100µg/day increase in FP exposure increases the approximate risk of adrenal sufficiency by 7.6%, cataracts by 5%, non-vertebral fracture by 2.4%,diabetes by 6% and pneumonia by 10%. In the AIR algorithm study, a total of 810 inhalers were dispensed, with 797 (98.4%) returned at follow-up visits, thereby enabling analyses of ICS exposure. The mean (SD) ICS exposure per day (budesonide µg per day) observed in the AIR algorithm study was 214 (233). Based on ICS exposure per day seen in the AIR algorithm study, accounting for a 5% dropout rate, a sample size of 152 participants (76 per arm) has >90% power to detect a mean change of 100µg Fluticasone Propionate per day (160µg Budesonide equivalent per day), alpha 5% based on a t-test.



Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
31/01/2025
Actual
Date of last participant enrolment
Anticipated
31/01/2026
Actual
Date of last data collection
Anticipated
31/01/2027
Actual
Sample size
Target
152
Accrual to date
Final
Recruitment outside Australia
Country [1] 26718 0
New Zealand
State/province [1] 26718 0

Funding & Sponsors
Funding source category [1] 317595 0
Other
Name [1] 317595 0
Medical Research Institute of New Zealand
Country [1] 317595 0
New Zealand
Primary sponsor type
Other
Name
Medical Research Institute of New Zealand
Address
Country
New Zealand
Secondary sponsor category [1] 320120 0
None
Name [1] 320120 0
Address [1] 320120 0
Country [1] 320120 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 316546 0
Northern B Health and Disability Ethics Committee 
Ethics committee address [1] 316546 0
Ethics committee country [1] 316546 0
New Zealand
Date submitted for ethics approval [1] 316546 0
14/11/2024
Approval date [1] 316546 0
13/12/2024
Ethics approval number [1] 316546 0

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

Contacts
Principal investigator
Name 137446 0
Dr Ross Sayers
Address 137446 0
Medical Research Institute of New Zealand, 7 CSB Building Wellington Hospital, Riddiford Street, Newtown, Wellington, Wellington, 6021
Country 137446 0
New Zealand
Phone 137446 0
+64 4 805 0147
Fax 137446 0
Email 137446 0
ross.sayers@mrinz.ac.nz
Contact person for public queries
Name 137447 0
Ross Sayers
Address 137447 0
Medical Research Institute of New Zealand, 7 CSB Building Wellington Hospital, Riddiford Street, Newtown, Wellington, Wellington, 6021
Country 137447 0
New Zealand
Phone 137447 0
+64 4 805 0147
Fax 137447 0
Email 137447 0
ross.sayers@mrinz.ac.nz
Contact person for scientific queries
Name 137448 0
Ross Sayers
Address 137448 0
Medical Research Institute of New Zealand, 7 CSB Building Wellington Hospital, Riddiford Street, Newtown, Wellington, Wellington, 6021
Country 137448 0
New Zealand
Phone 137448 0
+64 4 805 0147
Fax 137448 0
Email 137448 0
ross.sayers@mrinz.ac.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


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.

Documents added automatically
No additional documents have been identified.