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Trial registered on ANZCTR


Registration number
ACTRN12624000533594
Ethics application status
Approved
Date submitted
14/12/2023
Date registered
29/04/2024
Date last updated
29/04/2024
Date data sharing statement initially provided
29/04/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Minimising Oral Corticosteroid Use in Asthma using Treatable Traits
Scientific title
A treatable traits model-of-care versus enhanced usual care in adults with asthma to assess cumulative oral corticosteroid dose over the 52 week trial.
Secondary ID [1] 309512 0
Nil Known
Universal Trial Number (UTN)
Trial acronym
TTOCS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Asthma 329796 0
Condition category
Condition code
Respiratory 326691 326691 0 0
Asthma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention is a 24-week individualised treatment programme consisting of three key components:
1. A Multidimensional Assessment (MDA). Participants will undergo assessments of 12 pulmonary (including blood collection), extra-pulmonary and risk-factor/behavioural traits that relate to asthma exacerbations and oral corticosteroid use, and that are feasible to assess and manage. This assessment will be completed by the Clinical Research Officer and will take approximately 2.5 hours to complete.
2. An individualised multidisciplinary treatment plan will be developed by the MDT guided by the results of the MDA and a biomarker-driven inflammatory treatment-decision algorithm that involves interventions targeted to the identified traits. Targeted treatments are standardised according to best available evidence. Participants will only receive the targeted treatment if that trait is identified. This plan will be developed within 2 weeks of the MDA.
3. A respiratory case-manager. The case-manager will summarise the traits identified, co-ordinate a case discussion with the multidisciplinary team (MDT), communicate the list of traits identified with each individual participant, communicate the treatment plan to the patient, provide education regarding the traits and the individualised treatments, co-ordinate the visits between the members of the MDT, and deliver the case manager interventions. Other members of the MDT will include a physician , speech pathologist and other appropriately trained clinicians. The number of visits over the 24 week intervention period is estimated to be up to 4 visits per participant .The total contact time for the intervention visits is estimated to be 3 hours per participant. The visits will be conducted face to face or via telehealth.

The following traits will be targeted in this study:

1. Sub-optimal adherence
Assessment: Self-report <80% of treatment by open-ended questions. Test of Inhaler Adherence Questionnaire
Intervention: Tailored based on reasons for nonadherence including simplification of medication regimen, and education. This will be delivered by the Case Manager.

2. Inadequate inhaler device technique
Assessment: Observation and assessment.
Intervention: Education and training delivered by the Case Manager.

3. Inhaler device polypharmacy
Assessment: Greater than 2 different inhaler device types.
Intervention: Optimise inhaler technique and rationalise number of devices used. This will be delivered by the Case Manager and Doctor.

4. No written asthma action plan (WAAP)
Assessment: WAAP not prescribed or used.
Intervention: Provision of WAAP. This will be delivered by the Doctor.

5. Eosinophilic Airway inflammation
Assessment: Blood eosinophils greater than or equal to 0.3 x 10^9/L
Intervention: Step 1: Optimise Inhaled Corticosteroid use, Step 2: PBS approved monoclonal antibody OR Azithromycin if ineligible for PBS approved monoclonal antibody. This will be delivered by the Doctor.

6. Airflow limitation
Assessment: FEV1 <80% predicted.
Intervention: Long acting beta2-agonists +/- Long- acting muscarinic antagonist. This will be delivered by the Doctor.

7. Frequent chest infection
Assessment: Greater than or equal to 2 courses of antibiotics per year.
Intervention: Antibiotic tailored action plan and self- management education. E.g. Azithromycin 500mg three times per week. This will be delivered by the Doctor.

8. Frequent Exacerbations
Assessment: Greater than or equal to 2 courses of OCS/year OR A cumulative OCS greater than or equal to 500mg over the past 24 months.
Intervention: SMART Therapy (budesonide/formoterol). This will be delivered by the Doctor.

9. Vocal Cord Dysfunction
Assessment: If Pittsburgh VCD Score greater than or equal to 4, then laryngoscopy.
Intervention: Multicomponent intervention comprised of education, vocal fold release & vocal hygiene. This will be developed by the Speech Pathologist.

10. Rhinitis
Assessment: SNOT questionnaire score >40.
Intervention: Step 1. Determine rhinitis severity. Step 2: Trigger avoidance, intranasal steroids, antihistamines, and saline washes. Step 3. Referral to Specialist. This will be delivered by the Doctor.

11. Dysfunctional breathing
Assessment: Nijmegen Score greater than or equal to 19 OR mMRC score greater than or equal to 1.
Intervention: Breathing retraining. This will be delivered by the Case Manager or qualified clinician.

12. Smoking
Assessment: Admit to smoking or exhaled CO greater than or equal to 10 ppm
Intervention: Smoking cessation counselling +/- pharmacotherapy. This will be delivered by the Case Manager and Doctor.
Intervention code [1] 325944 0
Treatment: Other
Intervention code [2] 326045 0
Treatment: Drugs
Comparator / control treatment
Following a multidimensional assessment, the participants will be treated according to enhanced usual care. A letter will be sent to the primary care physician summarising asthma control, lung function, and exacerbation history. The Enhanced Usual Care study entry letter provides advice about expert review recommendations with particular attention to frequent exacerbations and oral corticosteroid use, as outlined in the Global Initiative for Asthma (GINA). The usual care team will schedule follow-up appointments including the number and timing. This letter will be sent within 2 weeks of the participants multidimensional assessment. The participants will be provided asthma education resources. Please see TTOCS Asthma Education Resources for more information (below).

https://asthma.org.au/wp-content/uploads/2020/05/AA2023_Asthma-Basic-Facts-A4_v10_web.pdf

https://treatabletraits.org.au/wp-content/uploads/2022/03/Side-Effects-of-Treatment-OCS-infographic.pdf
Control group
Active

Outcomes
Primary outcome [1] 334555 0
Cumulative oral corticosteroid dose will be assessed This outcome will be assessed using a validated standardised exacerbation module modified to capture additional detail regarding OCS use (i.e., daily OCS dose and duration of the prescribed OCS course) and will be corroborated using patient diaries kept throughout the 52-week study period.
Timepoint [1] 334555 0
at 52 weeks after randomisation
Secondary outcome [1] 421176 0
% participants oral corticosteroid free. This will be assessed using a validated standardised exacerbation module modified to capture additional detail regarding OCS use (i.e., daily OCS dose and duration of the prescribed OCS course) and will be corroborated using patient diaries kept throughout the 52-week study period.
Timepoint [1] 421176 0
at 12-months after randomisation
Secondary outcome [2] 421177 0
Health-related quality of life measured using the Saint George Respiratory Questionnaire (SGRQ)
Timepoint [2] 421177 0
at 24 and 52 weeks after randomisation
Secondary outcome [3] 421178 0
Total number of moderate to severe asthma exacerbations. This will be assessed using a self-report, validated standardised exacerbation module that captures use of oral corticosteroids, hospitalisation, emergency department visits, use of written action plan, worsening of symptoms and use of rescue bronchodilators.
Timepoint [3] 421178 0
at 52 weeks after randomisation
Secondary outcome [4] 421510 0
Asthma control measured using the validated Asthma Control Questionnaire (ACQ-5)
Timepoint [4] 421510 0
at 24 and 52 weeks after randomisation
Secondary outcome [5] 430498 0
Cost – intervention costs (e.g., clinical tests, medication costs, phone consults), comparator arm costs, consequent health care resource use.

The study-related costs, such as clinical tests, medications, and phone consultations, will be collected using a study-specific logbook. Healthcare resource utilisation will be collected via PBS/MBS data linkage.
Timepoint [5] 430498 0
at 52 weeks after randomisation

Eligibility
Key inclusion criteria
- Able to provide written informed consent
- Aged 18 years or over
- Doctor diagnosis of asthma
- Asthma diagnosis for at least 18 months
- Prescribed treatment for doctor-diagnosed asthma.
- Have a cumulative OCS dose greater than or equal to 500mg over the previous 24 months (self-reported).
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Current lung cancer or other blood, lymphatic or solid organ malignancy.
- Cognitive impairment, poor English language skills or significant untreated hearing impairment that prevents completion of data collection forms or understanding verbal instructions.
-Inability to attend study visits.
-High dependence on medical care.
- Significant life-limiting comorbidity (<12 months life expectancy)
- Current participation in any other clinical trial, or participation in another clinical trial within the 4 weeks preceding study entry.
-Currently Pregnant or breastfeeding



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)
Concealed random allocation will be employed using an online randomisation system developed at the HMRI.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomisation algorithm will be determined by an independent statistician. We will use permuted randomisation, with blocks of size 4 and 6, stratified by site. The allocation ratio will be 1:1.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
Pilot data for cumulative OCS dose in severe asthma patients shows a right-skewed distribution with a median 250 mg and range: 5 - >6000 mg per course. Anticipating a similarly skewed distribution in our population, we will analyse the primary outcome after transformation to approximate normality. We hypothesise that our treatable traits intervention will produce a between-group, standardised mean difference (SMD) of 0.4 (moderate effect), consistent with other OCS-sparing therapies such as monoclonal biologic therapies. A sample size of 150 per group (N=300) will provide 90% power to detect a baseline-adjusted SMD of 0.4 at two-sided alpha=0.05, conservatively assuming a within-person correlation of 0.3 between the baseline and 12- month dose and allowing for 20% attrition.

The RCT will be analysed under the intention-to-treat principle using generalised linear models. The group difference in the primary outcome (transformed cumulative OCS dose) will be estimated using linear regression, adjusted for baseline (ANCOVA), with significance a=0.05. The treatment effect will be expressed as the baseline-adjusted mean group difference with 95% CI. Primary analyses will use all available data; sensitivity analyses such as multiple imputation will investigate the robustness of conclusions to different assumed missing data mechanisms. The group difference in the secondary outcome of exacerbation rate and HRQoL will be estimated using negative binomial models, with a significance of a=0.05.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
6/05/2024
Actual
Date of last participant enrolment
Anticipated
1/06/2026
Actual
Date of last data collection
Anticipated
1/06/2027
Actual
Sample size
Target
300
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,WA
Recruitment hospital [1] 24685 0
John Hunter Hospital - New Lambton
Recruitment hospital [2] 24686 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment postcode(s) [1] 40306 0
2305 - New Lambton
Recruitment postcode(s) [2] 40307 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 313706 0
Government body
Name [1] 313706 0
National Health and Medical Research Council - Medical Research Future Fund
Country [1] 313706 0
Australia
Primary sponsor type
University
Name
University of Newcastle
Address
University Dr, Callaghan, New South Wales 2308
Country
Australia
Secondary sponsor category [1] 315514 0
Hospital
Name [1] 315514 0
John Hunter Hospital
Address [1] 315514 0
Locked bag 1 Hunter Region Mail Centre, Warabrook 2310, NSW
Country [1] 315514 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312879 0
Hunter New England Human Research Ethics Committee
Ethics committee address [1] 312879 0
John Hunter Hospital Locked Bag 1 Hunter Region Mail Centre , Warabrook , 2310, NSW
Ethics committee country [1] 312879 0
Australia
Date submitted for ethics approval [1] 312879 0
27/09/2023
Approval date [1] 312879 0
24/10/2023
Ethics approval number [1] 312879 0
2023/ETH00612

Summary
Brief summary
Asthma is a common disease and significant public health problem in Australia, affecting one in nine adults. Current asthma management approaches treat all patients the same, using a step up- step down approach, which fails to recognise the complexity and heterogeneity that is evident, particularly in those with more severe disease. While this approach significantly improved asthma outcomes, in the early 21st century its limitations have become apparent, as improvements in asthma outcomes have stalled. Indeed, people continue to die from asthma, have an ongoing burden from acute attacks and symptoms, and suffer severe iatrogenic consequences of treatment, in particular from oral corticosteroids (OCS). Alarmingly, in Australia it has been demonstrated that more than 25% of patients using inhaled corticosteroids reach a cumulative OCS dose of >1000mg which is associated with increased risk of serious adverse side effects and irreversible harm. Management approaches that address the heterogeneity of asthma, including risk factors and comorbidities associated with the prevalence and persistence of the disease, and that incorporate advances in knowledge are urgently needed. “Treatable Traits” have been proposed as a useful concept to implement precision medicine. This approach recommends an assessment of traits or disease characteristics that fall within three domains: pulmonary, extra pulmonary and risk factor/behavioural, and the application of targeted individualised interventions based on the identified traits. This project will test the clinical and cost-effectiveness of a Treatable Traits model-of-care as an OCS-sparing strategy for the management of adults with asthma, while gathering information on its potential for implementation in real-world settings.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 126194 0
Prof Vanessa McDonald
Address 126194 0
Level 2, Hunter Medical Research Institute1 Kookaburra Circuit, New Lambton Heights NSW 2305
Country 126194 0
Australia
Phone 126194 0
+61 2 4042 0146
Fax 126194 0
Email 126194 0
vanessa.mcdonald@newcastle.edu.au
Contact person for public queries
Name 126195 0
Miss Amber Smith
Address 126195 0
Level 2, Hunter Medical Research Institute1 Kookaburra Circuit, New Lambton Heights NSW 2305
Country 126195 0
Australia
Phone 126195 0
+61 2 40420134
Fax 126195 0
Email 126195 0
amber.smith@newcastle.edu.au
Contact person for scientific queries
Name 126196 0
Prof Vanessa McDonald
Address 126196 0
Level 2, Hunter Medical Research Institute1 Kookaburra Circuit, New Lambton Heights NSW 2305
Country 126196 0
Australia
Phone 126196 0
+61 2 4042 0146
Fax 126196 0
Email 126196 0
vanessa.mcdonald@newcastle.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Anonymised demographic and primary outcome data underlying published results.
When will data be available (start and end dates)?
Following publication - no end date.
Available to whom?
Case by case basis at the discretion of the primary sponsor.
Available for what types of analyses?
Individual patient data meta-analysis.
How or where can data be obtained?
Access subject to approvals by Principal Investigator Professor Vanessa McDonald 02 40420146


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.