Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000232730p
Ethics application status
Submitted, not yet approved
Date submitted
24/12/2021
Date registered
9/02/2022
Date last updated
9/02/2022
Date data sharing statement initially provided
9/02/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Monitoring Intermittent vs Regular inhaled corticoSteroids in asthma: MIRSA study
Scientific title
A 18-week, randomised, controlled, open-label, parallel-group study in adults with mild asthma, evaluating the efficacy and safety of Arnuity® (fluticasone furoate) Ellipta® 100mcg once daily plus Ventolin® (salbutamol) 100mcg as needed and Flixotide® (fluticasone propionate) Junior Accuhaler® (FP) 100mcg twice daily plus Ventolin® (salbutamol) 100mcg as needed compared with Symbicort® (budesonide/formoterol) Turbuhaler® 200/6mcg as needed.
Secondary ID [1] 306076 0
Protocol Number: 217680
Universal Trial Number (UTN)
Trial acronym
MIRSA: Monitoring Intermittent vs Regular inhaled corticoSteroids in asthma
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Asthma 324726 0
Condition category
Condition code
Respiratory 322176 322176 0 0
Asthma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A 18-week, randomised, controlled, open-label, parallel-group study in adults with mild asthma; the first 12-weeks evaluating the efficacy and safety of Arnuity® (fluticasone furoate, FF) Ellipta® 100mcg once daily plus Ventolin® (salbutamol) 100mcg as needed (Arm A) and Flixotide® (fluticasone propionate, FP) Junior Accuhaler® (FP) 100mcg twice daily plus Ventolin® (salbutamol) 100mcg as needed (Arm B) compared with Symbicort® (budesonide/formoterol, BUD/FORM) Turbuhaler® 200/6mcg as needed (comparator)(Arm C). For the last 6 weeks, Arm B will remain the same however from week 12-18, Arm A and C will have their dosage changed to: Arnuity® (fluticasone furoate, FF) Ellipta® 100mcg once every other day (3 doses per week) plus Ventolin® (salbutamol) 100mcg as needed (Arm A) and Pulmicort® (budesonide, BUD) Turbuhaler® 200mcg twice daily plus Ventolin® (salbutamol) 100mcg as needed (Arm C). All these formulations are administered via inhalation. Efficacy will be assessed by assessing improvement in airway hyperresponsiveness using inhaled mannitol (AridolTM), a bronchial provocation test. The outcome for this test is the provoking dose of mannitol to cause a 15% fall in FEV1 (PD15). Adherence to medications throughout the trial will be monitored using electronic adherence monitors (HailieTM).
Intervention code [1] 322481 0
Treatment: Drugs
Comparator / control treatment
Symbicort® (budesonide/formoterol, BUD/FORM) Turbuhaler® 200/6mcg as needed
Control group
Active

Outcomes
Primary outcome [1] 329945 0
Primary Outcome 1: Shift of Geometric Mean PD15 >0.0 doubling dose in the regular FF (Arm A) relative to the BUD/FORM as-needed (Arm C). This outcome is assessed from the test report from the bronchial provocation test using inhaled mannitol. PD15 or provoking dose of inhaled mannitol to cause a 15% Fall in FEV1 is calculated via linear interpretation of the dose response curve. This is a measure of airway sensitivity.
Timepoint [1] 329945 0
Primary Outcome 1: PD15 to mannitol is measured before commencement of treatment and at 2, 6, 12 and 18 weeks. At 12 weeks, Arm's A vs C will be compared for treatment effects. Measurements are made at other weeks to monitor disease severity in the presence of treatment.
Primary outcome [2] 330182 0
Primary Outcome 2: Shift of Geometric Mean PD15 >0.0 doubling dose in the regular FP (Arm B) relative to the BUD/FORM as-needed (Arm C). This outcome is assessed from the test report from the bronchial provocation test using inhaled mannitol. PD15 or provoking dose of inhaled mannitol to cause a 15% Fall in FEV1 is calculated via linear interpretation of the dose response curve.
Timepoint [2] 330182 0
Primary Outcome 2: PD15 to mannitol is measured before commencement of treatment and at 2, 6, 12 and 18 weeks. At 12 weeks, Arm's B vs C will be compared for treatment effects. Measurements are made at other weeks to monitor disease severity in the presence of treatment.
Secondary outcome [1] 404372 0
RDR100<1 (Response-Dose Ratio; the degree to which the dose response curve is flat when the PD15 is abolished). This is a measure of airway reactivity. It is calculated from the final % fall in FEV1 to the mannitol challenge and divided by the cumulative dose of mannitol to cause that fall in FEV1, with the final result multiplied by 100.


Timepoint [1] 404372 0
Measured before commencement of treatment and at 2, 6, 12 and 18 weeks. At 12 weeks after the commencement of the treatments assigned at the initial treatment visits for Arm's A vs C and Arm's B vs C for treatment effects. Measurements are made at other weeks to monitor disease severity in the presence of treatment.
Secondary outcome [2] 405158 0
Change in asthma control using the asthma control questionnaire (ACQ5).
Timepoint [2] 405158 0
ACQ5 is measured before commencement of treatment and at 2, 6, 12 and 18 weeks. At 12 weeks after the commencement of the treatments assigned at the initial treatment visits for Arm's A vs C and Arm's B vs C for treatment effects. Measurements are made at other weeks to monitor disease severity in the presence of treatment.
Secondary outcome [3] 405159 0
Change in lung function measured using a spirometer to pre-bronchodilator forced expiratory volume in one second (FEV1)
Timepoint [3] 405159 0
FEV1 is measured before commencement of treatment and at 2, 6, 12 and 18 weeks. At 12 weeks after the commencement of the treatments assigned at the initial treatment visits for Arm's A vs C and Arm's B vs C, Change in FEV1 will be compared for treatment effects. Measurements are made at other weeks to monitor disease severity in the presence of treatment.
Secondary outcome [4] 405160 0
Change in the fraction of exhaled nitric oxide (FeNO) measured in parts per billion using a portable exhaled nitric oxide analyser.
Timepoint [4] 405160 0
FeNO is measured before commencement of treatment and at 2, 6, 12 and 18 weeks. At 12 weeks after the commencement of the treatments assigned at the initial treatment visits for Arm's A vs C and Arm's B vs C will be compared for treatment effects. Measurements are made at other weeks to monitor disease severity in the presence of treatment.
Secondary outcome [5] 405161 0
Adherence to regular and usage of as-needed medication (via electronic dose counters for all inhalers)
Timepoint [5] 405161 0
Measured before commencement of treatment and at 2, 6, 12 and 18 weeks. At 12 weeks after the commencement of the treatments assigned at the initial treatment visits for Arm's A vs C and Arm's B vs C. Measurements are made at other weeks to monitor adherence and safety in relation to beta2 agonist usage.
Secondary outcome [6] 405162 0
Treatment failure/severe asthma exacerbation (Patients were withdrawn because of treatment failure if they had one severe asthma exacerbation, three exacerbations separated by at least 7 days, unstable asthma that resulted in a change in the treatment assigned to them, or any combination of these.) Data will be collected at each study visit or if an event happens between study visit by telephone.
Timepoint [6] 405162 0
At 12 weeks after the commencement of the treatments assigned at the inital treatment visits for Arm's A vs C and Arm's B vs C.
Secondary outcome [7] 405825 0
Comparison of treatment response to attenuating PD15 (provoking dose of mannitol to cause a 15% fall in FEV1 in Arm C before and following the treatment change at 12 weeks with as needed BUD/FORM with twice daily BUD.
Timepoint [7] 405825 0
Measured before commencement of treatment and at 2, 6, 12 and 18 weeks. Comparing data from as needed usage of BUD/FORM at weeks 12 with that obtained at 18 weeks following the switching to BUD taken twice daily.
Secondary outcome [8] 406008 0
Change in asthma quality of life measured using the asthma quality of life questionnaire (AQLQ).
Timepoint [8] 406008 0
AQLQ is measured before commencement of treatment and at 2, 6, 12 and 18 weeks. At 12 weeks after the commencement of the treatments assigned at the initial treatment visits for Arm's A vs C and Arm's B vs C for treatment effects. Measurements are made at other weeks to monitor disease severity in the presence of treatment.

Eligibility
Key inclusion criteria
· Provision of informed consent
· Adults 18 years of age or older
· Physician diagnosis of asthma as mild disease as per GINA 2021 classification
· Symptomatic ACQ5 greater than 0.75
· Pre-bronchodilator FEV1 more than 80% of predicted
· AHR to mannitol at screening with a PD15 to mannitol of less than or equal to 155mg
· No ICS use for 1 month prior
· Willing and able to give informed consent for participation in the trial
· In the Investigator’s opinion, able and willing to comply with all trial requirements
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
· Participation in another clinical study
· Any asthma worsening requiring change in asthma treatment other than SABA within 30 days prior to Visit 1
· Use of oral, rectal or parenteral glucocorticosteroids (GCS) within 30 days and/or depot parenteral GCS within 12 weeks prior to Visit 1
· Use of leukotriene receptor antagonists within 30 days prior to Visit 1
· Known or suspected hypersensitivity to study drugs or excipient
· Smoker (current or previous) with a smoking history of less than or equal to 10 pack years
· Use of any ß-blocking agent including eye-drops
· Medical history of life-threatening asthma including intubation and intensive care unit admission
· Hospital admission for asthma in the 12 months prior to Visit 1
· Other significant respiratory disease (COPD, bronchiectasis, lung cancer…)
· Any significant disease or disorder which, in the opinion of the investigator, may either put the patient at risk because of participation in the study, or may influence the results of the study, or the patient’s ability to participate in the study
· Planned hospital stay
· Pregnancy, breast-feeding or planned pregnancy during the study. Fertile women not using acceptable contraceptive measures, as judged by the investigator
· Unwilling or unable to switch from current asthma treatment regimen
· Not ready to comply with required medication withholding times for Mannitol challenge testing
For randomisation at Visit 3, patients should not fulfil any of the following criteria:
· Use of 6 or more SABA ‘as needed’ inhalations per day for at least 4 days of run-in
· Any asthma worsening requiring change in asthma treatment other than inhaled SABA from Visit 1 until Visit 3 and/or requiring any asthma treatment other than run-in study medication from Visit 2 until randomisation

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e., sequence generation).
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Participants will be randomised to one of the three study treatment arms at Visit 3 following run-in (Arms A, B or C) and asked to return for a repeat of all outcome measures at 2-, 6- and 12-weeks (known as Visits 4, 5 and 6, respectively). At week 12 (visit 6), participants in Arms A and C will have the treatments changed as described above whilst there’s no change to the treatment for patients in Arm B. All patients will return following a further 6 weeks of treatment (18 weeks or Visit 7) for a final assessment of all outcome procedures.
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
Descriptive summaries will be reported as mean, SD, median, minimum and maximum for untransformed data or reported as Geometric mean (GM), 95% confidence interval of the GM) and coefficient of variation for log transformed data. Paired t-tests will be used for within group changes from baseline to follow up visits. Categorical variables will be reported as frequency and percentages. Independent sample t-tests will be performed to assess differences between groups. Spearman’s correlation will be used to assess the relationships between variables between baseline and follow up and between improvements in variables at follow-up visits. Repeated mixed model analysis will be performed to assess differences when using three or more independent groups. All data will be assessed for normal distribution before statistical analysis however it is common for the primary outcomes of airway sensitivity (provoking dose of mannitol to cause a 15% fall in FEV1, PD15) and airway reactivity (response dose ratio; final percent fall in FEV1 divided by the cumulative dose of mannitol to cause that final fall in FEV1 multiplied by a factor of 100, RDR100). Differences between PD15 and RDR100 will be expressed as doubling dose and fold changes.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
28/02/2022
Actual
Date of last participant enrolment
Anticipated
29/10/2022
Actual
Date of last data collection
Anticipated
28/04/2023
Actual
Sample size
Target
135
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 21357 0
John Hunter Hospital - New Lambton
Recruitment postcode(s) [1] 36249 0
2305 - New Lambton

Funding & Sponsors
Funding source category [1] 310410 0
Commercial sector/Industry
Name [1] 310410 0
GlaxoSmithKline
Country [1] 310410 0
Australia
Primary sponsor type
Individual
Name
Dr John D Brannan
Address
Department of Respiratory & Sleep Medicine, John Hunter Hospital, Lookout Rd, New Lambton NSW 2305
Country
Australia
Secondary sponsor category [1] 311791 0
None
Name [1] 311791 0
Address [1] 311791 0
Country [1] 311791 0
Other collaborator category [1] 282099 0
Individual
Name [1] 282099 0
Maximilian W Plank
Address [1] 282099 0
GlaxoSmithKline, Level 3, 436 Johnston Street, Abbotsford, Victoria, 3067.
PO Box 18095, Melbourne, Victoria, 8003.
Country [1] 282099 0
Australia

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 310058 0
The Hunter New England Human Research Ethics Committee
Ethics committee address [1] 310058 0
John Hunter Hospital, Lookout Rd, New Lambton NSW 2305
Locked Bag No 1, Newcastle Region Mail Centre NSW 2310
Ethics committee country [1] 310058 0
Australia
Date submitted for ethics approval [1] 310058 0
18/01/2022
Approval date [1] 310058 0
Ethics approval number [1] 310058 0

Summary
Brief summary
The Global Initiative for Asthma (GINA) and various national guidelines have recently recommended the use of Symbicort (a combination inhaled corticosteroid or ICS and long acting beta2 agonist formoterol or FORM) as-needed as an alternative treatment strategy (track-1) for patients with mild asthma. The existing evidence comparing regular ICS plus a short acting beta2 agonist (SABA) as-needed with ICS/FORM as-needed in GINA Step 2 asthma patients, however this data is limited to only four clinical trials. These have consistently demonstrated benefits in favour of regular ICS plus SABA as-needed in terms of symptom control and lung function improvement compared to ICS/FORM as-needed. An open-label study demonstrated a significantly greater reduction in forced exhaled nitric oxide (FeNO) with regular ICS plus SABA as-needed compared to ICS/FORM as-needed despite suboptimal adherence of 56% to twice-daily ICS. This suggests that regular ICS plus SABA as-needed provides more effective attenuation of inflammation compared to ICS/FORM as-needed in patients with mild asthma. To date there is no evidence evaluating the effect of ICS/FORM as-needed on airway hyperresponsiveness (AHR) a key feature of asthma that identifies active asthma. Thus, based on the established understanding of the mechanisms of attenuation of indirect AHR to inhaled mannitol, the hypothesis of this study is that regular ICS plus SABA as-needed suppresses AHR more effectively than ICS/FORM as-needed.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 116342 0
A/Prof John D Brannan
Address 116342 0
John Hunter Hospital, Lookout Rd, New Lambton NSW 2305
Locked Bag No 1, Newcastle Region Mail Centre NSW 2310
Country 116342 0
Australia
Phone 116342 0
+61 435 206 232
Fax 116342 0
Email 116342 0
john.brannan@health.nsw.gov.au
Contact person for public queries
Name 116343 0
A/Prof John D Brannan
Address 116343 0
John Hunter Hospital, Lookout Rd, New Lambton NSW 2305
Locked Bag No 1 Newcastle Region Mail Centre NSW 2310
Country 116343 0
Australia
Phone 116343 0
+61 435 206 232
Fax 116343 0
Email 116343 0
john.brannan@health.nsw.gov.au
Contact person for scientific queries
Name 116344 0
A/Prof John D Brannan
Address 116344 0
John Hunter Hospital, Lookout Rd, New Lambton NSW 2305
Locked Bag No 1, Newcastle Region Mail Centre NSW 2310
Country 116344 0
Australia
Phone 116344 0
+61 435 206 232
Fax 116344 0
Email 116344 0
john.brannan@health.nsw.gov.au

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.