Breathing Retraining for Asthma Trial of Home Exercises for Teenagers (Breathe4T); Re-purposing, Refining and Feasibility - Stage 3
Phase: NA
Conditions: Adolescent Behavior, Asthma
Sponsor: University of Southampton

 
 
BREATHE4T protocol – Stage 3         26th March 2021        Version 1.1                  1 
Breathing REtraining for Asthma Trial of Home 
Exercises for Teenagers; repurposing, refining 
and feasibility – Stage 3  
 
 
 
 
 
 
 
 
Short trial title: BREATHE4T – Stage 3 
 
 
 
 
 
 
This protocol has regard for the HRA guidance and order of content with modification for a non-CTIMP 
study (Version 1.2 March 2016) 
 
 
 

 
 
BREATHE4T protocol – Stage 3         26th March 2021        Version 1.1                  2 
RESEARCH REFERENCE NUMBERS 
 
TRIAL REGISTRY NUMBER AND DATE: NCT05006703; 16th August 2021 
 
PROTOCOL VERSION NUMBER AND DATE: Version 1.0; 26th March 2021 
 
UNIVERSITY HOSPITAL SOUTHAMPTON NHS FOUNDATION TRUST RESEARCH REFERENCE 
NUMBER: RHM CHI1071 
 
IRAS NUMBER: 290847 
 
FUNDER NUMBER: PB-PG-0817-20038 
 
 
 
 
 
 

 
 
BREATHE4T protocol – Stage 3         26th March 2021        Version 1.1                  3 
SIGNATURE PAGE 
The undersigned confirm that the following protocol has been agreed and accepted and that the Chief 
Investigator agrees to conduct the trial in compliance with the approved protocol and will adhere to the 
principles outlined in the GCP guidelines, the Sponsor’s (and any other relevant) SOPs, and other 
regulatory requirements as amended. 
I agree to ensure that the confidential information contained in this document will not be used for any 
other purpose other than the evaluation or conduct of the clinical investigation without the prior written 
consent of the Sponsor 
I also confirm that I will make the findings of the trial publicly available through publication or other 
dissemination tools without any unnecessary delay and that an honest accurate and transparent 
account of the trial will be given; and that any discrepancies and serious breaches of GCP from the 
trial as planned in this protocol will be explained. 
 
For and on behalf of the Trial Sponsor: 
Signature:  
...................................................................................................... 
 
Date: 
....../....../...... 
Name (please print): 
...................................................................................................... 
 
 
Position: 
...................................................................................................... 
 
 
 
Chief Investigator: 
Signature: 
...................................................................................................... 
 
Date: 
....../....../...... 
Name: (please print): 
......................................................................................................
 
 
 
 
 
 
Statistician: 
 
 
Signature: 
...................................................................................................... 
 
 
Name: (please print): 
......................................................................................................
 
 
 
 
 
Position: 
......................................................................................................
 
 
 
 
 
 

 
 
BREATHE4T protocol – Stage 3         26th March 2021        Version 1.1                  4 
KEY TRIAL CONTACTS 
 
Chief Investigator 
Professor Graham Roberts 
Professor and Honorary Consultant, Paediatric Allergy and 
Respiratory Medicine 
University Child Health (MP803), University Hospital 
Southampton NHS Foundation Trust, Tremona Road, 
Southampton SO16 6YD 
Telephone: 02381206160 
Email: g.c.roberts@soton.ac.uk   
Trial Co-ordinator 
Stephanie Easton 
University Child Health (MP803), University Hospital 
Southampton NHS Foundation Trust, Tremona Road, 
Southampton SO16 6YD 
Telephone: 02381 205227 
Email: s.e.easton@soton.ac.uk    
Sponsor 
University Hospital Southampton NHS Foundation Trust,  
Mrs Sharon Davies-Dear, R&D office, E level, Southampton 
Centre for Biomedical Research, Laboratory and pathology 
block (MP138), Southampton General Hospital, Tremona 
Road, Southampton, SO16 6YD 
Telephone: 023 8120 5424 
Email: sponsor@uhs.nhs.uk 
Funder(s) 
National Institute of Health Research, Research for Patient 
Benefit 
Key Protocol Contributors 
Primary care lead: Professor Mike Thomas, Professor of 
Primary Care Research, University of Southampton, UK; 
Telephone: 02380241050; Email: 
D.M.Thomas@soton.ac.uk  
Physiotherapy lead: Denise Gibson; Telephone: 
02381206725; Email: denise.gibson@uhs.nhs.uk 
Behavioural change lead: Professor Lucy Yardley; 
Professor of Health Psychology, University of Southampton, 
UK; Telephone: 02380594581; Email 
L.Yardley@soton.ac.uk  
With additional input from Dr Rebecca Knibb, Reader in 
Psychology, University of Aston, UK; Telephone: 
01212043402; Email: r.knibb@aston.ac.uk  
Digital intervention lead: Dr Benjamin Ainsworth, Lecturer 
in Health Psychology, University of Bath, UK; Telephone: 
01225383114; Email: B.Ainsworth@bath.ac.uk  

 
 
BREATHE4T protocol – Stage 3         26th March 2021        Version 1.1                  5 
Qualitative lead: Professor Sue Latter, Professor of 
Nursing, University of Southampton, UK; Telephone: 
02380597959; Email: S.M.Latter@soton.ac.uk  
Adolescent lead: Dr Simone Holley, Senior Research 
Fellow, University of Southampton, UK; Email: 
S.L.Holley@soton.ac.uk  
Asthma UK lead: Erika Kennington, Head of Research, 
Asthma UK, UK; Telephone: 02077864939; Email: 
ekennington@asthma.org.uk  
Statistician 
Dr Sam Wilding, Trial Statistician, University of 
Southampton, UK; Telephone: 02381205674; Email: 
S.A.Wilding@soton.ac.uk  
Committees 
Trial Management Group chaired by Professor Graham 
Roberts (CI) 
Trial Steering Committee chaired by Professor Steve Turner 
 
 
 

 
BREATHE4T protocol – Stage 3         26th March 2021              Version 1.1                  6 
i. LIST of CONTENTS 
GENERAL INFORMATION 
Page No. 
TITLE PAGE  
1 
RESEARCH REFERENCE NUMBERS 
 
2 
SIGNATURE PAGE 
3 
KEY TRIAL CONTACTS 
 
4 
i. LIST of CONTENTS 
6 
ii. LIST OF ABBREVIATIONS 
7 
iii. TRIAL SUMMARY  
8 
iv. FUNDING  
9 
v. ROLE OF SPONSOR AND FUNDER 
9 
vi. ROLES & RESPONSIBILITIES OF TRIAL MANAGEMENT COMMITTEES, GROUPS 
AND INDIVIDUALS   
10 
vii, PROTOCOL CONTRIBUTERS 
10 
viii. KEYWORDS 
11 
ix. TRIAL FLOW CHART 
 
11 
SECTION  
1. BACKGROUND 
 
12 
2. RATIONALE 
 
15 
3. ASSESSMENT AND MANAGEMENT OF RISK 
16 
4. RESEARCH OBJECTIVE 
16 
5. STAGE 3 – THE PILOT TRIAL 
17 
6. SAFETY 
24 
7. STATISTICS AND DATA ANALYSIS 
26 
8. DATA MANAGEMENT  
28 
9. MONITORING, AUDIT & INSPECTION 
29 
10.  ETHICAL AND REGULATORY CONSIDERATIONS 
30 
11. DISSEMINATION POLICY 
32 
12. REFERENCES 
32 
13. APPENDICIES 
34 
 

 
BREATHE4T protocol – Stage 3         26th March 2021              Version 1.1                  7 
ii. LIST OF ABBREVIATIONS 
Define all unusual or ‘technical’ terms related to the trial.  Add or delete as appropriate to your trial.  
Maintain alphabetical order for ease of reference. 
AE 
Adverse Event 
AR 
Adverse Reaction 
CI 
Chief Investigator 
CRF 
Case Report Form 
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of technical 
requirements for registration of pharmaceuticals for human 
use. 
ISF 
Investigator Site File (This forms part of the TMF) 
NHS R&D 
National Health Service Research & Development   
PI 
Principal Investigator 
PIC 
Participant Identification Centre 
PIS 
Participant Information Sheet 
PPI 
Patient and Public Involvement 
QA 
Quality Assurance 
QC 
Quality Control 
QP 
Qualified Person  
RCT 
Randomised Control Trial 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SDV 
Source Data Verification 
SOP 
Standard Operating Procedure  
SSI 
Site Specific Information 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TMF 
Trial Master File 
TMG 
Trial Management Group 
TSC 
Trial Steering Committee 
 
 

 
 
BREATHE4T protocol – Stage 3         26th March 2021        Version 1.1                  8 
iii. TRIAL SUMMARY 
 
Trial Title 
Breathing REtraining for Asthma Trial of Home Exercises for Teenagers; 
repurposing, refining and feasibility – Stage 3 
Short title 
BREATHE4T – Stage 3 
Clinical Phase  
Phase 2a clinical trial 
Trial Design 
Pilot trial 
Trial Participants 
Young people (12-17 years) with physician diagnosed asthma, impaired 
quality of life. All will be under the care of a general practitioner, community 
asthma nurse specialist or hospital healthcare professional.  
Exclusion criteria: already using breathing techniques; co-existent respiratory 
conditions; member of the study PPI groups, learning difficulties. 
Planned Sample Size 
116 in pilot trial 
Treatment duration 
6 months 
Follow up duration 
6 months 
Objectives 
i. To assess the recruitment rate. 
ii. To assess the acceptability and uptake of the intervention, using both 
internet/telephone interviews with a sample of participants and online 
questionnaires at 2 and 6-month assessment; 
iii. To estimate the follow-up rate at the 2 and 6-month assessment (will also 
look at relative rates for participants recruited from primary care, secondary 
care and Asthma UK); 
iv. To monitor the change in and estimate the variance of asthma-related 
quality of life and asthma control in each group; 
v. To determine if data collection methods for process, effectiveness and 
cost-effectiveness endpoints are appropriate for this population by 
assessment of completeness of data at 2 and 6-month assessment; 
vi. To assess the relative uptake and quality of qualitative data collection from 
participants via in-person, online video platforms (e.g. Microsoft Teams) or 
telephone interviews, to inform format and necessary staffing requirements 
for a trial. 
Intervention 
• a theoretically informed, mobile-friendly website, based on the successful 
adult Breathe intervention 
• motivational information about the benefits of breathing retraining, 
• short and engaging videos demonstrating breathing retraining techniques, 
• supportive elements such as a daily planner and progress chart, 
• advice on how to integrate breathing retraining techniques into daily life, 
• advice addressing common barriers to engagement. 
 
 
 
 

 
 
BREATHE4T protocol – Stage 3         26th March 2021        Version 1.1                  9 
iv. FUNDING AND SUPPORT IN KIND 
FUNDER(S) 
FINANCIAL AND NON FINANCIAL SUPPORT 
GIVEN 
National Institute of Health Research, Research 
for Patient Benefit  
£247,376.00 
National Institute of Health Research 
Southampton Biomedical Research Centre 
The BRC paediatric research nursing team will 
be able to support the project. The BRC will also 
support the PPI activities. Lastly the BRC 
management team will support the project, as 
required.  
 
 
v. ROLE OF TRIAL SPONSOR AND FUNDER 
Trial sponsor: University Hospital Southampton NHS Foundation Trust 
The trial sponsor has delegated responsible to the Chief Investigator for:  
• 
Obtaining required authorisations to commence the trial (clinical trial authorisation and 
favourable ethics committee opinion) 
• 
Keeping records of all amendments to the authorisations and obtain approval where approvals 
are required 
• 
Undertaking to allow inspection of premises in third countries if required 
• 
Notifying all relevant bodies of the conclusion or termination of the trial within the specified 
timeframes 
• 
Keeping a trial master file to hold all documents relating to that trial 
The trial sponsor and Chief Investigator will be responsible for: 
• 
Ensuring that the conditions and principles of Good Clinical Practice (GCP) are satisfied and 
adhered to 
• 
Ensuring that the trial is conducted in accordance with the protocol and subsequent amendments  
• 
Appointing named individuals responsible for archiving the trial essential documents  
The trial sponsor will be responsible for:  
• 
Notifying any serious breaches of Good Clinical Practice or the protocol, or any urgent safety 
measures taken to the appropriate authorities  
 
Trial funder: National Institute of Health Research, Research for Patient Benefit  
The funder will have no role in the trial design, conduct, data analysis and interpretation, and generation 
of publications. 
 
 
 
 

 
 
BREATHE4T protocol – Stage 3         26th March 2021        Version 1.1                  10 
vi. ROLES AND RESPONSIBILITIES OF TRIAL MANAGEMENT COMMITEES 
Trial Steering Committee 
Trial Steering Committee (TSC) will have an important advisory role in the study reviewing progress and 
data and providing feedback and guidance to the TMG. It will be chaired by an independent academic 
clinician with experience in clinical trials. All the members of the TMG will be represented, together with 
our collaborators and independent members from key stakeholder groups (eg asthma clinician, general 
practitioner, asthma nurse specialist, academic clinician, patient with asthma and a parent of a young 
person with asthma (from the PPI panels). The TSC will meet twice a year face-to-face and its activities 
will relate to the strategic oversight of the project to ensure it meets its overall objectives and provides 
robust data. The TSC will send reports to the TMG and sponsor.  
 
Trial Management Group 
Trial Management Group (TMG) will be the main operational group meeting monthly (face-to-face or 
webconference). It will comprise the co-investigators plus the research assistant. The TMG will be 
responsible for: 
• Monitoring the technical and financial aspects including reviewing progress against timelines and 
developing a strategy to address unforeseen occurrences; 
• Monitoring the ethical and safety aspects; 
• Ensuring effective external (including dissemination) and internal communications; 
• Developing a plan for using and disseminating the knowledge accruing through the study activities. 
 
vii. Protocol contributors 
Professor Graham Roberts, Professor and Honorary Consultant, Paediatric Allergy and Respiratory 
Medicine, University of Southampton and University Hospital Southampton NHS Foundation Trust, 
Southampton.  
Professor Mike Thomas, Professor of Primary Care Research, University of Southampton.   
Professor Anne Bruton, Professor of Respiratory Rehabilitation (retired), University of Southampton 
Professor Lucy Yardley, Professor of Health Psychology, University of Southampton 
Dr Rebecca Knibb, Reader in Psychology, University of Aston 
Dr Benjamin Ainsworth, Lecturer in Health Psychology, University of Bath 
Professor Sue Latter, Professor of Nursing, University of Southampton 
Dr Simone Holley, Senior Research Fellow, University of Southampton 
Erika Kennington, Head of Research, Asthma UK 
Dr Amy Whitehead, Senior Statistician, University of Southampton 
Dr Sam Wilding, Trial Statistician, University of Southampton 
Dr Denise Gibson, Consultant Physiotherapist, University Hospital Southampton NHS Foundation Trust 
Stephanie Easton. Research Assistant, BREATHE4T study, University Hospital Southampton NHS 
Foundation Trust 
BREATHE4T Public and Patient Involvement Committees and Michael Bahrami-Hessari, 
Patient and Public Involvement Officer, University Hospital Southampton NHS Foundation Trust 
 

 
 
BREATHE4T protocol – Stage 3         26th March 2021        Version 1.1                  11 
viii. Key words: adolescents, asthma, breathing retraining, person-based approach, development, 
pilot trial 
 
ix. Trial flow chart  
Figure 1. Overview of entire BREATHE4T project 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This protocol deals with Stage 3, bottom of the figure.  
 
 

 
 
BREATHE4T protocol – Stage 3         26th March 2021        Version 1.1                  12 
Figure 2. Flow of participants in the BREATHE4T pilot trial 
 
 
 

 
 
BREATHE4T protocol – Stage 3         26th March 2021        Version 1.1                  13 
1 
BACKGROUND AND THEORETICAL FRAMEWORK 
 
1.1 
The problem – suboptimal health experience for young people with asthma 
The problem we aim to address is impaired asthma-related quality of life (despite appropriate 
pharmacotherapy) for young people (12-17 years) with asthma [1]. A non-pharmacological intervention 
(breathing retraining) has been shown to be both effective and cost-effective in adults [2, 3]. Breathing 
retraining improved their asthma related quality of life, the key patient orientated outcome measure. 
Implementation of the adult BREATHE study intervention is underway. An online version of the DVD 
intervention is available to patients and health professionals (www.breathestudy.co.uk). This effective 
approach needs to be evaluated in young people with asthma, who have real potential to benefit from 
this simple, inexpensive intervention [4]. 
 
1.2 
Why this research is important to improve the health of patients and the NHS 
Asthma: Asthma prevalence is high in adolescence (around 15%) [5] and hospital admissions are more 
common in young people than adults. Asthma is a heterogeneous condition [6] and pharmacological 
approaches do not meet all patients’ needs [1]. We know the majority of people with asthma continue 
to have symptoms and impaired quality of life [1, 7]. A personalised, holistic approach to asthma 
management may improve outcomes [8]. 
Adolescent asthma: Young people have poor asthma outcomes, particularly in relation to quality of life 
(1). They have different issues and needs to adults [9, 10]. For example, we and others have 
demonstrated that they often have limited engagement in self-managing their asthma and often 
inefficiently communicate with healthcare professionals [4, 11, 12]. Hence there is a pressing need to 
identify suitable, alternative, healthcare solutions for this group. Our recent systematic review on self-
management [4] revealed that young people are reluctant to take asthma medications and attend 
asthma clinic reviews but, more positively and highly relevant to this application, they find technological 
interventions particularly acceptable. Unlike younger children, young people are able to manage 
interventions without parental supervision. They therefore represent a very good target for a behavioural 
change health intervention, especially as self-management skills support life-long asthma management. 
Breathing retraining: Patients and parents are interested in non-pharmacological asthma treatments 
with a third of children and young people resorting to complementary and alternative medicine therapies, 
often without the knowledge of their clinicians [13]. One approach for asthma is breathing retraining, 
which we have recently demonstrated to be successful and cost-effective in adults with asthma in a 
large HTA funded study [2, 3] and is already being implemented. However, we know that young people 
will need to be engaged differently ([4], our ongoing Asthma UK funded study) and so we propose an 
adapted, web-based intervention. A recent Delphi exercise from the European Asthma Research and 
Innovation Partnership Self-Management working group highlighted behavioural strategies and new 
information technologies in their top three priorities for asthma self-management [14]. As per the adult 
intervention, once we have evidence for the effectiveness of the young person intervention, it should be 
easy to implement as an online training tool. 
 
1.3 
Current state of the art knowledge 
Breathing retraining in adult asthma: A systematic review of studies of breathing retraining in adult 
asthma demonstrated improvements in asthma quality of life, control, symptoms and exacerbations [15]. 
This approach is now advocated in adult guidelines [16]. One problem limiting the NHS use of this 
treatment is the lack of respiratory physiotherapists therefore only a small proportion of patients who 
might benefit are able to access breathing retraining. In the HTA funded, adult, randomised controlled 
BREATHE study [2] an audio-visual breathing retraining programme was effective in improving asthma 
quality of life (adjusted mean difference 0.28, 95% confidence interval: 0.11-0.44, p<0.001) [2, 3]. The 

 
 
BREATHE4T protocol – Stage 3         26th March 2021        Version 1.1                  14 
number needed-to-treat to deliver a clinically important improvement of 0.5 units was 8. There was an 
equivalent improvement with face-to-face physiotherapy (0.24, 0.04-0.44; p<0.05). The process 
evaluations showed good patient engagement and acceptability for the DVD based intervention. 
Importantly, healthcare costs (mostly unscheduled care) were lower in the audio-visual DVD-based 
breathing retraining programme group compared to usual care, with reduced asthma healthcare 
utilisation outweighing the £2.85 per participant cost of the intervention. 
Breathing retraining in young people with asthma: Young people with asthma also exhibit dysfunctional 
breathing with a recent study suggesting 55% are affected [17]. This may manifest as hyperventilation 
or occasionally vocal cord dysfunction [18]. These add to breathing difficulties seen with an asthma 
exacerbation and both respond well to breathing retraining. Young people differ cognitively, 
psychologically and behaviourally from adults so properly conducted studies are required before we can 
extrapolate from adults to younger age groups. For example, even if there are good physiological 
reasons as to why an intervention should be equally effective in adults and young people, it may not 
work in young people because they fail to take up the intervention. There are case reports and case 
series pointing to the effectiveness of breathing training programmes in young people [19, 20]. However, 
in contrast with adults, there are no well-designed published randomised controlled studies. A recent 
systematic review concluded that “We could draw no reliable conclusions concerning the use of 
breathing exercises for children with asthma” [21]. We therefore wish to test the BREATHE study 
approach to breathing retraining in asthma in young people. 
 
 
1.4 
The ‘Breathing Freely’ intervention 
The intervention being developed in BREATHE4T – Stage 1 and 2 is a self-guided, breathing retraining 
digital intervention, that will be delivered via a mobile friendly, online platform. The research team has 
successfully used internet-based approaches to implement behaviour change for weight-loss and hand-
hygiene. In addition, in the BREATHE study we developed the adult ‘Breathing Freely’ intervention, a 
DVD-based remote intervention that was shown to improve asthma related quality of life in an NIHR-
funded HTA adult trial by investigators (Thomas, Bruton, Yardley) [2, 3]. The intervention was developed 
using the iterative, user-centred ‘person-based approach [22]’ in order to ensure that it was acceptable 
and engaging to patients. The intervention has been fully disseminated in a digital format and is available 
here: http://www.breathestudy.co.uk.  
The existing adult intervention includes a detailed explanation and illustration of how to perform the 
breathing exercises alongside professionally developed footage showing a physiotherapist teaching 
them to patients. To ensure that the intervention is engaging to adults, both the video content and 
accompanying advice contain motivational components that explain the rationale of the exercises, and 
address common doubts and concerns. Additional ‘supportive’ elements were also included such as a 
daily planner, and progress chart, in order to support practicing and implementing the techniques into 
daily life.  
From our ongoing research with this target population (Asthma UK funded project “It’s My Asthma”), 
and detailed PPI input we are aware that the current BREATHE intervention is not in a format that young 
people are likely to interact with and will need to be adapted and refined. For example, the video content 
will need to use younger actors with whom they can relate and it would benefit from increased 
gamification and personalisation. For the motivational content, advice and support, young users will 
benefit from a mobile app/website (rather than a dedicated website that is appropriate for older primary 
care adults) that can be easily accessed on a smartphone. 
 
1.5 
The need for an adolescent version of the “Breathing Freely” intervention 
In our recent Asthma UK funded adolescent asthma study we have evaluated the acceptability of a 
novel young person approach for asthma self-management (manuscript in preparation). From this we 

 
 
BREATHE4T protocol – Stage 3         26th March 2021        Version 1.1                  15 
know that changes to the materials and format will be required to engage this age group. For example, 
a young person’s training package needs to be relevant for them in terms of how the intervention is 
explained and how it is presented. So the intervention needs to be repurposed and then optimised for 
this population. Age-appropriate materials and the technology platform need to be developed in 
collaboration with young people. Our work with this age group suggests that a smartphone/ tablet/ 
internet accessible intervention would be required, rather than DVD technology. We have used a 
‘person-based approach’ [22] to develop an intervention platform and content that is acceptable and 
feasible, by iteratively modifying the intervention according to user feedback to maximise engagement 
to the intervention and effective behaviour change.  
 
1.6 The BREATHE4T intervention 
The repurposing, optimisation and acceptability of the intervention in the adolescent age group has been 
undertaken in Stages 1 and 2 of the BREATHE4T project. In line with the person-based approach [22], 
a rapid scoping review and behavioural analysis examined the key adolescent-specific issues, needs 
and challenges that the intervention must address. Qualitative interviews were conducted with 18 
participants to explore barriers and facilitators to adolescent engagement and specific design features, 
which has informed the development of a mobile-friendly web application. The intervention was refined 
and optimised using feedback from teenagers that took part in think-aloud interviews, additional to 
regular input from key stakeholders, including a panel of 6 teenagers and 6 parents who met every 3 
months with regular contact between meetings. Guiding principles have been created and outline the 
specific design needs and objectives to target the key behaviours.   
 
2 
RATIONALE  
From our research and clinical experience with young people with asthma we know many have impaired 
quality of life despite pharmacotherapy [1]. Young people (and their parents) tell us that during an 
asthma attack they have to calm themselves down to control their breathing [23]. Although 
physiotherapist-delivered breathing retraining programmes now have a clear evidence base in adults 
with asthma, improving quality of life [2, 3], there is a lack of evidence assessing its use in younger 
patients. There is a need to redesign and develop this behavioural change intervention to make it 
appropriate for young people, and then assess how effective such an intervention would be in this 
population.  
If similar results were to be seen with young people, this intervention would improve their asthma related 
quality of life reducing their need for unscheduled emergency healthcare for asthma exacerbations for 
a minimal cost. 
If this intervention proves to be cost-effective, it is envisaged that an updated version of the intervention 
would be hosted on the web. This may be within a NHS network or within the Asthma UK website. The 
adult digital intervention has been made freely available to patients and professionals through the web 
link www.breathestudy.co.uk, and is receiving considerable traffic. We would provide similar access for 
this intervention in the event of a positive study. NHS professionals involved in the care of young people 
with asthma would be alerted to the website to disseminate it. Professionals would be able to signpost 
patients to the site. Additionally, patient organisations would also be able to signpost patients to the 
site. We will also consider using the CLAHRC/AHC networks in an implementation study. 
To design this substantive trial needed to demonstrate cost-effectiveness, we have repurposed the adult 
BREATHE intervention. This pilot trial will provide the necessary information for a substantive cost-
effectiveness trial. This includes the likely i) recruitment rate (ii) acceptability, uptake and engagement 
with the intervention; (iii) follow-up rate; (iv) change in and estimated variance of asthma-related quality 
of life and asthma control in each group; (v) effectiveness of data collection methods; (vi) determine the 
validity of the PEDSQL Asthma Module quality of life questionnaire [24] and (vii) uptake and quality of 
qualitative data collection. 

 
 
BREATHE4T protocol – Stage 3         26th March 2021        Version 1.1                  16 
A future full trial would be a randomised, controlled trial recruiting young people (aged 12-17 years) with 
asthma cared for in both primary and secondary care. It is expected that 300-400 participants would be 
required. The intervention would be the self-guided, breathing retraining digital intervention, delivered 
via a mobile friendly, online platform developed in this proposed project. The comparator group would 
experience usual UK asthma management and access to the intervention at the end of the trial. 
Outcome data would likely be collected via telephone and online with the primary outcome being 
determined by this project. The cost-effectiveness analysis would employ methods and perspective 
endorsed by NICE.  
  
3 
ASSESSMENT AND MANAGEMENT OF RISK 
Breathing re-training is a well-known approach to managing breathing problems in children, adolescents 
and adults. As described above (Section 1), there is evidence for its effectiveness in treating asthma in 
adults and some evidence for asthma in children. In the adult BREATHE study, there was a significant 
improvement in asthma related quality of life.  
There are no known adverse effects for breathing retraining [3]. The BREATHE study enrolled 655 
adults with asthma of whom 261 were randomised to breathing retraining via DVD and 132 to breathing 
retraining by face-to-face teaching [3]. Adverse events were seen in 39% of the DVD group, 42% of the 
face-to-face group and 50% of the usual care group. Percentages experiencing severe adverse events 
were 4%, 3% and 8% respectively. There was one death in the DVD group and two in the usual care 
group; none of these were related to the intervention. 
The risk for patients with asthma are asthma exacerbations which can be severe and require 
hospitalisation. To minimise the risk, all participants will be under the management of their general 
practitioner, community asthma nurse specialist or hospital healthcare professional. Patients with 
asthma are regularly reviewed to ensure their symptoms are controlled. Additionally, the intervention 
will emphasise how to recognise and appropriately respond to deteriorating asthma control. This means 
that participants will understand when they need to take additional therapy and seek medical help in the 
event of an asthma exacerbation.  
 
4 
RESEARCH OBJECTIVES 
 
4.1 
Aim: This pilot trial aims to determine the acceptability and feasibility of conducting a definitive 
Phase III randomised controlled trial (RCT) comparing immediate access to the breathing retraining 
intervention to delayed access to the intervention in young people with asthma.  
 
4.2 
Specific objectives for stage 3: 
To achieve the overall aim, the pilot trial has the following objectives:  
i. To assess the recruitment rate; 
ii. To assess the acceptability and uptake of the intervention, using both internet/video/telephone or in-
person interviews with a proportion of participants and online questionnaires at 2 and 6-month 
assessment; 
iii. To estimate the follow-up rate at the 2 and 6-month assessment (will also look at relative rates for 
participants recruited from primary care, secondary care, Asthma UK and social media); 
iv. To monitor the change in and estimate the variance of asthma-related quality of life and asthma 
control in each group; 

 
 
BREATHE4T protocol – Stage 3         26th March 2021        Version 1.1                  17 
v. To determine if data collection methods for process, effectiveness and cost-effectiveness endpoints 
are appropriate for this population by assessment of completeness of data at 2 and 6-month 
assessment; 
vi. To determine whether the PedsQL Asthma Module (with and without additional emotion 
questions[25]) provides a valid assessment of quality of life, by comparing it with the Paediatric 
Asthma Quality of Life Questionnaire [26]  
vii. To assess the relative uptake and quality of qualitative data collection from participants via in-person, 
video or telephone interviews, to inform format and necessary staffing requirements for a trial; 
 
Achieving these objectives would allow us to develop a Phase III cost-effectiveness trial to address the 
questions (i) “Does breathing retraining provided via a digital intervention result in clinically important 
improvements in patient-related asthma measures above 'usual care'?” and (ii) “What is the cost-
effectiveness of the programme?”. 
 
5 
Stage 3 – THE PILOT TRIAL 
The pilot trial will be a multicentre, open-label, two-group, individually randomised, controlled trial.  
 
5.1 
Outcome measures/endpoints 
As this is a pilot trial, a number of outcome measures / endpoints will be included to establish which is 
the optimal one for a definitive trial.  
 
Objectives 
Outcome Measures  
Time point(s) of 
evaluation of this 
outcome measure  
Asthma 
specific 
quality of life 
PedsQL Asthma Module  
This will be assessed using the validated paediatric 
asthma quality of life asthma module (short form) 
questionnaire and presented as a total score (sub-scores 
will also be presented)([24]).  
From the adult BREATHE study [2] we expect the 
intervention to have most benefit on asthma related 
quality of life. This is also an important patient outcome.  
As the questionnaire does not have complete coverage 
for emotional issues, some additional questions will also 
be asked [25].   
This is the expected primary outcome for the definitive 
phase III study.  
Baseline, after 2 months 
and at the end of the 
study after 6 months.  
  
Paediatric asthma quality of life  
This will be assessed using the validated paediatric 
asthma quality of life questionnaire and presented as a 
total score (sub-scores will also be presented) [26]. 
It is not possible for this to be recorded for all participants 
as the copyright owner does not allow it to be used as an 
online questionnaire.  
Baseline, after 2 months 
and at the end of the 
study after 6 months for 
participants seen in 
person, where they can 
post a paper 
questionnaire to the 

 
 
BREATHE4T protocol – Stage 3         26th March 2021        Version 1.1                  18 
study team or complete 
it over the telephone.  
Asthma 
control  
This will be assessed using the validated asthma control 
test and presented as a total score [27]. This is an 
important asthma endpoint reflecting the presence of 
ongoing symptoms, impact on quality of life and likely risk 
of an exacerbation. 
Baseline, after 2 months 
and at the end of the 
study after 6 months. 
Healthcare 
utilisation 
This will be assessed using a very short questionnaire. It 
will be presented as: 
• Episodes of prescriptions of 3 or more days of 
prednisolone (or similar), 
• attendance at emergency department for an 
exacerbation of asthma, 
• hospital admission for an exacerbation of asthma. 
Unplanned healthcare utilisation represents a disruption 
to the lives of patients and families and a major cost of 
the NHS. 
Baseline, after 2 months 
and at the end of the 
study after 6 months. 
 
5.2  
Trial design 
The pilot trial will aim to assess the acceptability, uptake and success in collecting follow up data and 
variance in asthma-related outcome measures. A parallel group design will be used with participants 
being randomised to intervention or normal management. The intervention will be a self-guided, 
breathing retraining digital intervention, delivered via a mobile-friendly, online platform. The intervention 
will continue to be used for 6 months after which both groups will be reassessed. The usual management 
control group will then have access to the intervention (delayed access).  
 
5.3  
Trial setting 
The setting is primary and secondary care in England. Recruitment would be from primary care and 
hospital clinics. Asthma UK will sign-post potential recruits to the website. Participants will access the 
trial via a web-based platform.  
 
5.4 
Participant eligibility criteria 
 
Inclusion criteria  
i. 
Young people aged 12-17 years 
ii. 
Physician diagnosed asthma 
iii. 
Impaired quality of life (<85) 
iv. 
Under the care of a general practitioner, community or hospital practitioner for their asthma 
 
Exclusion criteria  
i. 
Co-existent respiratory conditions such as bronchiectasis 
ii. 
Already using breathing techniques 
iii. 
Already enrolled in another interventional study 
iv. 
Lack of informed consent 
v. 
Learning difficulties  

 
 
BREATHE4T protocol – Stage 3         26th March 2021        Version 1.1                  19 
5.5 
Trial procedures  
The trial procedures are summarised in Figure 3 below.  
 
5.5.1 Recruitment and identification 
Adolescent with asthma will be recruited in a number of ways:  
• 
20 secondary clinics in Southampton, Isle of Wight and other centres: 
(i) database search by NHS staff with invitation letters; invitation letters will be sent; letter will invite 
interested adolescents; 
(ii) opportunistically via posters in clinics and clinic staff mentioning to potential participants; poster 
will invite interested adolescents. 
• 
Up to 20 local primary care clinics (general practitioner, primary care nurses and community nurses) 
who will be study participant identification centres (PICs): 
(i) primary care staff will perform a database search; invitation letters will be sent; letter will invite 
interested adolescents;  
(ii) opportunistically via posters in surgeries and primary care staff mentioning to potential 
participants; poster will invite interested adolescents.  
• 
Asthma UK – advert in newsletters, on website and social media inviting interested adolescents. 
• 
Social media (eg Twitter, Instagram, Facebook) adverts and flyers - those interested will click a 
button/link which opens the BREATHE4T study website where they can leave their details for the 
study team to contact them.  
• 
Professional networks (eg respiratory and paediatric physio teams informing patients of the study) 
• 
Snowballing  
• 
Posters, adverts and flyers in various local locations (examples include GP surgeries, chemists, 
supermarket notice boards, schools, colleges, leisure and sport clubs, coffee shops, asthma 
support groups and charities (e.g. No Limits), local newspapers) 
• 
Press release 
This approach will mean that we will not be able to identify the total number of potential participants who 
would have seen information about the trial and we will not have information about their basic demographics 
nor asthma status.  
 
 
 
 
 
 
 
 
 

 
BREATHE4T protocol – Stage 3         26th March 2021              Version 1.1                  20 
Figure 3. Overview of participant journey in the Stage 3 pilot study 
 

 
BREATHE4T protocol – Stage 3         26th March 2021              Version 1.1                  21 
5.5.2    Consent 
In person 
Study research staff will obtain informed consent prior to the participant undergoing any study activities. 
This process will involve:  
• discussion between the potential participant and  their parent/guardian and a trained research project 
staff member about the nature and objectives of the study and possible risks associated with their 
participation.  
• presentation of the approved information leaflet and consent/assent documents. Two different 
participant information sheets will be used, for younger and older adolescents written in appropriate 
language.  
• the aims will be framed in age and developmentally appropriate language. This will acknowledge that 
adolescents have different maturities. For younger teenagers (12-14 years), the process will be 
undertaken with their parents or guardians. 
• an opportunity for potential participants and/or their parent/guardian to ask questions.  
• contact point where the participant /parent or guardian may obtain further information about the trial 
from the research team.  
• Participants aged 15 years and above will be asked to sign an informed consent form; for participants 
less than 15 years of age, parents will be asked to sign an informed consent form and teenagers will 
be asked to sign an assent form. 
Via website 
Parents and potential participants will be directed to the trial home page where they will be taken through 
informed consent/assent process. Informed consent/assent will be obtained prior to the participant 
undergoing any study activities. This process will involve:  
• presentation of the approved information on the web pages (also available in printable leaflet form)  
• information will cover the nature and objectives of the study and possible risks associated with their 
participation;  
• participants and/or their parents will be informed that they are able to withdraw from the trial at 
anytime without giving reasons and without prejudicing his/her further treatment, explanation will be 
given about the right to withdraw permission to use previously collected data;  
• an opportunity for potential participants and/or their parent/guardian to ask questions before signing 
consent/assent by sending a message to the trial team;  
• contact point where the participant /parent or guardian may obtain further information about the trial 
from the research team.  
For younger participants (12-14 years), when the parent consents, an invitation will be sent via email to 
the adolescent participant. This will take them through a similar but age appropriate assent process. 
Older participants (15-17 years) will be able to give their own consent to participate and will be given 
immediate access to the study. 
 
5.5.3 Screening 
Questions on the trial web site will assess their eligibility for the trial (age 12-17 years, physician 
diagnosed asthma, under the care of a general practitioner, community or hospital practitioner for their 
asthma, no co-existent respiratory conditions and not used breathing techniques).  

 
 
BREATHE4T protocol – Stage 3         26th March 2021        Version 1.1                  22 
 
5.5.4 The randomisation scheme  
Participants will be randomised via the study website to the next treatment allocation in the 
randomisation sequence by the trial team. The list will be generated using block randomisation with 
variable block sizes with a 1:1 allocation ratio between the intervention and usual management. Those 
randomised to the intervention will have immediate access to the intervention pages. The control group 
will be able to access the full intervention website at the end of the trial. The website will alert the study 
team to a new randomisation by email.  
 
5.5.5 Blinding 
This is an open trial. It will not be possible to blind the breathing retraining intervention. Control participants 
will also gain access to the full intervention website once they have finished participating in the trial. 
 
5.5.6 Baseline data 
Minimal baseline information will then be collected:  
• Basic demographic information: age in year, gender; 
• Asthma history including treatment and any hospitalization; 
• Any other significant health issues. 
These data will be collected using an online questionnaire that the research team has used in previous 
studies [28] (Appendix 4). 
 
5.5.7 Trial assessments 
 
There are three assessments which will be completed online:  
• Asthma quality of life: this will be assessed using the validated PedsQL Asthma Module [24].  
• Asthma control: this will be assessed with the validated asthma control test [27].  
• Healthcare utilisation: this will be assessed using a very short questionnaire.  
The Paediatric Asthma Quality of Life Questionnaire will also be completed. As the copy write forbids this 
to be completed electronically, this will be completed in person or sent by post. The correlation between 
PedsQL Asthma Module (with and without the additional emotion questions [25] and the Paediatric Asthma 
Quality of Life Questionnaire will be assessed to ensure that the PedsQL Asthma Module (with and without 
the additional emotion questions) provides a valid assessment of quality of life.  
 
5.5.8 Long term follow-up assessments 
Participants will be re-assessed after 2 and 6 months. They will be contacted by email with a link to the 
study website. Instructions on the website will take them through:  
• PedsQL Asthma Module  
• Asthma control test 
• Asthma healthcare utilisation questionnaire 
These are the questionnaires they completed at baseline. Additionally, participants in the intervention 
arm will be asked whether or not they have used the breathing exercises.  
Participants will receive two email/text reminders.  

 
 
BREATHE4T protocol – Stage 3         26th March 2021        Version 1.1                  23 
Additionally, they will complete the paediatric asthma quality of life questionnaire on paper after 2 and 
6 months. This will either be at a face to face visit, will be posted to the study team, returned via email 
or completed over the telephone.  
 
5.5.9 Qualitative interviews  
The qualitative study will collect data both during participation and after participants finish using 
BREATHE4T. Qualitative interviews will seek to provide an in-depth understanding of the perspective 
of patients, to inform intervention and trial acceptability and to generate hypotheses about intervention 
mechanisms of action that can be tested in a larger trial. 
Participants and sampling: Patients will be asked whether they would consent to take part in an interview 
at a later point in the study. Purposive sampling will then be used to select patients from the intervention 
group to allow for a wide range of views and experiences of the BREATHE4T programme e.g. covering 
age ranges, gender, asthma severity. We will also interview a small sample of control group participants 
to understand their experiences of trial participation. Additionally, we intend to interview participants who 
withdraw / drop out of the intervention arm, in order to understand reasons for doing so, to inform the 
larger trial design. It is anticipated that 10-20 intervention group patients will be interviewed both during 
and following the study. Sampling will continue until saturation is reached.  
Data collection: Factors that may facilitate or diminish the acceptability of the BREATHE4T programme, 
adherence to implementation and mechanisms of action of the intervention will be explored, as well as 
acceptability of trial participation across patient interviews. Interviews will be conducted during months 
4, 5 and 6 of the study. Open-ended questions within a semi-structured interview guide will be used to 
elicit user perspectives and experiences of the intervention, allowing participants to freely describe their 
experiences and views in their own way and to focus on whatever is most salient to them.  
Interviews will be face to face, by telephone or video call and will be audio-recorded and fully transcribed.  
Transcriptions will be anonymised (identifiable data removed) using participant numbers. To ensure that 
we remain open to and grounded in users’ perspectives we will carry out inductive thematic analysis of 
all textual data, triangulated where appropriate with quantitative self-report measures and web usage 
data. A 10% sample of interviews will be double-coded using the initial thematic framework, to enhance 
the rigour of the analysis process. 
The findings will be used to inform any modifications needed to BREATHE4T programme or the trial 
procedures for a potential future full RCT. 
 
 
5.5.10 Withdrawal criteria  
Where a participant or their parent or doctor wishes them to withdraw from the intervention, this will 
happen. Where possible follow up of the participant in the trial will continue. There will be no replacement 
of withdrawn participants.   
 
5.5.11 Trial intervention 
Breathe4T is a digital, self-management intervention for adolescents to control their asthma using 
breathing retraining exercises. The mobile-friendly website provides information about asthma and how 
it affects the lungs, as well as how breathing patterns can be dysfunctional, using developmentally 
appropriate language. Information is presented using short (30sec-2min), engaging video clips featuring 
a combination of physiotherapists, researchers and young adolescent role models. Users are given tips 
and information about their practice, including choosing a suitable time and place and building up 
gradually. Users can plan their practice, log how their practice went and record their confidence in using 
the breathing techniques in situations. There are 8 sessions to progress through. Each session includes 

 
 
BREATHE4T protocol – Stage 3         26th March 2021        Version 1.1                  24 
a video of a peer role model demonstrating the breathing exercise with a voiceover to explain the 
technique. Written, step-by-step instructions are also provided, in addition to a short description of the 
benefits of each exercise. All features and sessions can be accessed via a main dashboard where 
participants are also able to tailor the intervention to allow parental involvement, reminders around 
inactivity and their preferred format of notifications (email or text). A “frequently asked questions” section 
answers the common queries and concerns of breathing retraining. Users can view their asthma 
progress on a chart, which upon logging in requests information about their inhaler (preventer) use 
across time. The intervention has been designed to be easy to use on a mobile-device and with 
engaging colours and images. 
 
5.5.12 Trial restrictions  
There are no trial restrictions.  
 
6 
SAFETY 
6.1 
Definitions 
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence in a participant including 
occurrences which are not necessarily caused by or related to the 
trial intervention. 
Serious Adverse 
Event (SAE) 
A serious adverse event is any untoward medical occurrence that: 
• results in death 
• is life-threatening 
• requires inpatient hospitalisation or prolongation of existing 
hospitalisation 
• results in persistent or significant disability/incapacity 
• consists of a congenital anomaly or birth defect 
Other ‘important medical events’ may also be considered serious if 
they jeopardise the participant or require an intervention to prevent 
one of the above consequences. 
NOTE: The term "life-threatening" in the definition of "serious" refers 
to an event in which the participant was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe. 
non-IMP SUSAR 
 Non-IMP SUSAR is an SAE that occurs in a non-IMP trial and is: 
a) 
“Related” – that is, possibly, probably or definitely resulted from 
administration of any of the research procedures, and 
b) 
“Unexpected” – that is, the type of event is not listed in the 
protocol as an expected occurrence. 
 
 “Severe” is used to describe intensity of a specific event, which may be of relatively minor medical 
significance. “Seriousness” is the regulatory definition supplied above. 
 
6.2 
Operational definitions for (S)AEs  
Exceptions including hospitalisation as a SAE are: 

 
 
BREATHE4T protocol – Stage 3         26th March 2021        Version 1.1                  25 
• Routine treatment or monitoring of the studied indication not associated with any deterioration in 
condition. 
• Treatment which was elective or pre-planned, for a pre-existing condition not associated with any 
deterioration in condition. 
• Treatment on an emergency, outpatient basis for an event not fulfilling any of the definitions of serious 
as given above and not resulting in hospital admission. 
Given the nature of the study, related SAEs are unlikely to occur.  
 
6.3 
Recording and reporting of SAEs  
Participants will be asked to provide details of any potential AEs at the 2 and 6 month follow up 
assessments. An email alert will be sent to the study team.  
For any SAEs, an assessment of seriousness, causality and expectedness will be made by the PI or 
delegate as per local reporting standard operating procedures.  
Where SAEs occur, they will be notified to the Sponsor at sponsor@uhs.nhs.uk within 24 hours of the 
occurrence or knowledge of the occurrence, using the SAE reporting form. .  
Where a non-IMP SUSAR has occurred this must be notified to the sponsor at sponsor@uhs.nhs.uk 
immediately upon the study teams’ knowledge of the event, the sponsor will then notify the REC within 
15 days using the SAE report form.   
 
6.4 
Responsibilities 
Principal Investigator (PI):  
Checking whether participants report AEs when they are reassessed at 2 and 6 months. 
1. Using medical judgement in assigning seriousness and causality. 
2. Ensuring that all SAEs are recorded and reported to the sponsor within 24 hours of 
becoming aware of the event and provide further follow-up information as soon as 
available. Ensuring that SAEs are chased with Sponsor if a record of receipt is not 
received within 2 working days of initial reporting.  
Chief Investigator (CI) / delegate: 
1. Clinical oversight of the safety of patients participating in the trial, including an ongoing 
review of the risk / benefit. 
2. Using medical judgement in assigning the SAEs seriousness and causality where it has 
not been possible to obtain local medical assessment. 
3. Review of specific SAEs in accordance with the trial risk assessment and protocol as 
detailed in the Trial Monitoring Plan. 
4. Assigning Medical Dictionary for Regulatory Activities (MedDRA) or Body System coding 
to all SAEs. 
5. Reporting safety information to the Trial Steering Committee (TSC). 
Sponsor:  
1. Central data collection and verification of AEs and SAEs according to the trial protocol 
onto a database.  
2. Reporting safety information to the CI, delegate or independent clinical reviewer for the 
ongoing assessment of the risk / benefit according to the Trial Monitoring Plan. 
 
Trial Steering Committee (TSC):  

 
 
BREATHE4T protocol – Stage 3         26th March 2021        Version 1.1                  26 
In accordance with the Trial Terms of Reference for the TSC, periodically reviewing safety data 
to determine patterns and trends of events, or to identify safety issues, which would not be 
apparent on an individual case basis.  
 
6.5 
Notification of deaths  
All deaths will be reported to the sponsor irrespective of whether the death is related to disease 
progression, the intervention, or an unrelated event. This report will be sent to the sponsor at 
sponsor@uhs.nhs.uk within 24 hours of the study team being aware. 
 
6.6 
Reporting urgent safety measures  
If any urgent safety measures are taken the CI/Sponsor shall immediately and in any event no later than 
3 days from the date the measures are taken, give written notice to the REC of the measures taken and 
the circumstances giving rise to those measures. 
 
 
7 
STATISTICS AND DATA ANALYSIS 
The analysis of this trial will be mainly descriptive focusing on estimation rather than hypothesis testing. 
All baseline measures and outcomes will be summarised for each allocated group using the appropriate 
descriptive statistics and presented with their associated confidence intervals. No formal comparison of 
groups will take place. A Statistical Analysis Plan will be developed, setting out the details of all analyses 
and assumptions for the stage 3 pilot trial before the last patient is recruited.  
 
7.1 
Sample size calculation 
Stage 3 represents a pilot trial so the effectiveness of the intervention is not being evaluated, therefore a 
formal power calculation is not appropriate. The sample size is based on a 95% confidence interval 
approach. For each of the expected proportions/means in the key objectives below, the precision to which 
we would be able to estimate the proportion/mean given this sample size is presented (nQuery and nTerim 
v4.0). 
For the specific pilot trial objectives, the following are descriptions of the precision of our estimates with the 
stated assumptions: 
i. Recruitment rate: It is estimated that the percentage of those approached who are randomised is around 
30% therefore the approached sample size will be approximately 387 resulting in a half width for the 
confidence interval of 5%. The widest confidence interval for this approximation results when the 
percentage of randomised to approached is around 70% giving an approached sample size of 166 and a 
95% confidence interval half width of 7%. 
ii. Acceptability and uptake of the intervention: it is estimated that the uptake rate across those randomised 
to the intervention will be 90%, with 58 available participants for this estimation; this would result in a 
confidence interval half width of 8%. 
iii. Number of participants assessed at 6-months: It is estimated that the dropout rate from the trial will be 
20% of those randomised. With 116 participants randomised into the trial this would result in a confidence 
interval half width of 7% for the estimate of the dropout rate. Even when considering the statistical worst-
case scenario of 50% the resulting confidence interval for this sample size has a half width of 9%. 
iv. Mean asthma related quality of life at 6 months in the control group: with an estimated standard deviation 
of 1.4 from the UBIOPRED cohort (1), if data from 46 participants are available at 6 months and therefore 

 
 
BREATHE4T protocol – Stage 3         26th March 2021        Version 1.1                  27 
available for this estimation, this would give a confidence interval half width of 0.4 units approximately 0.3 
standard deviations. 
v. Completeness of data for asthma related quality of life and healthcare utilisation data across the study in 
the two groups: this is estimated at 95% across those randomised and still in the trial at 6 months, giving 
92 participants available for this estimation therefore giving a confidence interval half width of 5%. 
Additionally, we plan to interview 10-20 participants in each intervention group. 
 
7.2 
Planned recruitment rate 
The recruitment target for this study is 116 participants, or 58 per arm. It is planned that recruitment 
occurs at University Hospital Southampton, St Mary’s Hospital Isle of Wight and eighteen other hospitals 
in England. Each site will be expected to recruit up to 5 participants over a 3 month period with the 
balance being recruited by University Hospital Southampton and St Mary’s Hospital using 20 primary 
PIC sites.  
 
7.3 
Primary outcome analysis 
As this stage 3 protocol outlines a pilot stage for a definitive phase-3 trial, the primary outcomes will be 
related to feasibility. All patients will be analysed as randomised (intention-to-treat). Feasibility outcomes 
include: 
i. Assessing the recruitment rate by presenting the proportion of participants recruited among those 
approached; 
ii. Assessing the acceptability, uptake and use of the intervention, by presenting the proportion of 
intervention patients who use the intervention website, in conjunction with findings from qualitative 
data collection; 
iii. Estimating the follow-up rate at the 6-month assessment (additionally, looking at relative rates for 
participants recruited from primary care, secondary care, Asthma UK, social media, professional 
networks and snowballing); 
iv. To monitor the change in and estimate the variance of asthma-related quality of life and asthma 
control in each group; 
v. To determine if data collection methods for process, effectiveness and cost-effectiveness endpoints 
are appropriate for this population by assessment of completeness of data at 2 and 6-month 
assessments; 
vi. To determine whether the PedsQL Asthma Module (with and without the additional emotion 
questions) and the Paediatric Asthma Quality of Life Questionnaire provide similar information by 
estimating their pairwise correlation. 
vii. To assess the relative uptake and quality of qualitative data collection from participants via in-person, 
video or telephone interviews; 
 
7.4 
Secondary outcome analysis 
There are no planned secondary outcome analyses. 
 
7.5 
Subgroup analyses 
Younger (12-14 years) verses older (15-17 years) adolescents 
Male verses female adolescents 

 
 
BREATHE4T protocol – Stage 3         26th March 2021        Version 1.1                  28 
 
7.6 
Adjusted analysis 
There are no planned adjustments in the analyses described above. Responses to the PedsQL Asthma 
Module and Paediatric Asthma Quality of Life Questionnaire will be transformed into summary scores 
using questionnaire-specific published methodology. 
 
7.6 
Interim analysis and criteria for the premature termination of the trial 
There are no planned interim analyses or specified stopping rules. 
 
7.7 
Participant population 
The trial analysis will include all participants randomised into the trial, regardless of whether they 
received the intervention. In addition, an analysis will be undertaken on the protocol-compliant 
population who will be defined as those who have covered at least half of the training sessions in the 
online website.  
 
7.8 
Procedure(s) to account for missing or spurious data  
Participants will be encouraged to submit follow-up data via email/text reminders. Missing values will 
not be inputed, as completeness of data is a key feasibility outcome. 
 
7.9 
Other statistical considerations. 
There are no further anticipated statistical considerations. All deviations from the Statistical Analysis 
Plan will be recorded. 
 
8 
DATA MANAGEMENT  
8.1 
Data collection tools and source document identification 
Source data will be recorded on the trial website. This will downloaded into one of two CSV files:  
(a) Personal data file – this will include names and contact information that is required to conduct the 
trial. This will be kept within the University Southampton NHS Foundation Trust IT environment. 
(b) Trial data file – this will include trial data but no personal data (exception will be ethnicity coded as 
white/non-white and date of birth which will be coded as month/year). This will be read into statistical 
software (e.g. STATA, SPSS).  
The exceptions will be:  
• the paediatric asthma quality of life questionnaire which will be collected on paper (source document). 
These data will be entered into SPSS and double checked. Data will then be transferred to statistical 
software (e.g. STATA, SPSS).  
• Transcripts of interviews which will be kept as word document (source document) and any recordings 
destroyed to maintain confidentiality.  
 
8.2 
Data handling and record keeping  
Participants will be labelled with a unique identification number assigned by the trial website.  
Copies for source data will be kept.  

 
 
BREATHE4T protocol – Stage 3         26th March 2021        Version 1.1                  29 
Source data from the trial website and paediatric asthma quality of life questionnaires will be merged to 
form the trial database in statistical software (e.g. STATA, SPSS). Data will be cleaned with identification 
of values outside set ranges and unlikely give other data; these will be corrected where possible in the 
trial analysis data set. A list of any edits will be kept.  
 
8.3 
Access to Data 
Direct access will be granted to authorised representatives from the Sponsor, host institution and the 
regulatory authorities to permit trial-related monitoring, audits and inspections- in line with participant 
consent. 
 
8.4 
Archiving 
The source data and trial analysis data set with explanatory documentation will be achieved at the end 
of the trial. For this, the trial questionnaires will be scanned.  
Documents with confidential information will be archived by University Hospital Southampton NHS 
Foundation Trust.  All other documents will be archived by the University of Southampton. All data will 
be kept for a minimum of 10 years after the completion of the trial.  
 
9 
MONITORING, AUDIT & INSPECTION 
The Trial Monitoring Plan is:  
• 
Study team will monitor all trial informed consent documentation, trial data and transcripts to 
ensure that study conduct is as per the protocol. Additionally, the team will undertake a face to 
face or virtual review of activity at each site after the first participant is recruited.  
• 
Trial management group will monitor recruitment, trial data (whole trial, not grouped) and serious 
adverse events at least 2 monthly. 
• 
Trial Steering Group will review recruitment, trial data (whole trial, not grouped) and serious 
adverse events at 6 monthly. 
It is expected that the Sponsor may also choose to monitor the study.  
 

 
 
BREATHE4T protocol – Stage 3         26th March 2021        Version 1.1                  30 
10  
ETHICAL AND REGULATORY CONSIDERATIONS 
10.1 
Assessment and management of risk 
The study team have evaluated the risks associated with the trial and classified it as low risk.  
Risk 
Level 
Mitigation 
Participant’s asthma 
deteriorates over the course of 
the study and this is not 
adequately managed.  
Low 
It is likely that some participant’s asthma control will 
deteriorate over the 6-month trial as this is the natural 
course of asthma and half of the participants will be in the 
control group. The trial website informs participants and 
their parents that they should contact their asthma doctor if 
they have increasing symptoms that are not controlled by 
their medication. Where a participant contacts the study 
team with worrying symptoms, one of the trial doctors will be 
involved and appropriate advice given to keep the 
participate safe.   
Participant reveals concerning 
information during an interview, 
for example they are having 
suicidal ideation.  
Very 
low 
In our experience, this is very unlikely. If this was to occur, 
the study team will initially talk to the participant’s parent or 
guardian and, if necessary, their doctor to ensure they are 
kept safe.  
Data breach from the trial 
website 
Very 
low 
There is a need for the trial website to collect some personal 
data to conduct the trial, for example contact details for 
participants and parents. This is a very small risk of a data 
breach from the trial website. This will be minimised by the 
use of use https, SSL certificates and JWT secure tokens. 
Personal data will not be downloaded with trial data. Where 
it is downloaded to enable the conduct of the trial, it will be 
held on a secure NHS sever. 
 
10.2  Research Ethics Committee (REC) review & reports 
Before the start of the trial, approval will be sought from a REC for the trial protocol, informed consent forms 
and other relevant documents. Substantial amendments that require review by REC will not be 
implemented until the REC grants a favourable opinion for the trial. All correspondence with the REC will 
be retained in the Trial Master File/Investigator Site File. The Chief Investigator will submit an annual 
progress report (APR) to the REC within 30 days of the anniversary date on which the favourable opinion 
was given, and annually until the trial is declared ended. The Chief Investigator will notify the REC of the 
end of the Study. Within one year after the end of the trial, the Chief Investigator will submit a final report 
with the results, including any publications/abstracts, to the REC.  
 
10.3  
Peer review 
The NIHR RfPB panel has peer reviewed this study.  
 
10.4 
Public and Patient Involvement 
We have and will involve young people and their parents in: 
• Interpreting the findings of stage 1 and 2 
• designing the pilot trial 
• interpreting the findings of stage 3 
• reporting and dissemination 

 
 
BREATHE4T protocol – Stage 3         26th March 2021        Version 1.1                  31 
We plan to achieve this with: 
• Two local Patient and Public Involvement (PPI) panels: 7 young people and 7 parents – quarterly 
meetings, in parallel, outside school hours, facilitated by study personnel, with feedback from project 
and TSC – panels will receive training. 
• Asthma UK – are involved in the management of the trial  
• PPI representation on the Trial Steering Committee – We would support one member of each of the 
local young person and parent PPI panels to represent the panels’ views on the trial steering committee. 
 
10.5  Protocol compliance  
Any protocol deviations will be documented in the site investigator’s file. Any serious will be 
immediately reported to the Chief Investigator and Sponsor. A “serious breach” is a breach which is 
likely to effect to a significant degree: (a) the safety or physical or mental integrity of the participants of 
the trial; or (b) the scientific value of the trial.  
 
10.6  Data protection and patient confidentiality  
All investigators and trial site staff will comply with the requirements of the General Data Protection 
Regulations 2018 with regards to the collection, storage, processing and disclosure of personal 
information and will uphold the Act’s core principles.  
Personal information will be kept secure in the site investigator file. Each participant will have a 
numerical identifier which will be used to label the participant’s CRF and transcripts.  
Prior to analysis, the data will be anonymised by destroying the file linking personal details with the 
participants’ identifiers.   
Data will be stored for 10 years. Professor Graham Roberts is the data custodian.  
 
10.7 
Financial and other competing interests for the chief investigator, PIs at each site and 
committee members for the overall trial management  
None of the investigator have any commercial interests. They are though in receipt of funding from the 
NIHR RfPB to undertake the study. Also one of the investigators works for Asthma UK which is a charity 
that aims improve the life of people with asthma. A list of conflicts of interest will be reviewed at each 
TSC meeting and updated as needed.  
 
10.8  Indemnity 
The sponsor of the project is University Hospital Southampton NHS Foundation Trust. For NHS 
sponsored research HSG (96) 48 reference no.2 refers. If there is negligent harm during the clinical 
project when the NHS body owes a duty of care to the person harmed, NHS Indemnity covers NHS 
staff, medical academic staff with honorary contracts, and those conducting the project. NHS Indemnity 
does not offer no-fault compensation and is unable to agree in advance to pay compensation for non-
negligent harm. Ex-gratia payments may be considered in the case of a claim. 
 
10.9  Amendments  
Any amendments will be made by the TMG. The Sponsor will decide whether an amendment is substantial 
or non-substantial They will be notified to the UHS R&D office (as the lead organisation) and communicated 
to other participating organisations so participating sites to assess whether the amendment affects the NHS 
permission for that site. 

 
 
BREATHE4T protocol – Stage 3         26th March 2021        Version 1.1                  32 
10.12  Access to the final trial dataset 
All the trial investigators will have access to the anonymised study dataset.  
 
11  
DISSEMINIATION POLICY 
11.1  
Dissemination policy 
The study data will be owned by the University of Southampton. At the end of the trial, the investigators will 
analyse the data and generate a final trial report. The intention is that it will be published in a peer reviewed 
journal acknowledging the funder. It may also be presented at meeting. Additionally, a summary of the 
study findings will be provided to the study participants.  
 
11.2  Authorship eligibility guidelines  
Authorship will follow the International Committee of Medical Journal Editors criteria for manuscripts 
submitted for publication.  
 
12 
REFERENCES 
 
1. 
Fleming, L., et al., The burden of severe asthma in childhood and adolescence: results from the 
paediatric U-BIOPRED cohorts. European Respiratory Journal, 2015. 46(5): p. 1322-1333. 
2. 
Bruton, A., et al., Physiotherapy breathing retraining for asthma: a randomised controlled trial. 
The Lancet Respiratory Medicine, 2018. 6(1): p. 19-28. 
3. 
Thomas, M., et al., A randomised controlled study of the effectiveness of breathing retraining 
exercises taught by a physiotherapist either by instructional DVD or in face-to-face sessions in 
the management of asthma in adults. 2017. 
4. 
Holley, S., et al., Barriers and facilitators to asthma self‐management in adolescents: A 
systematic review of qualitative and quantitative studies. Pediatric pulmonology, 2017. 52(4): p. 
430-442. 
5. 
Arshad, S.H., et al., Pathophysiological characterization of asthma transitions across 
adolescence. Respiratory research, 2014. 15(1): p. 153. 
6. 
Lefaudeux, D., et al., U-BIOPRED clinical adult asthma clusters linked to a subset of sputum 
omics. Journal of Allergy and Clinical Immunology, 2017. 139(6): p. 1797-1807. 
7. 
Shaw, D.E., et al., Clinical and inflammatory characteristics of the European U-BIOPRED adult 
severe asthma cohort. European Respiratory Journal, 2015. 46(5): p. 1308-1321. 
8. 
Holgate, S.T., Stratified approaches to the treatment of asthma. British journal of clinical 
pharmacology, 2013. 76(2): p. 277-291. 
9. 
de Benedictis, D. and A. Bush, Asthma in adolescence: Is there any news? Pediatric 
pulmonology, 2017. 52(1): p. 129-138. 
10. 
Sawyer, S.M. and R.A. Aroni, Self‐management in adolescents with chronic illness. What does 
it mean and how can it be achieved? Medical Journal of Australia, 2005. 183(8): p. 405-409. 
11. 
Edgecombe, K., et al., Health experiences of adolescents with uncontrolled severe asthma. 
Archives of disease in childhood, 2010. 95(12): p. 985-991. 
12. 
van Es, S.M., et al., Adherence-related behavior in adolescents with asthma: results from focus 
group interviews. Journal of Asthma, 1998. 35(8): p. 637-646. 
13. 
Slader, C.A., et al., Complementary and alternative medicine use in asthma: who is using what? 
Respirology, 2006. 11(4): p. 373-387. 
14. 
Garcia-Marcos, L., et al., What asthma self-management tools and systems should have higher 
priority in future research: a Delphi exercise from the EU, in A102. HIGHLIGHTS IN PATIENT-
CENTERED RESEARCH: METHODS AND OUTCOMES. 2016, American Thoracic Society. p. 
A2669-A2669. 

 
 
BREATHE4T protocol – Stage 3         26th March 2021        Version 1.1                  33 
15. 
Freitas, D.A., et al., Breathing exercises for adults with asthma. Cochrane Database of 
Systematic Reviews, 2013(10). 
16. 
 ; Available from: https://www.brit-thoracic.org.uk/standards-of-care/guidelines/btssign-british-
guideline-on-the-management-of-asthma/. 
17. 
Gridina, I., et al., Prevalence of chronic hyperventilation syndrome in children and teenagers. 
Archives de pediatrie: organe officiel de la Societe francaise de pediatrie, 2013. 20(3): p. 265-
268. 
18. 
de Groot, E.P., Breathing abnormalities in children with breathlessness. Paediatric respiratory 
reviews, 2011. 12(1): p. 83-87. 
19. 
Lima, E., et al., Inspiratory muscle training and respiratory exercises in children with asthma. J 
Bras Pneumol, 2008. 34(8): p. 552-558. 
20. 
McHugh, P., B. Duncan, and F. Houghton, Buteyko breathing technique and asthma in children: 
a case series. The New Zealand Medical Journal (Online), 2006. 119(1234). 
21. 
Macêdo, T.M., et al., Breathing exercises for children with asthma. Cochrane Database of 
Systematic Reviews, 2016(4). 
22. 
Yardley, L., et al., The person-based approach to intervention development: application to digital 
health-related behavior change interventions. Journal of medical Internet research, 2015. 17(1): 
p. e30. 
23. 
Holley, S., et al., Barriers and facilitators to self‐management of asthma in adolescents: An 
interview study to inform development of a novel intervention. Clinical & Experimental Allergy, 
2018. 48(8): p. 944-956. 
24. 
Varni, J.W., et al., The PedsQL™ in pediatric asthma: reliability and validity of the Pediatric 
Quality of Life Inventory™ generic core scales and asthma module. Journal of behavioral 
medicine, 2004. 27(3): p. 297-318. 
25. 
Roberts, G., C. Hurley, and G. Lack, Development of a quality-of-life assessment for the allergic 
child or teenager with multisystem allergic disease. Journal of allergy and clinical immunology, 
2003. 111(3): p. 491-497. 
26. 
Juniper, E.F., et al., Measuring quality of life in children with asthma. Quality of life research, 
1996. 5(1): p. 35-46. 
27. 
Nathan, R.A., et al., Development of the asthma control test: a survey for assessing asthma 
control. Journal of Allergy and Clinical Immunology, 2004. 113(1): p. 59-65. 
28. 
Holley, S., et al., Development and validation of the Adolescent Asthma Self-Efficacy 
Questionnaire (AASEQ). European Respiratory Journal, 2019. 54(1). 
 
 
 
 
 
 

 
 
BREATHE4T protocol – Stage 3         26th March 2021        Version 1.1                  34 
13.  
APPENDICIES 
 
13.1  Appendix 1 – Schedule of Procedures – Stage 3  
Procedures 
Visits and timing (range) 
Screening 
Baseline 
Intervention 
2 month 
follow up 
6 month 
follow up 
Interviews 
 
0 (-1 to 0) 
months 
0 months 
0 months 
2 (2 to 3) 
months 
6 (5 to 8) 
months 
 
Informed 
consent/assent  
✓ 
 
 
 
 
 
Inclusion & exclusion 
criteria 
✓ 
 
 
 
 
 
Demographics 
 
✓ 
 
 
 
 
Medical history 
 
✓ 
 
 
 
 
PedsQL asthma 
module  
 
✓ 
 
✓ 
✓ 
 
Asthma control test 
 
✓ 
 
✓ 
✓ 
 
Health utilisation 
 
✓ 
 
✓ 
✓ 
 
Paediatric asthma 
quality of life (paper) 
 
✓ 
 
✓ 
✓ 
 
Randomisation 
 
✓ 
 
 
 
 
Access to trial website 
 
 
✓ 
 
 
 
Web based 
intervention 
 
 
✓ (intervention 
group only) 
 
 
 
Qualitative interviews 
 
 
 
 
 
✓ 
Adverse event 
assessments  
 
 
 
✓ 
✓ 
 
 
 
 

 
 
BREATHE4T protocol – Stage 3         26th March 2021        Version 1.1                  35 
13.2  Appendix 2 – baseline data questionnaire  
 
1. How old are you?  ___years 
 
2. Are you male or female? Please circle one:   Male  
  Female    Prefer not to say  
 
3. Which professionals do you see about your asthma? Please circle all that apply.   
General practitioner (GP)     
Nurse at GPs    
 
Hospital consultant 
Nurse at hospital   
 
School nurse    
 
Community nurse   
Pharmacist   
 
Psychologist   
Other, please state_____________ 
 
4. How often do you use your blue reliever asthma inhaler? Please circle one:  
Never   
 
Less than once a month   
Once a month    
 
 
    Once a week   
2-3 times a week   
 
 
4 or more days per week 
 
5. What type of preventer medication do you use? Please circle all that apply:   
Clenil   
 
Flixotide (fluticasone)   
Pulmicort (budesonide)  
   
Alvesco (ciclesonide)     Seretide 
   
Symbicort 
Qvar 
 
Singular (montelukast) 
 
Slo-phy (theophylline)  
       
Other (please specify _________ ) 
 
6. How often do you miss taking your preventer inhalers? Please circle one:            
Never miss        Occasionally        Once a week   
  Half the time    Most of the time 
 
7. How many courses of steroid tablets (eg prednisolone) did you need in the last 2 months? 
 
8. How many days of school did you miss in the last 2 months because of your asthma (if you aren’t 
sure, please estimate)?  
 
9. How many hospital stays (over 4 hours) have you ever had because of your asthma (if you aren’t 
sure, please estimate)?  
 
10. How would you best describe the ethnic origin of your family? Please circle:  
White/English/Scottish/Welsh   White Irish    
White other    
Black African   
Black Caribbean   
Black other   Indian   
Pakistani 
Bangladeshi   
Chinese   
Other 
 

 
 
BREATHE4T protocol – Stage 3         26th March 2021        Version 1.1                  36 
13.3 
Appendix 3 – Amendment History 
Amendment 
No. 
Protocol 
version no. 
Date issued 
Author(s) of 
changes 
Details of changes made 
1 
V1.1 
2021 03 26 
SE 
Updated consent/assent process and 
participant journey, to comply with 
feedback from REC. 
 
Protocol amendments will be submitted to the Sponsor for approval prior to submission to the REC 
committee.