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Trial registered on ANZCTR


Registration number
ACTRN12613000038796
Ethics application status
Approved
Date submitted
19/12/2012
Date registered
14/01/2013
Date last updated
14/01/2013
Type of registration
Retrospectively registered

Titles & IDs
Public title
Predicting steroid responsiveness in patients with asthma using exhaled breath profiling.
Scientific title
Predicting steroid responsiveness in patients with asthma using exhaled breath profiling.
Secondary ID [1] 281702 0
Nil
Universal Trial Number (UTN)
U1111-1138-0046
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Asthma 287995 0
Condition category
Condition code
Respiratory 288374 288374 0 0
Asthma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
For patients with asthma, there are three phases in the study: run-in (phase 1), steroid withdrawal if appropriate (phase 2), and open label treatment with oral steroid (phase 3).
Initial measurements consists of FENO, spirometry and skin prick testing. During phase 1, patients are provided with a 14-day diary to generate data to determine prospective individualized loss of control (LOC) criteria. Criteria for LOC are: greater than20% decrease in morning/evening peak expiratory flow (PEF) for 2 days; greater than 40% decrease in morning/evening PEF on any one day; greater than 10% decrease in mean morning PEF over a week; reliever beta-agonist use greater than 4 doses in any one day more than the average daily use during run-in; waking due to asthma greater than 2 nights per week above run-in weekly mean.
During phase 2, ICS and other maintenance asthma treatments are withdrawn. Patients are contacted thrice weekly, and instructed to contact the investigators if/when LOC criteria are reached. The next study visit is planned within 24 hours of LOC occurring, or after 28 days, whichever occurs sooner. If LOC is due to likely respiratory infection, based on clinical judgment, patients were excluded from the study. Data obtained at the end of phase 2 are used for comparisons with healthy controls.
Patients entered phase 3 only if they have AHR (PD15HS less than 12mL (provocative dose of hypertonic saline causing a 15% fall in forced expiratory volume in one second (FEV1)) and/or a greater than 12% improvement in post-bronchodilator FEV1 at LOC. This is done to prevent a ceiling effect in which patients are unable to respond to the initiated steroid treatment because they are clinically stable. Other measurements at LOC/28 days included, in sequential order: Asthma Control Questionnaire (ACQ), FENO, exhaled breath analysis by eNose, spirometry, hypertonic saline challenge and sputum induction. AHR to adenosine monophosphate (AMP) is assessed on the subsequent day, but omitted for safety reasons if FEV1 was less than50% predicted or less than1.2L.
Patients then commence a 14-day course of oral prednisone 30mg/day, at the end of which interval all study procedures except for hypertonic saline challenge and sputum induction, are repeated in the same order. Data obtained at the end of phase 3 are used to identify steroid responsive and steroid unresponsive patients. Steroid responsiveness is defined as one or both of the following: increase in FEV1 of equal or greater than 12%; increase in provocative concentration of AMP causing a 20% fall in FEV1 (PC20AMP) of equal or greater than 2 doubling doses.
FENO is measured using the NiOX MINO (Aerocrine, Solna, Sweden). Exhaled breath collection using the eNose is performed according to previously validated and published methodology showing adequate repeatability and reproducibility. In short subjects inhale VOC-filtered air during a 5-minute wash out period, and thereafter breath will be collected during a vital capacity manoeuvre into a inert bag. Breath is subsequently analyzed within 10 minutes by a Cyranose 320(Registered Trademark) eNose.
Intervention code [1] 286237 0
Treatment: Drugs
Comparator / control treatment
All asthmatic patients will be treated with oral steroids 40mg/day for 14days. This treatment will be initiated to assess steroid responsiveness in patients. Subsequently exhaled breath biomarkers will be compared between steroid responsive and unresponsive subjects as a potential diagnostic test.

An untreated control group of non-asthmatic patients will serve as a population to asses whether the eNose can discriminate between healthy controls and asthmatic patients, both treated and untreated.
Control group
Active

Outcomes
Primary outcome [1] 288547 0
An algorithm showing the potential of the electronic nose to discriminate between steroid responsive and unresponsive patients.
Timepoint [1] 288547 0
This will be assessed after 14days of steroid treatment.
Secondary outcome [1] 300438 0
The potential of the eNose to discriminate between patients reaching loss of control after steroid withdrawal and those not.
Timepoint [1] 300438 0
After reaching personalized loss of control criteria or a maximum of 28days after steroid withdrawal

Secondary outcome [2] 300598 0
And an algorithm showing the potential of VOC analysis to discriminate healthy controls from subjects with asthma regardless of treatment status.
Timepoint [2] 300598 0
Both after reaching loss of control criteria or a maximum of 28days after steroid withdrawal and after treatment.

Eligibility
Key inclusion criteria
Patients with mild to moderate doctors diagnosed asthma and healthy controls participate.

Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Subjects were excluded if they had experienced any respiratory tract infection or had used oral prednisone during the previous 4 weeks.

healthy controls were non-atopic and non-asthmatic, and had negative skin prick allergen tests, FENO <25ppb, no evidence of airways hyper-responsiveness to hypertonic saline, and no reversibility to bronchodilator.

Study design
Purpose of the study
Diagnosis
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
For patients with asthma, there are three phases in the study: run-in (phase 1), steroid withdrawal if appropriate (phase 2), and open label treatment with oral steroid (phase 3) (see Figure 1).

Initial measurements consists of FENO, spirometry and skin prick testing. During phase 1, patients are provided with a 14-day diary to generate data to determine prospective individualized loss of control (LOC) criteria. Criteria for LOC are: greater than20% decrease in morning/evening peak expiratory flow (PEF) for 2 days; greater than 40% decrease in morning/evening PEF on any one day; greater than 10% decrease in mean morning PEF over a week; reliever beta-agonist use greater than 4 doses in any one day more than the average daily use during run-in; waking due to asthma greater than 2 nights per week above run-in weekly mean.

During phase 2, ICS and other maintenance asthma treatments are withdrawn. Patients are contacted thrice weekly, and instructed to contact the investigators if/when LOC criteria are reached. The next study visit is planned within 24 hours of LOC occurring, or after 28 days, whichever occurs sooner. If LOC is due to likely respiratory infection, based on clinical judgment, patients were excluded from the study. Data obtained at the end of phase 2 are used for comparisons with healthy controls.

Patients entered phase 3 only if they have AHR (PD15HS less than 12mL (provocative dose of hypertonic saline causing a 15% fall in forced expiratory volume in one second (FEV1)) and/or a greater than 12% improvement in post-bronchodilator FEV1 at LOC. AHR to adenosine monophosphate (AMP) is assessed on the subsequent day, but omitted for safety reasons if FEV1 was less than50% predicted or less than1.2L.
Patients then commence a 14-day course of oral prednisone 30mg/day, at the end of which interval all study procedures except for hypertonic saline challenge and sputum induction, are repeated in the same order. Data obtained at the end of phase 3 are used to identify steroid responsive and steroid unresponsive patients.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The study was designed as an open label study because the placebo effect on the VOC-profile and parameters used to assess steroid responsiveness can be assumed to be very limited.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
1 group of asthmatic subjects undergoing the intervention of steroid therapy

1 group of controls not undergoing any intervention
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Principal component analysis (PCA) will be used to capture the variance of the eNose sensor data into a set of orthogonal principal components. Discriminating components will be selected by unpaired t-test. Selected principal components, FENO values and sputum eosinophils (% of total cell count) will individually be used in a canonical discriminant analysis (CDA) to classify subjects according to each of these predictors. The canonical functions were used to construct receiver operator characteristic curves. These will be internally cross-validated by bootstrapping procedure. Optimum (upper left corner) single spot sensitivity, specificity, positive and negative likelihood ratios will be calculated. Pearson correlation coefficients will be used to assess associations between breath profile and the other predictors.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/12/2010
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
45
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 4768 0
New Zealand
State/province [1] 4768 0

Funding & Sponsors
Funding source category [1] 286491 0
University
Name [1] 286491 0
Otago Respiratory Research Trust
Country [1] 286491 0
New Zealand
Primary sponsor type
University
Name
Otago Respiratory Research Trust
Address
Department of Respiratory Medicine
Dunedin School of Medicine,
University of Otago,
P. O. Box 913,
Postcode 9054
Dunedin,
New Zealand.
Country
New Zealand
Secondary sponsor category [1] 285281 0
None
Name [1] 285281 0
Address [1] 285281 0
Country [1] 285281 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 288569 0
Lower South Island Ethics Committee
Ethics committee address [1] 288569 0
Ethics committee country [1] 288569 0
New Zealand
Date submitted for ethics approval [1] 288569 0
Approval date [1] 288569 0
Ethics approval number [1] 288569 0
LRS/09/10/043

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

Contacts
Principal investigator
Name 36710 0
Prof Robin Taylor
Address 36710 0
Professor D. Robin Taylor,
Dunedin School of Medicine,
University of Otago,
P. O. Box 913,
Postcode 9054
Dunedin,
New Zealand.

Country 36710 0
New Zealand
Phone 36710 0
+64 3 474 0999
Fax 36710 0
+64 3 477 6246
Email 36710 0
[email protected]
Contact person for public queries
Name 36711 0
Marc van der Schee
Address 36711 0
Academic Medical Center
University of Amsterdam
Dept. Pulmonology, F5-158
Meibergdreef 9
1105 AZ Amsterdam
The Netherlands
Country 36711 0
Netherlands
Phone 36711 0
0031640883602
Fax 36711 0
Email 36711 0
[email protected]
Contact person for scientific queries
Name 36712 0
Marc van der Schee
Address 36712 0
Academic Medical Center
University of Amsterdam
Dept. Pulmonology, F5-158
Meibergdreef 9
1105 AZ Amsterdam
The Netherlands
Country 36712 0
Netherlands
Phone 36712 0
0031640883602
Fax 36712 0
Email 36712 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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