The Effectiveness and Risks of Treating People With Idiopathic Pulmonary Fibrosis With the Addition of Lansoprazole: a Randomised Placebo-controlled Multi-centre Clinical Trial
Phase: PHASE3
Conditions: Idiopathic Pulmonary Fibrosis
Sponsor: Norfolk and Norwich University Hospitals NHS Foundation Trust

 
 
 
 
 
TIPAL 
The effectiveness and risks of Treating people with Idiopathic 
Pulmonary fibrosis with the Addition of Lansoprazole (TIPAL): a 
randomised placebo-controlled multi-centre clinical trial 
Version 
2.4 
Date 
23/03/2023 
Sponsor 
Norfolk and Norwich University Hospitals NHS 
Foundation Trust 
Trial registration 
ISRCTN13526307 
CTA # 
2020-000041-14 
NRES # 
20/EE/0043 
 
Authorisation: Chief Investigator 
Name 
Professor Andrew Wilson 
Role 
Chief Investigator 
Signature 
[insert wet signature] 
Date 
[insert date] 
 
Authorisation: Sponsor  
Name 
[name of Sponsor Representative] 
Role 
Sponsor Representative 
Signature 
[insert wet signature] 

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Authorisation: CTU Director or Representative 
Name 
[name of CTU director or Representative] 
Role 
[Norwich CTU Director or role of Representative] 
Signature 
[insert wet signature] 
Date 
[insert date] 
 
Authorisation: Trial Statistician 
Name 
Dr Allan Clark 
Role 
Medical Statistician 
Signature 
Date 
[insert wet signature] 
[insert date] 
 
 

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Table of Contents 
1 
Administrative information ............................................................................................................. 8 
1.1 
Compliance ............................................................................................................................. 8 
1.2 
Sponsor ................................................................................................................................... 8 
1.3 
Structured trial summary ........................................................................................................ 9 
1.4 
Roles and responsibilities...................................................................................................... 14 
1.4.1 
Protocol contributors .................................................................................................... 14 
1.4.2 
Role of trial sponsor and funders .................................................................................. 16 
1.4.3 
Trial Team...................................................................................................................... 16 
1.4.4 
Trial Management Group .............................................................................................. 16 
1.4.5 
Trial Steering Committee .............................................................................................. 18 
1.4.6    Data Monitoring Committee ............................................................................................. 18 
2 
Trial Diagram ................................................................................................................................. 19 
3 
Abbreviations ................................................................................................................................ 20 
4  
Glossary ......................................................................................................................................... 21 
5 
Introduction .................................................................................................................................. 22 
5.1 
Background and Rationale .................................................................................................... 22 
5.1.1 
Explanation for choice of comparators ......................................................................... 24 
5.2 
Objectives.............................................................................................................................. 24 
5.3 
Trial Design ............................................................................................................................ 25 
5.3.1 Pilot Phase ............................................................................................................................ 25 
6 
 Methods ....................................................................................................................................... 26 
6.1 
Site Selection ......................................................................................................................... 26 
6.1.1 
Study Setting ................................................................................................................. 26 
6.1.2 
Site/Investigator Eligibility Criteria ............................................................................... 26 
6.1.2.1 
Principal Investigator’s (PI) Qualifications and Agreements ..................................... 27 
6.1.2.2 
Resourcing at site ...................................................................................................... 27 
6.2 
Site approval and activation ................................................................................................. 27 
6.3 
Participants ........................................................................................................................... 28 
6.3.1 
Eligibility Criteria ........................................................................................................... 28 
6.3.1.1 
Participant selection ................................................................................................. 28 
6.3.1.2 
Participant Inclusion Criteria ..................................................................................... 28 
6.3.1.3 
Participant Exclusion Criteria .................................................................................... 29 
6.3.1.4 
Eligibility criteria guidance ........................................................................................ 29 

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6.3.1.5 
Co-enrolment Guidance ............................................................................................ 30 
6.3.1.6 
Screening Procedures and Pre-randomisation Investigations .................................. 30 
6.4 
Interventions ......................................................................................................................... 31 
6.4.1 
Active treatment arm .................................................................................................... 31 
6.4.1.1 
Products .................................................................................................................... 31 
6.4.1.2 
Treatment Schedule .................................................................................................. 31 
6.4.1.3 
Dispensing ................................................................................................................. 31 
6.4.1.4 
Dose Modifications, Interruptions and Discontinuations ......................................... 31 
6.4.2 
Placebo Arm .................................................................................................................. 32 
6.4.2.1 
Products .................................................................................................................... 32 
6.4.2.2 
Treatment Schedule .................................................................................................. 32 
6.4.2.3 
Dispensing ................................................................................................................. 32 
6.4.2.4 
Dose Modifications, Interruptions and Discontinuations ......................................... 32 
6.4.3 
Accountability ............................................................................................................... 32 
6.4.4 
Compliance and Adherence .......................................................................................... 32 
6.4.5 
Concomitant Care ......................................................................................................... 32 
6.4.6 
Overdose of Trial Medication ....................................................................................... 34 
6.4.7 
Protocol Treatment Discontinuation ............................................................................ 34 
6.5 
Outcomes .............................................................................................................................. 35 
6.5.1 
Primary Outcome .......................................................................................................... 35 
6.5.2 
Secondary Outcomes .................................................................................................... 35 
6.5.3  
Study within a Trial (SWAT): The influence of patient support group delivered 
research awareness strategies on research recruitment and retention (PURPOSE Study).......... 36 
6.6 
Participant Timeline .............................................................................................................. 38 
6.6.1  
Participant Assessments ............................................................................................... 41 
6.6.1.1 Visit settings .................................................................................................................. 41 
6.6.1.2 Participant Correspondence ......................................................................................... 41 
6.6.1.3 Screening ....................................................................................................................... 41 
6.6.1.4 Baseline ......................................................................................................................... 42 
6.6.1.5 Randomisation .............................................................................................................. 43 
6.6.1.6 3 Months ....................................................................................................................... 44 
6.6.1.7 6 Months ....................................................................................................................... 44 
6.6.1.8 9 Months ....................................................................................................................... 45 
6.6.1.9 12 Months ..................................................................................................................... 46 
6.6.2  
Human Tissue Samples ................................................................................................. 47 

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6.6.3 
Early Stopping of Follow-up .......................................................................................... 48 
6.6.4 
Participant Transfers ..................................................................................................... 48 
6.6.5 
Loss to Follow-up .......................................................................................................... 48 
6.6.6 
Trial Closure .................................................................................................................. 49 
6.7 
Sample Size ........................................................................................................................... 49 
6.8 
Recruitment and Retention .................................................................................................. 49 
6.8.1 
Recruitment .................................................................................................................. 49 
6.8.2 
Retention....................................................................................................................... 51 
6.9 
Assignment of Intervention .................................................................................................. 52 
6.9.1 
Allocation ...................................................................................................................... 52 
6.9.1.1 
Sequence generation - .............................................................................................. 52 
6.9.1.2 
Allocation concealment mechanism ......................................................................... 52 
6.9.1.3 
Allocation Implementation ....................................................................................... 52 
6.9.2 
Blinding ......................................................................................................................... 52 
6.9.3 
Emergency Unblinding .................................................................................................. 52 
6.9.3 
Non-emergency Unblinding .......................................................................................... 53 
6.10 
Data Collection, Management and Analysis ......................................................................... 53 
6.10.1 
Data Collection Methods .............................................................................................. 53 
6.10.2 
Data Management ........................................................................................................ 55 
6.10.3 
Non-Adherence and Non-Retention ............................................................................. 56 
6.10.4 Statistical Methods ............................................................................................................ 56 
6.10.4.1 Outcomes .................................................................................................................... 56 
6.10.4.2 Statistical Analysis Plan (SAP) ..................................................................................... 59 
6.10.4.3 Additional Analyses ..................................................................................................... 59 
6.10.4.4 Analysis Population ..................................................................................................... 59 
6.10.4.5 Missing Data ................................................................................................................ 59 
6.10.5 
Economic evaluation ..................................................................................................... 59 
6.10.6  
Analysis of Tissue Samples ............................................................................................ 60 
6.11 
Safety reporting .................................................................................................................... 60 
6.11.1 Safety reporting ................................................................................................................. 60 
6.11.2 
Investigator responsibilities relating to safety reporting .......................................... 61 
6.11.2.1 Seriousness assessment .......................................................................................... 61 
6.11.2.2 Severity or grading of Adverse Events .................................................................... 61 
6.11.2.3 
 Causality ........................................................................................................... 62 
6.11.2.4 Expectedness .......................................................................................................... 63 

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6.11.3 
Notifications .............................................................................................................. 63 
6.11.3.1 
 Notifications by the Investigator to NCTU ....................................................... 63 
6.11.3.2 NCTU responsibilities .............................................................................................. 64 
6.12 
Data Monitoring .................................................................................................................... 64 
6.12.1 
Data Monitoring Committee ......................................................................................... 64 
6.12.2 
Interim Analyses ............................................................................................................ 64 
6.12.3 
Quality Assurance and Control ..................................................................................... 64 
6.12.3.1 Risk Assessment .......................................................................................................... 64 
6.12.3.2 Central Monitoring at NCTU ....................................................................................... 64 
6.12.3.3 On-site Monitoring ...................................................................................................... 65 
6.12.3.3.1 Direct access to participant records .................................................................... 65 
6.12.3.4 Trial Oversight ............................................................................................................. 65 
6.12.3.4.1 Trial Management Team ...................................................................................... 65 
6.12.3.4.2 Trial Management Group ..................................................................................... 65 
6.12.3.4.3 Independent Trial Steering Committee ............................................................... 65 
6.12.3.4.4 Independent Data Monitoring Committee .......................................................... 66 
6.12.3.4.5 Trial Sponsor ........................................................................................................ 66 
7 
Ethics and Dissemination .............................................................................................................. 66 
7.1 
Research Ethics and Health Research Authority Approval ................................................... 66 
7.2 
Competent Authority Approvals ........................................................................................... 66 
7.3 
Other Approvals .................................................................................................................... 66 
7.4 
Amendments ......................................................................................................................... 67 
7.5 
Consent or Assent ................................................................................................................. 67 
7.6 
Confidentiality ....................................................................................................................... 67 
7.7 
Declaration of Interests ........................................................................................................ 68 
7.8 
Indemnity .............................................................................................................................. 68 
7.9 
Finance .................................................................................................................................. 68 
7.10 
Archiving ............................................................................................................................... 69 
7.11 
Access to Data ....................................................................................................................... 69 
7.12 
Ancillary and Post-trial Care .................................................................................................. 69 
7.13 
Publication Policy .................................................................................................................. 69 
7.13.1 
Trial Results ................................................................................................................... 69 
7.13.2 
Authorship..................................................................................................................... 69 
7.13.3 
Reproducible Research ................................................................................................. 69 
7.14 
Patient and Public Involvement ............................................................................................ 69 

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8 
Ancillary Studies ............................................................................................................................ 70 
9 
Protocol Amendments .................................................................................................................. 71 
10 References .................................................................................................................................... 79 
11 Appendices .................................................................................................................................... 82 
Appendix 1 - The influence of patient support group delivered research awareness strategies on 
research recruitment and retention (PURPOSE Study) .................................................................... 82 
12 Principal Investigator compliance statement ............................................................................... 89 
 
END 

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1 
Administrative information 
This document was constructed using the Norwich Clinical Trials Unit (NCTU) Protocol template 
Version 4. It describes the TIPAL trial, sponsored by the Norfolk and Norwich University Hospitals NHS 
Foundation Trust and co-ordinated by NCTU.  
It provides information about procedures for entering participants into the trial, and provides 
sufficient detail to enable: an understanding of the background, rationale, objectives, trial population, 
intervention, methods, statistical analyses, ethical considerations, dissemination plans and 
administration of the trial; replication of key aspects of trial methods and conduct; and appraisal of 
the trial’s scientific and ethical rigour from the time of ethics approval through to dissemination of the 
results. The protocol should not be used as an aide-memoire or guide for the treatment of other 
patients. Every care has been taken in drafting this protocol, but corrections or amendments may be 
necessary. These will be circulated to registered investigators in the trial. Sites entering participants 
for the first time should confirm they have the correct version through a member of the trial team at 
NCTU. 
NCTU supports the commitment that its trials adhere to the SPIRIT guidelines. As such, the protocol 
template is based on the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 
2012 Statement for protocols of clinical trials(1) The SPIRIT Statement Explanation and Elaboration 
document(2) can be referred to, or a member of NCTU Protocol Review Committee can be contacted 
for further detail about specific items.  
1.1 
Compliance  
The trial will be conducted in compliance with the approved protocol, the Declaration of Helsinki 
(2008), the principles of Good Clinical Practice (GCP) as laid down by the Commission Directive 
2005/28/EC with implementation in national legislation in the UK by Statutory Instrument 2004/1031 
and subsequent amendments, the Human Tissue (Quality and Safety for Human Application) 
Regulations 2007, the UK Data Protection Act 2018 and General Data Protection Regulation (GDPR) 
2018, and the UK Policy Framework for Health and Social Care Research, the European Directive 
2001/20/EC (where applicable) and other national and local applicable regulations. Agreements that 
include detailed roles and responsibilities will be in place between participating sites and NCTU. 
Participating sites will inform NCTU as soon as they are aware of a possible serious breach of 
compliance, so that NCTU can fulfil its requirement to report the breach if necessary within the 
timelines specified in the UK Clinical Trials Regulations (currently 7 days). For the purposes of this 
regulation a ‘serious breach’ is one that is likely to affect to a significant degree: 
• 
The safety or physical or mental integrity of the subjects in the trial, or 
• 
The scientific value of the trial. 
1.2 
Sponsor 
Norfolk and Norwich University Hospitals NHS Foundation Trust is the trial sponsor and has delegated 
responsibility for the overall management of the TIPAL trial to the Chief Investigator (CI) and NCTU. 
Queries relating to sponsorship of this trial should be addressed to the CI or via the trial team. 

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1.3 
Structured trial summary 
Primary 
Registry 
and 
Trial 
Identifying Number 
EudraCT number: 2020-000041-14 
Date of Registration in Primary 
Registry 
03/01/2020 
Secondary Identifying Numbers 
ISRCTN number: ISRCTN13526307 
IRAS number: 269050 
Source of Monetary or Material 
Support 
National Institute for Health Research Health Technology 
Assessment (HTA) Project: NIHR127479  
Sponsor 
Norfolk and Norwich University Hospitals NHS Foundation 
Trust 
Contact for Public Queries 
tipal@uea.ac.uk  
Contact for Scientific Queries 
Professor Andrew M Wilson 
Professor of Respiratory Medicine 
Floor 2, Bob Champion Research and Education Building 
Rosalind Franklin Road 
University of East Anglia 
Norwich Research Park 
Norwich,  
Norfolk 
NR4 7TJ 
A.M.Wilson@uea.ac.uk   
Short Title or Acronym 
TIPAL: Treating people with Idiopathic Pulmonary fibrosis 
with the Addition of Lansoprazole 
Scientific Title 
The effectiveness and risks of Treating people with Idiopathic 
Pulmonary fibrosis with the Addition of Lansoprazole (TIPAL): 
a randomised placebo-controlled multi-centre clinical trial 
Countries of Recruitment 
United Kingdom 
Health Condition(s) or Problem(s) 
Studied 
Idiopathic Pulmonary Fibrosis 
Intervention(s) 
Patients will be randomised on a 1:1 basis to receive either;  
ACTIVE ARM:  
Oral lansoprazole 30 mg (as 2 x 15mg capsules) twice daily, 
12 hours apart, for 12 months 

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or 
CONTROL ARM:  
Matched placebo (2 capsules) twice daily, 12 hours apart, 
for 12 months 
Trial drug is to be taken at least 30 minutes before food.  
Dose may be reduced to one capsule twice daily in those 
developing adverse reactions (see section 6.4.1.4) 
Key Inclusion and Exclusion Criteria 
Inclusion Criteria: 
1. People aged greater than or equal to 40 years. 
2. A diagnosis of Idiopathic Pulmonary Fibrosis (IPF) 
based on local or regional multi-disciplinary 
consensus according to the latest international 
guidelines. 
3. Patients may be receiving licensed anti-fibrotic 
medication (for at least 4 weeks prior to 
randomisation with no planned amendments for at 
least 4 weeks post-randomisation). 
4. Able to provide informed consent. 
 
Additional Inclusion Criteria for cough count sub-study: 
1. Pre-existing diagnosis of persistent cough (defined as 
a troublesome cough for more than 8 weeks prior to 
enrolment). 
 
Exclusion Criteria: 
1. Patients unable to comply with study assessments 
including the ability to complete reliable spirometry 
assessments. 
2. Concomitant use of a proton pump inhibitor (PPI), 
prokinetic 
drugs 
(cisapride, 
domperidone, 
metoclopramide, erythromycin, prucalopride etc.) 
or Histamine-2 receptor antagonists (H2RA) within 2 
weeks prior to randomisation. 
3. Patients with a self-reported significant respiratory 
tract infection, including COVID-19, within 4 weeks 
of screening. 
4. Significant co-existing respiratory disease (defined as 
respiratory condition that exhibits a clinically 
relevant effect on respiratory symptoms and disease 
progression as determined by the Principal 
Investigator 
(PI). 
The 
presence 
of 
traction 
bronchiectasis is permitted. 
5. Patients with FEV1/FVC<0.7.  
6. Significant medical, surgical or psychiatric disease 
that in the opinion of the patient’s attending 
physician would affect subject safety or influence the 
study outcomes including liver failure (e.g. serum 

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transaminase > 2 x upper limit of normal, Bilirubin > 
1.5 upper limit of normal (unless the patient has 
Gilbert’s Syndrome) and chronic kidney disease 
(CKD) greater than stage 3, erosive oesophagitis, 
Barrett’s oesophagus or any condition requiring 
lifelong proton pump inhibitor use.  
7. Known allergy to proton pump inhibitors or the 
contents of placebo. 
8. Concomitant use of atazanavir, ketoconazole, 
itraconazole, tacrolimus, methotrexate, fluvoxamine 
(see section 6.4.5). 
9. Females who are of childbearing potential or 
lactating.  A post-menopausal state is defined as no 
menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone 
(FSH) level in the postmenopausal range may be 
used to confirm a post-menopausal state in women 
not using hormonal contraception or hormonal 
replacement therapy. However in the absence of 12 
months of amenorrhea, a single FSH measurement is 
insufficient. 
10. Receipt of another investigational drug or biological 
agent associated with another clinical trial within the 
4 weeks prior to TIPAL study enrolment or 5 times 
the drug half-life, whichever is the longer. 
11. Receiving long term oxygen therapy. 
12. Patients 
with 
hypomagnesemia 
(defined 
as 
magnesium ≤0.6 mmol/L). 
 
Potential patients receiving PPIs may undergo a washout 
period of 2 weeks if clinically acceptable with randomisation, 
upon completion of baseline assessments, into the study to 
follow if asymptomatic at the end of this period. In the event 
a potential participant is in receipt of prokinetics and/or 
H2RA alongside PPIs, sites are encouraged to contact the 
TIPAL CI via the NCTU trial team, for guidance. 
 
In the event a patient fails screening due to presentation 
with magnesium deficiency or self-reported respiratory tract 
infection within four weeks of screening, they may be re-
screened once magnesium levels have returned to 
≥0.7mmol/L and/or four weeks have elapsed since 
respiratory tract infection symptom onset. 
 
Study Type 
This study is an interventional clinical trial of an 
investigational medicinal product: a phase III, randomised, 
placebo-controlled, two arm parallel group, double-blind, 
multicentre clinical trial. Randomisation will be generated by 
a secure web-based system on a 1:1 basis with minimisation 

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for recruiting site, baseline IPF treatment, reflux and cough 
sub-study status. 
Date of First Enrolment 
September 2021 
Target Sample Size 
298 participants (149 per group); 160 (80 per group) of 
whom will be recruited into the cough count sub-study. 
Primary Outcome(s) 
Absolute change in percentage predicted (%) forced vital 
capacity (FVC) at 12 months post-randomisation of 
lansoprazole versus placebo.  
Key Secondary Outcomes 
The following secondary outcomes will be assessed at the 
timepoints specified: 
At 3 months post-randomisation: 
• 
cough frequency measured using a VitaloJAK cough 
monitor, over a 24 hour period 
At 3, 6, 9 and 12 months post-randomisation: 
• 
cough score measured using a 100mm visual 
analogue scale (VAS) 
• 
cough related quality of life measured by the 
Leicester cough questionnaire (LCQ) 
• 
breathlessness measured by the Medical Research 
Council (MRC) Dyspnoea scale 
• 
disease specific quality of life measured using the 
King’s Brief Interstitial Lung Disease (K-BILD) 
questionnaire  
• 
health related quality of life (HR-QoL) measured 
using the EQ5D-5L questionnaire (quality adjusted 
life years will be estimated) 
• 
adverse events with particular relevance to 
respiratory 
tract 
infection 
and 
pneumonia, 
Clostridium difficile infection and hypomagnesaemia 
At 3, 6 and 12 months post-randomisation: 
• 
total lung diffusing capacity of carbon monoxide 
(DLCO) measured (corrected for haemoglobin) 
where possible 
• 
Laboratory assessment of FVC and FEV1 where 
possible 
At 3 and 12 months post-randomisation: 

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• 
sleep quality measured by the short Pittsburgh Sleep 
Quality Index (PSQI) 
• 
reflux characteristics measured by the DeMeester 
score 
At 12 months post-randomisation: 
• 
participant acceptability measured by a study-
specific  questionnaire 
• 
risk of sleep apnoea measured by the STOP-bang 
questionnaire 
• 
progression free survival (with progression defined 
as time from date of randomisation to week of all-
cause death, lung transplant, a 10% absolute 
reduction in FVC % predicted from baseline 
measured by weekly domiciliary spirometry) 
• 
hospital-free survival defined as death (all-causes) or 
first non-elective (all-cause) hospital admission. 
• 
Respiratory related hospital free survival 
• 
difference in change in weighted reticulovascular 
score (WRVS) on high resolution CT (HRCT) chest 
scans by the Brainomix electronic Interstitial Lung 
Disease (e-ILD) programme  
Over the course of 12 months: 
• 
the decline and rate of decline in absolute %FVC 
based on %FVC measured weekly 
 
 
 
 
 
 
 
 
 
 

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1.4 
Roles and responsibilities 
These membership lists are correct at the time of writing; please see terms of reference 
documentation in the Trial Master File (TMF) for current lists. 
1.4.1 
Protocol contributors 
Name 
Affiliation 
Role 
Professor 
Andrew 
Wilson 
UEA  
CI 
Dr Wendy Adams 
Action for Pulmonary 
Fibrosis 
Research Officer 
Dr Nazia Chaudhuri 
Manchester 
University 
NHS Foundation Trust 
Co-applicant 
Dr Allan Clark 
UEA 
Senior Medical Statistician 
Stef Cormack 
Action for Pulmonary 
Fibrosis 
Research Champion Lead  
Dr Ian Forrest 
The 
Newcastle 
upon 
Tyne 
Hospitals 
NHS 
Foundation Trust 
Co-applicant 
Matthew Hammond 
NCTU 
Deputy Director of NCTU 
Megan Jones 
NCTU 
Trial Manager 
Stephen Jones 
Action for Pulmonary 
Fibrosis/Royal Papworth 
Hospital NHS Foundation 
Trust 
Co-applicant/lay member 
Prof Toby Maher 
Royal 
Brompton 
& 
Harefield 
NHS 
Foundation Trust 
Co-applicant 
Dr Helen Parfrey 
Royal Papworth Hospital 
NHS Foundation Trust 
Co-applicant 
Ian Perry 
The 
Newcastle 
upon 
Tyne 
Hospitals 
NHS 
Foundation Trust 
Co-applicant/lay member 
Martin Pond 
NCTU 
Head of Data Management 
Professor 
Ganesh 
Raghu 
University 
of 
Washington 
Co-investigator 

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Professor John Smith 
Newcastle University 
Co-applicant 
Professor 
Jaclyn 
Smith 
University 
of 
Manchester/Manchester 
University 
NHS 
Foundation Trust 
Co-applicant 
Dr Lisa Spencer 
Aintree 
University 
Hospital NHS Foundation 
Trust 
Co-applicant 
Sue Stirling 
UEA 
Statistician 
Professor Ann Marie 
Swart 
NCTU 
Co-applicant/NCTU Director 
Professor 
David 
Thickett 
University 
of 
Birmingham 
Co-applicant 
Mr Shajahan Wahed 
The 
Newcastle 
upon 
Tyne 
Hospitals 
NHS 
Foundation Trust 
Co-applicant 
Dr Chris Ward 
Newcastle University 
Co-applicant 
 
TIPAL-Brainomix CT Scan Sub-Study protocol contributors: 
Name  
Affiliation 
Role 
Professor Andrew Wilson 
UEA 
CI 
Dr Anand Devaraj 
Brainomix/Royal Brompton and 
Harefield Hospitals 
Medical 
Director, 
Thoracic 
Radiology/Consultant Thoracic 
Radiologist 
Claire Fernandez  
Brainomix 
Respiratory 
Programme 
Manager 
Dr Peter George 
Brainomix/Royal Brompton and 
Harefield Hospitals 
Medical 
Director, 
Respiratory/Consultant 
Respiratory Physician and ILD 
Clinical Lead 
Dr George Harston 
Brainomix/Oxford 
University 
Hospitals NHS Foundation Trust 
Chief Medical and Innovation 
Officer/Consultant Physician in 
Stroke and General Medicine  

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Megan Jones 
NCTU 
Trial Manager 
Aliki Sifostratoudaki  
Brainomix 
Research Project Manager 
 
1.4.2 
Role of trial sponsor and funders 
Name 
Affiliation 
Role  
Julie Dawson 
NNUH 
Sponsor: Research Services Manager 
Basia Brown 
NNUH 
Sponsor: Research Governance Coordinator 
Michael Sheridan 
NNUH 
Sponsor: Research Grants Coordinator 
Vanessa Grove 
NNUH 
Sponsor: Research Study Officer 
Andrea Ingram 
NIHR HTA 
Funder: Research Manager 
 
1.4.3 
Trial Team 
Name 
Affiliation 
Role and responsibilities 
Professor 
Andrew 
Wilson 
UEA 
CI 
Dr Allan Clark 
UEA 
Senior Medical Statistician 
Antony Colles 
NCTU 
Senior Data Programmer 
Matthew Hammond 
NCTU 
Deputy Director of NCTU 
Megan Jones 
NCTU 
Trial Manager 
Martin Pond 
NCTU 
Head of Data Management 
Sue Stirling 
UEA 
Statistician 
Tom Conway 
NCTU 
Trial Assistant 
 
1.4.4 
Trial Management Group 
Name 
Affiliation 
Role and responsibilities 
Professor 
Andrew 
Wilson 
UEA 
CI 
Dr Anthony Cahn 
Bedford 
Hospital 
NHS 
Trust/GlaxoSmithKline 
Co-investigator 

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Dr Nazia Chaudhuri 
Manchester 
University 
NHS Foundation Trust 
Co-investigator 
Dr Allan Clark 
UEA 
Senior Medical Statistician 
Antony Colles 
NCTU 
Senior Data Programmer 
Dr Ian Forrest 
The Newcastle upon Tyne 
Hospitals NHS Foundation 
Trust 
Co-investigator 
Matthew Hammond 
NCTU 
Deputy Director of NCTU 
Megan Jones 
NCTU 
Trial Manager 
Stephen Jones 
Action 
for 
Pulmonary 
Fibrosis/Royal Papworth 
Hospital NHS Foundation 
Trust 
Patient 
and 
Public 
Involvement 
Representative/co-applicant 
Prof Toby Maher 
Royal 
Brompton 
& 
Harefield NHS Foundation 
Trust 
Co-investigator 
Dr Helen Parfrey 
Royal Papworth Hospital 
NHS Foundation Trust 
Co-investigator/SWAT 
Ian Perry 
The Newcastle upon Tyne 
Hospitals NHS Foundation 
Trust 
Patient 
and 
Public 
Involvement 
Representative/co-applicant 
Professor 
Ganesh 
Raghu 
University of Washington 
Co-investigator 
Professor 
John 
Simpson 
Newcastle University 
Co-investigator 
Professor 
Jaclyn 
Smith 
The 
University 
of 
Manchester/ Manchester 
University 
NHS 
Foundation Trust 
Co-investigator 
Dr Lisa Spencer 
Aintree 
University 
Hospital NHS Foundation 
Trust 
Co-investigator 
Sue Stirling 
UEA 
Statistician 

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Professor Ann Marie 
Swart 
NCTU 
NCTU Director/Co-applicant 
Prof David Thickett 
University of Birmingham 
Co-investigator 
Professor Luke Vale 
Newcastle University 
Co-investigator/Professor of Health Economics 
Mr Shajahan Wahed 
The Newcastle upon Tyne 
Hospitals NHS Foundation 
Trust 
Co-investigator 
Dr Chris Ward 
Newcastle University 
Co-investigator 
 
1.4.5 
Trial Steering Committee 
Name 
Affiliation 
Role and responsibilities 
Professor Ann Millar 
Retired/University of Bristol 
Independent Chair 
Professor Adam Hill 
NHS Lothian/University of Edinburgh 
Independent Member 
Dr Katherine O’Reilly 
Mater Misericordiae University Hospital 
Independent Member 
Dr Oleg Blyuss 
University of Hertfordshire 
Independent Statistician 
Sam Moonoosamy 
N/A 
Patient and Public Involvement 
Representative 
Martin Ruddock 
N/A 
Patient and Public Involvement 
Representative 
 
1.4.6    Data Monitoring Committee  
Name 
Affiliation 
Role and responsibilities 
Dr Nik Hirani 
University of Edinburgh 
Independent Chair 
Professor Sarah Pett 
Medical Research Council Clinical 
Trials Unit at University College 
London 
Independent Member 
Dr Mona Kanaan 
University of York 
Independent Statistician 
 
 
 

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2 
Trial Diagram  
Figure 1: TIPAL trial diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening 
Inclusion criteria: ≥40 years old; IPF; able to provide informed consent.  
Cough (and activity) sub-study additional inclusion criterion: pre-existing cough (for more than 8weeks 
prior to randomisation) 
 
Exclusion Criteria: unable to complete study measurements; concomitant PPI/prokinetic/H2RA use; self-
reported respiratory tract infection; significant co-existing respiratory disease;FEV1/FVC<0.7; significant 
medical/surgical/psychiatric disease; PPI/placebo allergy; concomitant use of prohibited medications; 
females of child-bearing potential or lactating; receipt of another IMP; long-term oxygen therapy; 
hypomagnesaemia. 
*160 patients (80 per group) for cough sub-study 
Full eligibility criteria details listed in section 6.3.1, outcomes described in section 6.5 and participant assessments outlined in 
section 6.6.1. 
Consent and baseline assessments  
including 24h cough, activity and sleep  
monitoring and chest HRCT scan if agreed  
Randomisation  
(n = 298)* 
Lansoprazole 
30mg (2 x 15mg capsules) twice daily, 12h 
apart, at least 30 minutes before food, for 12 
months 
(reduced to 15mg capsule twice daily if 
adverse effects experienced) 
Placebo 
2 capsules twice daily, 12h apart, at least 30 
minutes before food, for 12 months  
(reduced to 1 capsule twice daily if adverse 
effects experienced) 
3 month follow-up visit 
including 24h cough, activity and sleep   
monitoring if agreed 
3 month follow-up visit  
including 24h cough, activity and sleep 
monitoring if agreed 
6, 9 and 12-month follow-up visits 
including chest HRCT at 12M if agreed 
6, 9 and 12 month follow-up visits 
including chest HRCT at 12M if agreed 
Primary outcome: absolute change in % predicted FVC  
Secondary outcomes: rate of change of FVC, cough frequency (sub-study); cough score by the VAS scale; 
LCQ; MRC Dyspnoea scale; K-BILD; EQ5D-5L; DLCO; participant acceptability; adverse events; progression 
free survival (death or lung transplant or 10% decline in FVC); hospital-free survival or first non-elective 
hospitalisation (all-cause); respiratory related hospital free survival; STOP-bang, short PSQI, DeMeester 
score, difference in change of WRVS. 
 
 
 
 
 
 
 
 
Enrolment 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
  
& 
Follow-up 
 
 
 
 
 
Randomisation 
 
 
Outcomes 
 
 

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3 
Abbreviations 
AE 
Adverse Event 
APF 
Action for Pulmonary Fibrosis 
AR 
Adverse Reaction 
ARTP 
Association for Respiratory Technology and Physiology 
ATS 
American Thoracic Society 
BTS 
British Thoracic Society 
CACE 
Compliance-Adjusted Causal Effect 
CAP 
Community acquired pneumonia 
CDAD 
Clostridium difficile associated diarrhoea 
CI 
Chief Investigator 
COVID-19 
Coronavirus disease 2019 
CRF 
Case Report Form 
CTA 
Clinical Trial Authorisation 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLCO 
Diffusing capacity of Carbon Monoxide 
DMC 
Data Management Committee (aka IDMC) 
DSUR 
Development Safety Update Report 
eCRF 
Electronic Case Report Form 
e-ILD 
Electronic Interstitial Lung Disease 
EME-TIPAC 
The Efficacy and Mechanism Evaluation of Treating Idiopathic Pulmonary fibrosis 
with the Addition of Co-trimoxazole 
ERS 
European Respiratory Society 
EU 
European Union 
FBC 
Full Blood Count 
FDA 
Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
FVC 
Forced Vital Capacity 
GCP 
Good Clinical Practice 
GOJ 
Gastro-oesophageal junction  
GOR 
Gastro-oesophageal reflux 
GORD 
Gastro-oesophageal reflux disease 
GP 
General Practitioner 
H2RA 
Histamine-2 receptor antagonists 
HH 
Hiatus hernia 
HRA 
Health Research Authority 
HRCT 
High-resolution computed tomography 
HTA 
Health Technology Assessment 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee (aka DMC) 
ILD 
Interstitial Lung Disease 
IMP 
Investigational Medicinal Product 
INR 
International normalised ratio 
IPF 
Idiopathic Pulmonary Fibrosis 
ISF 
Investigator Site File 
ITT 
Intention to Treat 
ISRCTN 
International Standard Randomised Clinical Trial Number 
K-BILD 
King’s Brief Interstitial Lung Disease questionnaire 
LCQ 
Leicester Cough questionnaire 

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LFTs 
Liver Function Tests 
MDT 
Multi-Disciplinary Team 
MHRA 
Medicines and Healthcare products Regulatory Agency 
NCTU 
Norwich Clinical Trials Unit 
NHS 
National Health Service 
NICE 
National Institute for health and Care Excellence 
NIHR 
National Institute of Health Research 
NNUH 
Norfolk and Norwich University Hospitals NHS Foundation Trust 
PI 
Principal Investigator 
PID 
Participant Identification Number 
PIS 
Participant Information Sheet 
PPI 
Proton Pump Inhibitor 
PPIPF 
Proton Pump Inhibitors in idiopathic Pulmonary Fibrosis 
PRES 
Participant in Research Experience Survey 
PSQI 
Pittsburgh Sleep Quality Index 
QA 
Quality Assurance 
QC 
Quality Control 
QMMP 
Quality Management and Monitoring Plan 
QoL 
Quality of Life 
R&D 
Research and Development 
RCT 
Randomised Controlled Trial 
REC 
Research Ethics Committee 
R-Scale for 
PF 
The Raghu Scale for Pulmonary Fibrosis 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Serious Adverse Reaction 
SOC 
Standard of Care 
SPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SWAT 
Study Within A Trial 
TIPAC 
Treating Idiopathic Pulmonary fibrosis with the Addition of Co-trimoxazole 
TIPAL 
Treating Idiopathic Pulmonary fibrosis with the Addition of Lansoprazole 
TMF 
Trial Master File 
TMG 
Trial Management Group 
TMT 
Trial Management Team 
ToR 
Terms of Reference 
TSC 
Trial Steering Committee 
UAR 
Unexpected Adverse Reaction 
UEA 
University of East Anglia 
ULN 
Upper Limit of Normal 
U&Es 
Urea and Electrolytes 
WRVS 
Weighted reticulovascular score 
VAS 
Visual Analogue Scale 
 
4  
Glossary 
None. 

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5 
Introduction 
5.1 
Background and Rationale 
Idiopathic pulmonary fibrosis  
Idiopathic pulmonary fibrosis (IPF) is a chronic fibrotic interstitial lung disease (ILD) of unknown cause 
with a poor prognosis and limited treatment options. It is progressive and usually fatal with a 5-year 
survival of 20-40%(3). More people will die each year from IPF than from ovarian cancer, leukaemia 
or mesothelioma(4). People with this condition experience progressive breathlessness and a socially 
isolating cough, with cough being particularly difficult to treat. They frequently have comorbid disease, 
gastro-oesophageal reflex disease (GORD) being one of the most common.  
Reflux disease and anti-reflux therapy in IPF: clear associations 
The cause of IPF is unknown, however, there are well-accepted aetiological factors including genetic 
variants and environmental exposures, for example smoking and aspiration of gastric fluid(5). IPF itself 
may increase gastro-oesophageal reflux (GOR) by reducing intra-thoracic pressure or because of 
increased oesophageal traction(6). Indeed nearly 90% of people with IPF have GOR(7), with a 
correlation between radiological evidence of lung fibrosis and oesophageal reflux episodes(8). Despite 
this, only half of individuals have classic reflux symptoms(7). 
Case series and secondary analysis of randomised clinical trials (RCTs), suggest that anti-reflux therapy 
slows disease progression. In a pooled analysis of 242 individuals taken from the placebo arms of three 
trials, anti-acid therapy resulted in a statistically and clinically significant difference in absolute forced 
vital capacity (FVC) decline over a 30-month period(9). This amounted to a 50% reduction in FVC 
decline. However these findings were not replicated in a post-hoc analysis of data from individuals 
with IPF and FVC > 50% predicted, randomised to the placebo(10) arm of the CAPACITY studies, 
possibly due to the unadjusted nature of the analysis(11). 
Two systematic reviews have reported the effect of anti-acid therapy on mortality. Tran and Suissa(12) 
examined all-cause mortality and reported an overall reduction with anti-acid therapy but argued that 
the signal for this difference mostly came from studies subject to possible immortal time bias. Fidler 
et al(11) found no effect on all-cause mortality but reported a reduction of  IPF-related mortality. 
PPIs are the cornerstone of anti-reflux therapy 
Proton Pump Inhibitors (PPIs) are the first-line anti-acid treatments for people with reflux disease 
according to current National Institute for Health and Care Excellence (NICE) guidelines 
(www.nice.org.uk/CG184). Histamine-2 receptor antagonists (H2RA), previously first-line treatment, 
have been superseded by PPIs given the clear evidence of greater acid suppression and symptomatic 
control(13). Thus, HR2A are only now offered to those with an inadequate response to PPIs. 
Prokinetics are not recommended by NICE guidelines, cannot be used for long-term therapy due to 
concerns about adverse effects and do not improve symptomatic or endoscopic response in 
GORD(14). Laparoscopic fundoplication results in better symptom control but worse side effects than 
PPIs(15), but this intervention can only be advocated for highly selected individuals with IPF. Lifestyle 
changes are recommended by guidelines and may improve symptom burden(16). A review found 
evidence to support sleeping head-up and weight loss improved pH profiles and symptoms(17). 

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Antacids and raft alginates also have a limited role in treating dyspepsia, with alginates being better 
than antacids but less effective than PPIs or H2RA(18). 
Overall, nearly all of the evidence about anti-reflux therapy in IPF comes from people receiving PPIs. 
All of the individuals in the initial case series were taking PPIs and more than 90% of individuals in the 
secondary analysis of clinical trials were receiving PPIs. PPIs have anti-inflammatory, anti-oxidant and 
anti-fibrotic properties demonstrated in vitro(19) and in vivo(20). Thus, there are plausible biological 
mechanisms by which they may reduce disease progression in addition to their anti-acid effects(21). 
A small randomised control trial of a PPI in people with IPF (PPIPF)(22) showed that a definitive large-
scale trial was feasible. As expected, the main reason for exclusion was due to existing PPI therapy, 
however 25 out of 59 people taking PPIs were eligible for a trial of withholding therapy for two weeks 
after which 16 (64%) did not have a return of symptoms and were able to successfully enter into the 
trial.  PPIs were well tolerated in IPF with slightly increased lower respiratory tract infections in the 
active arm. Invasive assessment of GORD was not considered feasible but there was a suggesting of a 
meaningful improvement in objective cough scores. GORD may influence sleep quality in people with 
IPF due to nocturnal coughing, which was shown to be improved in the PPIPF trial(22) indeed GORD, 
IPF, coughing and obstructive sleep apnoea may be interrelated(23).   
Of the five licensed PPIs in the UK, omeprazole and esomeprazole induce cytochrome enzymes 
potentially 
resulting 
in 
reduced 
efficacy 
of 
the 
anti-fibrotic 
drug 
pirfenidone 
(www.medicines.org.uk/emc/medicine/29932). The acid suppression potency(24) and symptom relief 
of the remaining PPIs is similar(25), however lansoprazole is the cheapest available PPI and the one 
with which UK physicians are most familiar.  
Non-erosive oesophagitis occurs at a higher pH than erosive gastritis and therefore higher doses of 
PPIs are often required to increase the pH to a degree that will treat non-reflux symptoms such as 
cough(26). Lansoprazole 30mg twice per day results in significantly greater acid suppression and for 
longer duration than lower doses(27), with a pH greater than 4 occurring 75% of the time with 30mg 
twice daily compared to 60% of the time with 30mg once daily or 15 mg twice daily. However very 
high doses do not produce greater acid suppression(27). A dose of 30mg twice daily (with a dose step-
down option if adverse effects emerge), will minimise resistant reflux disease although may result in 
slightly higher rates of diarrhoea (5.0% compared to 3.7% for 30mg daily)(28).  
PPI: potential adverse effects Long-term PPI therapy may result in significant adverse effects. A 
systematic review and meta-analysis of 26 studies evaluating six million people showed that PPI 
therapy increases the risk of community-acquired pneumonia (CAP), including CAP requiring 
hospitalisation(29), by 50%. This is in keeping with the suggestion of a higher incidence of pneumonia 
with PPI therapy in patients with IPF randomised to the placebo arm of the CAPACITY studies(38), 
albeit in those with more severe disease(30). Pneumonia is common in people with IPF(31) and a 
frequent cause of death(32). Alkaline stomach pH is thought to permit bacterial colonisation, which 
can be aspirated – a risk that may be increased in IPF-related GOR and micro-aspiration. Osteoporosis 
is also increased by 25-50% with PPI treatment(33). Clostridium difficile-associated diarrhoea (CDAD) 
is increased with PPI use and outcomes for CDAD are worse for those receiving PPIs(34). 
Primary outcome data collection 
 

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FVC is regarded as a clinically meaningful endpoint for phase 3 clinical trials(35) and the most 
appropriate option given that mortality is impractical(36) (37). FVC has been utilised as the primary 
endpoint in nearly all published late phase clinical trials in IPF, including those of pirfenidone and 
nintedanib, which were used for licensing purposes. FVC has been accepted by the Food and Drug 
Administration (FDA) as an appropriate endpoint for licensing of medication(38). The change in FVC 
over time has been repeatedly shown to be highly predictive of mortality(39) and is a component of 
prognostic algorithms. Furthermore, as it is captured at least annually by all centres entering data onto 
the British Thoracic Society (BTS) ILD Registry (www.brit-thoracic.org.uk/standards-of-care/lung-
disease-registries/bts-ild-registry/), long-term follow-up using FVC can be undertaken at minimal 
inconvenience to patients and the service. 
 
Spirometry 
is 
considered 
to 
be 
an 
aerosol 
generating 
procedure 
(https://www.artp.org.uk/News/artp-guidance-respiratory-function-testing-and-sleep-services-
during-endemic-covid-19) and as a result provision for undertaking laboratory FVC measurements is 
limited. For this reason, along with the technological advances in spirometers and internet network 
connections, home spirometry is increasingly used as a clinical method of monitoring chronic 
respiratory disease. Home spirometry has been shown to be a good predictor of mortality(40) and has 
good adherence at least up to 24 weeks(41). Home spirometry has been repeatedly shown to have 
good correlation with laboratory spirometry(40, 41) with correlation coefficients greater than 0.9. It 
has been utilised in as an endpoint in a clinical trial of unclassifiable fibrotic interstitial lung disease 
but linear regression modelling was not possible (42).  
5.1.1 
Explanation for choice of comparators 
Lansoprazole will be compared with matched placebo as this is the most robust way to determine the 
efficacy and adverse effects of lansoprazole. All patients involved in the trial will continue to receive 
usual care (defined in section 6.4.5).  
Treatment allocation is double-blind to reduce potential bias in reporting of the primary outcome and 
patient reported secondary outcomes. 
5.2 
Objectives 
The primary research hypothesis is that participants treated with lansoprazole will have smaller 
absolute decline in percentage predicted (%) FVC at 12 months post-randomisation versus participants 
treated with placebo.  
The secondary research hypotheses are that participants treated with lansoprazole will: 
• 
cough fewer times over a 24h period at 3 months than participants treated with placebo  
• 
have a lower cough score assessed by the VAS score than participants treated with placebo at 
each study time point following baseline 
• 
have a better cough-related quality of life as measured by the LCQ than participants treated 
with placebo at each study time point following baseline 
• 
experience less breathlessness indicated by the MRC Dyspnoea scale than participants treated 
with placebo at each study time point following baseline 
• 
have a better disease specific quality of life as measured by the K-BILD than participants 
treated with placebo at each study time point following baseline 

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• 
have a higher DLCO than participants treated with placebo at each study time point following 
baseline 
• 
regard their trial treatment as acceptable at 12 months 
• 
experience fewer all-cause and respiratory-related hospitalisations and deaths as a group than 
the placebo treatment group at 12 months 
• 
experience longer progression free survival than participants treated with placebo  
• 
be at a lower risk of sleep apnoea according to the STOP-bang questionnaire at 12 months 
than participants treated with placebo 
• 
have a better sleep quality score indicated by the short PSQI at 3 and 12 months than 
participants treated with placebo 
• 
have a lower DeMeester score at 3 and12 months than participants treated with placebo 
• 
have a smaller absolute rate of decline in FVC over time than participants treated with placebo 
• 
will have a smaller change in WRVS score than those treated with placebo 
5.3 
Trial Design 
The study is a Phase III double blind, parallel group, 1:1 randomised, placebo controlled, multi-centre, 
clinical superiority trial of oral lansoprazole versus placebo in 298 participants with IPF diagnosed by 
multi-disciplinary team (MDT) meeting consensus, according to international criteria for IPF. 
Outcomes will be assessed during a treatment period of 12 months. The primary endpoint is absolute 
change in % predicted FVC measured between baseline and 12 months post-randomisation of 
lansoprazole versus placebo. FVC will be measured on a weekly basis during the trial by domiciliary 
spirometry. Randomisation will be performed centrally according to a computer-generated 
randomisation code by secure automated e-mail from NCTU to central research pharmacists only. 
Minimisation factors are: recruiting site, baseline anti-fibrotic therapy, presence of reflux and cough 
sub-study status. 
A subgroup of 160 participants (80 per group) will be recruited into the cough count sub-study. 
We will aim to recruit approximately 100 participants (up to a maximum of 126 participants) into the 
CT scan sub-study.  
5.3.1 Pilot Phase 
This study includes an internal pilot phase during which recruitment will be closely monitored by all 
relevant parties and oversight committees to ensure recruitment of the planned sample size is 
feasible, safe and ethical.  
Progression will be assessed constantly throughout the study according to a traffic light system, with 
green flagging if the study is progressing above target, red flagging if the study is not likely to deliver 
and amber flagging if in between. Observed total recruitment will be assessed against expected total 
recruitment to assign flags. A red flag is indicated where the observed recruitment total is less than 
50% of the expected recruitment total for the relative study timepoint. 
Actions to be taken according to the progression flagging status;  
• 
Green flagging – study and recruitment to continue as planned 
• 
Amber flagging – results in increased recruitment of sites and discussion and monitoring of 
existing sites regarding recruitment and best practice approached 

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• 
Red flagging – three consecutive red flag months will trigger discussion with the Data 
Monitoring Committee (DMC), Trial Steering Committee (TSC) and Sponsor regarding 
feasibility of continuing recruitment 
The Study Within A Trial (SWAT) will be abandoned with provisional findings incorporated into the 
recruitment strategy at all sites if there is amber flagging at 24 months or red flagging at 18 months. 
The pilot phase will commence from the date the first participant is randomised. At the end of the 
pilot phase a decision will be made by the funder, in consultation with the TSC and DMC, regarding 
progression to completion of the trial as intended. Recruitment will continue until this decision has 
been reached. All participants recruited during the pilot phase will be included in the further study 
analyses.  
There are no planned interim efficacy analyses.  
6 
 Methods 
6.1 
Site Selection 
The trial sponsor has overall responsibility for site and investigator selection and has delegated this 
role to the CI and NCTU. 
6.1.1 
Study Setting 
The study will be conducted primarily in secondary and tertiary care hospitals within the United 
Kingdom. Sites will be specialist ILD centres, meet the specifications required for specialist ILD centre 
status or work in association with specialist centres. Due to the restrictions in face-to-face clinical and 
research consultations, resulting from the COVID-19 pandemic, outcomes will be collected remotely 
without the requirement of hospital/research centre attendance along with opportunistic capture of 
routine clinical outcome assessments.  
6.1.2 
Site/Investigator Eligibility Criteria 
Once a site has been assessed as being suitable to participate in the trial, the trial team will provide 
them with a copy of this protocol and the Summary of Product Characteristics (SPC).  
To participate in the TIPAL trial, investigators and trial sites must fulfil a set of criteria, agreed by the 
TIPAL Trial Management Group (TMG), as defined below. In exceptional circumstances, a site may be 
excluded from some aspects of the study if they do not meet the criteria below following approval 
from the CI. 
Eligibility criteria: 
• 
A named clinician is willing and appropriate to take Principal Investigator (PI) responsibility 
• 
Suitably trained staff are available to recruit participants, undertake/observe study 
assessments and measurements, enter data and collect and store samples 
• 
Site is included on the BTS IPF and Sarcoidosis registry or willing to join registry prior to 
activation 
• 
The site has a suitable potential patient population to adequately recruit participants from 

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Sites are not required to have access to a pharmacy able to store, prepare and dispense Investigational 
Medicinal Product (IMP) as these processes will be managed through a central pharmacy (see section 
6.4.3). 
In addition, sites will be invited to approach and consent eligible patients for the cough  sub-study in 
parallel to the main trial, provided they agree and have capacity to do so. Similarly, sites will be 
approached to recruit consenting patients into the CT scan sub-study provided they agree and have 
the capacity and resources to do so. Site participation in the main trial is not dependent on sub-study 
involvement, thus sites are permitted to participate in all, either or no sub-studies. 
Trial sites meeting eligibility criteria will be issued with a TIPAL Investigator Site File (ISF) and a pack 
of documentation needed by the Research and Development (R&D) Department of their Trust to 
enable the Trust to provide confirmation of capacity and capability to undertake the study.  
6.1.2.1 Principal Investigator’s (PI) Qualifications and Agreements 
The investigator(s) must be willing to sign an investigator statement to comply with the trial protocol 
(confirming their specific role and responsibilities relating to the trial, and that their site is willing and 
able to comply with the requirements of the trial (see section 12)). This includes confirmation of 
appropriate qualifications, familiarity with the appropriate use of any investigational products, 
agreement to comply with the principles of GCP, to permit monitoring and audit as necessary at the 
site, and to maintain documented evidence of all staff at the site who have been delegated significant 
trial related duties. 
6.1.2.2 Resourcing at site 
The investigator(s) should be able to demonstrate a potential for recruiting the required number of 
suitable subjects within the agreed recruitment period (i.e. the investigator(s) regularly treat(s) the 
target population). They should also have an adequate number of qualified staff and facilities available 
for the foreseen duration of the trial to enable them to conduct the trial properly and safely.  
Sites will be expected to complete a delegation of responsibilities log and provide staff contact details. 
GCP training is required for all staff responsible for trial activities. The frequency of repeat training 
may be dictated by the requirements of their employing institution or 2 yearly where the institution 
has no policy, and more frequently when there have been updates to the legal or regulatory 
requirements for the conduct of clinical trials. 
The site should have sufficient data management resources to allow prompt data return to NCTU.  
6.2 
Site approval and activation 
The Clinical Trial Authorisation (CTA) for the trial requires that the Medicines and Healthcare products 
Regulatory Agency (MHRA) is supplied with the names and addresses of all participating site Principal 
Investigators (PIs). Trial staff at NCTU will perform this task.  
On receipt of the signed investigator statement, approved delegation of responsibilities log and staff 
contact details, written confirmation will be sent to the site PI. The trial manager or delegate will notify 
the PI in writing of the plans for site initiation. Sites will not be permitted to recruit any patients until 
a letter for activation has been issued. The Trial Manager or delegate will be responsible for issuing 
this after a green light to recruit process has been completed. 

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The site must conduct the trial in compliance with the protocol as agreed by the Sponsor, Health 
Research Authority (HRA) and, by the regulatory authority (as appropriate), and which was given 
favourable opinion by the Research Ethics Committee (REC). The PI or delegate must document and 
explain any deviation from the approved protocol and communicate this to the trial team at NCTU. 
A list of activated sites may be obtained from the Trial Manager. 
6.3 
Participants 
6.3.1 
Eligibility Criteria 
6.3.1.1 Participant selection 
There will be NO EXCEPTIONS (waivers) to eligibility requirements at the time of randomisation. 
Questions about eligibility criteria should be addressed PRIOR to attempting to randomise the 
participant.  
The eligibility criteria for this trial have been carefully considered and are the standards used to ensure 
that only medically appropriate participants are entered. Participants not meeting the criteria should 
not be entered into the trial for their safety and to ensure that the trial results can be appropriately 
used to make future treatment decisions for other people with similar diseases or conditions. It is 
therefore vital that exceptions are not made to these eligibility criteria. 
Participants will be considered eligible for enrolment in this trial if they fulfil all the inclusion criteria 
and none of the exclusion criteria as defined below. 
In the event a patient fails screening due to presentation with magnesium deficiency, changes to their 
anti-fibrotic(s) and/or self-reported respiratory tract infection within four weeks of screening, they 
may be re-screened once magnesium levels have returned ≥0.7mmol/L and/or four weeks have 
elapsed since respiratory tract infection symptom onset or changes to their IPF treatment regimen 
were made. Participants are permitted to repeat baseline FVC measurements upon receipt of the 
domiciliary spirometer to familiarise themselves on use of the equipment. Baseline FVC 
measurements should be attempted after a successful PPI washout period (where required), for a 
period up to a maximum of 28 days (unless extenuating circumstances apply) upon which, a decision 
as to whether to proceed to trial enrolment will be made by the local PI in collaboration with the CI, 
following review of the individual flow-volume and volume-time graphs by a separate lung function 
review committee, and, where appropriate, the patient , if clinically consistent results have been 
challenging to obtain. This timeframe will not apply where participants have undergone rescreening 
or there have been delays to completion of baseline assessments. Further details on spirometry data 
review are outlined in the TIPAL Quality Management and Monitoring Plan and study-specific remote 
spirometry work instruction. 
6.3.1.2 Participant Inclusion Criteria 
1. People aged greater than or equal to 40 years.  
2. A diagnosis of Idiopathic Pulmonary Fibrosis (IPF) based on local or regional multi-disciplinary 
consensus according to the latest international guidelines. 
3. Patients may be receiving licensed anti-fibrotic medication (for at least 4 weeks prior to 
randomisation with no planned amendments for at least 4 weeks post-randomisation). 
4. Able to provide informed consent. 
 
Additional Inclusion Criteria for cough count sub-study: 

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1. Pre-existing diagnosis of persistent cough (defined as troublesome for more than 8 weeks 
prior to study enrolment). 
 
6.3.1.3 Participant Exclusion Criteria 
1. Patients unable to comply with study assessments including the ability to complete reliable 
spirometry assessments.  
2. Concomitant use of a proton pump inhibitor (PPI), prokinetic drugs (cisapride, domperidone, 
metoclopramide, erythromycin, prucalopride etc.) or Histamine-2 receptor antagonists 
(H2RA) within 2 weeks prior to randomisation. 
3. Patients with a self-reported significant respiratory tract infection, including COVID-19, within 
4 weeks of screening. 
4. Significant co-existing respiratory disease (defined as a respiratory condition that exhibits a 
clinically relevant effect on respiratory symptoms and disease progression as determined by 
the PI). The presence of traction bronchiectasis is permitted.  
5. Patients with an FEV1/FVC<0.7.  
6. Significant medical, surgical or psychiatric disease that in the opinion of the patient’s attending 
physician would affect subject safety or influence the study outcomes including liver failure 
(e.g. serum transaminase > 2 x upper limit of normal (ULN), Bilirubin > 1.5 x ULN (unless the 
patient has Gilbert’s Syndrome) and chronic kidney disease (CKD) greater than stage 3, erosive 
oesophagitis, Barrett’s oesophagus or any condition requiring lifelong proton pump inhibitor 
use.  
7. Known allergy to proton pump inhibitors or the contents of placebo. 
8. Concomitant use of atazanavir, ketoconazole, itraconazole, tacrolimus, methotrexate, 
fluvoxamine (see section 6.4.5). 
9. Females who are of childbearing potential or lactating. A postmenopausal state is defined as 
no menses for 12 months without an alternative medical cause. A high FSH level in the 
postmenopausal range may be used to confirm a post-menopausal state in women not using 
hormonal contraception or hormonal replacement therapy. However in the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient. 
10. Receipt of another investigational drug or biological agent associated with another clinical trial 
within the 4 weeks prior to TIPAL study enrolment or 5 times the drug half-life, whichever is 
the longer. 
11. Receiving long-term oxygen therapy. 
12. Patients with hypomagnesemia (defined as magnesium ≤0.6 mmol/L). 
 
6.3.1.4 Eligibility criteria guidance 
Stable anti-fibrotics 
Participants may or may not be receiving licensed anti-fibrotic medication prior to study enrolment. 
There must have been no changes to the treatment regimen for at least 4 weeks prior to 
randomisation and no planned amendments for at least 4 weeks post-randomisation. This includes 
where a participant is not receiving any licensed anti-fibrotic medication. Dosing changes are 
permitted but starting and/or stopping therapeutics is not permitted within the 4 weeks preceding 
and following randomisation. Participants may be rescreened if required. 
 
PPI washout 
Patients receiving PPIs prior to study participation invitation, may undergo a 2 week washout period 
immediately following consent, if clinically acceptable, with randomisation into the study if they 
remain asymptomatic at the end of this period. The patient’s GP should be contacted, via the study 
GP letter, following the informed consent process in order to notify them of the intention for their 
patient to complete the washout period.  
 

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We advise caution again patients with any of the following diagnoses completing the washout period 
as it may not be considered clinically appropriate for them to do so: 
• 
Zollinger-Ellison syndromes 
• 
Barrett’s oesophagus – patients with previous dysplasia and/or adenocarcinoma or those with 
inflamed Barrett’s oesophagus should not attempt a washout. However, patients with non-
dysplastic Barrett’s oesophagus who are not exhibiting symptomatic reflux may be clinically 
appropriate to attempt a washout.   
• 
Previous oesophagectomy 
• 
Treatment for active peptic ulcer disease 
• 
Awaiting repeat investigation for confirmation of ulcer healing 
• 
Treatment for active oesophagitis 
• 
Prescribed as prophylaxis for short-term non-steroidal anti-inflammatory drugs (NSAIDs) 
• 
Previous history of gastrointestinal (GI) bleed in patients in receipt of long-term 
anticoagulation or anti-platelets treatments 
• 
Patients with refractory dyspepsia/reflux symptoms and failed previous cessation attempt 
• 
Patients under the care of a gastroenterologist or upper GI surgeon who feel continuation of 
PPI treatment is mandatory 
 
In the event a potential participant is in receipt of prokinetics and/or H2RA alongside PPIs, sites are 
encouraged to contact the TIPAL CI, via the NCTU trial team for guidance. 
 
FEV1/FVC review 
FEV1/FVC ratios should be assessed at screening from the most recent spirometry assessments taken 
in the clinic recorded in patient notes. 
 
Significant co-existing respiratory disease 
Participants may have co-existing respiratory disease/conditions provided they do not exhibit a 
greater effect than IPF, i.e. IPF must have greater impact on symptom burden than the other 
condition(s). 
 
Significant co-morbidity review 
Investigators are encouraged to contact the TIPAL CI, via the NCTU trial team, for guidance in assessing 
eligibility in relation to exclusion criterion six prior to approaching the patient about the trial if 
required. 
 
Magnesium 
Magnesium deficiency was defined based on 0.7 - 1.0mmol/L being regarded as a typical normal 
range(43). Magnesium must be assessed within baseline safety bloods and reviewed by a clinician 
prior to randomisation. 
 
6.3.1.5 Co-enrolment Guidance 
Concurrent participation in clinical trials of investigational medical products is not permitted. 
However, participants may be entered into other observational studies given prior agreement from 
the CI of both studies.  
6.3.1.6 Screening Procedures and Pre-randomisation Investigations 
Written informed consent to enter and be randomised into the trial must be obtained from 
participants after explanation of the aims, methods, benefits and potential hazards of the trial and 
BEFORE any trial-specific procedures. The only procedures that may be performed in advance of 

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written informed consent being obtained are those that would be performed on all patients in the 
same situation as part of usual standard of care.  
6.4 
Interventions 
6.4.1 
Active treatment arm 
6.4.1.1 Products 
Oral lansoprazole (generic).  
6.4.1.2 Treatment Schedule 
Participants will be asked to take 30mg (as 2 x 15mg capsules) twice daily (a total of four capsules per 
day: two in the morning and two in the evening), 12 hours apart, for 12 months. IMP should be taken 
at least 30 minutes before food.  
6.4.1.3 Dispensing 
Participants will have investigational medicinal product (IMP) dispensed 6 monthly. The IMP will be 
supplied in packages providing one month’s supply. IMP will be shipped to the participant’s home 
address by the study’s central pharmacy. A dosing card will be dispensed with the IMP stating the 
required treatment schedule. 
6.4.1.4 Dose Modifications, Interruptions and Discontinuations 
Treatment should be reduced to 15mg (as 1 x 15mg capsule) twice daily (a total of two capsules per 
day: one in the morning and one in the evening), at least 30 minutes before food, in those confirmed 
or suspected of developing adverse reactions as outlined below: 
• 
Respiratory tract infection and pneumonia 
• 
Clostridium difficile infection  
• 
Hypomagnesaemia defined as magnesium levels of ≤0.6mmol/L 
Participants with moderate to severe liver impairment (defined as 7 or more points (B/C class) on the 
Child Pugh score) who meet the eligibility criteria, should be prescribed the reduced dose throughout 
their involvement in the study. 
Trial treatment dose may be reduced to 15mg (1 x 15mg capsule) due to patient and/or clinician 
discretion. 
Site staff should ensure that all reports of these adverse effects are recorded on the electronic Case 
Report Form (eCRF) as completely as possible.  
Participants will be administered a new dosing card containing details of the reduced treatment 
schedule; the superseded dosing card should be returned to site, by post/freepost/courier or in 
person, at the next visit following dose reduction. 
If a participant forgets to take a dose and it is more than 24 hours after their scheduled dose, they 
should omit the missed dose and take the next dose when it is due. Participants must not take a double 
dose to make up for a forgotten dose. Interruptions should be avoided where possible, any reported 
should be recorded on the eCRF. 

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6.4.2 
Placebo Arm 
6.4.2.1 Products 
Placebo (manufactured to appear identical to IMP). 
6.4.2.2 Treatment Schedule 
Participants will be asked to take 2 capsules twice daily, 12 hours apart, for 12 months (a total of 
four capsules per day: two in the morning and two in the evening). Treatment should be taken at 
least 30 minutes before food.  
6.4.2.3 Dispensing 
The TIPAL trial is a double-blind study and so dispensing for the placebo arm will be managed 
identically to the active arm (see section 6.4.1.3).  
6.4.2.4 Dose Modifications, Interruptions and Discontinuations 
Treatment may be reduced to 1 capsule twice daily (a total of two capsules per day: one in the morning 
and one in the evening), at least 30 minutes before food, in those developing adverse reactions (see 
section 6.4.1.4), at the discretion of the PI or by participant choice. The reason for dose modification 
will be documented in the eCRF. Participants will be administered a new dosing card containing details 
of the reduced treatment schedule; the superseded dosing card should be returned to site, by 
freepost/courier or in person, at the next visit following dose reduction. 
If a participant forgets to take a dose and it is more than 24 hours after their scheduled dose, they 
should omit the missed dose and take the next dose when it is due. Participants must not take a double 
dose to make up for a forgotten dose. Interruptions should be avoided where possible, any reported 
should be recorded on the eCRF. 
6.4.3 
Accountability 
The central pharmacy will be responsible for drug accountability for all sites, this includes records of 
drug and placebo received at the pharmacy, dispensed to participants and unused drug and will ensure 
batch recall is possible in event of it being necessary. The central pharmacy are also responsible for 
ensuring IMP is handled and stored appropriately, dispensed accurately and for shipping IMP to each 
participant’s home address on a 6 monthly basis during trial participation (upon receipt of an 
appropriately signed prescription).   
IMP will be returned to the central pharmacy for destruction. 
6.4.4 
Compliance and Adherence 
Compliance to study treatment, in the form of returned capsule counts, will be monitored as part of 
drug accountability at relevant visits as outlined in section 6.6. 
6.4.5 
Concomitant Care 
Standard Care 
All participants will receive treatment as usual for their IPF regardless of randomisation into this trial. 
Standard care will be as defined by NICE guidelines (www.nice.org.uk/CG163) including anti-fibrotic 
therapy, pulmonary rehabilitation, oxygen, transplant referral and palliative care input as appropriate. 
Comorbidities are identified and managed according to individual disease-specific guidelines. All 
participants (in the control and intervention arms) will be provided with the publicly available British 
Digestive Disorder Charity (Guts UK (formerly known as CORE)) patient information leaflet about 

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heartburn and reflux at entry into the study/following consent for patients attempting a PPI washout 
period. This provides information about the causes, investigations and treatment for reflux including 
lifestyle changes. Dyspepsia will be managed with lifestyle changes, reviewing the requirement for 
medications causing dyspepsia and treatment with antacids and alginates in both groups as required 
at any time in the study. Participants still symptomatic with these treatments, or requiring PPIs for 
oesophagitis or duodenal ulcer, will be withdrawn from the study.  
Any incidental findings identified as a result of new scans obtained within the CT scan sub-study will 
be reported and followed-up at the discretion of the local clinical team at the participant’s recruiting 
site. 
Concomitant medication 
Patients receiving anti-fibrotic medication for their IPF must have been in receipt of the treatment for 
at least 4 weeks prior to randomisation and not have any planned amendments for at least 4 weeks 
post-randomisation. Use of antacids and raft alginates is permitted.  
All concomitant medication including over the counter and herbal remedies will be recorded at 
baseline with any changes during participation recorded.  
Non-permitted medication 
The following medications are not permitted due to interactions, described in the SPC, with 
lansoprazole as outlined below and thus patients are excluded from the study (see section 6.3.1.3): 
• 
HIV protease inhibitors – e.g. atazanavir- due to significant reduction in bioavailability when 
co-administered with lansoprazole 
• 
Ketoconazole and itraconazole – absorption is enhanced by the presence of gastric acid thus 
co-administration with lansoprazole may result in sub-therapeutic concentrations of these 
drugs 
• 
Methotrexate – serum levels may be elevated and prolonged (including of its metabolite) 
when co-administered with lansoprazole 
• 
Tacrolimus - increased plasma concentrations when co-administered with lansoprazole 
• 
Fluvoxamine – increases plasma concentrations of lansoprazole significantly 
• 
Prokinetics – due to potential to contaminate study results. Sites are therefore advised to 
review patient’s concomitant medication and amend prescriptions for prokinetics (cisapride, 
domperidone, metoclopramide, erythromycin, prucalopride etc.) accordingly if trial 
participation is otherwise deemed safe and appropriate and the patient wishes to consent 
(see exclusion criteria 2).  
N.B. Erythromycin is permitted for short-term antibiotic use only during the trial. 
Increased monitoring 
Concomitant medication requiring increased monitoring: 
• 
Warfarin – monitored for increase in international normalised ratio (INR) and prothrombin 
time. 
• 
Digoxin – increased plasma levels when co-administered with lansoprazole 

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• 
Theophylline – reduced plasma concentrations when co-administered with lansoprazole 
Sites are responsible for providing increased monitoring for participants receiving the 
abovementioned medication(s) and for any others the PI or sub-investigator deem appropriate. 
Results of additional monitoring procedures do not need to be recorded on the eCRF. 
Additional guidance 
Sucralfate and antacids may decrease the bioavailability of lansoprazole. Therefore, lansoprazole 
should be taken at least 1 hour after taking these medicinal products. 
Spirometry contra-indications 
Participants should not complete spirometry assessments at home where they are known or 
suspected to be experiencing any of the contra-indications listed below. This list is correct at the 
current time. Participants are informed of contra-indications to spirometry in the PIS, ethically 
approved study-specific spirometry leaflet and at their initial spirometry training call. 
• 
Haemoptysis of unknown origin (forced expiratory manoeuvre may aggravate the underlying 
condition) 
• 
Pneumothorax 
• 
Unstable cardiovascular status (forced expiratory manoeuvre may worsen angina or cause 
changes in blood pressure) or ‘recent’ myocardial infarction or pulmonary embolus 
• 
Thoracic, abdominal or cerebral aneurysms (danger of rupture due to variation in thoracic 
pressure) 
• 
Recent eye surgery (e.g. cataract). Recent is defined as within 3 weeks, however the advice of 
the participants attending physician will take precedence 
• 
Presence of an acute illness or symptom that might interfere with test performance (e.g. 
nausea, vomiting) 
• 
Recent thoracic or abdominal surgery 
Adverse events and interruptions to spirometry assessments must be recorded on the eCRF. 
6.4.6 
Overdose of Trial Medication 
The SPC for Lansoprazole states: “The effects of overdose on lansoprazole in humans are not known 
(although the acute toxicity is likely to be low) and, consequently, instruction for treatment cannot be 
given. However, daily doses of up to 180 mg of lansoprazole orally and up to 90 mg of lansoprazole 
intravenously have been administered in trials without significant undesirable effects.” 
Treatment is symptomatic and supportive care. Observe the patient for at least four hours and 
monitor Urea & Electrolytes (U&Es) and full blood count (FBC) in symptomatic cases. Lansoprazole is 
not significantly eliminated by haemodialysis. If necessary, gastric emptying, charcoal and 
symptomatic therapy is recommended.  
6.4.7 
Protocol Treatment Discontinuation 
In consenting to the trial, participants are consenting to trial treatment, trial follow-up and data 
collection. However, an individual participant may stop treatment early or be stopped early for any of 
the following reasons: 

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• 
Unacceptable treatment toxicity or adverse event 
• 
Inter-current illness that prevents further treatment 
• 
Any change in the participant’s condition that in the clinician’s opinion justifies the 
discontinuation of treatment 
• 
Withdrawal of consent for treatment by the participant 
• 
Where 
patients 
are 
unable 
or 
unwilling 
to 
continue 
to 
undertake 
study 
measurements/activities, the decision as to whether the participant should continue with trial 
treatment and/or follow-up assessments will be at the discretion of the local PI and/or CI. 
As participation in the trial is entirely voluntary, the participant may choose to discontinue trial 
treatment at any time without penalty or loss of benefits to which they would otherwise be entitled. 
Although not obliged to give a reason for discontinuing their trial treatment, a reasonable effort 
should be made to establish this reason, whilst remaining fully respectful of the participant’s rights. 
Participants who discontinue protocol treatment, for any of the above reasons, should remain in the 
trial for the purpose of follow up and data analysis.  
6.5 
Outcomes 
6.5.1 
Primary Outcome 
The primary outcome will be disease progression as assessed by absolute change in % predicted forced 
vital capacity (FVC) at 12 months post-randomisation of lansoprazole versus placebo. 
6.5.2 
Secondary Outcomes 
The following secondary outcomes will be assessed comparing lansoprazole to placebo: 
Cough frequency: 
• 
Measured using a VitaloJAK cough monitor over a 24 hour period at baseline and 3 months 
post-randomisation 
• 
160 patients (80 per group) will be included in this secondary outcome sub-study analysis 
Cough Score, general Health Related and Disease Specific Quality of Life and Breathlessness: 
Participants to complete the following questionnaires at baseline and 3, 6, 9 and 12 months post-
randomisation to assess outcomes listed: 
• 
Cough score using a 100mm VAS 
• 
Cough related quality of life as indicated by the LCQ(44) 
• 
Breathlessness measured by the Medical Research Council (MRC) Dyspnoea Scale(45) 
• 
Disease specific quality of life measured using the K-BILD questionnaire(46) 
• 
Health-related quality of life indicated by the EQ5D-5L questionnaire to estimate quality 
adjusted life years(47) 
Lung Function: 
• 
total DLCO (corrected for haemoglobin) will be measured at baseline and 3, 6 and 12 months 
post-randomisation where possible. (NB measurements will be taken regardless of whether 

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measurements were taken at the previous timepoint, i.e. DLCO may be measured at baseline 
and 12 months only) 
• 
FVC and FEV1 will be measured at baseline and weekly post-randomisation at home and 
obtained from laboratory assessments at baseline 3, 6 and 12 months post-randomisation 
where possible 
• 
the decline and rate of decline in absolute %FVC based on %FVC measured weekly from 
baseline to 12 months post-randomisation 
Acceptability: 
• 
measured by a study-specific non-validated questionnaire completed at 12 months post-
randomisation 
Sleep: 
• 
participant risk of sleep apnoea will be estimated by the STOP-bang questionnaire at 12 
months post-randomisation 
• 
participant sleep quality will be assessed using the short PSQI at baseline and 3 and 12 months 
post-randomisation 
Reflux characteristics: 
• 
a DeMeester score will be assessed at baseline and 3 and 12 months post-randomisation 
Safety, Hospitalisation and Death: 
• 
adverse events with particular relevance to confirmed or suspected diagnoses of respiratory 
tract infection and pneumonia, Clostridium difficile infection and hypomagnesaemia will be 
recorded at each study visit following randomisation 
• 
progression free survival (with progression defined as time from date of randomisation to 
week of all-cause death, lung transplant, a 10% absolute reduction in FVC % predicted from 
baseline measured by domiciliary spirometry) 
• 
hospital-free survival defined as death (all causes) or first non-elective (all cause) hospital 
admission 
• 
Respiratory related hospital free survival 
WRVS: 
• 
difference in change in weighted reticulovascular score (WRVS) between baseline and 12 
months post-randomisation will be assessed using the Brainomix e-ILD programme.  
6.5.3  Study within a Trial (SWAT): The influence of patient support group delivered research 
awareness strategies on research recruitment and retention (PURPOSE Study). 
The PURPOSE Study is a Study Within A Trial (SWAT), designed to evaluate the potential of patient 
support groups to improve recruitment and retention rates in clinical trials. The PURPOSE study will 
run in parallel to the TIPAL trial and will include up to 75 ILD patient support groups in the UK.  
NHS Trusts participating in the TIPAL trial will not be required to undertake any additional activities 
relating to the PURPOSE Study above those already required for TIPAL.  

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The PURPOSE Study was registered on the Northern Ireland Network for Trials Methodology Research 
registry on the 21.09.2020 (Reference: SWAT 132) 
Further details of the PURPOSE Study are provided in Appendix 1of this protocol. It is being 
implemented jointly with Action for Pulmonary Fibrosis (APF). 

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6.6 
Participant Timeline 
Figure 2. Schedule of Assessments 
 
Screening1 
Baseline1 
Randomisation 
3 Months2, 3  
(+/- 4 
weeks) 
6 Months3, 4 
(+/- 4 
weeks) 
9 Months3, 4 
(+/-4 weeks) 
12 Months3,4 
(+/-4 weeks) 
Informed Consent 
X 
 
 
 
 
 
 
Eligibility 
X 
 
 
 
 
 
 
Demographics, medical 
history and patient 
characteristics collected 
 
X 
 
 
 
 
 
Standard care CT scan 
collected/new scan 
performed10 
 
X 
 
 
 
 
X 
Randomisation 
 
 
X 
 
 
 
 
IMP dispensed 
 
 
X 
 
X 
 
 
IMP adherence 
 
 
 
 
X 
 
X 
Weekly domiciliary 
spirometry 
Undertaken weekly throughout trial 
Lung function (including 
spirometry & gas 
transfer) assessments 
where possible see 
section 6.10.18  
 
X 
 
X 
X 
 
X 

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Screening1 
Baseline1 
Randomisation 
3 Months2, 3  
(+/- 4 
weeks) 
6 Months3, 4 
(+/- 4 
weeks) 
9 Months 3,4 
(+/-4 weeks) 
12 Months3, 
4 
(+/-4 weeks) 
Cough count sub-study 
 
X 
 
X 
 
 
 
Leicester Cough 
Questionnaire, MRC 
Dyspnoea Scale, King’s 
Brief ILD Questionnaire, 
EQ-5D-5L & Cough score 
questionnaire 
 
X 
 
X 
X 
X 
X 
Study specific 
questionnaire and R-Scale 
for PF 
 
X 
 
 
 
 
X 
STOP-Bang 
Questionnaire, NIHR PRES 
survey & feedback 
questionnaire 
 
 
 
 
 
 
X 
Short Pittsburgh Sleep 
Quality Index and 
DeMeester Score 
 
X 
 
X 
 
 
X 
Adverse events 
 
 
 
X 
X 
X 
X 
Safety bloods (FBC, U&Es, 
LFT, Calcium and 
Magnesium)4 
 
X 
 
X9 
X9 
X9 
X 
Blood sample for 
genotype analysis5 
 
X 
 
X 
X 
X 
X 
Research bloods6 
 
X 
 
 
 
 
X 

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1 Where participants are not attending in person consent, spirometry, cough count sub-study and collection of up-to-date trial data not available in the 
patient notes will take place remotely via phone/video call. Questionnaires will be completed and returned by freepost/courier/electronically. Safety bloods 
will be taken at GP surgery, according to local policy for remote bloods or site. 
2 Where participants are not attending in person adverse events recorded during phone/video call with questionnaires completed and returned by 
freepost/courier/electronically and safety bloods taken at GP surgery, according to local policy for remote bloods or site. Cough count sub-study monitoring 
will be conducted remotely via phone/video call, or in person, at 3 months for sub-study participants. 
3 Visits should take place within 4 weeks either side of scheduled date. 
4 10mls blood to be taken for safety analyses at all study timepoints. Baseline bloods are acceptable within 6 months of randomisation assuming no 
change to the patient’s clinical condition at the discretion of the PI. 
5 10mls blood to be taken for genotype analysis once throughout the study at any timepoint. 
6 20mls blood to be taken for research blood analyses at baseline and 12 months where possible. 
7TIPAL participants will be asked to complete the NIHR PRES survey at 12 months if they are willing 
8This refers to laboratory-based lung function (including spirometry and gas transfer) assessments conducted as part of standard care only 
9Safety bloods to be taken only if deemed necessary by the PI or sub-I, due to a relevant change in the participants’ clinical status 
10Standard care chest HRCT scans will be collected from all trial participants. Patients consenting to the CT scan sub-study will undergo additional chest 
HRCT scans at baseline and/or 12 months, if no standard care scans are available, provided they are willing. New scans are required to be performed +/-3 
months of randomisation/12 months post-randomisation. 
 
NB where study assessments are completed within 28 days of randomisation for baseline or within the timeframes specified above, these observations can 
be recorded at the relevant time point to avoid patients having to repeat assessments unnecessarily provided they adhere to the requirements of this 
protocol. However, baseline bloods are acceptable within 6 months of randomisation assuming no change to the patient’s clinical condition at the 
discretion of the PI. Baseline questionnaires are acceptable within 6 weeks of randomisation. 
 
Participants are permitted to repeat baseline FVC measurements upon receipt of the domiciliary spirometer to familiarise themselves on use of the 
equipment. Baseline FVC measurements should be attempted after a successful PPI washout (where required), for a period up to a maximum of 28 days 
upon which, a decision as to whether to proceed to trial enrolment will be made by the local PI in collaboration with the CI and patient where appropriate if 
clinically consistent results have been challenging to obtain. Baseline and 12 month domiciliary spirometry measurements should be repeated daily for 5 
days.  

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6.6.1  Participant Assessments 
6.6.1.1 Visit settings 
All study visits may occur at the recruiting site or remotely e.g. at the participant’s home with safety 
bloods taken at the participant’s GP surgery or according to local policy for remote bloods. Each visit 
will occur in the setting best suited to the participant and the recruiting site. The study is intended to 
be conducted remotely throughout if required, as such there is no minimum on-site visit requirement. 
However, CT scan sub-study participants requiring new scans to be taken will be required to attend 
the recruiting site for the scans to be performed; all other study assessments for the relevant study 
visit may still occur remotely. 
Where remote visits are conducted, research staff (local or at NCTU depending on the assessment) 
will conduct phone / video calls to counsel participants where necessary i.e. in completion of 
domiciliary spirometry assessments, fitting cough monitors, to collect updated/trial data etc. 
In the event participants attend the site for standard care appointments and complete full lung 
function tests including spirometry and gas transfer assessments, this data should be entered onto 
the BTS IPF registry. Domiciliary spirometry assessments must continue to be completed weekly as 
outlined in section 6.10.1. 
Where safety bloods are to be taken at the participant’s GP surgery or other facility according to local 
policy for remote bloods, site staff will need to request the bloods are taken, ensure they are received 
and processed at the local laboratory and an authorised clinician will need to review the results at 
each timepoint. 
6.6.1.2 Participant Correspondence 
The NCTU TIPAL trial team will contact trial participants directly as required to facilitate centrally 
coordinated study assessments and data collection, and provide technical support where needed, 
where written informed consent is recorded to do so. Participants will also receive notifications, on 
their study tablet, to inform them of upcoming study appointments. 
6.6.1.3 Screening 
The PI or delegate is responsible for identifying eligible patients to invite to participate in the study in 
accordance with the eligibility criteria defined in section 6.3.1. Eligible patients will be approached in 
clinic or identified via a local database/IPF patient list or clinical records and provided with the relevant 
study specific literature explaining the aims, methods and potential hazards and benefits of 
participation in the trial (see section 6.8.1) either in person or by mail. Patients will be given adequate 
time to consider their participation prior to the site seeking written informed consent, electronically 
or paper-based, following consultation in person or via phone/video call. Informed consent will be 
sought prior to completion of any assessments/procedures etc. required by the study outside the 
remit of usual care for patients in the same situation. A PPI washout period must then be completed 
where required. 
Consenting patients will receive a TIPAL study supplies kit containing a CE marked calibrated 
domiciliary spirometer and mouthpieces, a smart device (i.e. smartphone or tablet) with pre-installed 
CE marked software required for the study and a pre-loaded data sim card if necessary (with sufficient 
data for trial purposes) for use during the trial. Supplementary training spirometry materials, both 
electronic and paper-based, will also be provided within this kit.  

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Patients consenting to the sub-study will also receive a cough monitor, and may receive a wrist-based 
accelerometer, with instructions and shipping labels for return, contact details for support if needed 
and a supplementary leaflet ahead of each monitoring period.  
Baseline FVC measurements should be attempted for a period up to a maximum of 28 days (unless 
extenuating circumstances apply), after successful completion of a PPI washout period (where 
required). This timeframe may be extended where required in the event of delays to baseline 
assessments. 
PPI use has been associated with an increase of 25-50% in osteoporosis(33). This should be considered, 
along with other risk factors for osteoporosis, by the recruiting clinician prior to enrolment in the trial 
who may wish to increase measures for reducing osteoporosis risk. 
6.6.1.4 Baseline 
Once written informed consent has been obtained, either in person, electronically or remotely via 
video/phone, and a successful PPI washout period (where required), the patient will be required to 
complete the following baseline assessments: domiciliary spirometry assessments, Leicester Cough 
Questionnaire, MRC Dyspnoea scale, K-BILD questionnaire, EQ-5D-5L questionnaire, a study-specific  
questionnaire, cough score questionnaire, short Pittsburgh Sleep Quality Index, DeMeester score, R-
Scale for PF, safety bloods,  genotype and research bloods where possible, and laboratory spirometry 
+/- gas transfer where possible (i.e. as part of standard care). Patient demographics, smoking status 
(including vaping), alcohol intake, body mass index (BMI), co-morbidities and relevant medical history 
and concomitant medication (including over-the-counter antacids) will be recorded in the eCRF. 
Where possible this data will be obtained from the BTS Registry, otherwise patient notes will be 
reviewed or patients asked directly for the relevant data.  
For all participants, where consent to provide them has been obtained, a pseudoanonymised copy of 
the most recent volumetric, high-resolution CT (HRCT) chest scan should be uploaded to the 
eCRF/relevant platform. If a HRCT scan is not available, then a pseudoanonymised copy of the 
diagnostic or most recent full lung coverage thoracic imaging volumetric scan should be uploaded to 
the eCRF/relevant platform.  
For patients consenting to the CT scan sub-study, if the most recent HRCT is not within +/- 3 months 
of randomisation, a new scan is required to be performed. Scanning requirements are outlined fully 
in the CT scan sub-study work instruction available from the TIPAL trial manager. In summary, scans 
should be conducted to produce standard of care (SOC), thin slice (ideally ≤2mm), volumetric, non-
contrast enhanced images from supine HRCT scans covering the complete lung at full inspiration.  
Blood samples (full blood count (FBC), urea and electrolytes (U&Es), liver function tests (LFTs), calcium 
and magnesium) will be taken for safety purposes at the GP surgery, according to local policy for 
remote bloods or recruiting site prior to enrolment. Results of safety bloods taken remotely/at the GP 
surgery must be reviewed by an authorised clinician. Baseline safety bloods are acceptable within 6 
months of randomisation assuming there has been no change to the clinical condition of the patient 
at the discretion of the PI. 
Where participants are attending baseline visits at the recruiting centre, and provided it is feasible and 
the participant is willing to do so, a separate research blood sample may be taken. A further blood 

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sample may also be taken and stored for genotyping for consenting participants (see section 6.6.2 for 
sample details); this will be taken once only at the recruiting site and may be taken at any timepoint 
following consent. 
Domiciliary spirometry assessment guidance is provided in section 6.10.1. Participants will be trained 
by video/phone call(s) with trained staff on how to reliably complete domiciliary spirometry 
assessments throughout the study. Participants should complete spirometry assessments daily for 5 
days at this timepoint. 
Where the abovementioned assessments and/or data is captured as part of standard care within 28 
days of randomisation within the requirements of this protocol, these observations may be recorded 
as the baseline values to avoid patients having to repeat procedures unnecessarily. Please note, 
baseline safety bloods are acceptable within 6 months of randomisation, unless there is any change 
in the clinical condition of the participant, and baseline questionnaires are acceptable within 6 weeks 
of randomisation. 
Participants eligible and consenting to the cough sub-study will also be required to undergo objective 
cough monitoring prior to starting trial treatment. Participants will be provided with a wearable cough 
recording device, a VitaloJAK monitor, to capture cough count over a 24-hour period. In addition, sub-
study participants may also be invited to wear a wrist-based accelerometer during this 24h period to 
monitor activity levels and sleep concurrently. Activity and sleep monitoring is an optional additional 
component of the sub-study; participants are therefore able to participate in the cough monitoring 
aspect only. Research staff trained in counselling participants on safe, accurate and reliable use of the 
devices and data extraction and processing following the monitoring period prior to activation to 
recruitment will conduct sub-study monitoring video calls with consenting participants to fit the 
equipment and initiate recording(s).Alternatively, participants may be fitted with the cough monitor 
in person where visits to the recruiting site are completed or participants may be counselled to fit the 
monitors remotely via video/phone calls with trained staff. Cough, and activity, monitors will be 
returned to the trials unit by courier upon completion of the monitoring period. 
Questionnaires will be completed on paper or electronically. During the consent process participants 
will be offered the option on how to complete questionnaires. Electronic questionnaires will be 
emailed via REDCap to the participant’s personal email address and/or trial-specific email address (set-
up for logistical reasons to facilitate remote spirometry assessments) depending on participant 
preference, for those opting to provide responses electronically. Participants opting not to receive the 
questionnaires electronically will complete paper copies of each questionnaire at each visit for return 
via courier or freepost to NCTU. 
6.6.1.5 Randomisation 
Upon completion of and when results of all baseline assessments are known, site staff delegated the 
appropriate responsibility will have the option to randomise the patient. Treatment allocation will be 
determined by a computer-generated randomisation code via a web-based system facilitated by 
NCTU. A semi-blinded randomisation outcome will be circulated via email to the central research 
pharmacy only. The site PI and delegates will receive a blinded randomisation notification email. 

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An initial 6-month supply of IMP will be dispensed by the central pharmacy following confirmation of 
treatment allocation and receipt of a completed trial prescription signed by the PI or delegated sub-
investigator. The central pharmacy are responsible for arranging shipment to the participant. 
Participants will be instructed to commence weekly domiciliary spirometry measurements from the 
date of receipt of their study drug. 
The participant’s General Practitioner (GP) will be informed of the patient’s randomisation into the 
study. 
6.6.1.6 3 Months 
The following assessments should be completed 3 months post-randomisation: full lung function 
(including spirometry and gas transfer assessments) where possible (i.e. as part of standard care), 
domiciliary spirometry data completeness review, Leicester cough questionnaire, MRC dyspnoea 
scale, K-BILD questionnaire, EQ-5D-5L questionnaire, cough score questionnaire, short Pittsburgh 
Sleep Quality Index, DeMeester score, adverse events and safety bloods (FBC, U&Es, LFTs, calcium and 
magnesium).  
Site staff will contact participants by phone/video call to assess adverse events and any changes to 
concomitant medication and/or medical history where visit occurs remotely. 
If deemed necessary by the PI or sub-I, due to a relevant change in the participants’ clinical status, 
safety bloods will be taken at the recruiting site where feasible or at the participants GP surgery or 
according to local policy for remote bloods for remote visits. Results of safety bloods taken 
remotely/at the GP surgery must be reviewed by an authorised clinician. Genotype blood samples may 
be collected for consenting participants only if visit occurs on site and a sample has not been obtained 
previously.  
Participants will be retrained in completing domiciliary spirometry assessments if needed. 
Where these assessments are completed as part of standard care and within the time frame permitted 
by and requirements of this protocol, the results may be recorded for those required at the 3 month 
study time point. 
Participants completing paper-based questionnaires will be provided with a freepost envelope to 
return them to the trials unit, otherwise they will be completed electronically via REDCap. 
Cough sub-study participants will again be required to complete objective cough monitoring over a 24 
hour period at applicable sites. Participants will be provided with a wearable VitaloJAK device to 
monitor cough frequency and coached by video call with trained research staff on how to fit the 
equipment and initiate recording(s). In addition, participants may again be invited to wear a wrist-
based accelerometer to measure concurrent activity levels and sleep during this 24h period. A courier 
will again be arranged to collect the device(s) from the participant’s home for return to the trials unit. 
This visit may take place +/- 4 weeks of the scheduled date. 
6.6.1.7 6 Months 
The following assessments should be completed 6 months post-randomisation: full lung function 
(including spirometry and gas transfer assessments) where possible (i.e. as part of standard care), 

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domiciliary spirometry data completeness review, Leicester cough questionnaire, MRC dyspnoea 
scale, K-BILD questionnaire, EQ-5D-5L questionnaire, cough score questionnaire, adverse events and 
safety bloods (FBC, U&Es, LFTs, calcium and magnesium).  
IMP adherence will be measured by a pill count completed by site staff/participant during the visit. 
This may be conducted at site where visits take place in person or participants will be asked to confirm 
the number of remaining capsules via phone/video call. If the participant has reduced their trial 
treatment dose due to adverse reaction(s) this should be documented in the eCRF and a new dosing 
card administered. Participants should return the superseded dosing card either in person or via 
freepost envelope where possible. 
Site staff will contact participants by phone/video call to assess adverse events and any changes to 
concomitant medication and/or medical history where visit occurs remotely. 
If deemed necessary by the PI or sub-I, due to a relevant change in the participants’ clinical status, 
safety bloods will be taken at the recruiting site where feasible or at the participants GP surgery or 
according to local policy for remote bloods for remote visits. Results of safety bloods taken remotely/ 
at the GP surgery must be reviewed by an authorised clinician. Genotype blood samples may be 
collected for consenting participants only if visit occurs on site and a sample has not been obtained 
previously.  
Participants will be retrained in completing domiciliary spirometry assessments if needed. 
Participants completing paper-based questionnaires will be provided with a freepost envelope to 
return them to the trials unit, otherwise they will be completed electronically via REDcap. 
Where these assessments are completed as part of standard care and within the time frame permitted 
by and requirements of this protocol, the results may be recorded for those required at the 6 month 
study time point. 
Participants will be supplied with a final 6 month supply of IMP as prescribed by the PI or delegate, 
dispensed by the central pharmacy. Site staff to ensure patient is administered dosing card with 
correct treatment schedule. The central pharmacy are responsible for arranging shipment to the 
participant. 
Where these assessments are completed as part of standard care and within the time frame permitted 
by and requirements of this protocol, the results may be recorded for those required at the 6 month 
study time point. 
This visit may take place +/- 4 weeks of the scheduled date. 
6.6.1.8 9 Months 
The following assessments will be completed 9 months post-randomisation: domiciliary spirometry 
data completeness review, Leicester cough questionnaire, MRC dyspnoea scale, K-BILD, EQ-5D-5L, 
cough score questionnaire, safety bloods (FBC, U&Es, LFTs, calcium and magnesium) and adverse 
events. 
Participants will be provided with a free post envelope to return completed paper-based 
questionnaires to the trials unit, otherwise they will be completed electronically via REDcap.  

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Site staff will contact the participant via phone/video call to record any adverse events experienced 
and any changes to concomitant medication and/or medical history where this visit occurs remotely.  
If deemed necessary by the PI or sub-I, due to relevant change in the participants’ clinical status, safety 
bloods will be taken at the recruiting site where feasible or at the participants GP surgery or according 
to local policy for remote bloods for remote visits. Results of safety bloods taken remotely/ at the GP 
surgery must be reviewed by an authorised clinician. Genotype blood samples may be collected for 
consenting participants only if visit occurs on site and a sample has not been obtained previously.  
Participants will be retrained in completing domiciliary spirometry assessments if needed.  
This visit may take place +/- 4 weeks of the scheduled date. 
6.6.1.9 12 Months 
The following assessments should be completed 12 months post-randomisation: full lung function 
(including spirometry and gas transfer assessments (where possible i.e. as part of standard care), 
domiciliary spirometry data completeness review, Leicester cough questionnaire, MRC dyspnoea 
scale, K-BILD questionnaire, EQ-5D-5L questionnaire, cough score questionnaire, study specific  
questionnaire, DeMeester score, STOP-bang questionnaire, the short Pittsburgh Sleep Quality Index 
questionnaire, R-Scale for PF, adverse events, safety bloods (FBC, U&Es, LFTs, calcium and magnesium) 
and research bloods where possible.  
All participants will be asked if they are willing to complete a participant feedback form. This is optional 
to give them the opportunity to appraise their research experience. Electronic or paper completion is 
permitted depending on participant preference. Where paper completion is preferred, a freepost 
return envelope (to return to NCTU) will be provided. Participants will be reimbursed with a shopping 
voucher for their time to complete this optional questionnaire. Vouchers will be distributed by the 
NCTU trial team upon receipt of completed questionnaire. 
For all participants, where consent to provide them has been obtained and a new (relative to that 
provided at baseline) HRCT chest scan performed as part of standard care is available, a 
pseudoanonymised copy should be uploaded to the eCRF/relevant platform. If a HRCT scan is not 
available, but a new (relative to that provided at baseline) full lung coverage thoracic imaging 
volumetric scan is available, then a pseudoanonymised copy of this should be uploaded to the 
eCRF/relevant platform.  
For patients consenting to the CT scan sub-study, if the most recent HRCT is not within +/- 3 months 
of the 12 months anniversary of randomisation, a new scan is required to be performed. Scanning 
requirements are outlined fully in the CT scan sub-study work instruction available from the TIPAL trial 
manager. In summary, scans should be conducted to produce standard of care (SOC), thin slice (ideally 
≤2mm), volumetric, non-contrast enhanced images from supine HRCT scans covering the complete 
lung at full inspiration. 
IMP adherence will be measured by a pill count completed by site staff/participants during the visit. 
If the participant has reduced dose due to adverse reaction(s) this should be documented in the eCRF. 
This may be conducted at site where visits take place in person or participants will be asked to confirm 
the number of remaining capsules via phone/video call. Dosing card(s) and any unused trial 
medication should also be returned. NB where the visit occurs remotely, return of unused trial 

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medication by courier from the participant to the recruiting site for interim storage prior to 
destruction, will be arranged by the trials unit. 
Safety bloods will be taken at the recruiting site where feasible or at the participants GP surgery or 
according to local policy for remote bloods for remote visits.  Results of safety bloods taken 
remotely/at the GP surgery must be reviewed by an authorised clinician. Genotype blood samples may 
be collected for consenting participants only if visit occurs on site and a sample has not been obtained 
previously. Research bloods will be taken separately if possible during an in person visit at the 
recruiting site (see section 6.6.2 for sample details).  
Participants should complete spirometry assessments daily for 5 days at this timepoint. 
Site staff will contact participants by phone/video call to assess adverse events and any changes to 
concomitant medication and/or medical history where visit occurs remotely. 
Participants completing paper-based questionnaires will be provided with a freepost envelope to 
return them to the trials unit, otherwise they will be completed electronically via REDCap. 
The TIPAL study supplies (domiciliary spirometer and smart device) should be returned in person to 
site or via courier to the trials unit upon study completion. Equipment returned in person to recruiting 
sites will be returned to the trials unit periodically. 
Where these assessments are completed as part of standard care and within the time frame permitted 
by and requirements of this protocol, the results may be recorded for those required at the 12 month 
study time point. 
This visit may take place +/- 4 weeks of the scheduled date. 
6.6.2  Human Tissue Samples 
10mLs of whole blood will be taken for safety at baseline and 12 months post-randomisation. At 3, 6 
and 9 months post-randomisation, 10mLs of whole blood will be taken for safety only if deemed 
necessary by the PI or sub-I due to a relevant change in the participants’ clinical status. These may be 
taken and processed at the recruiting site or taken at the participant’s GP surgery or according to local 
policy for remote bloods and processed at the recruiting site or local laboratory in accordance with 
local standard procedures. 
10mLs of whole blood for genotype analysis will be taken at the recruiting site from consenting 
participants only once at any timepoint during their participation. If appropriately consenting 
participants do not attend any study visits in person at the recruiting site, it will not be possible to 
obtain a sample for genotype analysis. 
20mLs of whole blood for future research purposes will be taken at baseline and 12 months post-
randomisation at the recruiting site where possible. As study visits may be conducted remotely, it may 
not be possible to obtain samples from all participants at any or both timepoints. Zero, one or both 
research blood samples will be obtained from participants willing to provide samples for analysis in 
future research projects where possible.  
NB research and genotype samples may not be obtained even when onsite visits are conducted. 

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Relevant samples will stored at -80°C at recruiting sites, and transported to the Norwich Research Park 
Biorepository for genotyping or future analysis of any potential biomarker including but not limited to 
interstitial lung disease, infection or reflux, pending additional ethical approval, at a later date.  
Sample handling training will be provided to all sites prior to activation detailing sample collection, 
handling and storage procedures. Sites are responsible for ensuring samples collected remotely/at GP 
surgeries are requested, taken, shipped, processed, reviewed and reimbursed in accordance with 
standard NHS procedures. Detailed written instructions and appropriate tissue transfer agreements 
will be put in place prior to the transfer of relevant material.  
 
6.6.3 
Early Stopping of Follow-up 
Sites must inform NCTU of all forms of early trial discontinuation via the eCRF. In instances where a 
participant has decided to withdraw consent, it is essential for the site to establish which aspects of 
the trial the participant is withdrawing consent from.  
• 
If a participant chooses to discontinue their trial treatment, they should continue to be 
followed up as closely as possible to the follow-up schedule defined in the protocol, providing 
they are willing. They should be encouraged and facilitated not to leave the whole trial, even 
though they no longer take the trial treatment.  
• 
If a participant who has discontinued trial treatment no longer wishes to attend any remaining 
follow-up visits, relevant follow up data will continue to be collected from the registry during 
the trial providing the participant is willing for this to continue. 
• 
If, however, the participant exercises the view that they no longer wish to provide data either 
through study visits or remotely via the registry, this view must be respected and the 
participant withdrawn entirely from the trial. Data already collected will be kept and included 
in analyses according to the intention-to-treat principle for all participants who stop follow up 
early. Any samples provided by the participants, which have yet to be analysed will be 
destroyed and the registry will be updated so that no further data is provided to NCTU. 
Where patients are unable or unwilling to continue to undertake study measurements/activities, the 
decision as to whether the participant should continue with trial treatment and/or follow-up 
assessments will be at the discretion of the local PI and/or CI. 
Participants who stop trial follow-up early will not be replaced. 
6.6.4 
Participant Transfers 
If a participant moves from the area making continued follow up at their consenting centre 
inappropriate, every effort should be made for them to be followed-up at another participating trial 
centre. Written consent should be taken at the new centre, either electronically or paper-based 
following consultation either in person or via video/phone call, and then a copy of the participant’s 
CRFs should be provided to the new centre. Responsibility for the participant remains with the original 
consenting centre until the new consent process is complete. 
6.6.5 
Loss to Follow-up 
Sites will be asked to account for the vital status and details of admission to hospital for all patients 
who have consented to participate in the study regardless of whether they have withdrawn from the 

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intervention or study assessments. Patients will be asked to provide consent so that all follow-up 
information on overall or hospital free survival can be obtained from the BTS registry if required.  
6.6.6 
Trial Closure 
The end of the trial is defined as 4 months following the last follow-up visit of the last patient 
randomised, to allow for data entry and data cleaning activities to be completed. 
6.7 
Sample Size 
A sample size of 270 individuals, 135 per group, will provide 90% power to detect a minimal important 
difference (MID) of 4% reduction in % FVC versus placebo assuming a standard deviation of 9% (from 
the TIPAC trial) and a loss to follow-up rate of 20% (from the TIPAC and EME-TIPAC trials) and a 
significance level of 5%.  However, we will randomise 298 patients (149 per group) in order to account 
for 10% of patients being asymptomatic. 
 
The sample size was based on references which used lab-based spirometry devices, due to COVID-19 
the measurement that will be used is the home-based spirometry. The trial team felt it was simpler to 
leave the sample size as it was originally as there is a lack of data available on the variability of the 
outcome in the devices used and no reason to think that the MID would be different due to the 
different devices. The DMC will monitor the assumptions of the sample size calculation in accordance 
with the Terms of Reference. 
A sample size of 160 patients (80 per group) will provide 90% power to detect a ratio of geometric 
means of 0.6 of cough frequency, which is smaller than the published MID (48), assuming a coefficient 
of variation of 1 (from the PPIPF trial) and a loss to follow-up rate of 30%. 
 
For the CT scan sub-study, a sample size of 82 participants will provide 80% power to detect a 3.45% 
difference in WRVS at a 5% significance level, assuming a standard deviation of 5.6 and a correlation 
coefficient of 0.6. We will aim to recruit up to 100 participants to allow for a 20% loss to follow-up 
rate. In addition, for a secondary outcome to this sub-study, a sample size of 126 participants will 
provide 80% power to detect a difference in WRVS between the two treatment groups at 12 months. 
 
6.8 
Recruitment and Retention 
6.8.1 
Recruitment 
Patients will be identified mainly by review of ILD MDT meeting minutes or summaries. Identification 
will also be via screening patient registries, hospital medical records and databases of research 
interested patients or clinical details. Recruitment strategies, summarised in figure 3, may include any 
of the following:  
• 
Patients will be approached by the clinical care team directly when they attend the hospital 
outpatient clinic who will give an invitation letter on hospital headed paper which provides an 
overview of the study and a participant information sheet. The clinic staff will arrange a 
subsequent screening visit.  
• 
The clinic team may also mail (by post or e-mail) an invitation letter with or without a 
participant information sheet along with a contact email address/phone number to respond 
to, detailing a range of methods for the interested potential patients to contact the local trial 
team to arrange a screening appointment.  

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• 
Where patients are due to attend clinic for a routine appointment in the near future, the 
clinical care team may mail (by post or e-mail) an invitation letter on hospital headed paper 
which provides an overview of the study, and a participant information sheet, so that the 
patient receives these documents at least 24 hours in advance of the forthcoming routine 
clinic assessment visit. After the participant has provided written informed consent, screening 
for eligibility and baseline assessments will be undertaken at the routine clinic visit. 
• 
For centres with access to a volunteer database, the researchers may mail the invitation letter 
and reply form directly to the volunteer. 
Figure 3: TIPAL Recruitment Strategies 
 
 
 
 
 
 
 
 
 
 
 
 
 
Potential patients may be contacted by phone between 3 and 7 days after the mailing of the 
letter/sending the email to ensure that they have received it. Enrolment will then be scheduled either 
via a face-to-face visit or by consultation via phone/video call for those willing to consent to 
participate. Potential participants and site staff will confirm whether consent will be recorded 
electronically or on paper, with the decision documented in the patient’s medical notes, to facilitate 
preparations for the enrolment visit.  
Remote consent 
For those being enrolled remotely and completing paper consent forms, a localised consent form with 
a stamped address envelope for return to the site, will be mailed to the potential participant in 
readiness for their completion at the end of the study consultation. The person taking consent will 
countersign the form upon receipt at the recruiting site.  
Clinic List 
MDT meeting  
Potentially eligible patients are 
identified after  
diagnosis in meeting 
List of IPF Patients  
Potentially eligible patients are 
identified from site’s list of IPF 
patients 
Potentially eligible  
patients are identified prior to 
upcoming clinic visit 
Site sends PIS with Patient Invitation Letter 
Patient is contacted a few days later to confirm receipt of participant information sheet.  
If appropriate site arranges an screening visit or arranges for enrolment at their next clinic appointment or consultation via 
video/phone call with consent to be documented on paper or electronically at least 24 hours after the participant receives the PIS. 
Study discussed with the patient in 
person or by phone/video call and  
patient given/mailed a copy of the PIS, 
verbal consent obtained and study 
supplies kit shipped 
Study discussed with the patient in 
person or by phone/video call and  
patient given/mailed a copy of the PIS 
Clinic Review if required including remote clinic 

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Where electronic consent is being sought, participants will verbally consent to the sharing of their 
email address in order to receive the link to the electronic consent form to facilitate the process. This 
will be documented by site staff in the patient’s medical notes. Both parties will complete the 
electronic consent form in real-time following the phone/video call consultation by providing a wet-
ink signature equivalent on the designated field via REDcap(49). 
Details of the consultation, including but not limited to the time/date of the phone/video call, 
confirmation of identification checks and the name of the staff member leading the call/ taking 
consent will be recorded in the patient’s medical notes. Copies of the completed forms will be mailed 
(by post or email) to participants. 
Alternatively, consent will be obtained and documented face-to-face in accordance with local policy 
at the recruiting site where the visit takes place onsite. 
Post-consent 
Consent will be obtained prior to any study related procedure. Following consent, a PPI washout 
period will be completed where required, screening bloods will be taken and other eligibility criteria 
will be assessed. Patients meeting all entry criteria (after review of screening bloods) and willing to 
consent to participate or having already provided consent, will be sent a TIPAL study supplies kit 
including the spirometer and smart device. Spirometry training will be arranged centrally, and 
participants instructed to complete baseline spirometry assessments. Participants may be randomised 
without a subsequent visit following central verification of spirometry data and local confirmation of 
eligibility. Medication will be dispensed by the central pharmacy and couriered (or sent via another 
signed for delivery service) directly to the participant and will require signature on receipt. Participants 
will be advised to store their medication below 25°C but there may not be any temperature monitoring 
after IMP has been dispensed. 
6.8.2 
Retention 
This study has been designed to be able to be conducted completely remotely reducing participant 
burden significantly by removing travel time and associated cost(s), allowing almost complete 
flexibility around completion of study assessments and removal of any risks associated with breaking 
COVID-19 social distancing guidelines. A remote study design also means trial participation can 
continue in the event of local lockdowns for any reason. Maintaining additional contact outside of 
standard clinic appointments may also encourage retention.  
The provision of a smart device, with a pre-loaded sim card if required and regular support where 
needed, affords all participants equal opportunity to participate despite any personal technological 
inequalities. 
Postage for participants opting to complete paper-based questionnaires and costs associated with 
couriering TIPAL study supplies kits including equipment required for the sub-study and IMP to, and 
from, where applicable, participants are not payable by participants at any point. Couriers will be 
scheduled following consultation with the participant where possible to ensure collection/delivery is 
convenient to the participant. 

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Participants will also be offered the option to subscribe to an email-based participant newsletter 
during the study’s recruitment period in order to help keep participants engaged and informed of 
study progress during and beyond their participation.  
The SWAT is also intended to improve participant retention at intervention sites. 
Participants will be given/posted a card with the contact details of the local PI that will request details 
of hospital admissions to be reported at consent/baseline. Patients will be asked to provide informed 
consent for their contact details to be stored in a trial contacts database at UEA. Participants can 
withdraw consent to this in writing at any time. Contact details will be deleted at the end of the study. 
6.9 
Assignment of Intervention  
6.9.1 
Allocation 
6.9.1.1 Sequence generation -  
The allocated treatment for a patient will be generated via computer written code using minimisation. 
Minimisation will be performed using Taves’ method with the factors measured at baseline: i) study 
site, ii) baseline licensed medication for IPF (yes/no), iii) reflux symptoms (presence/absence) and iv) 
and cough sub-study status (participating/not-participating). In order to decide on the treatment 
allocation the code will calculate the number of patients in each group that have the same 
characteristics as the patient awaiting allocation; they will be allocated to the intervention with the 
smaller number with a high probability. If the numbers are the same then simple randomisation is 
used.  
Full details of the minimisation algorithm (including the probability of allocation) will be documented 
in a separate document (TIPAL Allocation Schedule) stored in a shared file accessible to only the study 
statistician(s) and data management team as appropriate.  
6.9.1.2 Allocation concealment mechanism 
Allocation will be computer generated by a web-based system ensuring concealment prior to 
randomisation. Following consent and confirmation of eligibility the PI or delegate will enter data 
confirming eligibility into the eCRF generating a participant identification number. Blinded notification 
of randomisation will be sent to the PI and/or delegates, CI and NCTU trial team. A semi-blinded 
notification of randomisation will be sent to the central pharmacy. 
6.9.1.3 Allocation Implementation 
The PI or delegated sub-investigator is responsible for ensuring only eligible patients are randomised 
and prescribed study medication. Patients will be allocated to the intervention by a process embedded 
in the web-based data management system.  The randomisation code will be saved in the study 
database for later decoding and also for emergency unblinding purposes.  
6.9.2 
Blinding 
This is a double-blind study. The placebo and active treatments will appear identical and will be 
dispensed in identical containers. All trial participants, care providers and outcome assessors will 
remain blind throughout the study.  
6.9.3 
Emergency Unblinding 
The decision to unblind a single case should be made when knowledge of an individual’s allocated 
treatment is required: 

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• 
To enable treatment of severe adverse event/s, or 
• 
In the event of an overdose 
 
Where possible, requests for emergency or unplanned unblinding of individuals should be made via 
the trial manager and agreement of the CI will then be sought. However, in circumstances where there 
is insufficient time to make this request or for agreement to be sought, the treating clinician should 
make the decision to unblind immediately. This will be done via the study database (local PIs, sub-
investigators and the CI will have special logins which will allow unblinding and which will be closely 
audited within the database management system) or by contacting the CI who will authorise 
unblinding by the Data Management Team. All instances of unblinding should be recorded and 
reported to NCTU by the local PI, or delegate, including the identity of all recipients of the unblinding 
information. 
 6.9.3 Non-emergency Unblinding  
For circumstances where non-emergency unblinding is required e.g. GP/clinician or participant 
request, following confirmation from the CI, treatment allocation will be revealed by the eCRF, using 
log-ins and forms separate to those required to unblind in emergency situations. The blind will be 
maintained for as many of the local study and NCTU trial team members as possible. A record of non-
emergency unblinding and those individuals unblinded to trial treatment will be recorded and filed. 
6.10 Data Collection, Management and Analysis 
6.10.1 Data Collection Methods 
An on-line patient screening log will contain the details of the patient initials, date of contact and the 
route of identification for all potential participants who have received a patient information sheet 
(PIS).  Following confirmation of consent, each participant will be given a unique trial Participant 
IDentification Number (PID). Data will be collected at the time-points indicated in the Schedule of 
Assessments (see section 6.6).  
Data collection will vary according to the data variable in question.  
Laboratory spirometry will be captured according to European Respiratory Society (ERS)/American 
Thoracic Society (ATS) criteria(50) by an Association for Respiratory Technology & Physiology (ARTP) 
registered pulmonary function technologist (see relevant working instruction available from NCTU 
trial team) where possible. 
Once erroneous blows have been rejected as required, the FVC for the highest three blows will be 
recorded.  
Gas transfer measurements will be performed to ERS/ATS standards(51) by an ARTP registered 
pulmonary function technologist.  
Domiciliary spirometers are provided to participants following consent to obtain study spirometry 
data. Participants will be asked to perform at least three forced expiratory volume manoeuvres. 
Measurements will be made on 5  days at baseline and at twelve months, and once weekly for the 
remainder of the study. The domiciliary spirometer will transfer data for each blow via Bluetooth to 
the accompanying app pre-installed on the smart device provided. The assessments will be graded 
according to ERS/ATS criteria(50) within the app. The raw data including flow-volume loops and 

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volume-time curves will be automatically synced from the app on the participant’s smart device to a 
validated clinical trials data platform or entered into the eCRF. Upon completion of baseline 
spirometry assessments, a trained physiologist and/or clinician will review the data and accompanying 
flow/volume loops and volume/time curves to ensure accurate and clinically acceptable data has been 
obtained, in accordance with the ERS/ATS guidelines and study-specific work instruction and 
monitoring plan; providing this is the case the participant will be verified for randomisation pending 
local confirmation of eligibility. Participants may be re-trained if required.  
The following variables will be recorded during domiciliary spirometry assessments and automatically 
recorded onto the accompany clinical trials data platform or eCRF and/or should be observed during 
lung function (including spirometry and gas transfer assessments) and recorded onto the BTS 
registry/eCRF as required where assessments are possible: 
• 
FEV1 
• 
FVC 
• 
DLCO  
• 
KCO  
• 
The FEV1/FVC ratio will be calculated from the data provided. 
Further guidance for the conduct of domiciliary spirometry assessments is provided in the 
corresponding TIPAL working instruction available from the NCTU trial team. Participants will also be 
provided with ethically approved literature/training materials to assist them in the completion of their 
spirometry assessments in addition to the guidance given by the app during the measurements. 
Where participants complete lung function assessment including spirometry and gas transfer 
assessments in the laboratory, FEV1, FVC, DLCO, KCO and subsequently calculated FEV1/FVC ratio will 
be recorded in the BTS IPF registry. 
Participants will be asked to complete online questionnaires but there will be a provision of 
completing the questionnaires on paper if required or preferred. Paper questionnaires will be sent to 
NCTU upon completion (by post or email using high resolution scanning) for data entry. Online 
responses will be stored directly in the eCRF.  
Relevant data will be exported from the BTS registry at regular intervals and imported into the study 
database. The datasets will be matched on the TIPAL PID, which will be stored in the BTS Registry and 
domiciliary spirometer clinical data platform if applicable. The BTS Registry IDs will be stored in the 
TIPAL study database as a means of double-checking the correct records have been imported. Patient 
consent will be sought prior to data sharing.  
Data required only for study purposes will be entered by direct online entry into the eCRF by delegated 
members of research site staff.  
Positive tests for covid-19 during trial participation will be recorded on the eCRF following a review of 
patient medical notes/discussion with participants by site staff. Covid-19 infection will be confirmed 
at baseline and at each study visit thereafter as part of the adverse event review. 
Following specific consent, the clinically obtained full lung coverage thoracic imaging volumetric scan, 
closest to the time prior to randomisation (or within three months of randomisation) will be uploaded 

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in a pseudonymised form, i.e. with all patient identifiers removed and labelled by PID, onto the 
eCRF/relevant platform by sites. Likewise, any full lung coverage thoracic imaging volumetric scan, 
taken for clinical reasons or the CT scan sub-study between three months prior to and three months 
following randomisation and/or the 12 months anniversary of randomisation, will be uploaded onto 
the eCRF/relevant platform.  
Further information on data collection and management processes are provided in the TIPAL Data 
Management Plan. 
Data may be entered onto paper Case Report Forms (CRFs) prior to entry onto the database.  Staff will 
receive training on data collection and use of the online system (see Section 6.10.2). 
Data collection, data entry and queries raised by a member of the TIPAL trial team will be conducted 
in line with NCTU and trial specific Data Management Standard Operating Procedure. 
Identification logs and enrolment logs will be kept at the trial site in a locked cabinet within a secured 
room.  
Participant identifiable data will be stored on a Participants Database for the purpose of couriering 
IMP and TIPAL study supplies kits, contacting participants to collect trial data, arrange couriers etc., 
sending questionnaires and reminders and for sending newsletters during the trial. All participant 
identifiable data will be stored securely, with access only granted to those members of the study team 
who require it. 
Clinical trial team members will receive trial protocol training. All data will be handled in accordance 
with the Data Protection Act 2018 and GDPR 2018 and any subsequent revisions. 
6.10.2 Data Management 
Data will be entered under the participants PID number onto the central database stored on the 
servers based at NCTU. Access to the database will be via unique, individually assigned (i.e. not 
generic) usernames and passwords, and only accessible to members of the TIPAL trial team at NCTU, 
TIPAL study teams at sites and external regulators if requested. The servers are protected by firewalls 
and are patched and maintained according to best practice. The physical location of the servers is 
protected physically and environmentally in accordance with University of East Anglia’s General 
Information Security Policy 3 (GISP3: Physical and environmental security). 
Each participant will have a profile on the app which accompanies the domiciliary spirometer following 
consent. The app profile will contain clinically relevant data necessary to grade spirometry 
assessments and will be labelled by the PID.  
Cough count sub-study data will be held within a trial specific database developed and maintained by 
the cough monitor manufacturers. Participants will be identified by their PID. Access will be restricted 
to relevant members of the NCTU trial team and cough analysts via a unique username and password. 
The NCTU trial team, cough monitor manufacturer project team and cough analysts will have oversight 
of data for all trial participants with permissions allocated according to their role.  

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The Brainomix CT scan sub-study team will access the pseudoanonymised images via the 
eCRF/relevant platform for analysis using their e-ILD programme. Scans will be retained for archiving 
by UEA/Sponsor. 
The eCRF and associated code will be developed by NCTU Data Management, in conjunction with the 
TIPAL trial team. The eCRF software will provide a number of features to help maintain data quality, 
including; maintaining an audit trail, allowing custom validations on all data, allowing users to raise 
data query requests, and search facilities to identify validation failure / missing data. 
After completion of the trial the eCRF will be retained for at least 25 years on the servers of NCTU for 
on-going analysis of secondary outcomes. Cough count sub-study data will be retained by Vitalograph 
for at least 25 years.  
The identification and enrolment logs, linking participant identifiable data to the pseudoanonymised 
PID, will be held locally by the trial site. This will either be held in written form in a locked filing cabinet 
or electronically in password protected forms on hospital computers. After completion of the trial the 
identification and enrolment logs will be stored securely by the sites for 25 years unless otherwise 
advised by NCTU. 
6.10.3 Non-Adherence and Non-Retention 
The participant information sheet explains that if a participant wishes to withdraw from the study the 
data and samples acquired prior to that point will be retained. Reason for withdrawal will be recorded, 
if given, as will loss to follow up. 
Non-adherence to trial medication will be assessed through capsule counts of unused returned drug 
supplies at each relevant study visit.  
Where patients are unable or unwilling to continue to undertake study measurements/activities, the 
decision as to whether the participant should continue with trial treatment and/or follow-up 
assessments will be at the discretion of the local PI and/or CI. 
6.10.4 Statistical Methods 
6.10.4.1 Outcomes 
Primary outcome 
The primary outcome, absolute change in %FVC at 12 months post-randomisation, will be analysed 
using a general linear model adjusting for the minimisation factors used in the allocation algorithm. 
The largest FVC value with a grade A-C of each FVC value obtained over 5 days will be calculated. An 
adjusted analysis will also be undertaken adjusting for the baseline %FVC. Additional adjusted analysis 
may be undertaken for factors associated with the outcome.  In addition, a linear mixed model will be 
used to combine all the post-randomisation %FVC results into a single model which will adjust for the 
same factors and include a patient identifier as a random effect. An interaction between group and 
time will also be included to assess if the effect of the intervention is constant over time or varies as 
time progresses. A sensitivity analysis will be undertaken excluding asymptomatic individuals. 
Secondary outcomes 

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The decline and rate of decline in %FVC during the 12 months: This will be based on a longitudinal 
model with a factor for the intervention or control to represent the average change over the course 
of the trial, and a time-trend to represent the decline in %FVC during the 12 months of the control 
group, and a time-trend x intervention interaction to represent the additional decline in %FVC during 
the 12 months.  If there is evidence of a non-linear time trend, then to ease interpretation, the data 
will be averaged to the average %FVC each month and time will be treated as categorical. Different 
temporal correlation structures will be investigated. 
Cough frequency: This will be based on a log-transformed cough count at 3 months, the model used 
will be a general linear model adjusting for the minimisation factors used in the allocation algorithm. 
An adjusted analysis will also be undertaken adjusting for baseline cough count. The effect size will be 
estimated as the geometric mean. 
Cough score: This will be based on a general linear model with cough score at 12 months as the 
outcome, adjusting for the minimisation factors used in the allocation algorithm. An adjusted analysis 
will also be undertaken adjusting for baseline cough score. The effect size will be estimated as the 
mean difference. In addition, a linear mixed model will be used to combine all the post-randomisation 
cough score results into a single model which will adjust for the same factors and include a patient 
identifier as a random effect. An interaction between group and time will also be included to assess if 
the effect of the intervention is constant over time or varies as time progresses. 
Cough related Quality of Life (QoL): This will be based on a general linear model with cough related 
QoL at 12 months as the outcome, adjusting for the minimisation factors used in the allocation 
algorithm. An adjusted analysis will also be undertaken adjusting for baseline cough related QoL. The 
effect size will be estimated as the mean difference. In addition, a linear mixed model will be used to 
combine all the post-randomisation cough related QoL results into a single model which will adjust for 
the same factors and include a patient identifier as a random effect. An interaction between group 
and time will also be included to assess if the effect of the intervention is constant over time or varies 
as time progresses. 
MRC dyspnoea scale: This will be based on a Mann-Whitney U test comparing the MRC dyspnoea scale 
at 12 months between groups. It will not be possible to adjust for the minimisation factors used in the 
allocation algorithm or to report an effect size, however the median in each group will be reported. 
As the same analysis will be conducted at 3,6 and 9 months a Bonferroni adjustment will be made to 
the p-values.  
King’s Brief Interstitial Lung Disease (K-BILD): This will be based on a general linear model with K-BILD 
as the outcome, adjusting for the minimisation factors used in the allocation algorithm. An adjusted 
analysis will also be undertaken adjusting for baseline K-BILD. The effect size will be estimated as the 
mean difference. In addition, a linear mixed model will be used to combine all the post-randomisation 
K-BILD results into a single model which will adjust for the same factors and include a patient identifier 
as a random effect. An interaction between group and time will also be included to assess if the effect 
of the intervention is constant over time or varies as time progresses. 
EQ-5D-5L: This will be based on a general linear model with EQ-5D-5L as the outcome, adjusting for 
the minimisation factors used in the allocation algorithm. An adjusted analysis will also be undertaken 
adjusting for baseline EQ-5D-5L. The effect size will be estimated as the mean difference. In addition, 

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a linear mixed model will be used to combine all the post-randomisation EQ-5D-5L results into a single 
model which will adjust for the same factors and include a patient identifier as a random effect. An 
interaction between group and time will also be included to assess if the effect of the intervention is 
constant over time or varies as time progresses. 
DLCO: This will be based on a general linear model with DLCO as the outcome, adjusting for the 
minimisation factors used in the allocation algorithm. An adjusted analysis will also be undertaken 
adjusting for baseline DLCO. The effect size will be estimated as the mean difference. In addition, a 
linear mixed model will be used to combine all the post-randomisation DLCO results into a single 
model which will adjust for the same factors and include a patient identifier as a random effect. An 
interaction between group and time will also be included to assess if the effect of the intervention is 
constant over time or varies as time progresses. 
Study-specific questionnaire:  The analysis will be descriptive summarising the change in responses to 
each question from baseline. The acceptability of the treatment will be based on the response to 
questions five, six and seven. 
Sleep apnoea: The STOP-Bang will be analysed by a low, intermediate or high risk using an oridinal 
logistic regression model adjusting for minimisation factors used in the allocation algorithm.  
Sleep quality: The Pittsburgh score will be analysed using a general linear model, adjusting for 
minimisation factors used in the allocation algorithm. An adjusted analysis will also be undertaken 
adjusting for the baseline score.  
Reflux characteristics: The DeMeester score will be analysed using a Mann-Whitney U test at each 
time-point. 
Progression free survival: This will be assessed using the weekly home-based spirometry measures and 
hospital data. The effect size will be estimated as the hazard ratio. Cox proportional hazards will be 
used adjusting for the minimisation factors used in the allocation algorithm. Disease progression will 
be defined as date from randomisation until the week of all-cause mortality, lung transplant or a 10% 
absolute reduction in % FVC from baseline measured by domiciliary spirometry. 
Unplanned hospital-free survival:  This will be assessed at 3, 6, 9 and 12 months and will be presented 
as a number and percentage. The effect size will be estimated as the odds ratio. Logistic regression 
will be used adjusting for the minimisation factors used in the allocation algorithm. 
Respiratory-related hospitalisation: This will be assessed at 3, 6, 9 and 12 months and will be presented 
as a number and percentage. The effect size will be estimated as the odds ratio. Logistic regression 
will be used adjusting for the minimisation factors used in the allocation algorithm. 
Thoracic imaging: most recent CT scans from baseline, or within +/- 3 months of randomisation the  
12 months anniversary of randomisation, will be independently reviewed by blinded assessors, with 
consensus upon disparity if required, for prognostic (and potentially efficacy) outcomes after the 
conclusion of the study. The prognostic scoring may be used as a covariate in the study outcome 
analyses. This includes, but is not limited to, a grading score for hiatus hernia (HH) evaluation, 
aspiration and fibrosis.  

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WRVS: most recent HRCT standard care scans or new scans performed +/- 3 months of randomisation 
and the 12 months anniversary of randomisation will undergo blinded analysis using the Brainomix e-
ILD programme to obtain WRVS. The mean difference in WRVS between groups using general linear 
model including a fixed term in the model for the treatment arm, adjusting for the stratification factors 
used in randomisation and with baseline (adjusted) value included as a covariate will be compared. If 
the assumptions are incorrect, then a non-parametric bootstrap will be used to estimate the 95% 
confidence intervals and p-values. 
The assumptions of all the models will be checked using residual analysis and, if appropriate, 
alternative methods will be used.  
 
If there is sufficient non-compliance then a compliance-adjusted causal effect (CACE) analysis will be 
undertaken using the models above. In addition, if there is sufficient reduction in dose amongst 
participants, a dose-response relationship will be estimated using instrumental variable regression.  
6.10.4.2 Statistical Analysis Plan (SAP) 
A full SAP will be produced prior to the analysis of any data. Both the TSC and DMC will be given the 
opportunity to comment on the SAP prior to it being signed-off by the CI and lead statistician. 
6.10.4.3 Additional Analyses  
Study within a Trial (SWAT): The influence of patient support group delivered research awareness 
strategies on research recruitment and retention. 
A summary of the planned analyses for the SWAT is provided in Appendix 1.  
6.10.4.4 Analysis Population  
The analyses population are defined as: 
a) intention-to-treat (ITT): all randomised individuals regardless of adherence 
b) If compliance is less than 85% then a compliance adjusted causal effect (CACE) analysis will 
also be carried out defining compliance as taking at least 80% of study medication based on 
pill counts 
c) safety population: all patients randomised who received at least one dose of the trial 
treatment 
6.10.4.5 Missing Data 
The pattern of missing data will be assessed and if appropriate, multiple imputation will be used to 
account for missing data under the assumption that the data are missing at random. If the data are 
not considered missing at random then a sensitivity analysis of the results will be undertaken by 
considering appropriate scenarios, such as the worst-case scenario or pattern-mixture models.  
6.10.5 Economic evaluation 
Formal economic evaluation will not be completed as part of this trial. However, use of health services 
recorded throughout the trial will focus on use of secondary care services as they are significant events 
for both patients and the NHS. These data will be reported as summaries and analysed using the 
methods described above. 

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6.10.6  Analysis of Tissue Samples  
There is not any planned analysis of tissue samples other than safety analysis. Blood, serum and 
plasma will be stored for analysis in future studies following ethical approval. 
A laboratory analysis plan for genotype samples will be agreed and approved by the CI and TMG prior 
to analysis. In addition, a laboratory manual for sample handling will be developed and agreed by the 
CI and circulated to sites prior to activation to recruitment.  
6.11 Safety reporting  
6.11.1 Safety reporting 
Adverse events will be collected at each visit and analysed according to the SAP.  Adverse events by 
treatment group will be reviewed regularly by the DMC as described in their Terms of Reference (ToR). 
Definitions of harm of the EU Directive 2001/20/EC Article 2 based on the principles of ICH GCP apply 
to this trial.   
Table 2: Adverse Event Definitions 
Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical trial 
participant administered a medicinal product and which does 
not necessarily have a causal relationship with this product. 
Adverse Reaction (AR) 
Any untoward and unintended response to an investigational 
medicinal product related to any dose administered/trial 
treatment. 
Unexpected Adverse Reaction 
(UAR) 
An adverse reaction, the nature or severity of which is not 
consistent with the applicable product information (e.g. 
Investigator’s Brochure for an unauthorised product or SPC for 
an authorised product or treatment. 
Serious Adverse Event (SAE) or 
Serious Adverse Reaction (SAR) 
Any AE or AR that at any dose: 
• 
results in death  
• 
is life threatening*  
• 
requires 
hospitalisation 
or 
prolongs 
existing 
hospitalisation** 
• 
results in persistent or significant disability or incapacity 
• 
is a congenital anomaly or birth defect 
• 
or is another important medical condition*** 
* the term life threatening here refers to an event in which the patient is at risk of death at the time 
of the event; it does not refer to an event that might hypothetically cause death if it was more 
severe (e.g. a silent myocardial infarction). 
** Hospitalisation is defined as an in-patient admission, regardless of length of stay, even if the 
hospitalisation is a precautionary measure for continued observation. Hospitalisation for pre-

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existing conditions (including elective procedures that have not worsened) do not constitute an 
SAE. 
*** Medical judgement should be exercised in deciding whether an AE or AR is serious in other 
situations. Important AEs or ARs that may not be immediately life threatening or result in death or 
hospitalisation but may seriously jeopardise the participant by requiring intervention to prevent 
one of the other outcomes listed in the table (e.g. a secondary malignancy, an allergic 
bronchospasm requiring intensive emergency treatment, seizures or blood dyscrasias that do not 
require hospitalisation, or development of drug dependency). 
Adverse events include: 
• 
an exacerbation of a pre-existing illness 
• 
an increase in the frequency or intensity of a pre-existing episodic event or condition 
• 
a condition (regardless of whether PRESENT prior to the start of the trial) that is DETECTED 
after trial drug administration. (This does not include pre-existing conditions recorded as such 
at baseline – as they are not detected after trial drug administration) 
• 
continuous persistent disease or a symptom present at baseline that worsens following 
administration of the trial treatment 
Adverse events do NOT include: 
• 
Medical or surgical procedures: the condition that leads to the procedure is the adverse event 
• 
Pre-existing disease or a condition present before treatment that does not worsen 
• 
Hospitalisation where no untoward or unintended response has occurred e.g. elective 
cosmetic surgery 
• 
Overdose of medication without signs or symptoms 
AEs will be coded according to the current version of the Common Terminology Criteria for Adverse 
Events (CTCAE) dictionary. 
6.11.2 Investigator responsibilities relating to safety reporting 
All non-serious AEs and ARs, whether expected or not, should be recorded in the patient’s medical 
notes and reported on the adverse events form of the eCRF within 7 days of report/becoming aware.  
All SARs and SAEs should be notified to NCTU immediately after the investigator becomes aware of 
the event (in no circumstance should this notification take longer than 24 hours). 
6.11.2.1 Seriousness assessment  
When an AE or AR occurs, the investigator or delegated sub-investigator responsible for the care of 
the participant must first assess whether or not the event is serious using the definition given in Table 
2. If the event is classified as ‘serious’ an SAE form must be completed and NCTU notified immediately. 
Investigators will also assess causality of the event(s) according to Table 3. 
6.11.2.2 Severity or grading of Adverse Events 
The severity of all AEs and/or ARs (serious and non-serious) in this trial should be graded according to 
CTCAE grading criteria and be assigned a grade 1-5.  

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6.11.2.3 Causality 
The investigator must assess the causality of all serious events in relation to the trial treatment using 
the definitions in Table 3.  
Table 3: Adverse Event Causality Definitions 
Relationship 
Description 
Event type 
Unrelated 
There is no evidence of any causal 
relationship. 
Unrelated SAE 
Unlikely to be related 
There is little evidence to suggest 
that there is a causal relationship 
(e.g. the event did not occur 
within a reasonable time after 
administration of the trial 
medication). There is another 
reasonable explanation for the 
event (e.g. the participant’s 
clinical condition or other 
concomitant treatment). 
Unrelated SAE 
Possibly related 
There is some evidence to 
suggest a causal relationship (e.g. 
because the event occurs within a 
reasonable time after 
administration of the trial 
medication). However, the 
influence of other factors may 
have contributed to the event 
(e.g. the participant’s clinical 
condition or other concomitant 
treatment).  
SAR 
Probably related 
There is evidence to suggest a 
causal relationship and the 
influence of other factors is 
unlikely. 
SAR 
Definitely related 
There is clear evidence to suggest 
a causal relationship and other 
possible contributing factors can 
be ruled out. 
SAR 
 
If an SAE is considered to be related to trial treatment, and treatment is discontinued, interrupted or 
the dose modified, refer to section 6.4.1.4 of this protocol. 

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6.11.2.4 Expectedness 
If there is at least a possible involvement of the trial IMP (including any comparators), the investigator 
and NCTU must assess the expectedness of the event. An unexpected adverse reaction is one that is 
not reported in the approved SPC, or one that is more frequently reported or more severe than 
previously reported. See section 4.8 of the SPC for a list of expected reactions associated with the IMP 
being used in this trial. If a SAR is assessed as being unexpected, it becomes a suspected, unexpected, 
serious adverse reaction (SUSAR) and MHRA and REC reporting guidelines apply (see Notifications 
sections of the protocol section 6.11.3). 
6.11.3 Notifications 
6.11.3.1 Notifications by the Investigator to NCTU 
NCTU must be notified of all SAEs immediately and no later than 24 hours of the investigator becoming 
aware of the event. 
Investigators should notify NCTU of any SAEs occurring from the time of randomisation until 30 days 
after the last protocol treatment administration. SARs and SUSARs must be notified to NCTU until trial 
closure. Any subsequent events that may be attributed to treatment should be reported to the MHRA 
using the yellow card system (https://yellowcard.mhra.gov.uk/the-yellow-card-scheme/).  
The SAE form must be completed by the investigator or sub-investigator (a clinician named on the 
delegation of responsibilities list who is responsible for the participant’s care) with attention paid to 
the grading, causality and expectedness of the event. In the absence of the responsible investigator, 
the SAE form should be completed and signed by a member of the site trial team and emailed as 
appropriate within the timeline. The responsible investigator should check the SAE form at the earliest 
opportunity, make any changes necessary, sign and then email to NCTU. Detailed written reports 
should be completed as appropriate. Systems will be in place at the site to enable the investigator to 
check the form for clinical accuracy as soon as possible. 
The minimum criteria required for reporting an SAE are the trial number and date of birth, name of 
reporting investigator and sufficient information on the event to confirm seriousness. Any further 
information regarding the event that is unavailable at the time of the first report should be sent as 
soon as it becomes available. 
The SAE form must be scanned and sent by email to the NCTU SAE reporting email address: 
nctu.safety@uea.ac.uk   
Participants must be followed up until clinical recovery is complete and laboratory results have 
returned to normal or baseline values, or until the event has stabilised. Follow-up should continue 
after completion of protocol treatment and/or trial follow-up if necessary. Follow-up SAE forms 
(clearly marked as follow-up) should be completed and emailed to NCTU as further information 
becomes available. Additional information and/or copies of test results etc. may be provided 
separately. The participant must be identified by trial number, date of birth and initials only. The 
participant’s name should not be used on any correspondence and should be redacted and replaced 
with trial identifiers on any test results. 

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6.11.3.2 NCTU responsibilities 
Medically qualified staff at NCTU and/or the CI (or a medically qualified delegate) will review all SAE 
reports received and the NCTU trial team will notify the Sponsor as appropriate. In the event of 
disagreement between the causality assessment given by the local investigator and the CI, both 
opinions and any justifications will be provided in subsequent reports. The causality attributed to 
lansoprazole by the local investigator cannot be downgraded by other parties. 
NCTU is responsible for the reporting of SUSARs to the regulatory authorities (MHRA and competent 
authorities of other European member states and any other countries in which the trial is taking place) 
and REC as appropriate. Fatal and life threatening SUSARs must be reported to the competent 
authorities within 7 days of NCTU becoming aware of the event; other SUSARs must be reported within 
15 days.  
NCTU will keep investigators informed of any safety issues that arise during the course of the trial. 
The trial manager or delegate at NCTU will submit Development Safety Update Reports (DSURs) to 
competent authorities.  
6.12 Data Monitoring 
6.12.1 Data Monitoring Committee 
Details of the roles and responsibilities of the Data Monitoring Committee (DMC), including 
membership, relationships with other committees, decision making processes, and the timing and 
frequency of interim analyses (and description of stopping rules and/or guidelines where applicable) 
are described in detail in the TIPAL DMC ToR. 
6.12.2 Interim Analyses 
There are no interim analyses planned.  
6.12.3 Quality Assurance and Control 
6.12.3.1 Risk Assessment 
The Quality Assurance (QA) and Quality Control (QC) considerations for the TIPAL trial are based on 
the standard NCTU Quality Management Policy that includes a formal Risk Assessment, and that 
acknowledges the risks associated with the conduct of the trial and proposals of how to mitigate them 
through appropriate QA and QC processes. Risks are defined in terms of their impact on: the rights 
and safety of participants; project concept including trial design, reliability of results and institutional 
risk; project management; and other considerations. 
QA is defined as all the planned and systematic actions established to ensure the trial is performed 
and data generated, documented and/or recorded and reported in compliance with the principles of 
GCP and applicable regulatory requirements. QC is defined as the operational techniques and activities 
performed within the QA system to verify that the requirements for quality of the trial related 
activities are fulfilled.  
6.12.3.2 Central Monitoring at NCTU 
NCTU staff will review the eCRF data for errors and missing key data points. The trial database will also 
be programmed to generate reports on errors and error rates. Essential trial issues, events and 
outputs, including defined key data points, will be detailed in the TIPAL trial Data Management Plan. 

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The quality of the domiciliary spirometry data will be monitored regularly during the study by a 
Physiology Sub-Group comprised of members of the TMG, trial team and study physiologists. Data for 
all participants will be reviewed prior to randomisation and in accordance with the TIPAL Quality 
Management and Monitoring Plan (QMMP) and study-specific remote spirometry working instruction. 
Participants will be retrained as required. 
Patients are consented to enable NCTU to hold a copy of the completed consent form to allow central 
data monitoring checks to be completed. 
6.12.3.3 On-site Monitoring  
The frequency, type and intensity of routine and triggered on-site monitoring will be detailed in the 
TIPAL QMMP. The QMMP will also detail the procedures for review and sign-off of monitoring reports. 
In the event of a request for a trial site inspection by any regulatory authority, NCTU must be notified 
as soon as possible. 
6.12.3.3.1 Direct access to participant records 
Participating investigators must agree to allow trial related monitoring, including audits, REC review 
and regulatory inspections, by providing access to source data and other trial related documentation 
as required. Participant consent for this must be obtained as part of the informed consent process for 
the trial. 
6.12.3.4 Trial Oversight 
Trial oversight is intended to preserve the integrity of the trial by independently verifying a variety of 
processes and prompting corrective action where necessary. The processes reviewed relate to 
participant enrolment, consent, eligibility, and allocation to trial groups; adherence to trial 
interventions and policies to protect participants, including reporting of harms; completeness, 
accuracy and timeliness of data collection; and will verify adherence to applicable policies detailed in 
the Compliance section of the protocol. Independent trial oversight complies with the NCTU trial 
oversight policy. 
In multi-centre trials this oversight is considered and described both overall and for each recruiting 
centre by exploring the trial dataset or performing site visits as described in the TIPAL QMMP. 
6.12.3.4.1 Trial Management Team 
The Trial Management Team (TMT) will be set up to assist with developing the design, co-ordination 
and day-to-day operational issues in the management of the trial, including budget management. The 
membership, frequency of meetings, activity (including trial conduct and data review) and authority 
will be covered in the TMT terms of reference.  
6.12.3.4.2 Trial Management Group 
A Trial Management Group (TMG) will be set up to assist with developing the design, co-ordination 
and strategic management of the trial. The membership, frequency of meetings, activity (including 
trial conduct and data review) and authority will be covered in the TMG terms of reference. 
6.12.3.4.3 Independent Trial Steering Committee 
The Independent Trial Steering Committee (TSC) is the independent group responsible for oversight 
of the trial in order to safeguard the interests of trial participants. The TSC provides advice to the CI, 
NCTU, the funder and Sponsor on all aspects of the trial through its independent Chair. The 

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membership, frequency of meetings, activity (including trial conduct and data review) and authority 
will be covered in the TSC terms of reference. 
6.12.3.4.4 Independent Data Monitoring Committee 
The Independent Data Monitoring Committee (IDMC) is the only oversight body that has access to 
unblinded accumulating comparative data. The IDMC is responsible for safeguarding the interests of 
trial participants, monitoring the accumulating data and making recommendations to the TSC on 
whether the trial should continue as planned. The membership, frequency of meetings, activity 
(including review of trial conduct and data) and authority will be covered in the IDMC terms of 
reference. The IDMC will consider data in accordance with the SAP and will advise the TSC through its 
Chair. 
6.12.3.4.5 Trial Sponsor 
The role of the sponsor, Norfolk and Norwich University Hospitals NHS Foundation Trust, is to take on 
responsibility for securing the arrangements to initiate, manage and finance the trial. The Sponsor is 
responsible for ensuring that the study meets the relevant standards and makes sure that 
arrangements are put and kept in place for management, monitoring and reporting. A proportion of 
the Sponsor’s activities have been delegated to the CI, UEA and NCTU as outlined on the form for 
delegated activities agreed and signed by all parties before the start of the trial. 
7 
Ethics and Dissemination 
7.1 
Research Ethics and Health Research Authority Approval 
Before initiation of the trial at any clinical site, the protocol, all informed consent forms and any 
material to be given to the prospective participant will be submitted to the relevant REC and to HRA 
for approval. Any subsequent amendments to these documents will be submitted for further approval.   
The rights of the participant to refuse to participate in the trial without giving a reason must be 
respected. After the participant has entered the trial, the clinician remains free to give alternative 
treatment to that specified in the protocol, at any stage, if s/he feels it to be in the best interest of the 
participant. The reasons for doing so must be recorded. After randomisation the participant must 
remain within the trial for the purpose of follow up and data analysis according to the treatment 
option to which they have been allocated. However, the participant remains free to change their mind 
at any time about the protocol treatment and follow-up without giving a reason and without 
prejudicing their further treatment. 
7.2 
Competent Authority Approvals 
This protocol will be submitted to the MHRA.  
This is a Clinical Trial of an Investigational Medicinal Product (CTIMP) as defined by the EU Directive 
2001/20/EC. Therefore, a CTA is required in the UK.  
The progress of the trial, safety issues and reports, including expedited reporting of SUSARs, will be 
reported to the MHRA in accordance with relevant requirements and practices.  
7.3 
Other Approvals 
Documentation will need to be submitted to the R&D Department at each NHS Site in order to gain 
confirmation of capacity and capability prior to the study being initiated at that site.  Confirmation 

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from the site will take the form of a site agreement signed by the Sponsor, NCTU and the relevant 
site as required.  
A copy of the local R&D approval and of the Participant Information Sheet (PIS) and consent form on 
local hospital headed paper must be forwarded to the co-ordinating centre before participants are 
randomised to the trial.  
The protocol has received formal approval and methodological, statistical, clinical and operational 
input from the NCTU Protocol Review Committee. 
7.4 
Amendments 
Amendments to the Protocol and other documents (e.g. changes to eligibility criteria, outcomes, 
sample size calculations, analyses) will be agreed by the TMG. Such amendments will be forwarded to 
the Sponsor for confirmation as to whether it is either substantial or non-substantial and will then be 
submitted to the MHRA, HRA or Ethics Committee for categorisation and approval as required. Once 
the amendment has been categorised it will be sent to relevant sites for consideration in accordance 
with standard MHRA and/or HRA processes and timescales. Amendments must not be implemented 
until all approvals are received and sites have either confirmed acceptance or, no objection has been 
received within the defined timescale(s). Notification will be sent by NCTU to trial personnel to confirm 
when an amendment can be implemented. 
 
A summary of protocol amendments will be maintained within the protocol.  
 
7.5 
Consent or Assent 
Patients will be provided with a PIS and given time to read it fully. Following a discussion with a medical 
qualified investigator or suitably trained and authorised delegate, any questions will be satisfactorily 
answered and if the participant is willing to participate, written informed consent will be obtained 
either electronically or paper-based following consultation in person or via phone/video call.  During 
the consent process it will be made completely and unambiguously clear that the participant is free 
to refuse to participate in all or any aspect of the trial, at any time and for any reason, without incurring 
any penalty or affecting their treatment. 
 
Consent will be re-sought if new information becomes available that affects the participant’s consent 
in any way. This will be documented in a revision to the participant information sheet and the 
participant will be asked to sign an updated consent form. These will be approved by the ethics 
committee prior to their use.  
Participation in the sub-studies is optional for all patients. All participants (pending eligibility for the 
cough sub-study) are able to participate in all, either or no sub-studies with no impact on their 
involvement in the main TIPAL trial. 
A copy of the approved consent form and PIS are available from the NCTU trial team.  
7.6 
Confidentiality 
Any paper copies of personal trial data will be kept at the participating site in a secure location with 
restricted access.  

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Confidentiality of patient’s personal data is ensured by not collecting patient names on CRFs and 
limiting access to personal information held on the database at NCTU. At trial enrolment the patient 
will be issued a participant identification number and this will be the primary identifier for the patient, 
with secondary identifiers of date of birth and initials.  
The patient's consent form will carry their name and signature. These will be kept at the trial site, with 
a copy sent to NCTU for monitoring purposes. This copy will be destroyed/deleted once checks are 
complete. Consent forms will not be kept with any additional patient data.  
Identifiable data will be shared with the NCTU trial team only following written informed consent or 
verbal consent from the patient to participate in the study. Personal data will be accessed to allow 
shipment arrangements for study supplies and IMP to be facilitated and to contact participants for 
(re)training in trial related procedures where necessary. Only authorised NCTU trial team members 
and central pharmacy staff will have access to this data for the abovementioned purposes only and 
will ensure it is handled confidentially and in accordance with data protection regulations. Relevant 
identifiable data will be shared with central pharmacy staff and couriers only for shipping and 
administrative purposes only.  
In addition, spirometry data will be stored within the app and data platform used to collate domiciliary 
spirometry data following consent of participants only, this will be labelled according to the PID, held 
in accordance with data protection regulations and will not be shared with any third parties. Data 
stored relates to spirometry data collected for the study, with standard clinical demographics e.g. 
gender, ethnicity etc. and generic administrative details to identify the participant’s study supplies kit. 
No identifiable data will be held within either platform. 
Only pseudoanonymised images/data will be shared with relevant members of the Brainomix team 
for the CT scan sub-study. 
 7.7 
Declaration of Interests 
The investigators named on the protocol have no financial or other competing interests that impact 
on their responsibilities towards the scientific value or potential publishing activities associated with 
the trial. 
7.8 
Indemnity 
The NHS indemnity scheme will apply to the potential liability of the Sponsor for harm to participants 
arising from the management and conduct of the research.  
 
7.9 
Finance 
TIPAL is fully funded by National Institute for Health Research (NIHR) HTA grant reference number: 
NIHR127479. The views expressed are those of the author(s) and not necessarily those of the NIHR or 
the Department of Health and Social Care.  
Additional external funding was awarded directly to APF for the facilitation of the SWAT (Appendix 1). 
Brainomix will fund the conduct of the CT scan sub-study including the site costs associated with 
coordinating scans, performing, and reporting new scans, and anonymising and transferring images. 

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Travel expenses including car parking for patients to attend their recruiting site for new scans to be 
performed will also be funded by Brainomix. 
It is not expected any further external funding will be sought. 
7.10 Archiving 
The investigators agree to archive and/or arrange for secure storage of TIPAL trial materials and 
records for a minimum of 25 years after the close of the trial unless otherwise advised by NCTU. The 
Sponsor’s trial master file will be archived in accordance with regulatory requirements and local policy. 
7.11 Access to Data 
Requests for access to trial data will be considered, and approved in writing where appropriate, after 
formal application to the TMG and TSC. Considerations for approving access are documented in the 
TMG/TSC Terms of Reference. 
7.12 Ancillary and Post-trial Care 
There are no plans to offer trial treatment to individuals participating in this study after its conclusion. 
Lansoprazole is available on prescription should their usual care team wish to prescribe it.  
7.13 Publication Policy 
7.13.1 Trial Results 
The results of the trial will be disseminated regardless of the direction of effect. 
7.13.2 Authorship 
Ownership of the data arising from the study resides with the trial team. The publication policy will be 
in line with rules of the International Committee of Medical Journal Editors. The TMG will decide on 
authorship with any difficulties being resolved by the TSC. 
 7.13.3 Reproducible Research 
The trial will be registered on the International Standard Randomised Clinical Trials Number (ISRCTN) 
website granting public access to the trial outcomes. In addition, the clinical study protocol will be 
submitted for publication. Every effort will be made to grant access to the participant level dataset 
subject to TSC approval. 
7.14 Patient and Public Involvement 
Patient and public involvement representatives will assist the TIPAL trial team in the design, 
management and undertaking of the study, and in the dissemination of trial results. Representatives 
will be consulted during the development of trial documents to ensure they are acceptable to patients 
with amendments made accordingly.  
The TIPAL trial team will identify and appoint patient and public involvement representatives for each 
of the TMG and TSC. Their input will be used to guide the undertaking of the research as and where 
appropriate.  
The results of the trial will be discussed with the representatives prior to submission of any formal 
reports. 
 

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8 
Ancillary Studies 
The TIPAL SWAT is outlined in Appendix 1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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9 
Protocol Amendments 
Protocol 
Version 
Date 
Summary of Changes 
v1.1 
31/03/2020 
The majority of amendments were minor and made in response to the 
comments received following review by the Research Ethics Committee.  
The following changes were made in addition to those requested by 
ethics: 
• 
Addition of REC and ISRCTN reference numbers 
• 
Update of DMC composition 
• 
References to IMP as tablets replaced with capsules 
• 
Clarity added to section 6.11.2. 
• 
Amendment of severity assessments for consistency with AE 
coding system 
• 
Update of table numbers 
• 
References updated 
V1.2 
21/05/2020 
Amendments made relate solely to the notice of non-acceptance 
correspondence received from the MHRA:  
• 
Correction to exclusion criteria 6 and 9  
• 
Updates to section 6.11 to ensure all serious adverse events are 
reported to NCTU 
V2.0 
25/08/2020 
Amendments and updates required to ensure trial remains deliverable 
in the post-COVID19 setting: 
• 
Update of scientific query postal address (section 1.3) 
• 
Amendment of exclusion criterion 1 to exclude participants 
unable to complete study assessments (sections 1.3 and 6.3.1.3) 
• 
Update of date of first enrolment (section 1.3) 
• 
Addition of secondary outcome to assess laboratory FVC and 
FEV1 values where available (section 1.3 and 6.5.2) 
• 
Modification of the definition of disease-free progression to 
remove DLCO measurement and confirmation that progression 
will be assessed from the date of randomisation to the week of 
the progressive event (section 1.3, 6.5.2 and 6.10.4.1) 
• 
Addition of a secondary outcome assessing the decline and rate 
of decline in FVC (section 1.3, 6.5.2 and 6.10.4.1) 
• 
Update to protocol contributors and Sponsor and trial team 
personnel (sections 1.4.1 – 1.4.3) 
• 
Trial diagram (figure 1) updated (section 2) 
• 
Update to protocol abbreviations (section 3) 

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• 
Addition of ‘primary outcome data collection’ sub-section 
(section 5.1) 
• 
Amendment to allow all study visits to be conducted in person 
at recruiting sites or remotely (section 6.1.1 and 6.6.1.1) 
• 
Explanation of screening assessments related to domiciliary 
spirometry (section 6.3.1.1) 
• 
Clarification that FEV1/FVC ratios reviewed during screening 
should be assessed from most recent spirometry assessments 
recorded in patient medical notes (section 6.3.1.3) 
• 
Clarification that participants unwilling or unable to continue to 
complete study assessments may be withdrawn (sections 6.4.7, 
6.6.3 and 6.10.3) 
• 
Schedule of Assessments (figure 2) updated (section 6.6) 
• 
Screening visit updated to include shipping of study supplies kit 
(section 6.6.1.2) 
• 
Permit safety blood tests to be taken at participants GP surgery 
for all study visits (sections 6.6.1.3, 6.6.1.5, 6.6.1.6 and 6.6.1.8) 
• 
Permit the use of domiciliary spirometry to capture the primary 
endpoint (throughout protocol) 
• 
Permit participant fitting and initiation of cough and activity 
monitors with remote support from research team (sections 
6.6.1.3 and 6.6.1.5) 
• 
Provision of freepost envelopes for participant’s opting to 
complete paper-based questionnaires remotely (section 
6.6.1.5, 6.6.1.6 and 6.6.1.8) 
• 
Permit 
adherence 
assessments 
based 
on 
participant 
confirmation of number of remaining capsules (sections 6.6.1.6 
and 6.6.1.8) 
• 
Clarification that 0, 1 or 2 blood samples for research purposes 
may be taken from participants and that genotype samples may 
not be taken from consenting participants in the event that they 
do not attend a study visit in person (section 6.6.2) 
• 
Sample size calculation justification relative to domiciliary 
spirometry (section 6.7) 
• 
Permit electronic informed consent (section 6.8.1 and 7.5) 
• 
Permit remote informed consent (section 6.8.1) 
• 
Update to participant retention strategies (section 6.8.2) 
• 
Update to the data management requirements to undertake 
this study using remote capture of measurements (sections 
6.10.1 and 6.10.2) 
• 
Addition of recording positive COVID-19 infections (section 
6.10.1) 
• 
Central monitoring of domiciliary spirometry (section 6.12.3.2) 

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• 
Clarification and update to collection of identifiable data 
(section 7.6) 
• 
Clarification that laboratory lung function assessments will be 
conducted where possible (throughout protocol) 
In addition to the above, minor administrative, typographical and 
formatting changes have been made throughout the protocol. The 
reference list has also been updated where relevant and required. 
V2.1 
23/03/2021 
• 
Date of first enrolment updated in trial summary table 
• 
Update of protocol contributors and TMG and TSC membership 
lists (sections 1.4.1, 1.4.4 and 1.4.5 respectively) 
• 
Update of abbreviations list (section 3) 
• 
Clarity added relative to inclusion criterion 3 in section 6.3.1.3 
• 
British digestive disorder charity name updated (section 6.4.5) 
• 
SWAT summary updated with confirmation further details are 
outlined in appendix 1 (section 6.5.3) 
• 
Addition of RQ-LIFE-ILD questionnaire in participant table and 
descriptions of baseline and 12 months visits (section 6.6, 
6.6.1.4 and 6.6.1.9 respectively)  
• 
Addition confirmation of participant correspondence via the 
study smartphone/tablet (section 6.6.1.2) 
• 
Confirmation of spirometer app CE marked status and a data 
allowance sufficient for trial purposes (section 6.6.1.3) 
• 
Clarification that electronic questionnaires may be sent to the 
participant’s personal email address and/or their trial-specific 
email address for completion by those opting to complete 
questionnaires electronically (section 6.6.1.4) 
• 
Figure 3 updated in line with protocol text (section 6.8.1) 
• 
Update to include SWAT analysis summary in appendix 1 
(section 6.10.4.3) 
• 
Removal of sharing of participant contact information with 
spirometer manufacturer to reflect trial management process 
(section 7.6) 
• 
Update to archiving retention period to 25 years in line with 
relevant Sponsor SOPs (section 7.10) 
• 
Confirmation of SWAT inclusion in appendix 1 (section 8) 
• 
Addition of Appendix 1 the ‘PURPOSE SWAT’ (appendix 1) 
In addition to the above, minor administrative, typographical and 
formatting changes have been made throughout the protocol. The 
reference list has also been updated where relevant and required. 

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V2.2 
05/08/2021 
• 
Clarification that concomitant use of histamine-2 receptor 
antagonists two weeks prior to enrolment is not permitted 
(exclusion criterion 2) (sections 1.3, 2, 3 and 6.3.1.3) 
• 
Clarification that cough sub-study status will be used as a 
minimisation factor for randomisation (sections 1.3, 5.3, 
6.9.1.1) 
• 
Update to date of first enrolment (section 1.3) 
• 
Update to trial team and TSC membership (section 1.4.5) 
• 
Clarification that potential participants in receipt of PPIs must 
complete the washout period immediately after consent and 
that baseline spirometry will follow (sections 6.3.1.1, 6.3.1.4, 
6.6.1.3, 6.6, 6.6.1.4 and 6.8.1) 
• 
Addition of new sub-section heading ‘eligibility criteria 
guidance’ with relevant sub-headings (section 6.3.1.4) 
• 
Guidance regarding the PPI washout period (section 6.3.1.4) 
• 
Clarification that magnesium at screening is assessed via the 
baseline safety blood test (section 6.3.1.4) 
• 
Clarification that participants with moderate to severe liver 
impairment should be prescribed the reduced dose throughout 
their involvement in the trial (section 6.4.1.4). 
• 
Clarification the Guts UK leaflet will be given after consent to 
potential participants attempting a PPI washout period (section 
6.4.5) 
• 
RQ-LIFE-ILD questionnaire renamed to R-Scale for PF (sections 
6.6, 6.6.1.4, 6.6.1.9) 
• 
Clarification that safety bloods may be taken remotely in 
accordance with standard local policy (sections 6.6, 6.6.1.1, 
6.6.1.4, 6.6.1.6 – 6.6.1.9) 
• 
Clarification participant contact details will be deleted at the 
end of the study (section 6.8.2) 
V2.3 
24/05/2022 
• 
Section 1.3 – date of first enrolment updated 
• 
Sections 1.3 and 6.3.1.3 – exclusion criterion 3 amended to 
include reference to patients presenting with significant 
respiratory tract infections including COVID-19 and the removal 
of the definition of symptoms as this is considered surplus to 
requirements. 
• 
Sections 1.4.2 and 1.4.3 – updated following staff changes 
• 
Section 3 – updated as required 
• 
Section 6.1.2 – clarification on site sub-study responsibilities 
following 
previous 
amendment 
to 
central 
sub-study 
coordination. 
• 
Section 6.3.1.1 – clarification for sites on re-screening 
requirements. 
Description 
of 
spirometry 
data 
review 

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procedures to ensure accurate and verifiable data collection. 
Further details will be provided in study-specific internal 
documents.  
• 
Section 6.3.1.4 – additional guidance for sites on Barrett’s 
oesophagus and patients presenting with significant co-existing 
respiratory disease. 
• 
Section 6.4 – addition of total number of capsules to be taken 
per day added for clarification and consistency with other study 
documents. 
• 
Section 6.4.5 – addition of contraindications to spirometry for 
site information and consistency with participant facing 
documentation. 
• 
Section 6.6 – addition of collection of standard care CT scans at 
baseline and 12 months, clarification on PRES questionnaire 
completion at 12 months and amendment to reflect flexible 
safety blood collection relative to patient clinical status. 
Footnotes were updated as required as a result of amendments 
elsewhere within the protocol. 
• 
Section 6.6.1.2 – clarification added following finalisation of 
spirometry app. 
• 
Section 6.6.1.3 – clarification of spirometry training and 
equipment shipping logistics to ensure pragmatism based upon 
study conduct experience to date. 
• 
Section 6.6.1.4 – addition to collect standard care CT scans at 
baseline, extension of acceptable safety blood window to 6 
months to reflect clinical practice, clarification on sub-study 
monitoring 
arrangements 
and 
updates 
on 
electronic 
questionnaire completion. 
• 
Section 6.6.1.6 – clarification on sub-study monitoring 
arrangements following previous amendment to conduct sub-
study centrally. 
• 
Sections 6.6.1.7 – 6.6.1.9 – amendment to collect safety blood 
samples only where the PI or sub-I deem they are necessary 
based upon the participant’s clinical status to reflect clinical 
practice and reduce participant and site burden. 
• 
Section 6.6.1.9 – addition to collect standard care CT scans 
where available and clarification on handling of unused IMP 
returns. 
• 
Section 6.6.2 – clarification research/genotype samples may not 
be collected even if visit occurs on site. 
• 
Section 6.8.1 – clarification on documenting consent face-to-
face on site in accordance with local standard policy and 
procedure and clarification on timing of post-consent 
processes. Removal of option to provide participants with study 

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supplies kit following verbal consent as option is surplus to 
requirements with current study conduct. 
• 
Section 6.10.1 – clarification on spirometry data and e-
questionnaire data management. Removal of requirement for 
baseline/12-month spirometry data to be obtained across 
consecutive days to allow participant flexibility and ensure 
pragmatism. Addition of CT scans data management processes. 
• 
Section 6.10.2 – corrections as needed 
• 
Section 6.10.4.1 – clarification on spirometry data analysis to 
reflect trial oversight committee decision to ensure accurate, 
reliable, and robust analyses are conducted. Addition of 
thoracic imaging analyses for prognostic and potentially efficacy 
outcomes 
post-study. 
Subsequent 
addition 
to 
permit 
prognostic scoring to be used as covariate in study analyses 
where appropriately indicated. 
• 
Section 6.12.3.2 – clarification on spirometry data central 
monitoring process by the TIPAL Physiology Sub-Group to 
ensure accurate and reliable spirometry data collection. 
• 
Section 7.6 – correction to collect participant date of birth for 
prescription monitoring purposes. Clarification on spirometry 
app participant profiles and the data held within. 
• 
Section 7.9 – updated to reflect acquisition of additional funding 
for Study Within A Trial (to Action for Pulmonary Fibrosis) 
• 
Section 10 – references updated as required. 
• 
Section 11- Appendix 1 – clarification that a deputy/multiple 
research champions may be identified in participating 
groups/regions to ensure continuity of initiative delivery where 
the primary research champion’s circumstances and/or 
availability alter as the study progresses. Clarification that paper 
questionnaire responses are permitted to be collected. 
Clarification of focus group conduct/arrangements. 
In addition to the above, minor administrative, typographical and 
formatting changes have been made throughout the protocol. The 
reference list has also been updated where relevant and required. 
v2.4 
29/11/2022 
• 
Section 1.3 – first inclusion criterion wording updated for 
inclusivity. Addition of a secondary outcome assessing the 
difference in change between WRVS at 12 months post-
randomisation for the CT scan sub-study. 
• 
Section 1.4.1 – addition of a table outlining the CT scan sub-
study protocol contributors. 
• 
Section 2 – trial diagram updated to include CT scans at baseline 
and 12 months. 
• 
Section 3 – abbreviations updated as required. 

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• 
Section 5.2 – addition of WRVS hypothesis for the CT scan sub-
study. 
• 
Section 5.3 – updated to include reference to the CT scan sub-
study and its target recruitment. 
• 
Section 6.1.2 – clarification added to explain sub-study 
involvement is optional for sites and does not impact on 
involvement in the main trial. 
• 
Section 6.3.1.2 – first inclusion criterion wording amended for 
inclusivity. 
• 
Section 6.4.5 – updated to explain reporting procedures for any 
incidental findings identified as a result of the CT scan sub-
study. 
• 
Section 6.5.2 – secondary outcome for CT scan sub-study of 
difference in change in WRVS added. 
• 
Section 6.6 – participant schedule updated as required 
following amendments elsewhere, namely addition of new 
scans as required for CT scan sub-study at baseline and 12 
months, addition of participant feedback questionnaire at 12M, 
and extension of timeframe for baseline questionnaires to be 
acceptable within 6 weeks of randomisation. 
• 
Section 6.6.1.1 – clarification that attendance to recruiting site 
is required where new images are needed from CT scan sub-
study participants. 
• 
Section 6.6.1.4 – addition of details for coordination of CT scan 
sub-study at baseline including clarification most recent 
standard care images will be collected from all participants, 
confirmation of the timeframe which requires new images to be 
obtained from CT scan sub-study participants and a summary of 
imaging requirements where new scans need to be performed. 
Extension of the timeframe for baseline questionnaires to be 
acceptable within 6 weeks of randomisation for pragmatism in 
light of the multi-stage enrolment process into the study. 
• 
Section 6.6.1.9 – addition of participant feedback questionnaire 
completion by willing participants and details of coordination. 
addition of details for coordination of CT scan sub-study at 12 
months including clarification most recent standard care images 
will be collected from all participants, confirmation of the 
timeframe which requires new images to be obtained from CT 
scan sub-study participants and a summary of imaging 
requirements where new scans need to be performed. 
• 
Section 6.7 – addition of sample size calculation for the CT scan 
sub-study. 
• 
Section 6.10.1 – minor amendments for clarity on data 
collection of CT scans for main study and the sub-study. 

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• 
Section 6.10.2 – updated to include details regarding data 
management for CT scan sub-study including confirmation that 
pseudoanonymised scans will be accessed by Brainomix and 
scans will be retained by UEA/Sponsor for archiving. 
• 
Section 6.10.4.1 – addition of details for WRVS analysis for the 
CT scan sub-study. 
• 
Section 7.5 – clarification added confirming sub-study 
participation is optional for patients and does not impact on 
main trial involvement. 
• 
Section 7.6 – updated to confirm that only pseudoanonymised 
scans and data will be shared with Brainomix. 
• 
Section 7.9 – updated with funding details for the CT scan sub-
study coordination including summary of site and participant 
costs.  
• 
Section 11 – Appendix 1 - addition to retrospectively collect 
demographic data of patient support groups in the control arm 
from phase 2 lead contacts. 
In addition to the above, minor administrative, typographical and 
formatting changes have been made throughout the protocol. The 
reference list has also been updated where relevant and required. 
 
 

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10 
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11 
Appendices 
Appendix 1 - The influence of patient support group delivered research 
awareness strategies on research recruitment and retention (PURPOSE 
Study) 
 
Background 
Recruitment and retention rates in clinical trials can be low and many patients, who are keen to be 
involved in clinical trials cannot participate because they do not know about the research 
opportunities available to them. Patients are keen to ensure that clinical trials are delivered quickly so 
that clinical research questions can be answered and are generally supportive of research. Patient 
support groups are often keen to promote and support research.  
APF is the leading national UK pulmonary fibrosis charity. It supports patient support groups, gives 
patients a voice, raise awareness of pulmonary fibrosis and supports research. There are currently 77 
pulmonary fibrosis patient support groups in the UK and all NHS Trusts in England with specialist 
centres, and most of the main ILD hospitals in the other three nations, involved with TIPAL have an 
affiliated support group. ILD patient support groups generally meet every two months (fortnightly to 
quarterly), with interim mailing of newsletters, and groups are attended by between 20 and 60 
patients or relatives. 
This SWAT aims to assess the influence of patient support group research awareness and support 
strategies on clinical trial recruitment and retention. 
Methods 
This will be a cluster-randomised SWAT of enhanced patient support group engagement with 
assessment of research activity captured by screening logs and questionnaires. Clustering will occur 
at regional level to reduce contamination between support groups which cover one or more NHS Trust 
participating in the TIPAL Trial. A list of APF support groups and TIPAL sites by region is available from 
APF and the TIPAL trial manager respectively.  
 
The following regions will be randomised to either the PURPOSE intervention or control arm: 
• 
London 
• 
South East England 
• 
South West England 
• 
East Midlands 
• 
West Midlands 
• 
East of England 
• 
North East England 
• 
North West England 
• 
Yorkshire and Humberside 
• 
Wales 
• 
Scotland 
• 
Northern Ireland 
 

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Figure 4 PURPOSE study flowchart 
 
 
Cluster randomisation will be stratified by the approximate number of support group members from 
each region from a pre-randomised list generated by the study statistician prior recruitment 
commencing in the main trial. This will be calculated from the PURPOSE Registration Questionnaire 

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completed by the lead contact of each support group prior to the start of the study. The NCTU research 
team or APF Research Champion Lead will confirm arm allocation by email to all the APF support 
groups as soon as possible after the randomisation of their region (cluster unit). 
 
Participants - clusters 
Regions will only be included in the study if: 
1. 
At least one TIPAL site has opened or is expected to open to recruitment in the region within 
6 months of the start of the study. 
2. 
Interest has been confirmed by at least one of the regional APF support groups within the 
region. 
 
All APF support groups affiliated with NHS Trusts participating in the TIPAL trial are eligible to 
participate and will be invited.  The support group leads will be asked to confirm an interest in taking 
part by signing (electronically or wet ink) and returning a copy of a PURPOSE Study registration 
questionnaire sent by NCTU/APF. This document will detail the requirements of the PURPOSE study 
with further details provided in the APF PURPOSE support group information leaflet. The study 
registration questionnaire will also record support group membership size, name a lead contact for 
the PURPOSE study, describe the ways the group communicates with its members and list typical 
subjects discussed at meetings or sent out as part of newsletters. All support groups will be asked to 
complete the study registration questionnaire prior to the intervention period. Completion is optional 
and consent is inferred by virtue of completion. 
 
The PURPOSE study will not impact the usual role, function or activity of the patient support groups; 
groups in intervention regions will implement initiatives in addition to their usual remit and control 
groups will continue to operate as usual in the first 12 months of the study. 
 
Intervention 
Within regions randomised to the intervention arm, the lead contact at each support group will be 
asked to identify a local Research Champion(s) who will lead the TIPAL trial research awareness 
campaign.  
 
Champions may be patients or a patient’s carer, friend or relative. Research champions may act as a 
regional research champion supporting multiple support groups within the same region where the 
region is randomised to the intervention arm and individual support groups are unable to identify a 
research champion. Groups and/or regions may identify more than one Research Champion and/or a 
Deputy Research Champion to allow adequate support and/or continuation of the intervention where 
circumstances/availability change. Champions will be provided with a study information sheet and be 
asked to sign a written consent form if they are willing to take on the role prior to intervention delivery. 
Consent forms may be completed on paper or electronically following a study consultation in person 
or remotely (via video/phone call) with a member of the APF research team. Where electronic forms 
are completed, participants will need to verbally consent to providing their email address to receive 
the consent form and wet-ink equivalent signatures will be recorded. A research champion 
recruitment log will be maintained centrally. 
 
The intervention will consist of the following steps: 

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1. Recruitment of at least one volunteer research champion. 
2. Training of the champions/champion teams. 
3. Development and implementation of initiatives to promote the TIPAL study within the APF 
support group. 
4. Development and implementation of initiatives to approach and support their members who 
are participating in the TIPAL trial. 
 
Guidance regarding initiatives will be provided to champions in a non-prescriptive way to allow each 
APF support group to tailor them to their group specificities. Initiatives will most likely encompass 
activities such as discussion about research within the group, providing generic and study-specific 
information about the TIPAL study, writing and disseminating newsletters.  
 
The APF Research Champion Lead will facilitate regular meetings (online or in-person) as an 
opportunity for research champions to collaborate and discuss initiatives as a closed, dedicated 
platform. 
 
Support groups randomised to the intervention arm in the first 12 months are referred to as phase 1 
groups in the participant/support group facing documents.  
 
Control 
Within regions randomised to the control arm, APF Support Groups will not undertake any formal 
method for enhancement of recruitment through the support groups, although local PIs are able to 
discuss research with those groups as standard practice. All patients will have access to the twitter 
feeds and generic information on the APF website and TIPAL webpage. Support group correspondence 
and communication will continue as normal.  
 
The control groups will have access to the intervention materials and training at the end of the 12-
months evaluation period for implementation from then onwards. Informed consent will be obtained 
from lead contacts prior to them completing APF led training in the delivery of the initiatives to 
increase research awareness within the support group. Therefore both groups will deliver the 
successful initiatives from month 13 onwards; this is referred to as phase 2 in the participant/support 
group facing documents. Demographic patient support group data relating to the control groups 
during phase 1 will be collected retrospectively from phase 2 lead contacts by a questionnaire 
(electronic or paper completion). 
 
Primary outcomes 
The following outcomes will be assessed at 12 months from the start of the study: 
• 
The difference between the number of trial participants recruited from control and intervention 
patient support groups, as obtained from the TIPAL screening log.  
• 
The difference between the numbers of withdrawn trial participants from control and 
intervention patient support groups, as obtained from the TIPAL screening log and eCRF.  
 
The following exploratory outcomes will also be assessed: 
• 
The difference in overall recruitment within regions allocated to control and intervention. 
• 
The difference in the overall number of withdrawn TIPAL participants. 

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• 
The number of self-reported self-referrals or enquiries to participate in the TIPAL study as 
obtained from the TIPAL trial screening log and support group member questionnaire  
• 
The difference in the completeness of primary endpoint between participants from control and 
intervention APF support groups, as obtained from the TIPAL eCRF.  
• 
The difference in hits on the TIPAL webpage from control and intervention regions from data 
analytics provided by the webpage host.  
• 
The perceived change in APF support group members’ general knowledge and enthusiasm about 
research as measured by a support group member questionnaire sent to all members of all APF 
support group involved in the PURPOSE study.  
• 
A description of the interventions undertaken, as obtained from a study-specific questionnaire 
completed by research champions/lead contacts at 12 months (intervention regions only) and 24 
months. 
• 
An appraisal of the intervention by a series of focus groups facilitated by a member of APF or 
another appropriate individual at 12 months 
 
Data Collection Methods 
Figure 4 outlines PURPOSE data collection. 
Data on the primary outcome measures and data on self-referrals will be obtained from the linked-
anonymised TIPAL screening log and eCRF.  
During screening for the TIPAL trial, patients will be asked whether they are members of an APF 
Support group and, if so, the name of the group and whether they self-referred to the TIPAL trial 
(meaning they approached their clinical team to enquire about the trial). TIPAL participants will be 
asked their ‘support group status’ at the 12 month follow-up visit.  
This linked-anonymised data will be collected by TIPAL sites on the TIPAL screening log and used to 
assess the difference between the overall number of trial participants recruited from control and 
intervention patient support groups. It will also be used to compare the rates of self-referral from 
control and intervention patient support groups. 
The screening data will also be used to compare withdrawal data, obtained from the TIPAL eCRF 
withdrawal form to assess the difference between the overall numbers of withdrawn trial participants 
from control and intervention patient support groups. 
Research Champions will be asked to complete a study-specific non-validated online questionnaire at 
12 months and 24 months. The questionnaire link will be sent via email by APF and/or the NCTU team 
at the relevant timepoints. Alternatively, questionnaire responses may be provided on paper where 
preferred. In this instance, APF will facilitate entry into the electronic questionnaire system, 
performing ad hoc quality checks for transcription accuracy. The questionnaire responses will be 
reviewed and discussed by a review group comprising members of APF and other members of the 
TIPAL team and will be used to refine the intervention.  
Data completeness of the primary endpoint of TIPAL participants, linked to a support group within. an 
intervention region, will be compared with those in control regions at 12 and 24 months from the start 
of the study.  

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At 12 months, a non-validated study-specific questionnaire will be distributed to control and 
intervention support group research champions/lead contacts for electronic dissemination to all 
support group members, to assess members’ general knowledge and enthusiasm about research and 
confirm the number of self-reported self-referrals or enquiries about the TIPAL study. Alternatively, 
questionnaire responses may be provided on paper where preferred. In this instance, APF will 
facilitate entry into the electronic questionnaire system, performing ad hoc quality checks for 
transcription accuracy. To supplement this, TIPAL participants will be asked if they are willing to 
complete the NIHR Participant in Research Experience Survey (PRES) questionnaire at the end of their 
participation as part of the standard delivery programme conducted by the Clinical Research Network. 
Participants will be asked to record the name of their patient support group (if applicable) on the PRES 
questionnaire.  
Routine web analytics data of traffic on the main TIPAL webpage will be collected throughout the trial. 
The webpage host will provide a report based on data exported from Google Analytics including the 
number of and location of webpage hits on the TIPAL webpage. This will be exported at the end of the 
trial and will enable a comparison between the traffic from control and intervention regions. 
Data captured on the TIPAL eCRF and questionnaire data will be kept securely on the UEA servers (in 
a SWAT specific office 365 folder). This data will be only accessible to members of the TIPAL trial team 
at NCTU, and external regulators if requested.  
Focus groups will be facilitated by APF at 12 months to allow feedback and discussions with support 
groups to appraise the interventions put in place. It is anticipated that 3 - 4 focus groups will occur, 
either online or in-person, with approximately 3 to 5 participants, including: a research-engaged 
support group, a less research-engaged support group and research champions (may be split into two 
groups to ensure effective discussions are feasible with the number of attendees). Level of research 
engagement will be subjectively assessed by APF based upon performance in Phase 1. Focus groups 
will be conducted online and facilitated either by APF or an independent qualitative researcher. 
Discussions will be recorded using the inbuilt recording feature will be used meaning that audio and 
video is recorded. Focus group meetings will take approximately 60 - 90 minutes and participants must 
consent to participate prior to the discussions taking place. Participation in focus groups is voluntary 
and does not affect participation in the rest of the PURPOSE study or TIPAL trial (if applicable). Focus 
group participants will be assigned a PID upon consent in order for a linked-anonymised transcript to 
be produced from each discussion. Consent may be documented electronically (with a wet-ink 
equivalent signature) or on paper. Only the PURPOSE study team will be able to link the participants 
to their PID. Discussions will follow the meeting structure outlined in the PURPOSE focus group topic 
guide.  
PURPOSE study data including focus group recordings will be stored securely for 25 years by NCTU.  
Analysis 
The analysis will be based on the intention-to-treat principle but as this is a cluster trial, a mixed model 
will be used with a random effect for the clustering variable of 'region'. For the outcome measures 
that are count data, a Poisson mixed model will be used. For the outcome of number of participants 
recruited, the model will adjust for the membership size of each APF support group at baseline 
(provided by APF). The choice of offset is to control for the different self-referrals from support groups 
in the study, the assumption being that the recruitment rate should depend on the size of the support 

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groups, with large support groups having larger numbers of self-referrals. For the outcome of the 
number of participants withdrawn, the model will adjust for the number of participants randomised 
at each APF support group. 
A descriptive analysis will be undertaken to compare the number of self-reported self-referrals or 
enquiries to participate in research studies from participants, the number of patients recruited via 
patient support groups and the number of hits on the study webpage. We will also compare the 
completeness of the primary endpoint data at each site and the results from a questionnaire to assess 
general knowledge and enthusiasm about research as well as the degree of empowerment and 
motives for participating in research, plus adverse or unintended consequences. 
The number of recruited participants per site: The analysis will be based on a random effects Poisson 
regression model with site included as a random effect and an offset of the size of the site. 
Primary outcome completeness: The analysis will be based on a random effect logistic regression 
model with site included as a random effect.  
Focus group transcripts: Thematic analysis of all transcripts will be conducted by an experienced 
individual affiliated with UEA, identified by the TIPAL trial team. 
Further information will be contained in a study specific Statistical Analysis Plan which will be finalised 
prior to the end of the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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12 
Principal Investigator compliance statement 
All TIPAL PI’s are required to sign a site specific copy of the investigator compliance statement below 
prior to activation. 
Principal Investigator agreement to confirm adherence to the protocol, the UK 
Policy Framework for Health and Social Care Research and GCP. 
TIPAL 
The effectiveness and risks of Treating people with Idiopathic 
Pulmonary fibrosis with the Addition of Lansoprazole (TIPAL): a 
randomised placebo-controlled multi-centre clinical trial 
Trial protocol version 
[insert current version number] 
Trial protocol date 
[insert date of current version] 
 
I, [Insert investigator name], confirm: 
1. that [insert name of site] site is willing and able to comply with the requirements of the 
TIPAL trial; 
2. that I regularly treat the target population and believe the site has the potential for 
recruiting the required number of suitable subjects within the agreed recruitment period 
(figures included in the trial recruitment plan); 
3. that I have sufficient time to properly conduct and complete the trial within the agreed trial 
period; 
4. that I have supplied an up to date curriculum vitae, GCP certificate and/or other relevant 
documentation requested by NCTU, to demonstrate that I am qualified by education, 
training and experience to assume responsibility for the proper conduct of the trial at this 
study site; 
5. that I am thoroughly familiar with the appropriate use of the investigational products as 
described in the protocol, in the current SPC, in the product information and in other 
information sources provided by NCTU; 
6. that I have an adequate number of qualified staff and adequate facilities available for the 
foreseen duration of the trial to conduct the trial properly and safely; 
7. that I will maintain a signature and delegation log of appropriately qualified persons to 
whom I have delegated trial related duties which includes confirmation that each member of 
staff is appropriately trained (including GCP) for the roles allocated to them, and will ensure 
this is made available to NCTU in a timely manner on request; 
8. a research CV for each member of staff on the delegation log will be stored in the site file 
according to site policy;  
9. that I take responsibility for ensuring all staff delegated trial related duties are adequately 
informed about the protocol, the investigational product and their trial related duties and 

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functions, and that I will continue to take responsibility for regularly updating them as new 
information becomes available; 
10. that the [insert name of site] site has sufficient resources to manage data generated by the 
trial to allow prompt and complete data and query return to NCTU;  
11. that I am aware of, and will comply with, the principles of GCP as given in the TIPAL protocol 
compliance statement and the applicable regulatory requirements, and that a record of my 
GCP training is accessible and described on my current curriculum vitae; 
12. that a record of GCP training is accessible for all staff delegated responsibilities in relation to 
the TIPAL trial and who are named and approved on the site signature and delegation of 
responsibilities log and that individual training evidence will be saved in the site file, for all 
staff, according to trust policies; 
13. that I will permit routine and for-cause monitoring and auditing by NCTU, and inspection by 
the appropriate regulatory authorities, including the provision of direct access to source 
data and other participant notes and files as required; and 
14. that I agree to archive and/or arrange for secure storage of TIPAL trial materials and records 
for a minimum of 25 years after the close of the trial unless otherwise advised by the NCTU. 
 
Agreement: Principal Investigator 
Name 
[insert name] 
Signature 
[insert wet signature] 
 
 
Date 
[insert date] 
 
 
Please return a copy of this signed agreement (to the NCTU trial team at tipal@uea.ac.uk).