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Trial registered on ANZCTR


Registration number
ACTRN12616000112460p
Ethics application status
Submitted, not yet approved
Date submitted
21/01/2016
Date registered
2/02/2016
Date last updated
2/02/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
The Fine Particle Aerosols in Uncontrolled Asthma Study: Efficacy of small aerosol versus large aerosol budesonide in the treatment of uncontrolled asthma in adults.
Scientific title
The pivotal role of targeting treatment to the small airways in patients with uncontrolled asthma.
Secondary ID [1] 288387 0
None
Universal Trial Number (UTN)
Trial acronym
TFPAUAS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Asthma 297392 0
Condition category
Condition code
Respiratory 297582 297582 0 0
Asthma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The run-in period of this study will involve participants taking 200ug/day budesonide (Pulmicort Turbuhaler) for 4 weeks.
This will be followed by a two arm interventional study period which involves administration of budesonide modified into either small or large aerosols, for the treatment of asthma.
For both arm 1 (small aerosols ~1um) and arm 2 (large aerosols ~5um) participants will take 800ug/day of the study drug for a period of 12 weeks.

Adherence throughout the run-in period and the study period will be monitored with daily peak flow diaries to record lung function, daily asthma control questionnaires, and fortnightly phone calls from the research team.
Intervention code [1] 293692 0
Treatment: Drugs
Comparator / control treatment
Arm 2 (large aerosols ~5um)
Control group
Active

Outcomes
Primary outcome [1] 297127 0
Change in small airway function (as Sacin) measured by multiple breath nitrogen washout (MBNW), with differences between groups to be compared by parametric or non-parametric comparisons as appropriate.
Timepoint [1] 297127 0
Small airway function in the two groups will be assessed at baseline following the run-in period, and at 12 weeks post commencement of the intervention.
Secondary outcome [1] 320100 0
Differences in asthma control between the two groups. This outcome will be assessed by reviewing daily Asthma Control Questionnaires (ACQs).
Timepoint [1] 320100 0
Asthma control in the two groups will be assessed at baseline following the run-in period, and at 12 weeks post commencement of the intervention.
Secondary outcome [2] 320101 0
Differences in lung function (which can be assessed by one of more of the following: FEV1, FVC, FEV1/FVC ratio, PEF, FEF25-75, and FIVC) in the groups will be assessed by spirometry.
Timepoint [2] 320101 0
Lung function (which can be assessed by one of more of the following: FEV1, FVC, FEV1/FVC ratio, PEF, FEF25-75, and FIVC) in the two groups will be assessed at baseline following the run-in period, and at 12 weeks post commencement of the intervention.
Secondary outcome [3] 320102 0
Relationships between changes in lung function (assessed by spirometry) and asthma control (assessed by daily ACQs).
Timepoint [3] 320102 0
The relationships between changes in lung function and asthma control in the two groups will be assessed at baseline following the run-in period, and at 12 weeks post commencement of the intervention.
Secondary outcome [4] 320210 0
Lung volumes (which can be assessed by one of more of the following: TLC, VC, FRC, RV, and RV/TLC ratio) in the two groups will be assessed by body plethysmography.
Timepoint [4] 320210 0
Lung volumes (which can be assessed by one of more of the following: TLC, VC, FRC, RV, and RV/TLC ratio) in the two groups will be assessed at baseline following the run-in period, and at 12 weeks post commencement of the intervention.
Secondary outcome [5] 320211 0
Diffusion capacity of the lung in the two groups will be assessed by Diffusing Capacity of Lung for Carbon Monoxide (DLCO).
Timepoint [5] 320211 0
Diffusion capacity of the lung (DLCO) in the two groups will be assessed at baseline following the run-in period, and at 12 weeks post commencement of the intervention.

Eligibility
Key inclusion criteria
1. Current asthma defined as having a doctor diagnosis of asthma and asthma symptoms and asthma medication use in the last 12 months.
2. Be taking less than 400 ug of budesonide daily or alternative, with or without LABA.
3. Currently clinically stable.
4. Asthma Control Questionnaire (ACQ) score of >1.
Minimum age
18 Years
Maximum age
45 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Current smoker (at least 1 cigarette/day >3 months) within the previous 12 months, or having past smoking history of >10 pack/years.
2. Had an asthma exacerbation (defined as an increase in asthma symptoms for >2 days requiring an increase in inhaled corticosteroid (ICS) treatment or administration of prednisone, within the last 6 weeks.
3. Admission to a hospital ward for 1 night or more for asthma, in the last 12 months.
4. Unable to provide written, informed consent.
5. Have significant co-existent pulmonary or cardiac disease that could, in the opinion of the Chief Investigators, affect small airway function and/or modify respiratory symptoms. These include but are not limited to emphysema, pulmonary fibrosis, pulmonary hypertension, bronchiectasis and heart failure.
6. Inability to satisfactorily use a pMDI after education on pMDI technique.
7. Taking >800ug budesonide equivalent.

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)
Both research staff and participants will be blinded to the identity of the small or large particle pressurised metered dose inhalers (pMDI’s). After production, the pMDIs will be blinded by Young and Traini and marked only as ‘Puffer A’ or ‘Puffer B’ and these will be stored in the Woolcock Institute of Medical Research Pharmacy. A person who is independent of the study (staff of the Airway Physiology and Imaging Group of The Woolcock Institute of Medical Research) will maintain the study code, in the unlikely event that the study code needs to be broken.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
15/02/2016
Actual
Date of last participant enrolment
Anticipated
30/09/2018
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
120
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 5107 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [2] 5108 0
Concord Repatriation Hospital - Concord
Recruitment hospital [3] 5109 0
The Alfred - Prahran

Funding & Sponsors
Funding source category [1] 292742 0
Government body
Name [1] 292742 0
NH&MRC
Country [1] 292742 0
Australia
Primary sponsor type
Other
Name
Woolcock Institute of Medical Research
Address
431 Glebe Point Rd
Glebe NSW 2037
Country
Australia
Secondary sponsor category [1] 291472 0
None
Name [1] 291472 0
Address [1] 291472 0
Country [1] 291472 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 294227 0
Northern Sydney Local Health District Human Research Ethics Committee
Ethics committee address [1] 294227 0
Level 13, Kolling Building
Royal North Shore Hospital
Reserve Rd
St Leonards NSW 2065
Ethics committee country [1] 294227 0
Australia
Date submitted for ethics approval [1] 294227 0
30/11/2015
Approval date [1] 294227 0
Ethics approval number [1] 294227 0

Summary
Brief summary
Asthma affects approximately 1:10 adults and 1:5 children. Although most subjects attained good control of their asthma with conventional treatment, there is a significant proportion who are resistant to conventional treatment and remain uncontrolled. Although there are several mechanisms that may explain incomplete asthma control, one important factor which is potentially easy to address, is the presence of severe small airways disease that is not effectively improved by inhaled corticosteroid treatment.

The small airways are an important determinant of asthma control and severity. They are airways with an internal diameter of 2 mm or less and because of the branching nature of the airway tree, occupy a very large surface area compared to the larger and more proximal airways. We have recently shown that small airway function improves with high dose inhaled corticosteroid treatment in parallel with improving asthma control. Furthermore, asthma control and severity are strongly related to small airways function.

It therefore follows that persisting small airways disease is an important determinant of severe asthma and that better treatment of the small airways will improve the treatment of severe asthma. The obvious problem with treating small airways that are severely affected by inflammation and tissue remodelling, is that it is difficult to deposit therapeutic aerosols there. This is because ventilation to those airways is poor, because of severe airway narrowing and closure. Therapeutic aerosols require ventilation to carry them to the target sites and so the worst affected airways receive less of the inhaled aerosols.

There is a theoretical advantage of using fine particle aerosols, because they are more likely to be carried to areas where ventilation is poor. Particles greater than 3 – 5 um deposit in the medium to large airways, while smaller particles will be carried into smaller and narrowed airways. Therefore, we propose that small particle aerosols will be more effective in uncontrolled asthma than larger particle aerosols.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 62970 0
A/Prof Greg King
Address 62970 0
Airway Physiology and Imaging Group
Level 4, Woolcock Institute of Medical Research
431 Glebe Point Rd
Glebe NSW 2037
Country 62970 0
Australia
Phone 62970 0
+61 2 9114 0413
Fax 62970 0
Email 62970 0
[email protected]
Contact person for public queries
Name 62971 0
Greg King
Address 62971 0
Airway Physiology and Imaging Group
Level 4, Woolcock Institute of Medical Research
431 Glebe Point Rd
Glebe NSW 2037
Country 62971 0
Australia
Phone 62971 0
+61 2 9114 0413
Fax 62971 0
+61 2 9114 0011
Email 62971 0
[email protected]
Contact person for scientific queries
Name 62972 0
Greg King
Address 62972 0
Airway Physiology and Imaging Group
Level 4, Woolcock Institute of Medical Research
431 Glebe Point Rd
Glebe NSW 2037
Country 62972 0
Australia
Phone 62972 0
+61 2 9114 0413
Fax 62972 0
+61 2 9114 0011
Email 62972 0
[email protected]

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