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Trial registered on ANZCTR


Registration number
ACTRN12621000772842
Ethics application status
Approved
Date submitted
13/05/2021
Date registered
21/06/2021
Date last updated
21/06/2021
Date data sharing statement initially provided
21/06/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Structural changes to the airways and lungs in older asthma patients with fixed airway obstruction
Scientific title
Using complex lung function tests, computed tomography and bronchoscopy to determine the relationships between proteolytic enzyme load, airway function and remodelling in older people with asthma.
Secondary ID [1] 297626 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
asthma 321908 0
Condition category
Condition code
Respiratory 319637 319637 0 0
Asthma

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
Participants with asthma will complete a clinical questionnaire and will undergo lung function tests, allergy tests, a CT-scan procedure and a bronchoscopy.
1). The lung function tests will include: spirometry, lung volumes, DLCO, methacholine challenge, exhaled nitric oxide, multiple breath nitrogen wash out, forced oscillation technique and lung elastic recoil measurements. The lung function tests will involve the study participants breathing into a mouth piece attached to different machines. During the methacholine challenge, an aerosol of methacholine will be inhaled to look at how sensitive the airways are. During the lung elastic recoil test a fine flexible tube with a latex balloon attached at the end, will be passed through the nose down to the oesophagus (with local anaesthetic, 1.5ml Xylocaine viscous, applied to the nostrils prior) to test the elasticity of the lungs.
2) A skin prick test will be used to test for allergies. A small droplet of allergen will be placed on the subject's forearm and the skin will be pricked lightly through the droplet. If subject is allergic to any of the allergens you will develop a small itchy lump.
3) A low-dose inspiratory and expiratory CT-scan will be performed by department technicians, from which the lung tissue density will be analysed (CT scans will be made without intravenous contrast injection).
4) The bronchoscopy involves placing a bronchoscope (thin flexible tube-like instrument with a mini camera at its tip) through the nose or mouth into the lungs to allow us to look into the airways. Local anaesthetic and sedating medications will be used prior to the bronchoscopy. The local anaesthetic (10% Xylocaine) will be applied topically to each nostril (1 spray each) and to the back of the throat (1 spray) 5-10 minutes before the procedure. Sedation will be administered intravenously (0.5-5mg diazepam +/- 12.5-100mcg fentanyl) before the procedure. Further local anaesthetic (1% Xylocaine) will be applied to the vocal cords and to the airways in 2.5 ml aliquots via the bronchoscope channel (maximum dose 4-5 mg/kg). During the bronchoscopy small samples from the lining of lung will be taken and fluid (sterile saline) will be flushed down the bronchoscope. This fluid will be sucked back up the bronchoscope and cells in the fluid will be analysed. A blood test will be taken at the time of the bronchoscopy and this will also be analysed.

The study will involve 3 visits: Visit 1 will involve the clinical questionnaire, lung function tests and allergy test and will take up to 3 hours. Visit 2 will involve the CT scan procedure and lung elastic recoil test and will take up to 3 hours. In visit 3 the bronchoscopy will be performed and this visit will take up to 6 hours. All visits will take place at the Royal North Shore Hospital, Sydney and the three visits will be separated by at least 48 hours.
Intervention code [1] 320551 0
Not applicable
Comparator / control treatment
No control arm
Control group
Uncontrolled

Outcomes
Primary outcome [1] 327501 0
Proteolytic enzyme load in Bronchoalveolar Lavage Fluid
Timepoint [1] 327501 0
This data will be collected at Visit 3
Primary outcome [2] 327502 0
Proteolytic enzyme load in airway biopsies
Timepoint [2] 327502 0
This data will be collected at Visit 3
Primary outcome [3] 327503 0
Lung density as assessed by CT scan
Timepoint [3] 327503 0
This data will be collected at Visit 2
Secondary outcome [1] 395428 0
Airway obstruction measured by spirometry
Timepoint [1] 395428 0
This data will be collected at Visit 1
Secondary outcome [2] 395429 0
Small airway function measured by forced oscillation technique and multiple breath nitrogen wash out
Timepoint [2] 395429 0
This data will be collected at visit 1
Secondary outcome [3] 396671 0
Lung elastic recoil measured by esophageal balloon technique (this is a primary outcome)
Timepoint [3] 396671 0
This data will be collected at visit 2
Secondary outcome [4] 396672 0
Gas trapping as assessed by CT scan (this is a primary outcome)
Timepoint [4] 396672 0
This data will be collected at visit 2
Secondary outcome [5] 396673 0
Airway hyperresponsiveness as assessed by methacholine challenge
Timepoint [5] 396673 0
This data will be collected at visit 1
Secondary outcome [6] 396674 0
Allergies as assessed by skin prick test
Timepoint [6] 396674 0
This data will be collected at visit 1
Secondary outcome [7] 396675 0
Diffusing capacity of the lungs will be assessed by DLCO test
Timepoint [7] 396675 0
This data will be collected at visit 1
Secondary outcome [8] 396676 0
Lung volumes will be measured by body plethysmography
Timepoint [8] 396676 0
This data will be collected at visit 1

Eligibility
Key inclusion criteria
1) Age 40-80 years
2) Physician-diagnosis of asthma
3) History of asthma medication use in the previous year
4) Willing and able to give written informed consent
5) Non smoker (no smoking for > 6 months and < 10 pack/year smoking history)
Minimum age
40 Years
Maximum age
80 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) Significant cardiac disease (ischemic heart disease or arrhythmia)
2) Documented hypersensitivity to, or intolerance of, anti-cholinergic therapies
3) Significant respiratory infection or exacerbation of Asthma within the previous 6 weeks
4) Intensive Care Unit admissions in the last 12 months.
5) Other active or chronic respiratory pathologies
6) History of lung surgery
7) Unable to perform lung function testing
8) Unable to provide informed consent
9) Current enrolment in other trials
10) Women who are pregnant or attempting to get pregnant due to radiation exposure

Study design
Purpose
Natural history
Duration
Cross-sectional
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
Assuming an r-value of 0.5 for Pearson or Spearman correlation analysis, we will require 35 subjects for a power of 0.80 at the 0.05 level of significance.

The relationships between proteolytic enzyme-load in BALf and airway biopsies and lung elastic recoil pressures and the proportion of lung of reduced lung density on computed tomography (CT) in older patients with asthma will be established using correlation analysis (either Pearson or Spearman correlation analysis, depending on the distribution of the data).

Measurements of inflammation, remodelling, elastic recoil in asthma patients with and without fixed airway obstruction will be compared used unpaired students t-tests.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 19444 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [2] 19445 0
Woolcock Institute of Medical Research - Glebe
Recruitment postcode(s) [1] 34033 0
2065 - St Leonards
Recruitment postcode(s) [2] 34034 0
2037 - Glebe

Funding & Sponsors
Funding source category [1] 302168 0
Charities/Societies/Foundations
Name [1] 302168 0
The Berg Family Foundation
Address [1] 302168 0
GPO BOX 4291 Sydney NSW 2001, Australia
Country [1] 302168 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Woolcock Institute of Medical Research
Address
431 Glebe Point Rd, Glebe NSW 2037
Country
Australia
Secondary sponsor category [1] 309452 0
None
Name [1] 309452 0
Address [1] 309452 0
Country [1] 309452 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302849 0
Northern Sydney Local Health District
Ethics committee address [1] 302849 0
Kolling, Building Level 14/10 Westbourne St, St Leonards NSW 2065
Ethics committee country [1] 302849 0
Australia
Date submitted for ethics approval [1] 302849 0
03/09/2019
Approval date [1] 302849 0
12/08/2020
Ethics approval number [1] 302849 0
2019/ETH13700

Summary
Brief summary
Fixed airway narrowing is a common complication of long standing asthma. It occurs despite good treatment with puffers that are effective in controlling inflammation. It causes symptoms such as wheeze, cough, shortness of breath and there is no known treatment for asthma related fixed airway narrowing because the mechanisms and causes are poorly understood. It is more common in older patients who have had asthma for many years, in whom there are also greater symptoms.

The underlying mechanism of airway and lung tissue remodelling are unknown but preliminary data support a crucial role for inflammatory cells, and in particular, neutrophils and macrophages. Neutrophils, as well as other inflammatory cells such as macrophages release proteolytic enzymes that mediate tissue remodelling and tissue destruction. This is supported by both CT and histological evidence of lung tissue remodelling that explains the loss of lung elastic recoil in longstanding asthma. Inflammation driven remodelling of peripheral airways and surrounding lung is therefore a likely mechanism causing FAO in older people with longstanding asthma. The aim of this research is to determine how neutrophils and macrophages affect the function of the smaller airways, and how they can cause airway and lung damage in older people with asthma.

We will recruit people with asthma who are >40 years of age, are non-smokers and have no other significant lung or heart problems. Participants will undergo breathing tests, CT scanning and a bronchoscopy, using a small camera on the end of a flexible tube, to obtain samples from their lungs.

The significance of this study will be the discovery of the mechanisms that underlies this major complication of asthma. It will assist in overcoming the major barrier halting progress to an effective treatment strategy for which the mechanisms are unknown.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 91602 0
Prof Gregory King
Address 91602 0
Department of Respiratory Medicine
Royal North Shore Hospital
Pacific Highway
St Leonards 2065, NSW
Country 91602 0
Australia
Phone 91602 0
+61 2 9463 2935
Fax 91602 0
Email 91602 0
ggk@woolcock.org.au
Contact person for public queries
Name 91603 0
Dr Sandra Rutting
Address 91603 0
Woolcock Institute of Medical Research
431 Glebe Point Rd
Glebe NSW 2037
Country 91603 0
Australia
Phone 91603 0
+61 481983461
Fax 91603 0
Email 91603 0
sandra.rutting@sydney.edu.au
Contact person for scientific queries
Name 91604 0
Dr Sandra Rutting
Address 91604 0
Woolcock Institute of Medical Research
431 Glebe Point Rd
Glebe NSW 2037
Country 91604 0
Australia
Phone 91604 0
+61 481983461
Fax 91604 0
Email 91604 0
sandra.rutting@sydney.edu.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 other documents available
Summary results
No Results