Please note that the ANZCTR website will be unavailable from 9am until 9.30am (AEST) on Monday 22nd July for website maintenance. Please be sure to log out of the system in order to avoid any loss of data. Thank you and apologies for any inconvenience caused.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12613000988752
Ethics application status
Approved
Date submitted
20/08/2013
Date registered
5/09/2013
Date last updated
11/10/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Monitoring inhaled corticosteroid efficacy in persons with asthma in pulmonary function laboratories.
Scientific title
To determine if clinically relevant and statistically significant improvements in asthma control questionnaire score can be achieved and sustained by monitoring bronchial hyperresponsiveness (BHR) to inhaled mannitol in individuals with asthma when compared to assessing spirometry alone.
Secondary ID [1] 282991 0
None
Universal Trial Number (UTN)
U1111-1137-4361
Trial acronym
N/A
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Asthma 287878 0
Condition category
Condition code
Respiratory 288244 288244 0 0
Asthma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
In patients with asthma commencing inhaled corticosteroid (ICS) therapy, we will evaluate if monitoring by inhaled mannitol bronchial provocation challenge testing will provide a greater and more sustained control of asthma over 18 weeks compared with monitoring by spirometry alone.

We will use the inhaled mannitol bronchial provocation test to monitor bronchial hyperresponsiveness (BHR) in the intervention group. Results of the test would be reviewed by the patients and their treating physicians to allow assessment of the current control of their asthma.

The intervention group will have the mannitol challenge at baseline, 6, 12 and 18 weeks. The control group will be seen at the same time points, but will receive the results of spirometry only.

The challenge involves inhaling a series of doses of mannitol powder using a small inhaler device, until a total of 635mg has been inhaled or the participant has had a fall in FEV1 of 15% or more from the baseline spirometry for the visit. A lower dose of mannitol required to induce a fall in spirometry indicates more severe bronchial hyperresponsiveness.

The participants will be followed for 18 weeks from baseline.
Intervention code [1] 286124 0
Other interventions
Comparator / control treatment
Using standard spirometry (Forced expiratory volume in one second) which is the current standard to monitor response to treatment.

Spirometry will be performed at each visit (baseline, 6, 12 and 18 weeks), both before and after the inhalation of bronchodilators.

The control group will be monitored for 18 weeks after commencing ICS treatment
Control group
Active

Outcomes
Primary outcome [1] 289991 0
Asthma Control Questionnaire (ACQ) score
Timepoint [1] 289991 0
6, 12 and 18 weeks from baseline
Primary outcome [2] 290310 0
The proportion of individuals with improved ACQ score (defined as a difference from baseline of greater than 0.5)
Timepoint [2] 290310 0
6, 12 and 18 weeks from baseline
Secondary outcome [1] 303731 0
Airway sensitivity to mannitol using the PD15; the provoking dose to cause a 15% fall in forced expiratory volume in one second (FEV1). Using the mannitol challenge bronchial provocation test.
Timepoint [1] 303731 0
Measured at 18 weeks from baseline
Secondary outcome [2] 304286 0
Airway reactivity using the dose response ratio (RDR) which is calculated using the percentage fall on the final dose of mannitol divided by the cumulative dose of mannitol in mg. Using the mannitol challenge bronchial provocation test.
Timepoint [2] 304286 0
Measured 18 weeks from baseline
Secondary outcome [3] 304287 0
Asthma quality of life questionnaire (AQLQ) score
Timepoint [3] 304287 0
Measrued at 6, 12 and 18 weeks from baseline
Secondary outcome [4] 304288 0
FEV1 (as percent predicted) measured using spirometry
Timepoint [4] 304288 0
Measured at 6, 12 and 18 weeks from baseline
Secondary outcome [5] 304289 0
Airway reactance (Xrs) and airway resistance (Rrs) in kPa/l/sec using impulse oscillometry
Timepoint [5] 304289 0
Measured at 6, 12 and 18 weeks from baseline
Secondary outcome [6] 304290 0
Exhaled nitric oxide (FeNO) in parts per billion using the Hypair nitric oxide analyser
Timepoint [6] 304290 0
Measured at 6, 12 and 18 weeks

Eligibility
Key inclusion criteria
-Males and females age 18-75 years
-Pre-bronchodilator FEV1 greater than or equal to 70% of predicted and greater than 1L
-A positive response to mannitol challenge (PD15 of less than 635mg)
-Prescribed ICS treatment after initial challenge
-Non-smokers; ex-smokers with less than 10 pack years and no cigarettes within the last 12 months
ACQ score greater than 0.75
Minimum age
18 Years
Maximum age
75 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
-Evidence of significant cardiovascular, haematological, hepatic, renal, neurological or psychiatric disease or any other major immunological or pulmonary disease other than asthma.
-Upper or lower respiratory tract infection within 2 weeks of the baseline visit, which may or may not have required a course of oral antibiotics
-Administration of an investigational drug in the preceding 4 months
-Subjects positive to mannitol that are being assessed as defence or police recruits

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)
Subject whom meet the inclusion criteria will be asked if they would like to participate in the study. Once they have consented they will be asked to attend their first visit 6 weeks after commencing their ICS treatment.
On attendence at their first visit they will be randomly allocated to either the BHR or control group. Randomisation will be stratified by asthma severity (mild vs moderate-to-severe), and allocation concealment will be achieved by the use of sequentially-numbered, opaque, sealed envelopes.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Two random allocation lists have been generated, each with randomly varying block sizes. Each block contains an equal number of allocations to each group. By using one list for participants with mild BHR (PD15 greater than 155mg to less than 635mg) and the other list for participants with moderate to severe BHR (PD15 of less than or equal to 155mg), stratification for severity will be achieved.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
All values will be expressed as mean and standard error when data is normally distributed and median and interquartile range when not normally distributed. Comparison between groups for the primary outcome of ACQ (as well as other relevant parameters) over the duration of the study will be performed using linear mixed-effects models. Differences between groups in demographic data and other key baseline outcomes will be performed using a standard t-test. p values less than 0.05 will be considered significant.


We have calculated that to detect a minimum clinically significant difference in ACQ score of 0.5 between two parallel arms of this study (mannitol vs spirometry monitoring) and at a significance level of 0.05 (two sided) with a power of 0.9 requires a minimum of 20 subjects in each arm. We wish to recruit at least 5 more in each arm to account for drop-outs during the study. Thus the study will require a total of 50 subjects to be randomised.

(1) Brannan JD, Koskela H, Anderson SD, Chan HK. Budesonide reduces sensitivity and reactivity to inhaled mannitol in asthmatic subjects. Respirology. 2002;7(1):37-44. Epub 2002/03/19.
(2) Turton JA, Glasgow NJ, Brannan JD. Feasibility and acceptability of using bronchial hyperresponsiveness to manage asthma in primary care: a pilot study. Prim Care Respir J. 2011. Epub 2011/09/23.

Recruitment
Recruitment status
Active, not 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] 596 0
Royal Prince Alfred Hospital - Camperdown
Recruitment postcode(s) [1] 6344 0
2050 - Camperdown

Funding & Sponsors
Funding source category [1] 286734 0
Charities/Societies/Foundations
Name [1] 286734 0
Australian & New Zealand Society of Respiratory Science
Address [1] 286734 0
PO Box 949
Kent Town SA 5071
Australia
Country [1] 286734 0
Australia
Primary sponsor type
Hospital
Name
Sydney Local Health District - Royal Prince Alfred Hospital
Address
Department of Respiratory & Sleep Medicine
Royal Prince Alfred Hospital
Missenden Road
Camperdown, NSW 2050
Country
Australia
Secondary sponsor category [1] 285510 0
None
Name [1] 285510 0
Address [1] 285510 0
Country [1] 285510 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 288467 0
Royal Prince Alfred Hospital-Research Development Office
Ethics committee address [1] 288467 0
Research Development Office
Suite 210(a)
RPAH Medical Centre
100 Carillon Avenue
NEWTOWN, NSW 2060
Ethics committee country [1] 288467 0
Australia
Date submitted for ethics approval [1] 288467 0
05/12/2012
Approval date [1] 288467 0
07/01/2013
Ethics approval number [1] 288467 0
HREC/12/RPAH/498

Summary
Brief summary
This is a parallel group, prospective randomised trial comparing two methods of monitoring asthma control.
Participants will be recruited from the Pulmonary Function Laboratory who have been referred for testing using inhaled mannitol to assess BHR in persons who are suspected of having asthma. Following the identification of a positive test, the provision of written consent and once there is confirmation the clinician has prescribed ICS, the subject will be contacted by phone and asked to return to the Laboratory at 6, 12 and 18 weeks to have either a mannitol challenge with spirometry performed or spirometry performed alone. The subject will be provided with feedback at each visit as to the benefit of ICS on the test outcomes and encouraged to seek the goal of achieving a reduction in their airway response to mannitol or improvement in lung function into the normal range. The referring clinician will also be provided with the results at each visit. Subjects will also perform an Asthma Control Questionnaire (ACQ) and Asthma Quality of Life Questionnaire (AQLQ) at each visit and both patient and clinician will be informed of these improvements. Prior to both spirometry and a mannitol challenge, participants will have two rapid non-invasive tests performed that measure the size of the small airways as well as the degree of inflammation by measuring a gas when expired known as nitric oxide.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 34990 0
Mr Dr John D Brannan
Address 34990 0
Department of Respiratory & Sleep Medicine, John Hunter Hospital, New Lambton, NSW 2305
Country 34990 0
Australia
Phone 34990 0
+61 2 4922 3115
Fax 34990 0
+61 2 4921 3469
Email 34990 0
john.brannan@sydney.edu.au
Contact person for public queries
Name 18237 0
Miss Clair Lake
Address 18237 0
Deptartment Respiratory & Sleep Medicine
Royal Prince Alfred Hospital
Missenden Road
Camperdown, NSW 2050
Country 18237 0
Australia
Phone 18237 0
+61 2 9515 6131
Fax 18237 0
+61 2 9515 5090
Email 18237 0
clair.lake@sswahs.nsw.gov.au
Contact person for scientific queries
Name 9165 0
Dr John Brannan
Address 9165 0
Department of Respiratory & Sleep Medicine, John Hunter Hospital, New Lambton, NSW 2305
Country 9165 0
Australia
Phone 9165 0
+61 2 4922 3115
Fax 9165 0
+61 2 4921 3469
Email 9165 0
john.brannan@sydney.edu.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary