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Trial registered on ANZCTR


Registration number
ACTRN12606000488505
Ethics application status
Approved
Date submitted
18/10/2006
Date registered
27/11/2006
Date last updated
13/11/2018
Date data sharing statement initially provided
13/11/2018
Date results information initially provided
13/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
The management of non-eosinophilic asthma: a randomised controlled trial
Scientific title
The management of non-eosinophilic asthma: a randomised controlled trial of alternative anti-inflammatory treatments for maintenance of asthma control in non-eosinophilic asthma.
Secondary ID [1] 296586 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Asthma 1465 0
Condition category
Condition code
Respiratory 1561 1561 0 0
Asthma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study will comprise three Phases:
Phase 1: Steroid withdrawal for 28 days (or less, if loss of control occurs). This has been undertaken frequently in previous studies for which Ethics Approval has been received. This permits the true “naïve” asthma state to be characterised (eosinophilic or non-eosinophilic) using a combined hypertonic saline challenge (via a nebuliser) and induced sputum analysis. Airway hyper-responsiveness (AHR) to adenosine monophosphate (AMP) will also be assessed. AMP challenge is the most sensitive objective measure for steroid response. The procedures have been routinely used in research studies over the last 10 years. Patients with sputum eosinophil count of less than 2% AND objective evidence of AHR will be allocated to Group A. Patients with sputum eosinophil count of greater than 2% will be allocated to Group B.

Phase 2: Trial of steroid. Forty patients in Group A and the first 40 patients in group B will undergo a fixed-order, double-blind, placebo-controlled trial of inhaled fluticasone 1000µg/day followed by matching placebo. Each treatment period will be for 21 days. At the end of each of the two treatment periods, a combined hypertonic saline challenge and induced sputum analysis, as well as AMP challenge will be undertaken. Data from these tests will be used to identify individual steroid responsiveness as well as between-group differences. This will confirm the premise that non-eosinophilic asthma is NOT steroid responsive.

Phase 3: Cross-over trial of alternative therapies. Patients in group A who are not steroid responsive will then enter a year-long randomised-order, double-blind, placebo-controlled, cross-over trial of inhaled formoterol (12µg b.i.d.), oral theophylline (300 mg. b.i.d.), and oral clarithromycin (250 mg. b.i.d.). Matching tablets and inhalers will be used to maintain blinding. Each treatment will be given for three months. Data for the first two weeks of each treatment period will be ignored (washout).
Intervention code [1] 1408 0
Treatment: Drugs
Comparator / control treatment
Placebo
Control group
Placebo

Outcomes
Primary outcome [1] 2156 0
Asthma Control as measured by the Juniper Questionnaire (ACQ)
Timepoint [1] 2156 0
At the end of each 3 month treatment period during phase 3. The number of patients with a clinically significant improvement in ACQ will be compared between treatments.
Secondary outcome [1] 3756 0
• Before / after changes in airway hyper-responsiveness (AHR) as measured by hypertonic saline challenge for each treatment
Timepoint [1] 3756 0
These end-points will be measured at end of steroid withdrawal phase (4 weeks); at end of trial of steroid (7 weeks), at end of trial of placebo (10 weeks); then at end of each 3 month period during phase 3 (22, 34, 46, and 58 weeks)
Secondary outcome [2] 3757 0
• Before / after changes in sputum cell counts with each treatment
Timepoint [2] 3757 0
These end-points will be measured at end of steroid withdrawal phase (4 weeks); at end of trial of steroid (7 weeks), at end of trial of placebo (10 weeks); then at end of each 3 month period during phase 3 (22, 34, 46, and 58 weeks)
Secondary outcome [3] 3758 0
• Before / after changes in inflammatory markers in sputum supernatant: tumour necrosis factor alpha (TNF-alpha), interferon gamma (IFN-gamma), interleukin-1ß (IL1ß), interleukin-5 (IL-5), interleukin-8 (IL-8) with each treatment
Timepoint [3] 3758 0
These end-points will be measured at end of steroid withdrawal phase (4 weeks); at end of trial of steroid (7 weeks), at end of trial of placebo (10 weeks); then at end of each 3 month period during phase 3 (22, 34, 46, and 58 weeks)
Secondary outcome [4] 3759 0
• Before / after changes in exhaled nitric oxide (ENO) (a surrogate marker for eosinophilia) and spirometry with each treatment.
Timepoint [4] 3759 0
These end-points will be measured at end of steroid withdrawal phase (4 weeks); at end of trial of steroid (7 weeks), at end of trial of placebo (10 weeks); then at end of each 3 month period during phase 3 (22, 34, 46, and 58 weeks)

Eligibility
Key inclusion criteria
Moderately severe chronic persistent asthma.
Minimum age
18 Years
Maximum age
70 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
History of life-threatening asthma episodes, current smoker, pregnant or likely to become pregnant.

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)
sealed opaque envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Block randomisation by independent hospital pharmacy
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
subjects and therapist will be blinded within this study
Phase
Phase 4
Type of endpoint(s)
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
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 outside Australia
Country [1] 21021 0
New Zealand
State/province [1] 21021 0
Otago

Funding & Sponsors
Funding source category [1] 1702 0
Charities/Societies/Foundations
Name [1] 1702 0
Asthma and Respiratory Foundation of New Zealand
Address [1] 1702 0
The Asthma Foundation
Level 3, Greenock House
39 The Terrace
Wellington 6011
Country [1] 1702 0
New Zealand
Primary sponsor type
University
Name
University of Otago, Dunedin, New Zealand
Address
University of Otago
PO Box 56, Dunedin,9054
New Zealand
Country
New Zealand
Secondary sponsor category [1] 1502 0
Charities/Societies/Foundations
Name [1] 1502 0
Further applications for funding will be submitted to The Asthma and Respiratory Foundation of New Zealand
Address [1] 1502 0
The Asthma Foundation
Level 3, Greenock House
39 The Terrace
Wellington 6011
Country [1] 1502 0
New Zealand
Secondary sponsor category [2] 1503 0
Government body
Name [2] 1503 0
the Lottery Grants Board of New Zealand
Address [2] 1503 0
Department of Internal Affairs
Wellington, 6011
New Zealand
Country [2] 1503 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 3157 0
Lower South Regional Ethics Committee
Ethics committee address [1] 3157 0
South Island
Ethics committee country [1] 3157 0
New Zealand
Date submitted for ethics approval [1] 3157 0
17/11/2006
Approval date [1] 3157 0
03/04/2007
Ethics approval number [1] 3157 0
LRS/07/10/037

Summary
Brief summary
1. The first hypothesis is that non-eosinophilic asthma is steroid resistant
2. The second hypothesis is that non-eosinophilic asthma will respond to one or more of the currently available anti-inflammatory agents i.e. clarithromycin, theophylline, formoterol


1. To identify patients with non-eosinophilic asthma from the research database of the Otago Respiratory Research Unit. This will involve a clinical assessment, a standard four-week period of inhaled steroid withdrawal, followed by a hypertonic saline challenge and induced sputum analysis to document the presence of airway hyper-responsiveness and eosinophilic / non-eosinophilic asthma.
2. To confirm the relationship between inflammatory cell type and steroid responsiveness
3. To undertake a randomized controlled trial of three currently available asthma treatments: formoterol, theophylline, and clarithromycin.
Trial website
Trial related presentations / publications
Biomarker-based asthma phenotypes of corticosteroid response
Cowan, D.C., Taylor, D.R., Peterson, L.E., Cowan, J.O., Palmay, R., Williamson, A., Hammel, J., Erzurum, S.C., Hazen, S.L., Comhair, S.A.A.
Journal of Allergy and Clinical Immunology
volume 135, issue 4, year 2015, pp. 877 - 883.
Sputum gene expression signature of 6 biomarkers discriminates asthma inflammatory phenotypes
Baines, K.J., Simpson, J.L., Wood, L.G., Scott, R.J., Fibbens, N.L., Powell, H., Cowan, D.C., Taylor, D.R., Cowan, J.O., Gibson, P.G.
Journal of Allergy and Clinical Immunology
volume 133, issue 4, year 2014, pp. 997 - 1007
Simvastatin in the treatment of asthma: Lack of steroid-sparing effect
Cowan, D.C., Cowan, J.O., Palmay, R., Williamson, A., Taylor, D.R.
Thorax
volume 65, issue 10, year 2010, pp. 891 - 896
Effects of steroid therapy on inflammatory cell subtypes in asthma
Cowan, D.C., Cowan, J.O., Palmay, R., Williamson, A., Taylor, D.R.
Thorax
volume 65, issue 5, year 2010, pp. 384 - 390
Public notes

Contacts
Principal investigator
Name 27342 0
Prof Professor D Robin Taylor
Address 27342 0
Dunedin School of Medicine
University of Otago
PO Box 56
Dunedin,9054
New Zealand
Country 27342 0
New Zealand
Phone 27342 0
+64 3 4709362
Fax 27342 0
Email 27342 0
jan.cowan@otago.ac.nz
Contact person for public queries
Name 10597 0
Prof Prof D Robin Taylor
Address 10597 0
Otago Respiratory Research Unit
Dept of Medical and Surgical Sciences
Dunedin School of Medicine
POBox 913
Dunedin
Country 10597 0
New Zealand
Phone 10597 0
+6434740999 ext 8785
Fax 10597 0
+6434776246
Email 10597 0
jan.cowan@stonebow.otago.ac.nz
Contact person for scientific queries
Name 1525 0
Dr Douglas Cowan
Address 1525 0
Otago Respiratory Research Unit Dept of Medicine,Dunedin School of Medicine POBox 56 Dunedin,9054, New Zealand
Country 1525 0
New Zealand
Phone 1525 0
+64 4709362
Fax 1525 0
+6434776246
Email 1525 0
jan.cowan@otago.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
Not available. Note study date is 2006. Funding no longer available for work on this study.
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
Yes
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary