Treatable Traits in Interstitial Lung Disease
Phase: NA
Conditions: Interstitial Lung Diseases (ILD)
Sponsor: The University of Western Australia

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TREATABLE TRAITS IN INTERSTITIAL LUNG 
DISEASE (TTRILD) STUDY PROTOCOL 
 
A randomised controlled trial comparing 
the targeted management of treatable 
traits versus standard practice: the TRRILD 
study.  
 
Protocol Number:  5.020231213 
Version: 6.2   
Date:  10th Sep 2025 
Author/s:  
Dr. Megan Harrison  
Prof. Yuben Moodley  
Sharon Maxwell  
A/ Prof. Vinicius Cavalheri  
A/Prof. Kristin Gainey  
Dr. Emily Jeffery  
Dr. Damien Foo  
Caitlin Vicary  
A/Prof. Tamera Corte  
A/Prof. Yet Khor  
A/Prof. Nicole Goh  
Dr. John Mackintosh 
Dr. Ingrid Cox  
 

 
CONFIDENTIAL  
This document is confidential and the property of Dr. Megan Harrison and Prof. Yuben Moodley. 
No part of it may be transmitted, reproduced, published, or used without prior written 
authorisation.  
 
Statement of Compliance  
This document is a protocol for a research project. This study will be conducted in compliance 
with all stipulation of this protocol, the conditions of the ethics committee approval, the NHMRC 
National Statement on ethical Conduct in Human Research (2023) and the Note for Guidance on 
Good Clinical Practice.   
 
 
Dr Megan Harrison will be collaborating on the study as a student, to complete a Doctor of 
Philosophy.  Student supervision will be through the University of Sydney conducted by Professor 
Tamera Corte. Dr Harrison will be the lead author of publications using data from this research.  
The articles will be published in journals related to Respiratory Medicine and related to the topics 
noted below. A prospective multi-site analysis to define treatable traits in an Australian ILD 
population. Treatable Traits model of Care in Interstitial Lung Disease: A randomised controlled 
trial.  
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents  
 
STUDY SYNOPSIS .................................................................................................................................................... 2 
1. GLOSSARY OF ABBREVIATIONS AND TERMS ....................................................................................................... 6 
2. ADMINISTRATIVE INFORMATION ....................................................................................................................... 7 
2.1 Investigators ................................................................................................................................................... 7 
3.  INTRODUCTION AND BACKGROUND ................................................................................................................. 8 
4. STUDY OBJECTIVES ............................................................................................................................................. 9 
4.1. Hypotheses: ................................................................................................................................................... 9 
4.2. Study Aims ..................................................................................................................................................... 9 
4.3. Outcome measures........................................................................................................................................ 9 
5. DATA COLLECTION AND ASSESSMENTS: ........................................................................................................... 11 
6. STUDY DESIGN ................................................................................................................................................. 13 
6.1. Study type and Design ................................................................................................................................. 13 
6.2. Eligibility Criteria: ........................................................................................................................................ 13 
6.3. Recruitment and Consent: ........................................................................................................................... 14 
6.4. Randomisation and Stratification:............................................................................................................... 15 
7. INTERVENTIONS ............................................................................................................................................... 16 
7.1. Multidimensional assessment ..................................................................................................................... 16 
7.2 Intervention group: ...................................................................................................................................... 20 
7.3. Specific interventions:.................................................................................................................................. 22 
7.4. CONTROL GROUP: ......................................................................................................................................... 25 
8. FEASIBILITY ...................................................................................................................................................... 27 
9. PARTICIPANT SAFETY AND WITHDRAWAL ........................................................................................................ 27 
9.1. Risk management and safety ...................................................................................................................... 27 
9.2. Handling of withdrawals ............................................................................................................................. 27 
9.3. Replacements .............................................................................................................................................. 27 
10.  STATISTICAL METHODS .................................................................................................................................. 28 
10.1. Sample size calculation.............................................................................................................................. 28 
10.2. Statistical Methods .................................................................................................................................... 28 
11. STORAGE OF BLOOD AND TISSUE SAMPLING ................................................................................................. 28 
12. DATA STORAGE AND HANDLING ..................................................................................................................... 29 
13. REFERENCES ................................................................................................................................................... 30 
 
 

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Study Synopsis 
 
Title: 
A randomised controlled trial comparing the targeted 
management of treatable traits versus standard practice in 
people with interstitial lung disease (ILD)  
 
Short Title: 
TTRILD   
 
Study Objectives: 
 Aim 1. To compare the clinical efficacy of a treatable traits 
model of care (TTRILD) versus standard care in people with ILD. 
Hypothesis 1: People with ILD who are provided with TTRILD 
MDT care will experience improved health-related quality of life 
(HRQoL) (primary outcome), symptoms, anxiety, physical 
activity, and body composition (secondary outcomes). 
 
Aim 2. To compare the cost-effectiveness of TTRILD MDT clinic 
versus standard care in people with ILD.  
Hypothesis 2: TTRILD MDT care will be a cost-effective 
intervention compared to standard care, from a societal 
perspective. 
 
Aim 3. To establish the prevalence of pre-defined treatable 
traits and determine the association with quality of life and 
disease severity.  
Hypothesis 3: Increased number of traits will be associated with 
reduced quality of life and increased disease severity. 
 
Aim 4. To identify cellular, molecular, and genetic TT in ILD for 
future improved management.   
 
Design: 
Randomised controlled trial with an embedded economic 
evaluation 
 
Intervention Duration: 
6 months  
 
Population: 
People with fibrotic ILD 
 
Study Site 
South Metropolitan Health Service (Fiona Stanley Hospital) 
North Metropolitan Health Service (Sir Charles Gairdner 
Hospital)   
Inclusion Criteria: 
Adults ≥ 18 years 

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Physician-confirmed diagnosis of fibrotic interstitial lung 
disease (ILD)  
Able to provide consent to participate in the study  
On stable treatment for ILD for 1 month (no changes to ILD 
medications in the 1 month prior to recruitment) 
 
Exclusion Criteria:  
Unable to consent due to cognitive impairment or other reason 
Death or transplant anticipated within the study period 
An acute exacerbation within one month of recruitment 
Active suicidality, severe depression, active psychosis or mania, 
or other severe psychiatric concerns that require more 
intensive treatment. Any such participants could be referred for 
individual therapy and/or psychiatric treatment that would be 
more appropriate for their needs.  
 
Intervention group: 
Attendance and care as guided by the TTRILD MDT clinic. The 
MDT team includes respiratory physician, specialist nurse, 
physiotherapist, dietitian, and psychologist.  
 
Clinics will occur at initial review, 3 months, and 6 months. 
Telehealth clinic at 2 weeks will be undertaken with 
physiotherapy, dietitian, and psychology with an additional 4-
week dietitian phone review.  
 
Initial clinic review will identify presence of treatable traits 
including those amenable to MDT interventions and will 
conclude with a meeting attended by the allied health team to 
produce a comprehensive patient management plan.  
 
Physiotherapy interventions include 8-week pulmonary 
rehabilitation, home-based exercise program, pedometer use 
with goal setting.  
 
Dietetic intervention includes dietary counselling, education, 
and oral nutritional supplements.  
 
Psychological intervention provided will be self-management 
plan, or referral for individual treatment  
 
Physician care is provided as per standard of care with targeted 
recognition and management of treatable traits such as cough, 
pulmonary inflammation, and reflux. Handheld fans will be 
provided for those with significant dyspnoea. 

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Control group: 
Standard ILD care from their usual treating health care team.  
No limitation to MDT referrals including pulmonary 
rehabilitation, dietitian review and psychology.  
 
Outcomes: 
Primary outcome measure: Change in HRQoL score as 
measured using the Kings’ Brief Interstitial Lung Disease (K-
BILD) at 6 months. 
 
Secondary outcome measures:  
i) HRQoL using the EQ-5D-5L at 3 and 6 months, KB-ILD at 3 
months.  
 
ii) Dyspnoea measured using the Dyspnea-12.  
iii) Anxiety and depression measured with the Hospital Anxiety 
and Depression Scale (HADS).  
 
iv) Physical activity levels: International Physical Activity 
Questionnaire (IPAQ) will be measures at baseline and 6 
months. Physical activity also monitored by 6-monthly 6-
minute walk test (6MWT) and 3-monthly 1-minute sit-to-stand 
(STS). 
 
v) Muscle mass and body composition assessed using Dual-
Energy X-Ray Absorptiometry (DEXA) scan. 
 
vi) Lung function decline as measured by forced vital capacity 
(FVC) decline 
 
vii) Progression free survival: Time to progression, transplant, 
or death. Progression defined as a relative decline in either FVC 
of ≥10% or DLCO ≥15%  
 
viii) All-cause mortality.  
  
(viii) Economic evaluation: A comparison of per person direct 
(health system and all patient expenses) and indirect (lost 
productivity) costs will be performed for the treatable trait 
program versus standard care. We will perform an incremental 
cost-effectiveness analysis to compare differences in total costs 
in each treatment arm divided by differences in quality-
adjusted life years (calculated from EQ-5D-5L utility scores and 
survival). An additional incremental cost-effectiveness ratio will 

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be calculated based on incremental costs per hospitalisation 
avoided. 
 
(vii) To establish the prevalence of pre-defined treatable traits. 
This prevalence will be further assessed to understand inter-
relationships and patterns of clustering and co-occurrence. The 
relationship between traits and QOL (defined by K-BILD) and 
disease severity (defined by FVC) will also be assessed.  
  
Number 
of 
planned 
subjects 
110 
Safety considerations  
The Data Safety and Monitoring Board (DSMB) will meet twice 
yearly, chaired by a respiratory physician who is independent of 
the study team and trial sites. The DSMB will include a 
biostatistician. 
 
Trial Governance  
A Steering Committee, chaired by CIA Moodley, will include the 
chief investigators. The steering committee will meet 3-
monthly.  
An independent consumer advocacy group consisting of 2 
patients with ILD will review the protocol and progress 6-
monthly.  
 
Statistical Methods 
All data will be analysed using an intention-to-treat approach. 
Generalised linear models and Cox regression will be 
performed to illustrate the effects of the primary and 
secondary outcomes whilst adjusting for relevant covariates, 
with subgroup analyses by types of ILD, severity of the disease, 
and types of personalised program (sarcopenia, loss of 
appetite, anxiety, cough). All statistical analyses will be 
overseen by an experienced biostatistician. 
 
Funding: 
MRFF Chronic Respiratory Conditions.  
 
 
 

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1. Glossary of Abbreviations and Terms  
 
Abbreviation/ Term 
Description (using lay language)  
 
1STST 
1 minute sit to stand. A quick assessment tool that is validated to 
measure peripheral muscle function and functional sarcopenia 
6MWT 
6-minute walk test 
ACS 
Anorexia Cachexia Scale. Measures appetite and body perception 
DEXA 
Dual-Energy X-Ray Absorptiometry 
DSMB 
Data Safety and Management Board 
Dyspnea-12 
Tool to determine patient breathlessness 
EQ-5D-5L  
European Quality of Life 5-Dimensions 5-Levels questionnaire. A 
multidimensional patient-reported questionnaire 
that 
supports 
calculation of quality-adjusted life years 
fILD 
Fibrotic interstitial lung disease  
FSS 
Fatigue Severity Scale. Measure of fatigue 
FSH 
Fiona Stanley Hospital 
FVC 
Forced vital capacity 
HADS 
Hospital Anxiety and Depression Scale. Identifies psychological distress. 
HRCT  
High-resolution computed tomography 
HrQoL 
Health-related quality of life 
ILD 
Interstitial lung disease 
IPAQ 
International Physical Activity Questionnaire 
K-BILD 
questionnaire 
King’s Brief Interstitial Lung Disease. Assessment of health-related 
quality of life 
LCQ 
Leister Cough questionnaire. Assesses cough 
MBSR 
Mindfulness-Based Stress Reduction 
MDT 
Multi-disciplinary team 
OSA 
Obstructive sleep apnoea 
PGSGA-SF 
Patient-Generated 
Subjective 
Global 
Assessment 
Short 
Form. 
Determines participant nutritional status 
PSS 
 
Perceived Stress Scale. Validated tool to determine patient well-being in 
response to stress 
QoL 
Quality of life 
STOP-BANG 
Stop bang questionnaire. Effective screening tool for obstructive sleep 
apnoea  
TT 
Treatable trait 
TTRILD 
Treatable traits in interstitial lung disease  
 
 

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2. Administrative Information 
 
2.1 Investigators 
 
Chief Investigator 
 
Name 
Professor Yuben Moodley 
Role 
Chief Investigator 
Organisation 
University of Western Australia 
Address 
35 Stirling Hwy, Crawley WA 6009  
The Chief Investigator will be responsible for supervision and will have authorisation over all 
activities related to this study including the study design; collection, management, analysis, and 
interpretation of data; writing the report; and the decision to submit the report for publication. 
 
Co-investigators 
Chief Investigators: 
Dr. Megan Harrison  
Prof. Tamera Corte  
Prof. Yet Khor 
A/Prof Nicole Goh 
Dr. John Mackintosh  
A/ Prof. Vinicius Cavalheri  
Prof. Andrew Palmer 
Prof. Daniel Chambers 
Prof.  Jo Dickinson 
Dr. Emily Jeffery  
Dr. Alan Teoh  
Dr. Tim Luckett  
A/Prof. Kristin Gainey  
Associate Investigators 
Dr Ingrid Cox 
Dr. Jeremy Wrobel  
Dr. Michael Musk  
Dr. Vidya Navaratnam  
Dr. Melissa Simmonds 
Dr. Adelle Jee  
Anna Guo  
Lisa Bateman  
Dr. Damien Foo 
 
 
 
Key partners with which we will engage for the TTRILD study include the clinical trial sites Fiona 
Stanley Hospital (South Metropolitan Health Service) and Sir Charles Gairdner Hospital (North 
Metropolitan Health Service). Harry Perkins Institute of Medical Research, and the Centre of 
Research Excellence in Pulmonary Fibrosis and the Australasian ILD Registry. Other key partners 
are the NHMRC Clinical Trials Centre, providing clinical trials leadership, statistical expertise and 
oversight, the Thoracic Society of Australia, and New Zealand (TSANZ), and the patient advocacy 
organisation, Lung Foundation Australia (LFA). 
 
 
 
 

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3.  Introduction and Background 
 
Background:  
 
This project will develop a treatable trait-based precision-medicine approach to ILD. ILD 
encompasses a group of chronic lung disorders that share the hallmark of fibrosis and 
inflammation of lung tissue [1]. Whilst two anti-fibrotic drugs, nintedanib and pirfenidone, slow 
the deterioration of progressive fibrotic ILD by approximately 50%, they have minimal impact on 
common characteristics of ILD such as worsening breathlessness, cough, impaired exercise 
tolerance, and poor health-related quality of life (HRQoL) [2-4]. Based on the seminal study 
conducted by the Centre of Research Excellence in collaboration with consumer groups on ILD 
research priorities, patients emphasized the importance of a good quality of life (QoL). This 
included addressing key symptoms such as cough and fatigue, as well as answering the 
fundamental question: “What can make me feel better?”[5].  
 
Currently the cornerstone of ILD diagnosis and ongoing management is the multidisciplinary 
meeting (MDM).  During this meeting, attended by respiratory physicians, radiologists, 
pathologists +/- immunologists and rheumatologists, clinical cases are discussed, a diagnosis is 
provided, and management plan is suggested. This diagnosis and subsequent management are 
centered on the identification of patient underlying aetiology. The utility of this strategy is 
complex with significant heterogeneity within ILD subtypes, overlapping features and treatment 
approaches making this challenging. Furthermore, with up to 15% of ILD cases remaining 
unclassifiable, the potential benefit for a precision model in ILD is apparent [6].  
 
Treatable traits (TT) are a precision medicine approach developed and proposed for the 
management of obstructive airways diseases, including asthma. It has achieved global support 
including international guidelines for both Chronic Obstructive Pulmonary Disease (COPD) and 
severe asthma. Treatable traits are a model of care where a patient undergoes multidimensional 
assessment to identify clinically important and treatable problems (traits). A specific trait is 
defined as a ‘therapeutic target identified by phenotypes or endotypes through a validated 
biomarker’ [7]. In airways disease these traits fall into three domains: airway, behavioural/risk 
factor, and comorbidity (ABC). Clinical trials have demonstrated the effectiveness of the TT model 
in severe asthma and COPD. In a randomised controlled trial (RCT) of 55 patients the TT based 
intervention resulted in significant improvement in HRQoL (0.86 units, 95% CI 0.49-1.23) and 
improved asthma control (ACQ reduction of 0.72 (95% CI -1.25- -0.18) compared to standard care 
[8].  
 
 
For an ILD TT strategy the addition of a fourth domain has been proposed with the inclusion of 
aetiological traits. As such a TT model will target TTs across 4 domains: aetiological (e.g. 
inflammation, connective tissue disease), pulmonary (e.g. exertional hypoxia, cough) extra-
pulmonary (e.g. sarcopenia, anxiety/depression), and behavioural (e.g. smoking and physical 
inactivity) (Figure 1) [9]. ILD represents an ideal candidate for a TT mode of care. While airways 

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diseases are complex, chronic and have multiple inter-related factors this is even more so in ILD. 
ILDs have complex overlapping aetiologies, often multiple comorbidities, and significant symptom 
burden [10].   
 
A TT model of care differs from comprehensive care in several key aspects. The first is the 
cornerstone of management with the multidimensional assessment. In this process patients 
undergo intensive assessment to identify and subsequently manage traits in a methodical and 
detailed manner. The second is the early and intensive involvement of the multidisciplinary team 
with input from onset by specialised allied health members including physiotherapy, psychology, 
and dietetics. This is likely to improve targeting therapy of traits often overlooked including physical 
inactivity, malnutrition, fatigue, and sarcopenia.  
4. Study Objectives 
 
4.1. Hypotheses:  
 
Hypothesis 1: People with ILD who are provided with TTRILD multi-disciplinary team care will 
experience improved HRQoL (primary outcome), symptoms, anxiety, physical activity, and body 
composition (secondary outcomes). 
 
Hypothesis 2: TTRILD MDT care will be a cost-effective intervention compared to standard care, 
from a societal perspective. 
 
4.2. Study Aims  
 
Aim 1. To compare the clinical efficacy of a TTRILD MDT clinic versus standard care in people 
with ILD.  
 
Aim 2. To compare the cost-effectiveness of TTRILD MDT clinic versus standard care in people 
with ILD.  
 
Aim 3. To establish the prevalence of pre-defined treatable traits. 
 
Aim 4. To identify cellular, molecular, and genetic TT in ILD for future improved management.   
 
4.3. Outcome measures 
 
Primary outcome:  
The primary outcome of this trial is the absolute change in HRQoL at 6 months as measured using 
the King’s Brief questionnaire (K-BILD). The K-BILD questionnaire is a brief, validated 15-item, ILD-
specific HRQoL questionnaire assessing psychological well-being, breathlessness, activity 

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limitations, and chest symptoms [11]. It is widely used as an endpoint in international clinical 
trials.  
 
Secondary outcomes:  
 
(i) Further HRQoL assessment.  
Change in European QoL 5-Dimensions 5-Levels questionnaire (EQ-5D-5L) score at 6 months 
compared to baseline. The EQ-5D-5L questionnaire is a multidimensional patient-reported 
questionnaire that supports calculation of quality-adjusted life years [11]. The KB-ILD will also be 
measured at 3 months.  
 
(ii) Dyspnoea 
Measured using the Dyspnea-12, a simple scale (0-3) validated in fibrotic ILD (fILD) patients, which 
comprises the physical and affective components of dyspnoea [12].  
 
(iii) Anxiety and depression:  
Evaluated using the Hospital Anxiety and Depression Scale (HADS) which is validated to identify 
psychological distress. It has been shown to demonstrate increased rates of anxiety and 
depression in patients with ILD [13].  
  
(iv) Physical activity levels: 
1. Patient self-reporting of physical activity will be undertaken with the International Physical 
Activity Questionnaire (IPAQ), a 7-item questionnaire that includes open-ended questions 
around the participants last 7-day recall of physical activity [13]. This will be assessed at 3- 
and 6-months and will be compared to baseline.  
2. 6-minute walk test (6MWT). Walk distance from 6MWT at 3 and 6 months will be compared 
to baseline. 
 
(iv) Muscle mass and body composition:  
Patients will have their regional and whole-body lean mass and fat mass be assessed using whole-
body dual-energy X-ray absorptiometry (DEXA) scans at 6 months compared to baseline. Dual-
Energy X-Ray Absorptiometry is a gold standard measure of body composition providing reliable 
and accurate measures of body composition. It has been promoted by the European Society for 
Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) as a clinical trial 
secondary endpoint in sarcopenia research to identify increase in muscle mass [14]. 
 
(v) Lung function decline and mortality measures:  
Forced vital capacity (FVC) decline. A cut-off of 10% reduction in FVC will be recognised as 
significant FVC decline [15].  
Progression free survival: Time to progression, transplant, or death. Progression defined as a 
relative decline in either FVC of ≥10% or DLCO ≥15% [15]  
All-cause hospitalisation and mortality 
 
 

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(vi) Economic evaluation: A comparison of per person direct (health system and all patient 
expenses) and indirect (lost productivity) costs will be performed for the TTRILD program versus 
standard care.  
Direct costs will include staff time; visits to the GP, specialist or emergency room; hospitalisation; 
and use of chronic disease services including pulmonary rehabilitation, nursing and allied health 
services. Patient expenses include transportation and parking costs, co-payments for medications 
and consultations, and costs of equipment and household adaptations.  
 
Indirect costs associated with productivity losses include absenteeism and presenteeism 
(decreased productivity due to working whilst ill) of the participant and household members. 
Data will be drawn from hospital records, Medicare Benefits Scheme (MBS) and Pharmaceutical 
Benefits Scheme (PBS) data using data linkage, with linkage already approved between these and 
the Australian ILD Registry, and patient-completed cost diaries.  
 
Costs will be ascertained at baseline for the 6 months prior to trial entry, then during the trial 
period at 3- and 6-months for each treatment arm. We will perform an incremental cost-
effectiveness analysis to compare differences in total costs in each treatment arm divided by 
differences in quality-adjusted life years (calculated from EQ-5D-5L utility scores and survival). An 
additional incremental cost-effectiveness ratio will be calculated based on incremental costs per 
hospitalisation avoided. 
 
(vii) To establish the prevalence of pre-defined treatable traits. This will look at overall prevalence 
of traits at time of recruitment. This prevalence will be further assessed to understand inter-
relationships and patterns of clustering and co-occurrence. The relationship between traits and 
QOL (defined by K-BILD) and disease severity (defined by FVC) will also be assessed.  
 
5. Data Collection and Assessments:  
Baseline investigations and questionnaires for each participant will be undertaken prior to their 
initial clinic appointment as part of a multidimensional assessment.   
At the time of consent, patients will be enabled to complete their online REDCAP survey which 
will include information, such as demographics, comorbidities, medications, and exposure 
history, and the questionnaires. If it is patient preference to not complete these questionnaires 
virtually, physical questionnaires can be provided in a booked clinic with a research nurse. At this 
time demographics, comorbidities, medications, and exposure history will be input by the 
research nurse directly into REDCAP with permission by the patient.  
A research nurse will also review electronic medical records and input ILD MDT records and 
ensure correlation of comorbidities.  
Questionnaires to be undertaken at baseline, 3- and 6-months are:  

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• K-BILD – HRQOL assessment 
• Leister Cough questionnaire – assessment of cough 
• Stop bang questionnaire – screening tool for OSA  
• Dyspnea-12 – evaluation of breathlessness 
• Fatigue (FSS) – fatigue screening tool 
• Patient-Generated Subjective Global Assessment Short Form (PGSGA-SF) – questionnaire 
used to determine nutritional status 
• Perceived Stress Scale (PSS) – Validated tool to determine patient well-being in response 
to stress 
• Anorexia Cachexia Scale (ACS) – Measures appetite and body perception 
• SARC-F – simplified sarcopenia functional assessment tool  
• EQ-5D-5L questionnaire – QoL measure to support economic analysis  
• International Physical Activity Questionnaire – simple screening tool for inactivity 
• HADS – Identifies psychological distress. 
 
 
An initial cost diary (Appendix 16) will be undertaken as a summary of costs over the last 6 
months. Interval cost diary updates will also be performed at 3- and 6-months.  
Initial investigations to be performed include baseline blood and sputum samples, pulmonary 
function testing, 6MWT, 1STST, whole-body DEXA scan, and High-Resolution Computed 
Topography (HRCT) of the chest. If a HRCT Chest has been undertaken within the last 12 months 
this will be used as the initial screening HRCT.  
 
Blood tests performed will include FBC, UEC, CRP, LFT, CMP, ANA, ENA, ANCA, ESR, CK, myositis 
panel, avian, precipitans, and vitamin D. If bloods have been performed within the last 12 months 
these will not be repeated.  
 
Table 1 Assessments at each timepoint (Control and Intervention groups) 
 
Baseline 
3 month 
6 months  
Questionnaires 
+ 
+ 
+ 
Demographics 
+ 
 
 
PFTs 
+ 
+ 
+ 
6MWT 
+ 
 
+ 
1-min STS test 
+ 
 
+ 
Bloods 
+ 
 
 

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Sputum 
+ 
 
 
DEXA 
+ 
 
+ 
HRCT 
+ 
 
 
Cost diary  
+ 
+ 
+ 
All-cause hospitalisation / 
ED visits  
+ 
+ 
+ 
 
6. Study Design 
 
6.1. Study type and Design  
 
This study will be a randomised controlled trial with an embedded economic evaluation among 
110 patients with fibrotic ILD. Blinding of participants and personnel is not possible due to the 
nature of the intervention. Blinding of outcome assessor for the primary outcome is not possible 
due to the nature of the primary outcome measure (questionnaire completed by the participant 
who is not blind to group allocation).  
 
The trial will be conducted at Fiona Stanley Hospital in Western Australia with utilisation of 
research areas in Harry Perkins Institute of Medical Research. Patients will be recruited from ILD 
clinics in both South and North Metropolitan Health Services. Participants will be randomised 1:1 
into two groups. Group 1 will be the intervention group where participants will attend an TTRILD 
MDT clinic at Fiona Stanley Hospital, where treatable traits will be identified and targeted 
multidisciplinary interventions will be employed. These interventions will be administered by (a) 
a physiotherapist, with pulmonary rehabilitation, goal setting, or home strength training, (b) a 
dietitian with dietary counselling, oral nutritional supplements, and (c) a psychologist with self-
management techniques. Physician-led treatment will prioritise the management of identified 
traits as specified in Table 2 in accordance with international treatment guidelines. These will 
remain at the discretion of the treating respiratory physician for the intervention group. Group 2 
will be the control group and will receive the usual standard of care via their ILD clinics. There will 
be no limitation in referral for multidisciplinary assessment and management. 
 
 
6.2. Eligibility Criteria:  
 
Inclusion Criteria: Patients with a new or pre-existing diagnosis of fibrotic ILD who receive care 
via the Fiona Stanley Hospital (FSH) or Sir Charles Gairdner Hospital (SCGH) ILD service will be 
invited to participate. This ILD diagnosis must be made through an ILD MDT.  
 

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Included participants will be aged ≥ 18 years with a physician-confirmed diagnosis of fibrotic ILD. 
Fibrotic ILD is defined as presence of fibrotic changes on CT in the opinion of the investigator. All 
ILD subtypes, excluding sarcoidosis, will be included. Participants will need to be able to provide 
consent to participate and be established on stable ILD treatment for 1 month prior to study 
initiation.  
 
Exclusion Criteria: Participants will be excluded if they have experienced an acute exacerbation 4 
weeks prior to starting the study or are expected to experience either a transplant or death during 
the study period. Active suicidality, severe depression, active psychosis or mania, or other severe 
psychiatric concerns that require more intensive treatment. Any such participants could be 
referred for individual therapy and/or psychiatric treatment that would be more appropriate for 
their needs.  
 
 
6.3. Recruitment and Consent:  
 
Participants who meet the eligibility criteria will be approached by a member of the research 
team with the purpose of introducing the study and providing a study flyer (Appendix 18). If the 
participant expresses interest in joining the study further discussion with research coordinator 
will be undertaken via phone. The names and contact details of potential participants will be 
documented using a password-protected file stored on a secured network (Microsoft Teams). This 
will only be accessible to members of the research team and the study coordinator will be advised 
about new participant added to this list via email.  
  
Participants indicating an interest in participating will be provided with a Participant Consent and 
Information Form (PCIF) (Appendix 1 with Withdrawal Form 2b) either in person at the study site 
or via email/mail depending on their preference. Participants will be given at least 24 hours to 
read the PCIF and an opportunity to ask questions and discuss the study with their healthcare 
team and/or family before completing the consent form. If they wish to enrol, participants will be 
able to complete an online consent via the REDCAP link which will then proceed to the 
questionnaires. If patient prefers to do this in person, they can have this conducted on a written 
consent form during the screening clinic prior to initiating baseline investigations.  
 
In addition, individuals enrolled in the Australasian ILD Registry may consent to be contacted 
about future research or clinical trials at the time of enrolment. A cover letter (Appendix 1a) 
introducing the study and study flyer (Appendix 1) will be sent by mail or email to Australasian 
ILD Registry participants who are eligible for TTRILD, with instructions on how to contact the 
relevant site if they are interested in participating.  
 

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6.4. Randomisation and Stratification:  
Participants will be randomised via an online randomisation system in a 1:1 fashion to 
intervention or control group. Participants will be stratified by i) severity of FVC: mild (FVC 
predicted >80%), moderate (FVC predicted 50-80%) and severe (FVC predicted <50%). and ii) type 
of ILD: IPF and non-IPF with a limit of 50% IPF.   
Figure 1. Recruitment flow chart and assessment/ procedure timeline 
 

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7. Interventions 
 
This trial will aim to highlight that the targeted multidisciplinary treatment of TTs will improve 
patient outcomes, particularly quality of life.  
 
7.1. Multidimensional assessment  
 
Both groups will undergo an intensive multidimensional assessment as has been established in 
other chronic lung diseases including asthma [8,16] 
 
This assessment will aim to identify the following traits as outlined in Table 2 with the following 
identification markers.  
 
The results of this assessment will be correlated by the research nurse/ case manager and for the 
interventional team be provided within the TT patient management plan (Appendix 2). All 
investigations that are performed as standard of care will be provided to the standard of care 
treating clinical team. This includes HRCT Chest, lung function, 6MWT, 1-min STS test and bloods.  
 
Results of the DEXA scan will be provided to the treating clinician for control group if evidence of 
osteoporosis is identified. Patients that have an increased STOP-BANG and HADS scores will also 
be highlighted to treating physician.  
 
Table 2. Summary of treatable traits with their diagnostic tools and intervention. Appendix 2 
provides further details. 
 
Treatable Trait 
 
Diagnostic definition 
Intervention  
Aetiological traits: 
Pulmonary inflammation 
MDM consensus of inflammation 
utilising HRCT pattern, BAL, 
histopathology 
Consider immunosuppression 
Connective Tissue Disease  
Clinical diagnosis based on 
clinical features, CTD diagnosis, 
radiological features, serology 
[17].  
Consider rheumatology/ 
immunology input. 
Consider immunosuppression 
Drug Exposure  
Medication history – exposure of 
potentially causative drug as 
defined on pneumotox.com[18] 
 
Withdrawal of causative agent as 
appropriate  
Consider glucocorticoids if 
indicated 
Environmental exposures  
History of exposure to 
hypersensitivity-type or 
occupational exposures.  
Antigen avoidance 
Consider immunosuppression  

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Genetics 
Specialised testing: Telomere 
length, Whole genome 
sequencing  
Genetic counselling 
Discussion at national genetics 
ILD MDT 
Augmenting of 
immunosuppression if required  
Early transplant referral  
Pulmonary Traits: 
Progressive Pulmonary Fibrosis 
ATS/ERS/JRS/ALAT guidelines,  
Two or more of: 
(a) worsening respiratory 
symptoms 
(b) physiological deterioration 
with absolute decline in FVC% 
predicted ≥5% or decline in 
DLCO% predicted of ≥10% or  
(c) radiological progression over 
one year with no alternative 
explanation [19] 
Anti-fibrotics as per 
pharmaceuticals benefit scheme 
guidelines Australia [20] 
Emphysema 
HRCT Chest: emphysema ⩾10-
15% of total lung volume in the 
setting of fibrosis[21] 
+/- Spirometry FEV1/FVC < LLN 
Consider bronchodilator if 
obstructive spirometry 
Pulmonary Hypertension 
Transthoracic echocardiogram: 
TR jet velocity of >2.8 m/s ≈ 
mPAP ≥35 mmHg [22] 
 
Consider right heart catheter, 
referral to PH specialist centre 
and PH-specific therapies  
Resting hypoxia 
Baseline Sats O2 ≤ 88% and  
ABG PaO2 <60 mmHg with PH or 
<56mmHg [23] 
Long term oxygen therapy as per 
international guidelines [24] 
Exertional Hypoxia 
6MWT nadir Sats ≤ 88% [25] 
Consider titrated exertional 
oxygen prescription (titration 
performed by physiotherapy)  
Nocturnal Hypoxia 
Overnight oximetry/ 
polysomnography: Overnight 
oximetry >10% of total sleep 
time with SpO2 <90% 
(TST90)[26] 
 
Consider nocturnal oxygen 
prescription 
Obstructive Sleep Apnoea (OSA)  
STOP-BANG questionnaire score: 
3-4 (intermediate risk), 5-8 (high 
risk) 
Polysomnography evidence of 
OSA 
Referral for CPAP/ mandibular 
splint 

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Chronic Cough  
Clinical history of chronic cough 
Leicester cough questionnaire 
score of <17.68 [27,28]  
Address co-contributing drivers:  
- 
GORD: Treat if symptomatic 
with standard dose PPI 
- 
Postnasal drip: intranasal 
antihistamines/ intranasal 
steroids  
- 
VCD/ ILO: psychological 
counselling, speech therapy 
Cough suppression – speech 
pathology techniques, consider 
neuromodulators.  
 
Chronic Dyspnoea 
History of breathlessness 
Dyspnea-12 questionnaire with 
mild + dyspnoea symptoms 
Airflow – Handheld fan 
Pulmonary rehabilitation  
Consider opioids 
Extra-pulmonary traits: 
Peripheral muscle dysfunction  
 
1STST of < 20 repetitions 
Physiotherapy:  
Home based exercise 
prescription 
Exercise Intolerance 
6MWT <350m 
 
Physiotherapy:  
Pulmonary rehabilitation 
Sarcopenia 
1STS < 20 repetitions and  
DEXA demonstrating low muscle 
mass [29] 
SARC-F questionnaire [30] 
Physiotherapy:  
Home based exercise 
prescription. 
Dietitian:  
If borderline intake for high 
protein diet 
If poor intake for high protein 
diet + protein supplementation 
 
Frailty  
1STST < 20 repetitions and 
physician-judged clinical frailty 
scale (CFS) score of ≥ 4 [31].  
Physiotherapy:  
Pulmonary rehabilitation 
Osteoporosis  
Clinical history of low trauma 
fracture 
DEXA scan: T-score ≤ -2.5  
 
Dietary recommendations 
Supplements – calcium and 
vitamin D 
Consider Anti-resorptive therapy 
Poor Appetite and Malnutrition 
Poor appetite:  
Anorexia Cachexia Scale Score ≤ 
37 
Malnutrition: 
Dietitian:  
With borderline intake – small, 
frequent meals and snacks 
 
With poor intake – Small 
frequent meals and snacks,  

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Patient-Generated Subjective 
Global Assessment Short Form ≥ 
4 and/ or  
BMI < 18.5 
Nourishing drinks/ Oral 
nutritional supplements 
Anxiety and Depression features 
Hospital Anxiety and Depression 
(HADS) score of 7-10 (borderline) 
HADS ≥ 11 (significant) [13]  
and/or  
Perceived Stress Scale (PSS) ≥ 14 
[32].  
 
Psychology:  
Referral to self-help, treatment 
in Mindfulness-Based Stress 
Reduction, or GP referral for 
individual treatment 
Fatigue  
Fatigue Severity Scale (FSS) ≥ 36  
 
Physiotherapy:  
Graded exercise program  
Behavioural traits:  
Polypharmacy  
Medication list ≥ 5 regular 
medications   
Medication rationalisation 
Smoking  
History of smoking 
 
Smoking cessation: quitline 
referral, consider pharmaceutical 
cessation treatments 
Physical Inactivity 
International Physical Activity 
Questionnaire (IPAQ) categories 
1 (inactive) or 2 (minimally 
active)   
 
Physiotherapy:  
Goal setting with pedometer 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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7.2 Intervention group:  
 
Figure 2. Core aspects of the MDT intervention  
 
 
Baseline clinic visit  
 
Physiotherapist:  
This initial evaluation will involve a clinical assessment and review of pertinent investigations 
including 6MWT, PFTs, 1STST, and IPAQ. Based on clinical assessment and presence of treatable 
traits identified, including exercise intolerance, physical inactivity, sarcopenia, and frailty, patients 
will be offered a management plan that may include goal setting with a pedometer, pulmonary 
rehabilitation, and/or a home exercise program (see below for further details). Education will be 
provided at this time.  
 
 
Dietitian:  
This initial evaluation will involve a clinical assessment including discussion regarding patient diet 
and review of pertinent investigations including BMI, PGSGA-SF, and ACS. Based on clinical 

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assessment and presence of treatable traits identified, including malnutrition, sarcopenia, and 
frailty, patients will be offered a management plan that may include a dietary plan and/or oral 
nutritional supplements (see below for further details). Dietary counselling will be provided at 
this time.  
 
Psychologist:  
This initial evaluation will involve a psychological interview and review of pertinent investigations 
including HADS and PSS. Based on clinical assessment and presence of treatable traits identified 
(specifically anxiety and depression traits), participants will be offered a targeted management 
plan. Options for this will include patient self-management resources, MBSR administered via the 
study, or referral to GP for individual psychology/psychiatry treatment.  At this assessment a risk 
assessment will be performed. Any patient that is identified to be a concern for psychological 
safety will be referred on to the treating physician for consideration of psychiatric discussion and 
evaluation.  
 
Physician:  
This initial evaluation will involve a clinical assessment and review of pertinent investigations 
including 6MWT, PFTs, HRCT, and questionnaire data. Based on clinical assessment and presence 
of treatable traits that will be documented on patient management plan, the treating physician 
will offer therapies as per standard of care and international guidelines. Standard ILD therapies 
that include anti-fibrotics and immunosuppression will be offered as per standard care. There will 
be a specific focus on the identification and treatment of the additional TTs that include 
aetiological traits (drugs, exposures), pulmonary (cough, dyspnoea, exercise intolerance), extra-
pulmonary traits (reflux and anxiety/depression) and behavioural traits (physical inactivity, 
smoking).  
 
The post clinic-MDT  
Immediately post the initial clinic review an MDT meeting will be undertaken for approx. 60 
minutes. This will involve discussion of all patients seen in the initial clinic. Documentation will be 
via the patient management document and discussion will include ensuring agreement across 
MDT on presence of traits and the strategy to move forward. It is estimated each patient will 
require 15-20 minutes of discussion.   
 
2-week telehealth clinic  
 
Physiotherapist: 
For those patients undertaking goal setting with pedometer a 2-week review will be coordinated 
to review exercise diary and provide goal setting.  
 
Dietitian:  
A review to assess intervention tolerance and provide feedback/alternatives as required.  
 
Psychologist:  

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After discussion between the psychology team and at MDT, a decision will be made regarding 
offered therapies, including MBSR. This phone review will be an update to confirm intervention 
offered and answer any questions or concerns from patients.  
 
4-week telehealth clinic:  
Dietitian:  
A review to assess intervention tolerance and provide feedback/alternatives as required.  
 
3-month and 6-month clinics:  
 
Physiotherapist:  
This clinic review will involve a clinical assessment and review of further investigations including 
repeat 1STST and IPAQ. An assessment of progress regarding interventions offered will be 
performed and education provided.   
 
 
Dietitian:  
This clinic review will involve a clinical assessment and review of further investigations including 
repeat ACS and PGSGA-SF. An assessment of progress regarding interventions offered will be 
performed and education provided.   
 
 
Physician:  
This review will include clinical assessment regarding treatments to date, and patient status. 
Second line therapies of specific traits may be offered or considered. Review of investigations will 
be performed.  
 
 
7.3. Specific interventions:  
 
Pulmonary rehabilitation:  
For patients with evidence of exercise intolerance and/ or frailty pulmonary rehabilitation will be 
offered. This is an 8-week program that involves twice weekly 1 hour program. This will be an 
individually tailored exercise program, which may consist of warmups exercises, stretches, 
endurance exercises such corridor walking, incline walking on a treadmill, cycling, functional 
strengthening exercises such as sit to stands, step ups or calf raises. Upper limb endurance and 
strengthening exercises are incorporated with patient specific weights. Each patient program 
considers their goals and any musculoskeletal limitations they may have. All patients record their 
exercises on their own exercise log to enable monitoring of progress. Patients receive a written 
home exercise program once they have an established gym program, usually given out in session 
3 or 4.  See appendix 16 for further details.  
 
 

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Home exercise program:  
This will be planned between the participant and the treating physiotherapist. This will be in line 
with the lung foundation resource ‘Better living with exercise’ (Appendix 17). To enable an 
individualised plan the following questions will be asked and discussed with the participant (1) 
What are your exercise options? (2) What is important to you? (3) What is your SMART (specific 
measurable attractive realistic time-framed) plan? (4) What else needs to be considered?  
 
Goal setting and pedometer:  
 
In patients where physical inactivity is identified as a trait a personal pedometer will be provided. 
Participants will then be asked to diarise their daily step count during the first week. At the 2-
week physiotherapy phone review participant and physiotherapist can set the goals which will be 
further reviewed and managed at the 3-month clinic appointment.  
 
Dietitian counselling and education:  
Depending on patient appetite, intake, and presence of sarcopenia guidelines regarding meals 
and diet will be provided by dietitian as per table 4.  
 
 
 
 
 
 

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Initial Dietary Counselling Session – Poor Appetite and Malnutrition 
 
 
 
 
Follow up Dietary Counselling Session – Poor Appetite and Malnutrition 
 

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Oral nutritional supplements:  
Nutritional supplements will be recommended for those patients recognised to have the 
nutritional disorders that include frailty, sarcopenia, and malnutrition.  
 
For patients identified to have sarcopenia, treatment will focus on achieving adequate protein 
intake through dietary counselling. If adequate protein intake cannot be achieved through dietary 
intake alone, then a protein powder will be recommended. A whey protein isolate product, such 
as Bulk Nutrients WPI, is recommended in the first instance. A plant-based protein powder, such 
as Bulk Nutrients Earth Protein, can be recommended if the patient does not consume milk or 
animal products.  
 
Patients with frailty and malnutrition will have treatment to prioritise adequate calories and 
protein through dietary counselling. If adequate calorie and protein intake cannot be achieved 
through dietary intake alone, then an oral nutrition supplement will be recommended. A 
nutritionally complete and balanced powdered nutritional supplement, such as Sustagen Hospital 
Formula or Ensure Powder, is recommended in the first instance, and can be recommended one 
to three times daily to meet the deficit in calorie and protein intake. A plant-based protein 
powder, such as Bulk Nutrients Earth Protein, can be recommended if the patient does not 
consume milk or animal products. Patients with severe malnutrition or very poor oral intake (i.e., 
meeting <25% energy requirements with food) may require a nutritional supplement with higher 
calorie density, such as Resource 2.0, Fresubin 2.0 or Fortisip Compact Protein.  
 
 
Self-management psychology plan:  
 
Patients who have been identified to have low symptom burden will be supported through a self-
management plan. Specifically, they will be referred to the “Stress Management Program” 
created by This Way Up (https://thiswayup.org.au/programs/stress-management-program/), 
which is a freely available, online, on-demand program based on cognitive-behavioural therapy 
principles. 
 
 
GP referral for individual mental health treatment: 
 
For patients with moderate-severe psychological symptoms and/or at high risk for self-harm or 
suicide not identified at time of screening, we will contact their attending doctor to liaise with 
their GP to discuss a mental health treatment plan that includes psychology and/or psychiatry 
treatment as needed.   
 
 
Genetics assessment 
 
All patients within the intervention arm will be screened for genetic abnormalities variants known 
to contribute to inherited forms of ILD. This will include a detailed family history. Blood samples 

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will be sent to the Institute of Respiratory Health (IRH) for Flow-FISH (fluorescence in-situ 
hybridization) to determine telomere length. Blood/DNA samples will also be sent to Prof. Jo 
Dickinson at the University of Tasmania for whole genome sequencing and analysis to identify 
rare variants in genes previously associated with ILDs. Those variants classified as likely 
pathogenic/pathogenic variants (LP/P) according to the American College of Medical Genetics 
(ACMG) guidelines will be considered ‘positive’.  Variants of ‘unknown’ significance will be noted. 
Participants with a positive pathogenic variant (LP/P) will be referred to local geneticist by the 
treating physician for National Association of Testing Authorities (NATA) accredited testing and 
consultation with a clinical geneticist that will include pre- and post-genetic counselling. Patients 
may elect to not receive their genetic results.  
 
Circulatory Biomarkers 
 
We will use circulatory biomarkers with methods including proteomics, metabolomics, 
transcriptomics, EV analysis and scRNA sequence. These biomarkers will be used to try an identify 
the presence of biomarker signatures that can predict response to treatment that would help is 
predict a patient ‘fingerprint’ that would help us select treatment options.  
 
Telomeres 
 
FISH flow will be done on all blood samples from the intervention group to determine if shorter 
telomeres influence the outcomes in all ILD patients. Mechanisms of shortening to endotype 
patients will be done.  
 
Microbiome 
 
Prog. Phil Hansbro will undertake microbiome analysis of available sputum samples to better 
phenotype the microbiome of ILD and t determine if intervention in dysbiosis will improve 
outcomes for ILD patients.  
 
Personalised Treatment:  
 
We will analyse scRNAseq to determine if we can identify treatment targets for individual patients 
using bioinformatic clustering.  
7.4. Control group:  
 
All participants within the control group will receive baseline assessments as per the intervention 
group. This includes a 1STS test performed by a research nurse at baseline and at 3- and 6-month 
clinic appointments. Physician review will be as per standard of care including treatment of 
underlying ILD and consideration of comorbidity management.   
 

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8. Feasibility  
 
There are currently over 500 patients with fibrotic ILD receiving care at Fiona Stanley Hospital 
with an estimated 200 new patients to the ILD service per year. If 30% of these provide consent, 
which is in line with prior clinical experience in this service, a recruitment goal of 20 participants 
per quarter is achievable, resulting in the completion of recruitment within 18 months.  
 
If inadequate recruitment is achieved by the first quarter of 20, recruitment will be expanded to 
ILD patients receiving care at Sir Charles Gairdner Hospital.  
9. Participant Safety and Withdrawal 
 
9.1. Risk management and safety  
Data privacy and confidentiality considerations are protected by the University of Western 
Australia Information and Communications Technology procedures.  A Data Safety and 
Management Board (DSMB), consisting of external experts in the field and consumer 
representatives, will meet quarterly to review study progress and patient data safety to ensure 
protection. This DSMB will be include Prof. Vanessa McDonald, Prof Haydn Walters and Prof. 
Geoff Stewart. A consumer advocacy group made of 3 independent ILD patients will review trial 
protocol and best practice document and provide feedback. They will also meet with researchers 
at 6 months to discuss progress.  
 
9.2. Handling of withdrawals 
 
If a patient withdraws from the study, a member of the research team will discuss any concerns 
or issues linked to withdrawing. No further personal information will be collected from the 
participant from this time. Personal information already collected will be retained to ensure the 
results of the project can be measured properly. Participants will be informed that data collected 
up to the time of withdrawal will form part of the study results. If the participant is unhappy with 
this, the research team will be advised immediately.   
 
 
9.3. Replacements  
 
No withdrawn participants will be replaced in the study. If a participant agrees, they can 
undertake the remaining assessments to reduce the impact of study analysis and meet the 
intention-to-treat requirements.  
 

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10.  Statistical methods  
 
10.1. Sample size calculation  
Previous work in pulmonary rehabilitation and interstitial lung disease has demonstrated a 
minimum clinically important difference (MCID) of 4.2 (95% CI 3.0 to 5.3) point change in total 
score of the K-BILD following the intervention. Based on that data, we anticipate a between-
group difference of 4.2 points favouring the experimental group, which will receive 
multidisciplinary management of their treatable traits. With an α of 0.05 and 90% power, and 
accounting for a 15% expected attrition, the target sample size will be 110 participants.  
 
10.2. Statistical Methods  
 
All data will be analysed using an intention-to-treat approach. Descriptive statistics, such as mean 
and standard deviation (or median and interquartile range); and frequency and percentage, will 
be calculated to compare the patient demographic and clinical characteristics between the (i) the 
intervention group (TTRILD MDT care) vs. (ii) the control group (standard care). 
Generalised linear mixed model and Cox regression will be performed to evaluate the efficacy of 
the intervention on the primary and secondary outcomes, whilst adjusting for relevant 
covariates. Subgroup analyses will compare the effects by: types of ILD, severity of the disease, 
and types of personalised program (sarcopenia, loss of appetite, anxiety, cough). All analyses will 
be performed using Stata MP/18 (StataCorp, Texas). All statistics analysis will be performed with 
supervision and oversight by an experienced biostatistician.  
One-way repeated measures analysis of variance (ANOVA) will be performed to assess the main 
effects of group (two levels) and time (three levels), and the interaction effect between group 
and time. This will provide an overall understanding of whether the TTRILD intervention has met 
the primary outcome of a 6-month increase in HRQoL (K-BILD).  
The prevalence of each TT will be defined including number of TTs per participant with median 
and interquartile range (IQRR). Cluster analysis with k-mean clustering will be used to identify 
patterns of TTs within cohort and assess which traits tend to co-occur. To assess relationship 
between treatable traits and FVC (as a surrogate for ILD severity) we will use univariable 
regression analysis for each TT and multivariable logistic regression analysis with FVC as outcome. 
To assess relationship between treatable traits and QOL (using KB-ILD) will use univariable and 
multivariable logistic regression analysis with KB-ILD score as outcome. 
11. STORAGE OF BLOOD AND TISSUE SAMPLING  
 

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Blood samples will initially be stored securely at Harry Perkins Level2 University of Western 
Australia (UWA) Freezer (adjacent to Fiona Stanley Hospital).  The nurse will take the samples, 
they will be de-identified, processed in the lab, and then stored before being transported via 
courier to the laboratory of the Institute of Respiratory Health, UWA for analysis. Coded DNA 
samples will be sent to Professor Jo Dickinson’s laboratory for whole genome sequencing. Data 
will be entered into a secure online database against the patient unique code. No identifiable 
information will be entered into the secure online database. Information obtained for this 
research project will be treated as confidential and securely stored with the option for future use. 
If a patient does not consent for future use, samples will be destroyed after a period of 10 years. 
 
12. DATA STORAGE AND HANDLING  
 
Written information including patient management documents, paper questionnaires, and 
printed results will be stored in a locked filing cabinet within a locked office at Happy Perkins 
Institute. Only the named researchers will have access to the information.  
 
All other data will be input directly to the secure UWA REDCAP database. Trial data will be stored 
securely on the UWA Redcap data base and archived for a period of 15 years as per SMHS data 
management policy.  Access to participant data will be password protected and available only to 
the trial researchers. If at some stage in the future, the ethics committee deems storage is no 
longer required, then data will be deleted.  
 
13. List of Appendices  
 
Document name  
Page 
of 
Supplementary 
document 
1. Patient Consent and Information Document with withdrawal 
form  
1 - 13 
2. Patient management document 
 
14 - 50 
4. Kings Brief Interstitial Lung Disease Questionnaire  
51 - 53 
5. Leister Cough questionnaire 
 
54 
6. STOP BANG questionnaire 
 
55, 56 
7. Dyspnea-12 questionnaire 
 
57 
8. Fatigue Severity Scale  
 
58 

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9. Patient-Generated Subjective Global Assessment Short Form 
(PGSGA-SF) 
 
59, 60 
10. Anorexia Cachexia Scale (ACS) 
 
61 - 63 
11. Perceived Stress Scale (PSS) 
 
65, 66 
12. EQ-5D-5L questionnaire 
 
67, 68 
13. International Physical Activity Questionnaire (IPAQ)  
69, 70 
14. Hospital Anxiety and Depression Scale (HADS)  
 71 
15. SARC-F  questionnaire 
72 
16. Trial Cost Diary  
73 - 127 
17. Pulmonary rehabilitation material 
128 - 129 
18. Living Better with Exercise 
130 - 166 
 
 
 
14. References 
 
 
 
[1] 
Travis WD, Costabel U, Hansell DM, et al. An official American Thoracic Society/European 
Respiratory Society statement: Update of the international multidisciplinary 
classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 2013 
Sep 15;188(6):733-48. 
[2] 
Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic 
pulmonary fibrosis. N Engl J Med. 2014 May 29;370(22):2071-82. 
[3] 
Wells AU, Flaherty KR, Brown KK, et al. Nintedanib in patients with progressive fibrosing 
interstitial lung diseases-subgroup analyses by interstitial lung disease diagnosis in the 
INBUILD trial: a randomised, double-blind, placebo-controlled, parallel-group trial. 
Lancet Respir Med. 2020 May;8(5):453-460. 
[4] 
Behr J, Prasse A, Kreuter M, et al. Pirfenidone in patients with progressive fibrotic 
interstitial lung diseases other than idiopathic pulmonary fibrosis (RELIEF): a double-

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blind, randomised, placebo-controlled, phase 2b trial. Lancet Respir Med. 2021 
May;9(5):476-486. 
[5] 
Tikellis G, Tong A, Lee JYT, et al. Top 10 research priorities for people living with 
pulmonary fibrosis, their caregivers, healthcare professionals and researchers. Thorax. 
2021 Jun;76(6):575-581. 
[6] 
Ryerson CJ, Urbania TH, Richeldi L, et al. Prevalence and prognosis of unclassifiable 
interstitial lung disease. Eur Respir J. 2013 Sep;42(3):750-7. 
[7] 
Agusti A. The path to personalised medicine in COPD. Thorax. 2014 Sep;69(9):857-64. 
[8] 
McDonald VM, Clark VL, Cordova-Rivera L, et al. Targeting treatable traits in severe 
asthma: a randomised controlled trial. Eur Respir J. 2020 Mar;55(3). 
[9] 
Khor YH, Cottin V, Holland AE, et al. Treatable traits: a comprehensive precision medicine 
approach in interstitial lung disease. Eur Respir J. 2023 Jul;62(1). 
[10] 
Amati F, Spagnolo P, Oldham JM, et al. Treatable traits in interstitial lung diseases: a call 
to action. Lancet Respir Med. 2023 Feb;11(2):125-128. 
[11] 
Cox IA, Borchers Arriagada N, de Graaff B, et al. Health-related quality of life of patients 
with idiopathic pulmonary fibrosis: a systematic review and meta-analysis. Eur Respir 
Rev. 2020 Dec 31;29(158). 
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