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Trial registered on ANZCTR


Registration number
ACTRN12620000935932
Ethics application status
Approved
Date submitted
23/07/2020
Date registered
18/09/2020
Date last updated
15/04/2024
Date data sharing statement initially provided
18/09/2020
Date results provided
15/04/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Treatable traits algorithm guided management of adults with asthma: a feasibility study
Scientific title
Treatable traits algortihm guided management of adults with asthma: a feasibility study
Secondary ID [1] 301446 0
MRINZ/19/06
Universal Trial Number (UTN)
U1111-1218-7139
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Asthma 317775 0
Condition category
Condition code
Respiratory 315842 315842 0 0
Asthma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Protocolised adjustment of inhaled medication according to blood eosinophil level, exhaled nitric oxide, FEV1:FVC ratio and asthma control test score.

The minimum inhaled medication participants will receive is budesonide/formoterol 200/6mcg one inhalation as needed via the Turbuhaler device. Additional treatment will be given as below:

Corticosteroid dose escalation:
If a participant has evidence of Type 2 inflammation [an inflammatory pathway involving a subpopulation of CD4+ T cells known as Th2 cells that secrete IL-4, IL-5, and IL-13 and stimulate Type 2 immunity, which is characterized by high IgE antibody titers and eosinophilia] despite this level of treatment their budesonide/formoterol 200/6 will be increased to two inhalations twice daily plus one as-needed. If they still have protocol-defined evidence of Type 2 inflammation despite this level of treatment additional inhaled steroids will be given in the form of budesonide 200mcg turbuhaler two inhalations twice daily. If Type 2 inflammation persists despite this level of treatment oral corticosteroids will be added in the form of oral prednisone tablets 10mg once daily. This dose can be increased if no response to a maximum of oral prednisone tablets 20mg once daily.

Bronchodilator medication:
If a participant has an FEV1:FVC ratio below the lower limit of normal and they are not already receiving a regular long-acting beta agonist (LABA) the budesonide/formoterol 200/6 will be increased from one inhalation as-needed to two inhalations twice daily plus one as-needed. If the FEV1:FVC ratio remains below the lower limit of normal despite this level of treatment a long-acting muscarinic antagonist will be added in the form of tiotropium respimat 2.5mcg two inhalations once daily.

Participants will receive the dispensed medication until the next study visit (6 weeks between visit 1 and visit 2, 4 weeks between visit 2 and visit 3). At the next visit the amount of medication taken will be estimated by means of pill counts for oral medications and by documenting the inhaler dose counter reading for symbicort. Budesonide and tiotropium adherence will not be estimated.

At visit 3 there will be an extended assessment protocol in which participants will also complete a number of questionnaires to try and identify co-morbiditites which may be contributing to their symptoms. In this feasibility study these co-morbidities will not be treated as part of the study, but will be treated if clinically appropriate at the conclusion of the study. As this is a feasibility study there is no control group.
Intervention code [1] 317769 0
Treatment: Drugs
Intervention code [2] 318149 0
Diagnosis / Prognosis
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 324046 0
Estimation of recruitment rates, based on detailed screening log
Timepoint [1] 324046 0
End of the study
Primary outcome [2] 324864 0
Estimation of the proportion who find the intervention acceptable. Reported as the proportion of participants who 'Agree' or 'Strongly agree' with the statement: "I found having my medication adjusted according to my test results acceptable."
Timepoint [2] 324864 0
10 weeks post-enrolment (end of study)
Primary outcome [3] 324865 0
Estimation of the proportion of participants who would be willing to be randomised in a trial comparing usual care with management according to a treatable traits based management algorithm. Reported as the proportion of participants who 'Agree' or 'Strongly agree' with the statement: "I would be willing to take part in a study comparing usual care from my GP to ‘treatable trait based asthma management’."
Timepoint [3] 324865 0
10 weeks post enrolment (end of study)
Secondary outcome [1] 383616 0
Estimation of the proportion of participants requiring the extended assessment protocol at visit 3. Reported as the proportion of participants with either an asthma control test score (ACQ) greater than or equal to 1 at V3 or exacerbation between V1 and V3.

This is considered a primary outcome
Timepoint [1] 383616 0
10 weeks post-enrolment (End of study)
Secondary outcome [2] 383617 0
Estimation of the prevalence of the traits identified during the extended assessment, Reported as the proportion of participants in whom each trait is deemed to be present according to the study assessment algorithm.

This is considered a primary outcome

The traits assessed for and the criteria are:
Smoking: Urinary cotinine positive (if urine testing acceptable to patient). Exhaled breath carbon monoxide greater than or equal to 10 (if patient prefers).

Airway pathogen colonisation: Presence of bacterial pathogen via sputum culture.

Frequent chest infection: greater than or equal to 2 respiratory-related antibiotic courses in 12 months.

Rhinitis / Sinusitis: Present if Sinonasal Questionnaire score greater than or equal to 1.

Dysfunctional breathing: Present if Nijmegen questionnaire total score greater than or equal to 23.

Vocal Cord Dysfunction/Inducible Laryngeal Obstruction: Present if Pittsburg score is greater than or equal to 4 and/or Vocal Cord Dysfunction Questionnaire score is greater than 40.

Depression: Present if Hospital Anxiety and Depression Scale depression domain score greater than or equal to 8.

Anxiety: Present if Hospital Anxiety and Depression Scale anxiety domain score greater than or equal to 8.

Poor adherence: less than 80% adherence based on number of doses administered versus expected as estimated using dose counter recordings taken at visit 2 and 3.

Systemic inflammation: Elevation of at least two systemic inflammatory markers on more than one occasion, high sensitivity CRP greater than 3mg/L, and WCC greater than 9 x109/ L (these blood tests are performed at visits 1, 2 and 3 (weeks 0, 6 and 10).

Occupational exposure: Systematic exposure hx taken by the clinician reviewing the participant, comprising 3 questions. 1) Does being at work ever make your chest tight or wheezy? 2) Have you ever had to change or leave your job because it affected your breathing? 3) Have you ever worked in a job which exposed you to vapours, gas, dust, or fumes? An answer of yes to any of the 3 questions denotes the presence of the trait.
Timepoint [2] 383617 0
10 weeks post-enrolment (End of study)

Eligibility
Key inclusion criteria
1) Participant is willing and able to give informed consent for participation in the trial.
2) Aged 18 to 75 years on day of enrolment.
3) Self-report of a doctor’s diagnosis of asthma.
4) Asthma not well-controlled, as measured by an ACQ score greater than or equal to 1.
5) Severe asthma exacerbation within the previous year (defined as "a presentation to a general practice, after-hours clinic or emergency department resulting in a prescription for oral corticosteroids or treatment with spacer-delivered or nebulised bronchodilator or self-administration of prednisone for asthma for at least 3 days.")
6) Receiving treatment with an inhaled corticosteroid containing medication for at least 3 months
7) In the Investigator’s opinion, is able and willing to comply with all trial requirements.
8) Willing to allow his or her General Practitioner and consultant, where relevant, to be notified of participation in the trial.
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria:
1) Inhaled corticosteroid dose >1000mcg fluticasone propionate (FP)/day or equivalent.
2) Maintenance oral corticosteroid use for any indication(regular hydrocortisone or fludrocortisone are permitted).
3) Oral corticosteroid use within the previous 4 weeks for any indication (regular hydrocortisone or fludrocortisone are permitted).
4) Under the care of a severe asthma clinic
5)Anti-IgE or anti-IL5 biologics within the previous 4 weeks
6) Current immune suppression or immunodeficiency
7) Previous ICU admission due to asthma
8) Participant who is pregnant, lactating, or planning pregnancy during the course of the trial.
9) Serious co-morbidity liable to affect ability to perform study procedures or interpretation of study results, e.g. recent pneumothorax, interstitial lung disease, bronchiectasis, severe heart failure, myocardial infarction within the last 3 months.
10) Any other significant disease or disorder (including known contraindication to any of the IMPs or excipients) that, in the opinion of the Investigator, may put the participants at risk because of participation in the trial, or may influence the result of the trial, or the participant’s ability to participate in the trial.
11) Participants who have participated in another research trial involving an investigational product in the past 12 weeks.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
There is no allocation concealment as this is an open-label feasibility study
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
There is no sequence generation as this is a non-randomised open-label feasibility study
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The statistical analysis will address the five specified feasibility issues:
1) Estimation of recruitment rates. Reported descriptively based on detailed screening logs
2) Estimation of the proportion who find the intervention acceptable. Analysed as the proportion of participants answering the acceptability question on the end of study questionnaire as “Agree” or “Strongly agree”.
3) Estimation of the proportion of participants who would be willing to be randomised in a trial comparing guideline directed care with management according to a treatable traits based management algorithm. Analysed as the proportion of participants answering the future study question on the end of study questionnaire as “Agree” or “Strongly agree”.
4) Estimation of the proportion of participants requiring the extended assessment protocol at visit 3. Analysed as the proportion of participants with either an ACQ greater than 1 at V3 or exacerbation between V1 and V3.
5) Estimation of the prevalence of the traits identified during the extended assessment. Analysed as the proportion of participants in whom each trait is deemed to be present according to the assessment algorithm.

Estimates of 95% confidence intervals for proportions will be by small sample techniques e.g. the Clopper-Pearson method. Data for FeNO will be analysed using summary description of continuous variables for log FeNO as well as FeNO based on our previous experience with the skew distribution of this variable and that normality assumptions were better met on the logarithm transformed scale..

Sample size calculation:
The sample size calculation for the feasibility study takes into account the following considerations:
- A recruitment rate of less than 25% of those approached for participation in the main trial
means either that the main trial would need to run over a longer period of time or that more
centres would need to be involved for the recruitment to occur in the time period fundable
by a grant.
- This recruitment rate estimation of the feasibility study is made of two components: the
proportion of those approached for the feasibility study who agree to participate and the proportion of those who participate in the feasibility study that would agree to
enter a randomised trial. We anticipate that 50% of those approached for the
feasibility study would agree to participate in the feasibility study, and that 80%
of those who participate in the feasibility study would agree to be randomised,
for a potential recruitment rate of 40% of those who are approached. If this combined
proportion is less than 25% the main study would need either a longer duration or more
centres than we currently anticipate.
- A sample size for recruitment of 100 has about 90% power to rule out a lower confidence
bound for the recruitment proportion of less than 25%. If 50 participants are recruited into
the feasibility study then this gives a 95% CI for a proportion.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
24/09/2020
Actual
21/09/2020
Date of last participant enrolment
Anticipated
1/12/2020
Actual
7/12/2021
Date of last data collection
Anticipated
28/02/2021
Actual
22/02/2022
Sample size
Target
50
Accrual to date
Final
29
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 16847 0
Hunter Medical Research Institute - New Lambton Heights
Recruitment postcode(s) [1] 30492 0
2305 - New Lambton Heights
Recruitment outside Australia
Country [1] 22659 0
New Zealand
State/province [1] 22659 0
Wellington

Funding & Sponsors
Funding source category [1] 305882 0
Government body
Name [1] 305882 0
Health Research Council of New Zealand
Country [1] 305882 0
New Zealand
Funding source category [2] 305893 0
Charities/Societies/Foundations
Name [2] 305893 0
John Hunter Hospital Charitable Trust Research Scheme
Country [2] 305893 0
Australia
Primary sponsor type
Other
Name
Medical Research Institute of New Zealand
Address
Level 7,
CSB Building,
Wellington Hospital
Riddiford Street
Wellington 6021
Country
New Zealand
Secondary sponsor category [1] 306336 0
None
Name [1] 306336 0
Address [1] 306336 0
Country [1] 306336 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306143 0
Central Health and Disability Ethics Committee
Ethics committee address [1] 306143 0
Ministry of Health
Health and Disability Ethics Committees
PO Box 5013
Wellington 6140
Ethics committee country [1] 306143 0
New Zealand
Date submitted for ethics approval [1] 306143 0
07/01/2020
Approval date [1] 306143 0
12/03/2020
Ethics approval number [1] 306143 0
20/CEN/33

Summary
Brief summary
This study is a feasibility study looking at personalised medicine for asthma. A planned full randomised controlled trial would test whether tailoring a patients treatment according to an algorithm based on their asthma symptoms, level of airway inflammation and airway narrowing gives better results than usual care. Before we can run that full RCT we need to test 5 specific feasibility questions around recruitment, acceptability, and the proportion of participants with co-morbidities which may change how we run it.

This open-label single group cohort feasibility study will provide the answers to these five specific questions which may change how we run the full RCT:
1)How quickly can we recruit?
2)Do participants find the intervention acceptable?
3)In theory would participants be willing to take part in a randomised controlled trial testing this approach?
4)What proportion of patients still have not-well controlled asthma at the end of the study, or have had an exacerbation during the study?
5)How common are the additional conditions (e.g. sinus disease) that are looked for at the final visit?

Fifty participants will be recruited, 25 in New Zealand and 25 in Australia. Each participant will attend for 3 visits over 10 weeks and will have their medications adjusted according to the treatment algorithm specified in the protocol. All participants will receive inhaled steroid and long-acting bronchodilator medications in line with national and international guidelines. The difference is that the dose of inhaled steroid and whether or not participants are prescribed oral steroids (prednisone) will be adjusted according to the protocol algorithm rather than individual clinician's judgement.
Trial website
N/A
Trial related presentations / publications
Public notes
This is a single group cohort study with 50 participants designed to answer five pre-specified feasibility questions. Due to the constraints of the registry (which permits a maximum of 3 primary outcomes) the first three of the five questions has been listed as primary outcomes and the remaining two have been listed under secondary outcomes with a note that they are considered to be primary outcomes. As there is no formal hypothesis testing and all five outcomes are descriptive all five outcomes are of equal interest.

Contacts
Principal investigator
Name 102858 0
Dr James Fingleton
Address 102858 0
Respiratory Department,
Health NZ, Capital Coast and Hutt Valley
Wellington Hospital
Wellington
Country 102858 0
New Zealand
Phone 102858 0
+64 48050247
Fax 102858 0
+6443895707
Email 102858 0
james.fingleton@ccdhb.org.nz
Contact person for public queries
Name 102859 0
James Fingleton
Address 102859 0
Respiratory Department,
Health NZ, Capital Coast and Hutt Valley
Wellington Hospital
Wellington
Country 102859 0
New Zealand
Phone 102859 0
+64 48050247
Fax 102859 0
+6443895707
Email 102859 0
james.fingleton@ccdhb.org.nz
Contact person for scientific queries
Name 102860 0
James Fingleton
Address 102860 0
Respiratory Department,
Health NZ, Capital Coast and Hutt Valley
Wellington Hospital
Wellington
Country 102860 0
New Zealand
Phone 102860 0
+64 48050247
Fax 102860 0
+6443895707
Email 102860 0
james.fingleton@ccdhb.org.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All de-identified individual participant data
When will data be available (start and end dates)?
After manuscript publication for at least 10 years.
Available to whom?
These data will be available to researchers who provide a methodologically sound proposal.
Available for what types of analyses?
For the purposes of achieving specific aims outlined in the proposal.
How or where can data be obtained?
Proposals should be directed to Dr James Fingleton via email (james.fingleton@mrinz.ac.nz)


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
8575Study protocol    379950-(Uploaded-23-07-2020-07-36-02)-Study-related document.pdf



Results publications and other study-related documents

Documents added manually
TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
Basic resultsNo 379950-(Uploaded-15-03-2024-12-45-18)-Basic results summary.pdf

Documents added automatically
No additional documents have been identified.