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Trial registered on ANZCTR


Registration number
ACTRN12616001015437
Ethics application status
Approved
Date submitted
25/07/2016
Date registered
2/08/2016
Date last updated
27/05/2019
Date data sharing statement initially provided
27/05/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Management of severe asthma using a combination of exhaled and blood markers of inflammation
Scientific title
Markers of Inflammation in the management of severe asthma: the utility of peripheral blood eosinophils and fraction of exhaled nitrogen oxide
Secondary ID [1] 289750 0
nil known
Universal Trial Number (UTN)
Trial acronym
MIMOSA
Linked study record

Health condition
Health condition(s) or problem(s) studied:
asthma 299599 0
Condition category
Condition code
Respiratory 299569 299569 0 0
Asthma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will attend and be assessed at a total of 14 study clinic visits, which will be at 4 weekly intervals over a 52 week period. In the Inflammation management arm, at each scheduled study visit, adjustment of prednisone oral corticosteroid (OCS) dosage will be performed using the following algorithm based on their fractional of exhaled nitrogen oxide
(FeNO) and blood eosinophil count (cellx109/L). Starting dose of OCS will be dependent on their existing treatment plan.

* Blood eosinophil count (cellx10 to the 9/L) less than 0.2: Biomarker Score (BS) = -1
* Fractional of exhaled nitrogen oxide (FeNO) less than 15 BS = 0
* FeNO 15 to less than 30 BS = 1
* Blood eosinophil count (cellx10 to the 9/L) 0.2 to 0.4: BS = 1
* FeNO greater than or equal to 30 BS = 2
* Blood eosinophil count (cellx10 to the 9/L) greater than 0.4: BS = 2
The composite BS is calculated from the individual biomarker scores and is the AVERAGE of both scores rounded to the nearest integer to give the "composite score" [score of 0, 1 or 2].
Each participant will be assessed with a BS, and as falling into one of the following 6 categories at their study visit, which will allow their management based on the algorithm.
1. BS = 2, regardless of Asthma Sympton Score (ACQ): increase or (if treatment naïve) commence OCS at 7.5mg/day
2. BS = 1 and ACQ less than or equal to 1.5: no change
3. BS = 1 and ACQ greater than 1.5: no change OCS/inhaled corticosteroids (ICS), increase treatment with GINA (Global Initiative for Asthma)-based symptom algorithm (GBSA)
4. BS = 0 and ACQ less than or eual to 0.75: reduce OCS. If off OCS, decrease treatment with GBSA
5. BS = 0 and ACQ is 0.75 to 1.5: reduce OCS, maintain other treatment
6. BS = 0 and ACQ greater than 1.5: reduce OCS and increase treatment with GBSA
If BS = 2 on 50mg/day of OCS, clinician review will take place.
See attached Table 1 available on the original ANZCTR record for more details

Cut points for FeNO have been decided based on identification of the upper limit of FeNO for asthmatics that can undergo corticosteroid withdrawal, and that which is associated with control of eosinophilic inflammation. Cut points for peripheral blood eosinophils (PBE) have been determined as those previously associated with airway eosinophilia in asthma and COPD.

Monitoring of adherence to the drug protocol will be conducted via interview during the study visits as well as returning the drug packet to count unused drugs.
Intervention code [1] 295395 0
Treatment: Drugs
Comparator / control treatment
The participants in the standard care arm of the study will have their asthma control assessed according to standard clinical parameters based upon GINA treatment guidelines and treatment steps. GINA recommends assessment of asthma control by symptoms, lung function, and history and risk of exacerbations. Loss of control requires adjunctive therapy either within the current treatment step, or escalation to the next step. Well-controlled asthma requires dose reduction by 1 GINA treatment step. Short term, partial loss of control may require short term step up therapy, but otherwise no definite treatment change is recommended.

The assessment of control status at each visit will be based on symptom control scores and spirometry. We will use the ACQ with cut points as follows:
well controlled asthma: ACQ less than 0.75
partially controlled asthma: ACQ is 0.75 to 1.50
uncontrolled asthma: ACQ higher than 1.5
Clinicians will be blinded to PBE, FeNO and sputum eosinophil counts for participants in the control group. A change in ACQ score of greater than 0.5 will be determined to be significant, or a reduction in Forced Expiratory Volume (FEV1) greater than 20% from baseline.

Treatment will be adjusted according to GINA step guidelines, which have been summarized as recommendations for additional treatment in the GBSA. Treatment adjustment suggestions will be provided to the clinician, either up or down, based on ACQ score, and management enacted based on standard clinician judgement.
Control group
Active

Outcomes
Primary outcome [1] 299043 0
Time to first exacerbation

An asthma exacerbation will be defined as a worsening of asthma control (characterized by a progressive increase in symptoms and progressive decrease in lung function) requiring systemic glucocorticoids or an increase in the dose of regular systemic glucocorticoids for at least 3 days.

Asthma exacerbations which occur during the study will be treated according to current clinical guidelines.

Will be assessed through interview with the patient
Timepoint [1] 299043 0
Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48
Primary outcome [2] 299044 0
Number of exacerbations

An asthma exacerbation will be defined as a worsening of asthma control (characterized by a progressive increase in symptoms and progressive decrease in lung function) requiring systemic glucocorticoids or an increase in the dose of regular systemic glucocorticoids for at least 3 days.

Asthma exacerbations which occur during the study will be treated according to current clinical guidelines.

Will be assessed through interview with the patient
Timepoint [2] 299044 0
Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48
Secondary outcome [1] 325957 0
Patient asthma symptom scores measured by the Asthma Control Questionnaire (ACQ) to be completed at the study visit
Timepoint [1] 325957 0
Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48
Secondary outcome [2] 325958 0
Quality of life as measured by the Juniper Asthma Quality of Life Questionnaire (AQLQ) to be completed at the study visit
Timepoint [2] 325958 0
Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48
Secondary outcome [3] 325959 0
Total and maintenance dose of oral corticosteroid as measured by the participant's medication history (via interview with the patient)
Timepoint [3] 325959 0
Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48
Secondary outcome [4] 325960 0
Analysis of common markers of inflammation (blood and sputum cell counts), to include IL-6, IL-1b, cortisol, presnisone, CRP
Timepoint [4] 325960 0
Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48
Secondary outcome [5] 325961 0
Changes in the levels of exhaled nitric oxide (to compare changes in exhaled NO and relate this to change in PBE count) as measured using a portable fractional exhaled NO detector
Timepoint [5] 325961 0
Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48
Secondary outcome [6] 325962 0
Total dose of oral corticosteroids used during the period of the study as measured through interview with the patient
Timepoint [6] 325962 0
Week 48
Secondary outcome [7] 325963 0
Hospital admission or Emergency visit due to asthma as measured by interview with the patient
Timepoint [7] 325963 0
Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48

Eligibility
Key inclusion criteria
* Diagnosed severe treatment-resistant asthma (GINA step 4 or higher) with documented evidence of variable airflow limitation or Respiratory consultant diagnosis of asthma)
* Never or ex-smoker
* Prescribed greater than 1000 micrograms of inhaled beclomethasone (CFC) metered dose inhaler (or equivalent) and inhaled long acting beta-2 agonist (LABA) for at least 6 months
* Remain uncontrolled with an asthma control questionnaire (ACQ) score greater than or equal to 1.5 OR Have had a hospital admission for asthma in the last 12 months OR Have experienced at least 2 asthma exacerbations in the past 12 months requiring a course of OCS (at least 3 days).
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* Current smoker or smoking cessation within the last 6 months
* Severe exacerbation or alteration to asthma therapy within 4 weeks prior to Visit 1
* Eligible for commencing Omalizumab (according to current Pharmaceutical Benefits Scheme criteria), or currently within the first 6 months of commencing Omalizumab.
* Other medical comorbidity or research study requiring chronic systemic corticosteroid (for example rheumatologic conditions, adrenal insufficiency, etc.)
* Eligible for commencing Mepolizumab or currently within the first 6 weeks of commencing Mepolizumab

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)
Eligibility for the trial will be determined prior to randomisation, which will be carried out by an independent associate
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation by research staff using a random number list with stratification for blood eosinophil level and OCS maintenance dose
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
The target sample size is 30 participants. Prior data has shown a 60% reduction in the average rate of exacerbation when a corticosteroid algorithm is used with induced sputum analysis. In addition, uncontrolled prior data demonstrated a reduction in exacerbations from a median of 5 (IQR 5-8) to 0 (IQR 0-1) with the use of a similar algorithm based on PBE for asthma management. Assuming alpha = 0.05, and allowing power to range from 0.8 – 0.99, yields a range of sample sizes for each of the two groups of 9-16 with this information. Thus, a conservative estimate of the necessary total sample size would be 30.

Data will be analysed on an intention-to-treat basis using 2-sided tests with p values less than 0.05 considered significant. As described in other RCTs using exacerbations as the primary outcome, the time to the first asthma exacerbation will be described using Kaplan-Meier plots and a log-rank test, with analysis of instantaneous risk described using a Cox proportional hazards model. Total numbers of exacerbations will be compared using a Poisson regression model.

Other continuous variables such as ICS dosage, Beta 2 agonist use, and questionnaire results will be analysed by analysis of covariance.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/09/2016
Actual
9/01/2017
Date of last participant enrolment
Anticipated
8/12/2017
Actual
23/05/2018
Date of last data collection
Anticipated
8/05/2019
Actual
7/05/2019
Sample size
Target
30
Accrual to date
Final
30
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 6245 0
John Hunter Hospital Royal Newcastle Centre - New Lambton
Recruitment postcode(s) [1] 13670 0
2305 - New Lambton Heights

Funding & Sponsors
Funding source category [1] 294133 0
Government body
Name [1] 294133 0
National Health and Medical Research Council
Country [1] 294133 0
Australia
Primary sponsor type
Government body
Name
Hunter New England Health
Address
Locked BAG # 1
HRMC
Hunter Region MC
NSW 2310
Country
Australia
Secondary sponsor category [1] 292964 0
University
Name [1] 292964 0
University of Newcastle
Address [1] 292964 0
University Drive, Callaghan
NSW 2308
Country [1] 292964 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295547 0
HNE HREC
Ethics committee address [1] 295547 0
Ethics committee country [1] 295547 0
Australia
Date submitted for ethics approval [1] 295547 0
29/04/2016
Approval date [1] 295547 0
14/07/2016
Ethics approval number [1] 295547 0
16/05/18/3.03

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes
Attachments [1] 977 977 0 0
/AnzctrAttachments/371153-Table 1 Possible formulation outcomes for each biomarker score algorithm level.docx

Contacts
Principal investigator
Name 67670 0
Prof Peter Wark
Address 67670 0
Level 2, HMRI
John Hunter Hospital
Kookaburra Circuit
New Lambton
NSW
2305
Country 67670 0
Australia
Phone 67670 0
+61 2 4042 0110
Fax 67670 0
+61 2 4042 0046
Email 67670 0
peter.wark@hnehealth.nsw.gov.au
Contact person for public queries
Name 67671 0
Jodie Simpson
Address 67671 0
Level 2, HMRI
John Hunter Hospital
Kookaburra Circuit
New Lambton
NSW
2305
Country 67671 0
Australia
Phone 67671 0
+61 2 4042 0148
Fax 67671 0
+61 2 4042 0046
Email 67671 0
jodie.simpson@newcastle.edu.au
Contact person for scientific queries
Name 67672 0
Jodie Simpson
Address 67672 0
Level 2, HMRI
John Hunter Hospital
Kookaburra Circuit
New Lambton
NSW
2305
Country 67672 0
Australia
Phone 67672 0
+61 2 4042 0148
Fax 67672 0
+61 2 4042 0046
Email 67672 0
jodie.simpson@newcastle.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 Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.