Body Reprogramming as an Adjunct to Biologic Administration in Patients With Severe Asthma: a Feasibility Study
Phase: NA
Conditions: Severe Asthma
Sponsor: Royal Devon and Exeter NHS Foundation Trust

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Body Reprogramming as an adjunct to biologic administration in patients with Severe 
Asthma: a feasibility study 
 
 
Version 18 26.05.21 
 
 
 
 
SPONSOR REFERENCE: 2109166 
 
IRAS No: 285153 
 
 
 
Name & Role 
Date 
Signature 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Management Group 
Chief Investigator:  Dr Matthew Masoli 
 
Co-investigators: 
Dr Rupert Jones 

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Prof Michael Hyland 
Joseph Lanario 
Lucy Cartwright 
 
Study Coordination Centre  
For general queries, supply of study documentation, and collection of data, please contact  
 
Joseph Lanario,  
joseph.lanario@nhs.net    
Address: Rm N10, ITTC Building, Plymouth Science Park, Research Way, Plymouth, PL6 
8BX  
Tel: 01752 764 403 
 
Clinical Queries 
Clinical queries should be directed to Dr Matthew Masoli who will direct the query to the 
appropriate person. matthew.masoli@nhs.net  
 
Sponsor 
Royal Devon and Exeter NHS Foundation Trust is the research sponsor for this study.  For 
further information regarding the sponsorship conditions, please contact the research sponsor 
at: 
 
Royal Devon & Exeter NHS Foundation Trust 
Research and Development 
Bowmoor House 
Barrack Road 
Exeter 
EX2 5DW 
T: 01392 403055 
 
Funder 
GlaxoSmithKline  

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This protocol describes a study to assess the feasibility of adapting and using a novel intervention, Body Reprogramming, for 
patients with severe asthma. It provides information about procedures for entering participants into the study.  Every care 
was taken in its drafting, but corrections or amendments may be necessary. These will be circulated to investigators in the 
study.  Problems relating to this study should be referred, in the first instance, to the Chief Investigator.  
 
This study will adhere to the principles outlined in the NHS Research Governance Framework for Health and Social Care (2nd 
edition). It will be conducted in compliance with the protocol, the Data Protection Act and other regulatory requirements as 
appropriate.  
 
 

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Table of Contents 
1. 
INTRODUCTION 
8 
1.1 
BACKGROUND 
8 
1.2 
RATIONALE FOR CURRENT STUDY 
8 
1.3  
PATIENT AND PUBLIC INVOLVEMENT (PPI) 
9 
2.  
SUMMARY OF BODY REPROGRAMMING 
10 
3.  
STUDY DESIGN 
10 
4.0  
PHASE 1: PROOF OF CONCEPT, FOUR-WEEK TRIAL OF BR AND POST-TRIAL 
FOCUS GROUPS OR INTERVIEWS 
11 
4.1  
STUDY AIMS 
11 
4.2 
PRIMARY OBJECTIVES 
11 
FOUR-WEEK TRIAL OF BR 
11 
POST-TRIAL FOCUS GROUPS OR INTERVIEWS 
11 
4.3 
 INCLUSION CRITERIA 
12 
4.4  
EXCLUSION CRITERIA 
12 
4.5 
RECRUITMENT AND CONSENT 
12 
4.6  
DATA COLLECTION METHODS 
14 
FOUR-WEEK TRIAL OF BR. 
14 
4.7  
DATA COLLECTION TIME POINTS 
14 
4.8  
QUESTIONNAIRES 
15 
POST-TRIAL FOCUS GROUPS OR INTERVIEW 
17 
4.9 
DESCRIPTION OF DATA ANALYSES 
18 
FOR QUANTITATIVE DATA 
18 
FOR QUALITATIVE DATA 
19 
4.10 
THE NUMBER OF PARTICIPANTS 
19 
5.0  
PHASE 2: BIOLOGIC PRIMING STUDY 
19 
5.1  
STUDY AIMS 
19 
5.2 
PRIMARY OBJECTIVES 
20 
5.3  
INCLUSION CRITERIA 
20 

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5.4  
EXCLUSION CRITERIA 
20 
5.5 
RECRUITMENT AND CONSENT 
21 
5.6  
DATA COLLECTION METHOD 
21 
5.7 
 DESCRIPTION OF STATISTICAL METHODS 
21 
5.8  
THE NUMBER OF PARTICIPANTS 
21 
5.9 
THE LEVEL OF STATISTICAL SIGNIFICANCE 
22 
5.10 
WITHDRAWAL CRITERIA FOR BOTH PHASE ONE AND PHASE TWO 
22 
6.0 
ETHICAL AND REGULATORY CONSIDERATIONS / ROLE OF SPONSOR 
22 
6.1 
ASSESSMENT AND MANAGEMENT OF RISK 
22 
6.2  
 RESEARCH ETHICS COMMITTEE (REC) AND OTHER REGULATORY REVIEW & REPORTS 
22 
6.3 
REGULATORY REVIEW & COMPLIANCE 
23 
6.4 
PROTOCOL COMPLIANCE 
23 
6.5 
DATA PROTECTION AND PATIENT CONFIDENTIALITY 
24 
6.6 
INDEMNITY 
24 
6.7 
ACCESS TO THE FINAL STUDY DATASET 
24 
7.0  
REFERENCES 
26 
APPENDIX 1: GANTT CHART 
27 
APPENDIX 2: NICE DEFINITION OF HIGH DOSE INHALED CORTICOSTEROIDS 
28 
 
 
 

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Glossary of Abbreviations 
AE 
Adverse event 
AR 
Adverse reaction 
CI 
Chief Investigator 
CRF 
Case Report Form 
CT 
Clinical Trials 
DMC 
Data Monitoring Committee 
GCP 
Good Clinical Practice 
GP 
General Practitioner 
ICF 
Informed Consent Form 
ICH 
International Conference of Harmonisation 
NHS 
National Health Service 
NRES 
National Research Ethics Service 
PI 
Principal Investigator 
PIS 
Participant/ Patient Information Sheet 
R&D 
NHS Trust R&D Department 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SmPC/SPC 
Summary of Products Characteristics 
SOP 
Standard Operating Procedure 
TMF 
Trial Master File 
TSG 
Trials Steering Group 
SAQ 
Severe Asthma Questionnaire 
ACQ 
Asthma Control Test 
GINA 
Global Initiative for Asthma  
GRCQ 
Global Rating of Change Questionnaire  
 
Keywords 
Severe Asthma 
Biologic treatment 
Body Reprogramming  

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Study Summary 
Title 
Body Reprogramming as an adjunct to biologic administration in patients with 
symptomatic Severe Asthma: a feasibility study 
 
Design 
A feasibility study of Body Reprogramming (BR) in 2 patient groups one as an 
addition to normal treatment and one provided before starting a biologic 
treatment  
Aims 
• 
To assess the feasibility and acceptability of BR to people with severe 
asthma,  
• 
Using patient and other feedback to adapt and optimise the intervention 
for people with severe asthma. 
Outcome Measures 
• 
Number and percentage of participants taking part and completing the 
course including those completing the following questionnaires 
o Severe Asthma Questionnaire (SAQ)  
o General Symptom Questionnaire (GSQ) or GSQ-Asthma (GSA-A) 
o Positive and Negative Affect Schedule (PANAS) 
o Asthma Control Questionnaire (ACQ)  
o Global Rating of Change questionnaire (GCRQ) 
• 
Attendance to Body Reprogramming Zoom calls 
• 
Feedback received using the Friends and Family Test (FFT) 
Qualitative data from the focus groups or interviews analysed using thematic 
analysis concerning participants’ experiences of Body Reprogramming.  
Population 
Patients with symptomatic severe asthma attending the regional severe asthma 
clinic in RD&E Hospital Devon. 
Eligibility 
Phase 1 
Patient has severe asthma as per ERS/ATS definition and is receiving high dose 
inhaled corticosteroids as defined by NICE (Appendix 2)  
AND 
Eight or more non-respiratory symptoms per week recorded on the GSQ 
Phase 2 
Patients with severe asthma who have been approved to commence a biologic 
treatment for their severe asthma 
Duration 
15 months  
Timelines 
See Gantt Chart (Appendix 1) 

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1. 
INTRODUCTION  
1.1 
Background 
 
Research and clinical experience show that severe asthma is a polysymptomatic disease and 
that the contributions to health related quality of life (HRQoL) disutility is complex (1). As such, 
patients often live with a number of symptoms (related to both the disease and treatment) and 
including a high level of extra-pulmonary symptoms, all of which actively contribute to HRQoL 
deficit (2). 
 
Our research demonstrates that the HRQoL deficit in patients with severe asthma is affected 
by both pulmonary and extra-pulmonary symptoms (e.g. mental fog, fatigue, unexplained 
pain) that contribute equally to the total HRQoL deficit (3). We have also shown that the 
frequency and severity of extra-pulmonary symptoms in severe asthma are similar to those in 
patients diagnosed with syndromes of medical unexplained symptoms such as fibromyalgia 
and chronic fatigue syndrome (4), two conditions where outcome is improved by lifestyle 
change.  The current Covid-19 pandemic places additional lifestyle burden on patients with 
severe asthma as these patients fall into the high risk category. 
 
1.2 
Rationale for Current Study 
When assessing the impact of management and treatment interventions aimed at improving 
HRQoL, it is important to look beyond the lung. In a cross-sectional study of severe asthma, 
we found that the frequency of extra-pulmonary symptoms significantly increased with the 
cumulative burden of systemic corticosteroids. However, those patients on biologic treatments 
had lower symptom scores irrespective of their systemic steroid burden (4). 
 
We hypothesize that a specific intervention aiming to optimising patient knowledge on disease 
management, physical activity, relaxation (5) and other psychological and biological lifestyle 
changes that increase well-being and mood, may lead to improved self-management.  Severe 
asthma patients lack any form of rehabilitation provision analogous to pulmonary 
rehabilitation, which is an evidenced-based education and exercise programme for people 
with COPD and has additional benefits on top of drug therapies (6). Indeed evidence shows 
that pulmonary rehabilitation should be provided prior to stepping up drug treatments in 
COPD , leading to the hypothesis that a similar provision for severe asthma patients prior to 

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starting new treatments such as biologics would enhance response to treatment. Furthermore 
there is emerging evidence that pre-habilitation improves outcomes in high risk patients 
undergoing surgery  and is now being recommended to improve resilience in the face of the 
SARS-Cov-2 pandemic (7). BR may well act as a strategy to promote resilience to 
Coronavirus amongst an at risk group of severe asthma patients. 
 
We hope to see greater HRQoL improvements from severe asthma patients who have been 
“primed” by an education and behaviour change programme when they start biologics. 
Biologic therapies have a highly specific mode of action and may therefore interact positively 
with any reduction in systemic inflammation resulting from lifestyle improvement. We have 
provided a detailed theoretical rationale for potential mechanisms (8).  
 
1.3  
Patient and Public involvement (PPI) 
The original Body Reprogramming course structure and narrative was developed for and with 
patients with fibromyalgia (9). People with fibromyalgia have a wide variety of symptoms 
many of them shared with people who have severe asthma (4).  The present study is to 
examine the feasibility of an adaptation of the original course, an adaption specifically 
designed for people with severe asthma. 
 
The adapted course content consists of four half hour sessions designed to be presented via 
Zoom video call. The content of the course (Appendix 6) was discussed with a group of 8 
severe asthma patients and edited based on patient feedback. While most of the patients 
were happy to take part in an intervention run in groups, some interpreted the group nature of 
Body reprogramming as a form of “group therapy” where problems were discussed amongst 
the attendees. The wording of the patient information leaflet and course information was 
amended to clarify that Body Reprogramming is considered an educational intervention where 
participants attend a series of presentations.  It is now worded to make clear that patients can 
choose whether or not they say anything during the presentations.   They have the 
opportunity to ask questions but there is no requirement for active participation. 
 
Originally, Body Reprogramming was delivered in person over 7 weeks at a patients treating 
hospital. However, in response to the UK national Covid 19 regulations and social distancing 
rules, this study will be delivered via the Zoom video call platform. The original 7-week course 

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was discussed with asthma patients who suggested that a shorter 4-week course would be 
more appropriate for an online intervention and that each course should last no longer than 
about 30 minutes.  
 
2.  
Summary of Body Reprogramming 
 
Body Reprogramming (BR) is a non-drug, multi-component intervention originally developed 
in Plymouth for fibromyalgia patients (see www.bodyreprogramming.org) and provided to 
patients through the NHS with direct referral from a GP in Devon and Cornwall. BR is 
applicable to any patients whose polysymptomatic presentation cannot be explained by 
current disease models (10).  The aim of BR is to improve general health and well-being by 
evidence-based lifestyle change.  The unique feature of BR is a theoretical model that 
personalises lifestyle advice to the particular patient and provides patients with a narrative 
that explains how and why the changes can produce benefit.  
 
The theoretical model proposes that symptoms result from a network of biological symptom 
causing mechanisms (11).  The extra-pulmonary symptoms of severe asthma can be 
explained by inflammatory mediators being part of this network that include, but are not 
limited to, non-specific pro-inflammatory cytokines (8). Patients are provided with a simplified 
version of the theory based on an analogy of ‘hardware’ and ‘software’ faults in a computer 
(9). 
 
3.  
Study Design 
 
This is an unblended observational study, single-site feasibility study in two phases: 
Phase 1 Proof of concept. 
 
The aim of this study is to assess the feasibility and acceptability of BR, whilst optimising the 
intervention for people with severe asthma.  
 
Phase 2 Biologic priming feasibility study.   
 

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Patients expected to start a biologic treatment for their severe asthma will be invited to take 
part in a BR course.  
 
Participating sites include: 
• Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, UK (RD&E) 
 
4.0  Phase 1: Proof of Concept, Four-Week Trial of BR and Post-Trial 
Focus Groups or Interviews 
 
4.1  
Study Aims 
 
• To assess the feasibility and acceptability of BR to people with severe asthma in a 
feasibility study with remote delivery via on-line groups.  
• To adapt and optimise the intervention for people with severe asthma. 
 
4.2 
Primary objectives 
 
Four-week trial of BR 
 
• To assess patients’ willingness to attend BR and engage with the intervention as 
measured by course attendance and by their written feedback. 
• To record the user experience when participating in the trial. 
• To assess patient’s willingness to complete a series of questionnaires  
• To get patient feedback on the appropriateness of the questionnaires for assessing 
improvement in larger future studies 
Post-trial focus groups or interviews 
• To gain qualitative feedback on patients experience of BR following their participation 
in the four-week trial. 
• To assess the acceptability of BR for people with severe asthma. 
• To understand the barriers to attending BR by speaking those who did not attend the 
course.  

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• Using all the data from participants we will adapt the BR programme before 
commencing phase two. 
 
4.3 
 Inclusion criteria 
• Aged ≥18 years attending the regional specialist severe asthma service in Royal 
Devon and Exeter hospitals. 
• Diagnosed with severe asthma as per ERS/ATS definition. 
o Requiring high dose inhaled corticosteroids (NICE definition of high dose ICS, 
Appendix 2). 
• Eight or more non-respiratory symptoms per week (approximately 60% of patients with 
severe asthma have a moderate or high extra-pulmonary symptom burden) as 
measured by the General Symptom Questionnaire (12). 
4.4  
Exclusion criteria 
• Unable or unwilling to partake. 
• In the opinion of the patient’s treating physician, the patient has another condition 
which is significantly impairs their ability to take part in the BR. 
• No access to the internet or appropriate IT equipment 
 
4.5 
Recruitment and consent  
 
Patients attending a regional severe asthma service who have undertaken a systematic 
multidisciplinary assessment will be identified as eligible to participate by a health 
professional familiar with them. This multidisciplinary review is part of normal clinic practice for 
the identification and treatment of severe asthma patients.  
 
By post - Patients identified as eligible to participate will be sent a Letter of Invitation 
(Appendix 3) by their clinician. The letter will also include a study Participant Information 
Leaflet and Consent Form (Appendix 4), a General Symptom Questionnaire (GSQ) and a 
prepaid return envelope to be used to return the completed consent form and GSQ to the 
patient’s clinician at RD&E (study information pack). The Patient Information Leaflet includes 
the phone number details for the research team. The information leaflet will inform patients 
that they are welcome to contact the researcher if they have any questions about the 

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research that may be preventing from agreeing to participate. Participants will have all of their 
questions answered before they sign a consent form.  
Patients will be asked to return a completed Consent Forms within two weeks.  
The information leaflet explains that the GSQ that the patient completes will be used as an 
additional screening tool to assess the number of non-respiratory symptoms they experience 
each week.  
 
In clinic – Alternatively, eligible patients will be able to consent to take part in the study 
during a clinic appointment. When possible, patients identified as eligible to participate will be 
contacted by a health professional two weeks before they are due to have an asthma clinic 
appointment (remote or face to face) and invited to participate. This contact will be made by 
posting a Patient Invitation Letter (Appendix 3) and Patient Information Leaflet including a 
consent form (Appendix 4) out to the patient. The Invitation Letter and Patient Information 
Leaflet will include instructions to read the material carefully and to bring the consent form 
with them to their next scheduled clinic appointment. Contact details for the PI, and 
researcher will be included on the Patient Information Leaflet and can be contacted in the 
case that the patient has questions.  
 
If it is not possible to contact patients prior to the clinic appointment, they will be informed 
about the study during their remote or face to face appointment. At the consultation, patients 
who have been identified as eligible will be invited to participate. If they accept, a health 
professional will introduce the patient to a researcher who provides the patient with 
information on the study and a Participant Information Leaflet. The patient will have the 
opportunity to take this leaflet away with them and to think about participating before signing a 
consent form. A completed consent form can then be returned using a FREEPOST envelope 
if the patients decides to participate.  Alternatively, the patient will be able to complete the 
consent form before leaving clinic. 
 
Once a patient has provided a completed consent form, they will be given be given a GSQ to 
complete. 
 
The Patient Information Leaflet will outline what would be expected of the patient if they chose 
to participate including an outline of what the Body Reprogramming course involves and how 

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those who participated will be invited to a focus group at the end. During the project a video of 
the impact of severe asthma on patients and how this may be addressed by BR will be 
developed and will be available as an additional online information resource to patients and 
their families. The Patient Information Leaflet will also contain a contact number for a member 
of the research team if they have any questions. If a patient wants to participate, they will be 
asked to provide written informed consent which includes agreement to take part in the four-
week trial of BR and the post-trial focus groups or one to one interview.  
 
4.6  
Data collection Methods 
 
Four-week trial of BR.  
 
The intervention 
Body Reprogramming will be delivered to two groups of patients. The maximum group size 
will be 8 patients to allow time for questions from participants. The intervention will be 
delivered via the Zoom video call platform. There will be four sessions and each session will 
consist of a 25-30 minute presentation. At the end of the presentation there will be an 
opportunity for patients to ask questions or raise points of interest. Each session will include a 
‘practice and report back next week’ instruction. Participants will be provided with a list of web 
resources for tai chi, guided imagery, yoga and the Alexander technique (Appendix 5) and 
information on the course (Appendix 6). See Appendix 4 for further course details. 
 
4.7  
Data collection time points 
 
Participants will be asked to complete a series of questionnaires (see section 4.8) when they 
attend the Body Reprogramming course during the first and last week. These will be posted to 
the participant’s home address by a research nurse, completed, and returned to the patients’ 
clinic using a FREEPOST envelope.  
 
At the end of the course, participants will be asked to complete a course feedback form.  
 

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If participants have not returned the questionnaire within two weeks the questionnaire pack 
will be sent out again. If a further two weeks pass without the return of questionnaires a 
researcher will contact participant by phone and ask if they need assistance.  
 
Patients will be asked to text or email the course co-ordinator if they are unable to attend a 
course date for any reason.  Experience shows that heath and other problems can prevent 
patients from attending, so attendance monitoring requires this form of data. 
 
Demographic data 
The following demographic and clinical information will be collected from the participants’ 
clinical records at baseline by a researcher: 
 
Patient demographics:  
• Age 
• Sex 
• Ethnicity  
• Smoking status 
 
Clinical data 
Most recent spirometry (in the last 6 months),  
Major co-morbidities (respiratory and non-respiratory as identified by the patient’s clinician) 
• Current Drug treatment 
• Asthma exacerbations requiring systemic steroids in the last 12 months,  
• Cumulative steroid burden in the last 12 months,  
• Healthcare utilisation: hospital admissions / Emergency Department attendances in the 
last 12 months. 
 
4.8  
Questionnaires 
 
Severe Asthma Questionnaire (SAQ) (Appendix 7) 
The new questionnaire will provide a combined assessment of disease and its treatment on 
the quality of life of patients with severe asthma (13). The scale is based on existing HRQoL 

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scales but modified for the severe population and provides separate assessments of the 
effect of asthma symptoms and the effect of asthma medicines. The questionnaire has 16 
items assessing experience over the last two weeks and was produced from detailed 
qualitative research. An additional 3 items are included to assess overall QoL during the last 
two weeks, and QoL during different months of the year   
 
General Symptom Questionnaire (GSQ) (Appendix 8) 
The GSQ is a 65 item questionnaire that was designed to measure the symptoms of patients 
with fibromyalgia, irritable bowel syndrome and chronic fatigue syndrome (12). The 
questionnaire assesses the frequency of extra-pulmonary symptoms, such as somatic and 
psychological symptoms, on a 6 point Likert scale (the value scoring for each response 
shown in brackets): “Never or almost never” (1), “Less than 3 or 4 times per year” (2), “Every 
month or so” (3), “Every week or so” (4), “More than once per week” (5) or “Every day” (6). 
This questionnaire was used to measure the number and frequency of extra-pulmonary 
symptoms reported by patients.  The scale measures frequency of symptoms. This 
questionnaire be completed by potential participants at baseline to identify those that report 8 
or more non-respiratory symptoms per week and are eligible to participate. At subsequent 
time points, participants will complete the GSQ-A. 
 
General Symptom Questionnaire-A (Appendix 9) 
This is an abridged GSQ consisting of 16 non-respiratory symptoms that are associated with 
asthma severity. It uses the same 6 point Likert scale as the full GSQ.  
 
The Positive and Negative Affect Schedule (PANAS) (Appendix 10) 
This questionnaire measures positive and negative affect and consists 20 questions in total, 
10 measuring positive affect and 10 measuring negative affect. Participants respond to each 
question by using a 5 point scale where 1 indicates “not at all” and 5 indicates “very much”.  
 
Asthma Control Questionnaire (Asthma Control Questionnaire) (Appendix 11) 
This questionnaire contains 7 items and takes into consideration FEV1% predicted and daily 
use of rescue bronchodilator.  Patients respond to 7 items concerning their symptom severity 
on a 0-6 scale (0 = no impairment, 6 = maximum impairment) (14).  The questionnaire asks 
patients to assess their symptoms over the last week. 

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Note: the included questionnaires are available and validated in the majority of European 
languages and many non-European ones. However, if a participant requires a translation of a 
questionnaire that is not available, they will not be asked to complete the particular 
questionnaire.  
 
Post course questionnaires  
 
Global Rating of Change Questionnaire – Phase one (Appendix 12) 
This scale will be used by participants to indicate how much better they feel since 
commencing a BR. The 11-point scale ranges from -5 (a great deal worse) to 5 (A great deal 
better) (15). The time scale is between before the start of treatment and the current 
assessment. 
All questionnaires are presented in paper and pencil format, to be self-completed by the 
patient but with support if needed. 
 
Friends and Family Test (FFT) (Appendix 13) 
This is a one question questionnaire used throughout the NHS to assess patient’s thoughts 
on a health service they regularly use. The question we will use in the FFT asks “We would 
like you to think about your recent experience of our Body Reprogramming. How likely are 
you to recommend Body Reprogramming to friends and family if they needed a similar 
service? 
” Participants will respond on a 5 point scale from “Extremely Unlikely” to “Extremely Likely”. 
Questionnaire completion 
 
Data on the number and percentage of questionnaires collected at the two time points will 
recorded. This data will inform participants’ willingness to complete the above questionnaires.  
 
Post-trial focus groups or interview 
 
Focus groups will consist of 3-6 participants and moderated by one of the members of the 
research team with qualitative research experience (LC, MH, JL).  Two focus groups will be 

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conducted in total, and will explore the experience of participants after participating in a four-
week trial of BR.  
 
Each focus group will last for at most 2 hours, be recorded and transcribed verbatim. The 
focus groups will be conducted in a non-clinical setting near to the recruiting site (RD&E) or 
remotely via Zoom. Participants will have their transport costs reimbursed and provided with 
refreshments during the discussion. They will not be paid for taking part.  
 
If a participant declines to take part in a focus group, they will be given the option to 
participate in a one to one interview. Some people find group interactions challenging and the 
interview option will be included to make sure we do not miss out on participant feedback 
when possible.  
 
Overall the direction of conversation during the focus groups or interviews will be led by the 
participants in order to investigate their experiences of BR. Any problems that are brought to 
the attention of the research team during the trial will be discussed during these 
conversations. 
 
4.9 
Description of Data analyses  
 
For quantitative data  
This is a feasibility study and so not powered for statistical testing.  This section describes the 
data to be collected which will inform the design of future studies. 
• The number and percentage of participants that are invited, attended and completed 
the BR course will be reported.  
• All outcome measures will be summarised using means and standard deviations or 
median (range, IQR) for continuous outcomes (as appropriate), and frequencies and 
proportions for categorical outcomes. 
• The mean difference in all recorded scores (pre and post-trial at listed time points post-
trial) will be estimated and in addition using an analysis of covariance of the baseline 
value of the score as well as disease severity as a covariate in the model. 
• The number and percentage with complete data will be reported. The missing value 
guidance provided for questionnaires will be used. If no guidance is provided values 

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will be imputed for an individual if 20% or fewer items are missing. If greater than 20% 
of items are missing in the questionnaire then the questionnaire score will be treated 
as missing and excluded from the analysis. 
• The number of adverse events (AE) and serious adverse events (SAE) will be 
tabulated also by the number of patients reporting an event. No dictionary for coding 
adverse events will be used. Events will be recoded using terms of the clinical 
investigators choosing. 
• A full statistical analysis plan will be drawn up and agreed by the CI and study team 
prior to the final data extraction. 
For qualitative data  
 
Once transcribed, the audio recordings from the focus groups or one to one interviews will be 
analysed for recurring themes. The information gained from this phase will be used to make 
changes to practical aspects of the BR course, e.g. length of meetings or number of weeks, 
as well as adapt the narrative of the course for patients with severe asthma if required.  
 
4.10 The Number of Participants 
 
• 12-14 participants will be recruited for this phase of the study. No formal power 
calculation has been performed as this is a feasibility study. 
 
Post-trial focus groups or interviews:  
 
All participants in the four-week trial of BR will be asked to participate in one of the post-trial 
focus groups or an interview. With a trial withdrawal rate of 10%, this will mean at least 10 
participants complete the trial and are eligible for the focus groups. A minimum number of 
participants for each focus groups is 3 and we estimate that 3-4 focus groups will be needed.  
 
5.0  Phase 2: Biologic priming study 
 
5.1  
Study Aims 
 

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• To assess the feasibility of running a remote BR course before patients commence a 
biologic treatment for their severe asthma. 
• To assess the acceptability of BR, testing a modified intervention having learned 
lessons from this feasibility study, testing the performance of outcome measures to 
inform a potential randomised controlled trial of the intervention. 
 
5.2 
Primary objectives 
 
• To identify patients due to commence a biologic treatment for their severe asthma in 
normal care and offer them the opportunity to undertake the BR programme.  
• To run a BR course with these patients and assess process outcomes, quantitative 
and qualitative measures of the impact of the course. 
• To develop an information booklet on the principals of BR for patients with Severe 
Asthma who are starting or have started a biologic.  
 
5.3  
Inclusion criteria 
 
• Diagnosed with severe asthma as per ERS/ATS definition. 
o Requiring high dose inhaled corticosteroids (NICE definition of high dose ICS, 
Appendix 2). 
• Patients with severe asthma who have been approved for biologic treatment according 
to national guidance and have been assessed by a multi-disciplinary team will be 
offered the intervention pending starting their biologic treatment. 
• Patients with eight or more non-respiratory symptoms per week as measured by the 
GSQ. 
5.4  
Exclusion criteria 
 
• Unable or unwilling to take part. 
• Participated in phase 1 of the study  
• In the opinion of the patient’s treating physician, the patient has another condition 
which is significantly impairs their ability to take part in BR.  
 

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5.5 
Recruitment and consent 
 
Before commencing a biologic treatment for severe asthma in normal clinical care, patients 
are reviewed by a Multi-Disciplinary Team (MDT) responsible for their care. The PI at the 
participating hospital will identify patients eligible to take part in this study at this time.   
Recruitment of eligible patients will then proceed as outlined in phase one. Participants will be 
sent a Patient Invitation Letter (Appendix 14) and Patient Information Leaflet (Appendix 15) 
that describe phase two of the study.  
 
5.6  
Data collection Method 
 
Questionnaire collection time points are the same as for phase one: 
• The first and last week.  
 
Demographic and clinical information will be the same as for phase one.  
The outcome measures will be the same as for phase one. 
 
The Global Rating of Change Questionnaire (GRCQ) (Appendix 16) 
In this phase of the study the GRCQ will be used by participants to indicate how much better 
they feel since commencing a BR and a biologic treatment. The 11-point scale ranges from 
-5 (a great deal worse) to 5 (A great deal better) [17]. 
 
5.7 
 Description of Statistical Methods 
The statistical methods will be the same as that for phase one. The researchers will examine 
whether there is any trends indicating differences in outcome between phase one and phase 
two 
 
5.8  
The Number of Participants 
 
• 12-14 participants will be recruited for this phase of the study. No formal power 
calculation has been performed as this is a feasibility study. Two groups of BR will be 
run.  

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5.9 
The Level of Statistical Significance 
 
Not applicable  
 
5.10 Withdrawal criteria for both phase one and phase two 
 
Whilst participating in the study, a patient’s health or diagnosis may change. If this occurs 
during the study, the participant eligibility for the study they are in will be re-assessed by the 
clinician responsible for their care. If the participant no longer meets the eligibility criteria, their 
data will be removed from the database. The patient will be thanked for their time and told not 
to expect to be asked to participate further.  
 
6.0 
ETHICAL AND REGULATORY CONSIDERATIONS / ROLE OF 
SPONSOR 
The study sponsor is Royal Devon and Exeter Hospitals Trust (RD&E). The various roles of 
the Sponsor are stated below.  
 
6.1 
Assessment and management of risk 
We acknowledge the need to protect the dignity, rights, safety and wellbeing of participants 
taking part in this research study. Although the potential for harming participants as a direct 
result of being involved in the study are considered to be minimal, a contingency will be put in 
place, should a patient become distressed whilst taking part in the study. To begin patients 
will be made aware that the researchers are not there as clinicians, but as researchers. 
Should any patient appear distressed as a result of participating in BR or the focus groups, 
they will be given the opportunity to speak with a clinician. Should they have concerns about 
the conduct of the study, they will be given the contact details for the study CI and contact 
details for the Sponsor (RD&E), which will appear on the Patient Invitation Letter.  
 
6.2  
 Research Ethics Committee (REC) and other Regulatory review & reports 
This study is sponsored by Royal Devon and Exeter Hospitals R&D department. Positive 
approval from the sponsor will be obtained before submission to REC/HRA. The CI will obtain 
a positive opinion from a Health Research Authority (HRA) Research Ethics Committee (REC) 
for the study.  

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The CI will also require a HRA approval letter and a Capability and Capacity e-mail statement 
from the local R&D office before recruitment of participant’s into the study. 
Any amendments to the study protocol will require review by HRA (and possibly the REC if 
the amendment is deemed to be substantial by the study Sponsor) and will not be 
implemented until the HRA grants a favourable opinion for the amendment, which will also 
need to be reviewed and accepted by the participating NHS organisation’s R&D department 
before they can be implemented in practice. 
All correspondence with the HRA will be retained in the Trial Master File/Investigator Site File. 
An annual progress report (APR) will be submitted to the HRA within 30 days of the 
anniversary date on which the favourable opinion was given, and annually until the trial is 
declared ended. It is the CI’s responsibility to produce the annual reports as required. The CI 
will also notify the HRA and Sponsor of the end of the study. If the study is ended 
prematurely, the CI will notify the REC, including the reasons for the premature termination. 
Within one year after the end of the study, the CI will submit a final report with the results, 
including any publications/abstracts, to the HRA. The investigators will ensure that this study 
is conducted in full conformity with relevant national regulations and with the UK Policy 
Framework for Health and Social Care Research (2017). The research team will also bear in 
mind the principles of the Declaration of Helsinki when conducting the study. 
 
6.3 
Regulatory Review & Compliance  
The study may be subject to monitoring by RD&E under its remit as Sponsor and other 
regulatory bodies to ensure adherence to GCP and the UK Policy Framework for Health and 
Social Care Research (2017). It’s current policy that the R&D Office will monitor all studies 
sponsored by the RD&E NHS Trust 30 days after approval of the study (from the date of Trust 
Capacity & Capability e-mail). 
The research team will check completed study data collection documents for missing data or 
obvious errors.  
 
6.4 
Protocol compliance  
Any additional analysis or deviations will be reported as such to the study management group 
and the independent study steering committee and other appropriate authorities as per Good 
Clinical Practice (GCP). 
 

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6.5 
Data protection and patient confidentiality  
In accordance with the Data Protection Act (2018), RD&E Research Data Policy, all 
researchers will ensure that study participants’ anonymity is maintained and data is stored 
securely. Study participants will be assigned a study ID number which will replace the 
patient’s name on all data. All data will be password protected, stored securely and will only 
be accessible by researchers and authorised personnel from UoP and RD&E. The co-
investigator (Prof Michael Hyland) is employed by the University of St Mark and St John. 
However, as RD&E is the lead organisation, Prof Hyland will follow their data protection 
policy.  
 
Following completion of data analysis, the Sponsor will be responsible for archiving the study 
data and essential documentation in a secure location for a minimum period of 10 years after 
the end of the study. No study-related records should be destroyed unless or until the 
Sponsor gives authorisation to do so. Medical case notes containing source data or other 
trial-related information should be identified by a label “Keep until dd/mm/yyyy” where the 
date given is 10 years after the last participant’s final study visit. 
 
6.6 
Indemnity 
This is a Royal Devon and Exeter Hospitals Trust (RD&E) sponsored research study. If an 
individual suffers negligent harm as a result of participating in the study, RD&E indemnity 
covers RD&E staff and those people responsible for conducting the study.   
 
The University of Plymouth provides insurance for all of its employees through Zurich 
insurance. Public liability insurance is also provided by the same company. This indemnity 
policy can be found in Appendix 17. 
 
6.7 
Access to the final study dataset 
The study incorporates the following types of data, which will only be accessed by the 
research team: 
Qualitative data: Audio-recording of focus groups, Anonymised transcripts of focus group 
discussions 
Routinely recorded clinic data and research questionnaires 
Service use in the last 12 months; 

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Recruitment data (proportions of uptake, completion and attrition). 
A document linking research IDs with clinical identification numbers will be created and stored 
in a locked filing cabinet in Bowmoor House on the site of Royal Devon and Exeter Hospital. 
Anonymised data will be analysed by the research team (RJ, JL, MM, LC, and MH).  
After the end of the study, anonymised information collected during the study will be made 
available to other researchers under an appropriate data sharing agreement, but it will not be 
possible to identify participants personally from any information shared. 
 

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7.0  References 
1. 
Chen W, Lynd LD, FitzGerald JM, Marra CA, Balshaw R, To T, et al. Excess medical 
costs in patients with asthma and the role of comorbidity. Eur Respir J. 2016;48(6):1584-92. 
2. 
Zhang T, Carleton BC, Prosser RJ, Smith AM. The Added Burden of Comorbidity in 
Patients with Asthma. Journal of Asthma. 2009;46(10):1021-6. 
3. 
Lanario JW, Hyland ME, Wei Y, Jones RC, Masoli M. Comparison of the effects of 
pulmonary and extra-pulmonary symptoms on health-related quality of life in patients with 
severe asthma. Respiratory Medicine. 2020:105870. 
4. 
Hyland ME, Lanario JW, Wei Y, Jones RC, Masoli M. Evidence for similarity in 
symptoms and mechanism: The extra‐pulmonary symptoms of severe asthma and the 
polysymptomatic presentation of fibromyalgia. Immunity, inflammation and disease. 
2019;7(4):239-49. 
5. 
Hyland ME, Halpin DM, Blake S, Seamark C, Pinnuck M, Ward D, et al. Preference for 
different relaxation techniques by COPD patients: comparison between six techniques. 
International journal of chronic obstructive pulmonary disease. 2016;11:2315. 
6. 
Casaburi R, Kukafka D, Cooper CB, Witek Jr TJ, Kesten S. Improvement in exercise 
tolerance with the combination of tiotropium and pulmonary rehabilitation in patients with 
COPD. Chest. 2005;127(3):809-17. 
7. 
Silver JK. Prehabilitation could save lives in a pandemic. bmj. 2020;369. 
8. 
Hyland ME, Masoli M, Lanario JW, Jones RC. A possible explanation for non-
responders, responders and super-responders to biologics in severe asthma. Exploratory 
Research and Hypothesis in Medicine. 2019;4(2):35-8. 
9. 
Hyland ME, Hinton C, Hill C, Whalley B, Jones RCM, Davies AF. Explaining 
unexplained pain to fibromyalgia patients: finding a narrative that is acceptable to patients and 
provides a rationale for evidence based interventions. British Journal of Pain. 2016;10:156-61. 
10. 
Davies AF, Hill P, Fay D, Dee A, Locher C. Body Reprogramming: Reframing the 
Fibromyalgia narrative and providing an integrative therapeutic model. Health Psychology 
Open. 2020;7(2):2055102920971494. 
11. 
Melidis C, Denham SL, Hyland ME. A test of the adaptive network explanation of 
functional disorders using a machine learning analysis of symptoms. BioSystems. 
2018;165:22-30. 
12. 
Hyland ME, Bacon AM, Lanario JW, Davies AF. Symptom frequency and development 
of a generic functional disorder symptom scale suitable for use in studies of patients with 
irritable bowel syndrome, fibromyalgia syndrome or chronic fatigue syndrome. Chronic 
Diseases and Translational Medicine. 2019;5(2):129-38. 
13. 
Hyland ME, Bellesis M, Thompson PJ, Paul Kenyon CA. The constructs of asthma 
quality of life: Psychometric, experimental and correlational evidence. Psychology & Health. 
1996;12(1):101-21. 
14. 
Juniper EF, O'Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation 
of a questionnaire to measure asthma control. European Respiratory Journal. 1999;14:902-7. 
15. 
Kamper SJ, Maher CG, Mackay G. Global rating of change scales: a review of 
strengths and weaknesses and considerations for design. Journal of Manual & Manipulative 
Therapy. 2009;17(3):163-70. 
 

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Appendix 1: Gantt chart  
 
 
 
 
 
 
Timeline Post Funding
Month
Funding 
Confirmed
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Discuss Protocol Draft with 
collaborators 
Finalise Protocol 
Adapt patient invitation letter and 
information sheet for local centre 
use
Apply for Local R&D approval 
Apply for REC 
HRA approval
Brief centres 
Identify/Recruit participants for 
phase 1
Run Phase 1 BR groups
Collect data from phase 1
Identify/Recruit participants for 
phase 2
Run Phase 2 BR groups
Collect data from phase 2
Write up 

26/05/21 18
 
 
Appendix 2: NICE definition of high dose Inhaled Corticosteroids