National Validation and Sensitivity to Change of a Scale to Measure Quality of Life in Patients With Severe Asthma
Conditions: Asthma, Severe Asthma
Sponsor: University Hospital Plymouth NHS Trust

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NATIONAL VALIDATION AND SENSITIVITY TO CHANGE 
OF A SCALE TO MEASURE QUALITY OF LIFE IN PATIENTS 
WITH SEVERE ASTHMA 
 
 
 
Date: 05/04/19 

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Study Management Group – SAQ Team 
Chief Investigator:  
Dr Matthew Masoli: Email matthew.masoli@nhs.net 
Co-investigators:  
Prof. Michael Hyland: Email mhyland@plymouth.ac.uk 
Dr Rupert Jones: Email rupert.jones@plymouth.ac.uk 
Dr Yinghui Wei: Email yinghui.wei@plymouth.ac.uk  
Joseph Lanario: Email joseph.lanario@nhs.net   
Principal Investigators:  
Prof. Andrew Menzies-Gow, Royal Brompton and Harefield NHS Foundation Trust, London, UK 
Dr. Stephen Fowler, University Hospital of South Manchester, Manchester University NHS Foundation 
Trust, UK 
Dr. Adel Mansur, Heartlands Hospital of the University Hospitals Birmingham NHS Foundation Trust, 
UK 
 
Study Coordination Centre 
For general queries, supply of study documentation, and collection of data, please contact: 
Joe Lanario 
Address: Rm N10, ITTC Building, Plymouth Science Park, Research Way, Plymouth, PL6 8BX. 
Tel: 01752 764 267 
e-mail: joseph.lanario@nhs.net   
Clinical Queries 
Clinical queries should be directed to Dr Rupert Jones who will direct the query to the appropriate person 
Tel: 01752 764 403 
Sponsor 
University Hospitals Plymouth NHS Trust (UHPNT) is the main research sponsor for this study.  For 
further information regarding the sponsorship conditions, please contact the Research Manager at: 
Research Office, Plymouth Hospitals NHS Trust, Level 2, MSCP, Bircham Park Offices 
Roscoff Rise, Derriford, Plymouth, PL6 5FP 
Tel:  01752 431 046 
Email:  corinna.mossop@nhs.net  
Funder: GlaxoSmithKline 
The Proposal 
This proposal describes the planned programme of research and provides information about study 
design.  Every care was taken in its drafting, but corrections or amendments may be necessary. These 
will be circulated to investigators in the study.   
 
 

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Table of Contents 
STUDY SUMMARY ............................................................................................................................................ 4 
1. INTRODUCTION ........................................................................................................................................ 5 
1.1 BACKGROUND ............................................................................................................................................ 5 
1.2 RATIONALE FOR CURRENT STUDY ................................................................................................................... 7 
1.3 PATIENT AND PUBLIC INVOLVEMENT ............................................................................................................... 8 
2.0 NATIONAL VALIDATION STUDY ............................................................................................................... 9 
2.1 AIM......................................................................................................................................................... 9 
2.2 OBJECTIVES ............................................................................................................................................... 9 
2.3 STUDY DESIGN ........................................................................................................................................... 9 
2.4 STUDY OUTCOME MEASURES ......................................................................................................................... 9 
2.4.1 QUESTIONNAIRES: ................................................................................................................................................ 9 
2.4.2 CLINIC DATA TO BE COLLECTED: ............................................................................................................................10 
2.5 PATIENT INVITATION LETTER AND PATIENT INFORMATION LEAFLET ....................................................................... 11 
2.6 RECRUITMENT AND CONSENT. ...................................................................................................................... 11 
2.6.1 INCLUSION CRITERIA ...........................................................................................................................................11 
2.6.2 EXCLUSION CRITERIA ...........................................................................................................................................11 
2.6.3 SAMPLE SIZE CALCULATION ..................................................................................................................................12 
2.7 DATA COLLECTION METHOD ........................................................................................................................ 12 
2.8 ANALYSIS ................................................................................................................................................ 12 
3.0 SENSITIVITY TO CHANGE STUDY ............................................................................................................ 13 
3.1 AIM....................................................................................................................................................... 13 
3.2 STUDY DESIGN ......................................................................................................................................... 13 
3.3 STUDY OUTCOME MEASURES ....................................................................................................................... 13 
3.3.1 INVESTIGATION QUESTIONNAIRES: .........................................................................................................................13 
3.3.2 CLINIC DATA TO BE COLLECTED: ............................................................................................................................13 
3.4 RECRUITMENT AND CONSENT ...................................................................................................................... 14 
3.4.1 INCLUSION CRITERIA ...........................................................................................................................................15 
3.4.2 EXCLUSION CRITERIA ...........................................................................................................................................15 
3.4.3 SAMPLE SIZE CALCULATION ..................................................................................................................................15 
3.5 DATA COLLECTION METHODS ....................................................................................................................... 15 
3.6 ANALYSIS ................................................................................................................................................ 16 
4.0 WITHDRAWAL CRITERIA FOR STUDY PROGRAMME ............................................................................................ 17 
5.0 DATA MANAGEMENT FOR STUDY PROGRAMME ............................................................................................... 17 
5.1 PROCEDURE FOR ACCOUNTING FOR MISSING, UNUSED, AND SPURIOUS DATA. ....................................................... 18 
5.2 PROCEDURES FOR REPORTING ANY DEVIATION(S) FROM THE ORIGINAL STATISTICAL PLAN ......................................... 18 
5.3 ARCHIVING ............................................................................................................................................. 19 
6.0 REGULATORY ISSUES .................................................................................................................................. 19 
6.1 ETHICS APPROVAL .................................................................................................................................... 19 
6.2 ETHICAL ISSUES ........................................................................................................................................ 19 
6.3 CONFIDENTIALITY ..................................................................................................................................... 20 
6.4 INDEMNITY ............................................................................................................................................. 20 
6.5 SPONSOR ................................................................................................................................................ 20 
6.6 MONITORING, AUDIT & INSPECTION ............................................................................................................. 20 
7.0 STUDY MANAGEMENT ............................................................................................................................... 21 
7.1 STUDY MANAGEMENT GROUP ..................................................................................................................... 21 
8.0 DISSEMINATION AND PUBLICATION POLICY ..................................................................................................... 21 
9.0 FUNDING ................................................................................................................................................ 22 
10.0 IMPACT ................................................................................................................................................ 22 
11.0 REFERENCES .......................................................................................................................................... 24 

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Study Summary 
 
TITLE 
Further validation and determination of the Minimum Clinically Important Difference of a scale 
to measure quality of life in patients with severe asthma 
DESIGN 
A multi-centre mixed methods study of a new asthma specific quality of life questionnaire 
including limited clinic data, using the UK Severe Asthma Network. 
AIMS 
To collect further quantitative data to validate a new asthma quality of life scale, the Severe 
Asthma Questionnaire (SAQ). 
To determine the Minimum Clinically Important Difference (MCID) of the SAQ 
OUTCOME 
MEASURES 
Questionnaires: 
1. The Severe Asthma Questionnaire (SAQ) 
2. The Mini Asthma Quality of Life Questionnaire (MiniAQLQ) 
3. The EQ-5D-5L 
4. The Asthma Control Test (ACT)/ Asthma Control Questionnaire (ACQ)  
5. Global Rating of Change Questionnaire (GRCQ) 
6. Clinical data comprises:  
7. Spirometry 
8. BMI 
9. Asthma severity 
10. Health care utilisation: ED attendance in the last 12 months, Hospital admissions in the 
last 12 months;  
11. Number of exacerbations in the last 12 months requiring OCS Prednisolone dose mg/day 
(if oral steroid dependent). 
POPULATION 
All patients aged 16 years or over, who have attended one of three participating UK specialist 
asthma centres for the validation study and with data also collected from Derriford Hospital’s 
Chest Clinic (DHCC) for use in determining Minimum clinically Important difference. 
ELIGIBILITY 
Over 16 years of age 
Diagnosis of Severe Asthma 
DURATION 
18 months 
REFERENCE 
DIAGRAM 
Gantt chart (Appendix 1) 
 
 
 
 

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1. Introduction  
1.1 Background 
The global prevalence of asthma is estimated to be 300 million and is expected to grow by more than 
100 million by 2025 [1]. Patients with severe and difficult-to-treat asthma comprise a small proportion 
(5-10%) of all asthmatic patients, yet are responsible for a disproportionate degree of asthma morbidity 
and costs [2]. These patients have ongoing daily symptoms despite maximal medical therapy and are 
more likely to be admitted to hospital and to access out of hours’ emergency healthcare than asthmatics 
with mild or moderate disease [2]. 
Corticosteroids have proved extremely effective in the acute and chronic treatment of inflammatory 
diseases. However, despite their clinical success, oral corticosteroids (OCS) have many known side 
effects which limit their tolerability, particularly in the long term [3]. As the multi-faceted negative 
consequences of OCS therapy are becoming better understood, the drive to find OCS substitutes 
becomes more urgent. However, in order to fully appreciate the value of steroid sparing agents which 
tend to be more expensive than OCS, the wider picture of OCS adverse effects must be considered to 
determine the real cost offsets achievable by such therapies. 
While patients with mild and moderate asthma can usually be controlled using inhaled medication, in 
severe asthma OCS are often required. OCS exposure may be significant through either frequent short 
courses for exacerbations or as a maintenance dose. Studies on patients with mild and moderate 
asthma show that exacerbations are predicted by non-asthma related health problems [4] and by poor 
adherence [5]. In mild and moderate asthma, adherence to inhaled corticosteroids is affected by real or 
perceived medication side effects [6,7]. There is limited understanding of this relationship in severe 
asthma patients; qualitative data suggests that side effects impact on OCS use [7], but the relationship 
between OCS and inhaled medication adherence is complex [8]. Patients’ concerns differ from those of 
clinicians [7,8]. The consequences of poor adherence for those with severe asthma are extremely 
serious and include frequent disabling attacks, recurrent unpredictable admissions and death. 
While the consequences of non-adherence to OCS in patients with severe asthma may be dire, so too 
are the perceived side-effects.  Of major concern to patients are changes in facial and body appearance, 
weight gain, gastro-oesophageal reflux, mood changes and sleep disruption.  Metabolic changes 
including high blood pressure, precipitating diabetes mellitus and long-term effects on bone are of more 
concern to clinicians. 
Health-related quality of life (HRQoL) is one of several outcome measures used to inform treatment 
guidelines and economic decision-making for the treatment of asthma. HRQoL scales are important 
amongst outcome measures in that they inform whether treatment is worthwhile from the perspective of 
the patient, a perspective that includes the burden of disease and the burden of treatment. Asthma 
varies in severity, and increased doses or types of medication are required for the more severe patients. 
Severe asthma patients have uniquely different types of HRQoL deficits and in this population the 

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burden of treatment, particularly with OCS, becomes a larger determinant of HRQoL. The impact of 
OCS is known to be far greater than the impact of other asthma treatments [8], and therefore, severe 
patients, i.e. those exposed to high doses of OCS, are likely to have a greater treatment burden than 
other patients. 
Novel biologic agents are likely to become increasingly available to treat severe asthma. While these 
are more expensive than conventional treatments, if effective they may reduce symptoms, health care 
costs and reduce the need for oral steroids.  In order to understand the impact of these newer drugs, 
measures must be used to accurately reflect the specific issues of severe asthma burden, including the 
burden of treatment. Previous work has demonstrated that existing asthma-specific scales 
underestimate the burden of severe asthma, in particular treatment with OCS, and therefore will 
underestimate the benefits of steroid sparing agents [8]. Improved assessment procedures are needed 
to provide accurate information on which treatment and resourcing decisions are made. 
Research into severe asthma is limited by the lack of questionnaires suited to this population that 
capture both the health deficits experienced by severe asthma sufferers and the range of adverse 
experiences from treatment. It is therefore important that appropriate outcome and adherence measures 
are available to assess service development in relation to severe asthma. As a first step in questionnaire 
development, in-depth interviews were held in a sample of 23 patients attending the difficult asthma 
service at Derriford Hospital. These interviews revealed the substantial burden of symptoms associated 
with OCS that were not addressed by existing measures of health-related quality of life (HRQOL) [8]. 
The importance of such measures is emphasised by two major reports. The National Institute for Health 
and Care Excellence (NICE) is strongly supportive of the need for improved measurements which reflect 
the patients’ burden in severe asthma and the impact of OCS [9]: “the Committee concluded that other 
adverse effects (of oral steroids), such as obesity, hypertension, mood changes, depression, psychosis, 
thinning skin, delayed wound healing, reduced growth in children and increased risk of infection were 
additional important factors that had not been captured when calculating the quality adjusted life years.”  
When statutory bodies such as NICE compare the cost effectiveness of very cheap OCS versus novel 
biologic agents, it is possible to conclude that such treatments may not meet the Incremental Cost-
Effectiveness Ratio (ICER), particularly when compared to OCS. Only if the burden of OCS is accurately 
measured can the real cost effectiveness be established. 
In a qualitative study [8] in-depth interviews were held in a sample of 23 patients attending the difficult 
asthma service at Derriford Hospital. The main health deficits and burden of treatment were defined and 
compared to existing questionnaires. We found just how much patients suffer from side-effects of long-
term oral steroids and how these are poorly captured by existing scales. The National Review of Asthma 
Deaths [10] showed that asthma has many preventable factors, in particular, poor use of preventer 
medication. In addition, psychosocial factors such as depression contributed to the cause of death in 
25% of cases. OCS have profound psychosocial impacts. Since the publication of this report, there has 

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been increasing interest in identifying people at risk of asthma deaths, improving services for patients 
with severe asthma, and rational use of new treatments.  
The SAQ questionnaire was derived from a qualitative study [8] and questions and design were 
evaluated by a panel of international expert clinicians. The concepts and wording were modified and 
tested in an iterative series of four focus groups of patients attending the difficult asthma service [9]. The 
questionnaire was then field tested in 160 patients and compared to the MiniAQLQ, the Asthma Control 
test and clinic data including BMI, lung function, and health care consumption [10]. The final version 
takes into account the lessons learned from this quantitative study and further input from the panel of 
experts. 
The SAQ questionnaire has 16 questions rated on a 0-6 Likert scale and on a 0-100 scale rating of (i) 
overall quality of life  (ii) how your asthma symptoms and the side effects of your medicines have affected 
your quality of life during the last two weeks.   
1.2 Rationale For Current Study 
This research is the continuation of a project which provided preliminary validation of the SAQ. Whilst 
the preliminary validation provided evidence for the validity of the SAQ, a limited sample size made 
comparisons between groups of participants difficult. In addition, all data were collected in the South 
West of England (Plymouth, Devon), which may limit the studies generalisability to the rest of the UK. 
This further validation study will address these two issues by collecting more data from multiple centres 
around the UK. The second part of this research will collect data for the calculation of the SAQ’s 
Minimum clinically Important difference (MCID). This value is required if the SAQ is to be useful in clinical 
practice, clinical trials and research.  
Research into the burden of severe asthma, in particular treatment with OCS, is limited by the lack of 
questionnaires suited to this population that capture both the health deficits experienced by severe 
asthma sufferers, and the range of adverse experiences from treatment. As a consequence, the benefits 
of steroid sparing agents are underestimated [8].  
NICE has called for such a questionnaire to measure the impacts on patients of severe asthma and its 
treatment. The new biological treatments which are already developed or in the pipeline need to be 
tested with measures which reflect their impact specifically on people with severe asthma [11]. Content 
validity of the SAQ has been established through the qualitative studies as recommended by the FDA 
[12]. 
The aim of this study is to provide further construct validity for the SAQ using UK collaborators.  This 
will be done by showing that the SAQ is sensitive to differences in treatment, symptomatology, as well 
as being able to detect changes in patients’ HRQOL after the commencement of a new treatment for 
severe asthma. 

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1.3 Patient And Public Involvement 
Patients have been involved in the development of this questionnaire since the beginning of the 
research. As part of an initial study to identify the burden associated of living with severe asthma, 
qualitative interviews were conducted. In total 23 patients diagnosed with severe asthma were 
interviewed, and highlighted the burden they experienced as a result of taking OCS [8].  
Furthermore, four focus groups were conducted in which patients were presented with a draft version 
of the Severe Asthma Questionnaire (SAQ). In total 16 patients diagnosed with severe asthma were 
recruited [9]. These patients gave substantial feedback concerning the wording of questions and the 
response scale used on the questionnaire. Participants also suggested the addition of new items to the 
questionnaire, in order to better capture the burden associated with their disease or OCS.  
After gaining feedback from a panel of international expert clinicians, the wording of an item in the SAQ 
was changed to reflect a timescale of months, rather than seasons. This change was made in order to 
make the questionnaire internationally applicable, including in countries where they do not have four 
seasons. 
It was decided by the SAQ development team that this constituted a significant change to the 
questionnaire. Therefore, this final version of the SAQ was also presented to four patients diagnosed 
with severe asthma, to check that this change had not altered the ease at which the focus group patients 
had understood the wording of the original questionnaire item.  
Moreover, as this occurred in a clinic setting, this enabled us to ensure that patients found the SAQ as 
easy to complete in a clinic setting, which has considerable time constraints, compared to during the 
focus groups, where time was not a concern. Overall, these four patients reported that the final version 
of the SAQ was easy to comprehend and complete before their clinic appointment.   
Potential logos for the SAQ were also discussed with five patients diagnosed with severe asthma, whilst 
they waited for their clinic appointment. The final logo was chosen as it was described as distinguishing 
the questionnaire from others. The patients’ choice of logo was also considered by three specialist 
asthma nurses, who agreed that it would increase the chance of identifying the SAQ under the time 
constraints of day to day clinical practice. 
Finally, the design and concept of the questionnaire and this study were discussed with the Plymouth 
Breathe Easy group of the British Lung Foundation who provided positive comments (7.2.17). These 
varied and extensive forms of qualitative evaluation were carried out in order to ensure content validity 
of the scale as defined by the FDA, where it is asserted that “Content validity is supported by evidence 
from qualitative studies that the items and domains of an instrument are appropriate and comprehensive 
relative to its intended measurement concept, population, and use. Content validity is specific to the 
population, condition, and treatment to be studied [12]. 

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2.0 National Validation Study 
2.1 Aim 
To further validate the SAQ for use in the United Kingdom. 
2.2 Objectives 
To collect data from patients attending the UK specialist Asthma centres: 
To provide a description of the factor structure of the SAQ and to demonstrate equivalence across 
populations. 
To show that the SAQ correlates in an acceptable manner with the Mini Asthma Quality of Life 
Questionnaire (MiniAQLQ) and EQ-5D-5L (EQ5D) 
To show that the SAQ is a discriminator of patients who have different frequencies of exacerbations 
and different levels of prednisolone consumption. 
To show that the SAQ is equivalent in discrimination for exacerbations to the MiniAQLQ or EQ5D but 
is a better discriminator than these questionnaires for treatment levels of oral corticosteroids. 
2.3 Study Design 
Type of study: A multi-centre, cross-sectional study of four questionnaires including clinic data. 
Duration of the study: 12 months. 
Sample size:  80 – 107 participants from each of the three centres (N= 240 - 321): 
Royal Brompton and Harefield NHS Foundation Trust, London, UK 
Birmingham Heartlands Hospital NHS Foundation Trust, Birmingham, UK 
University Hospital of South Manchester, Manchester University NHS Foundation Trust, UK 
Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, UK 
 
2.4 Study outcome measures 
2.4.1 Questionnaires: 
Severe Asthma Questionnaire (SAQ) (Appendix 2) 
The new questionnaire will provide a combined assessment of disease and its treatment on the quality 
of life of patients with severe asthma. The scale is based on existing HRQoL 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 and was produced from detailed 
qualitative research. An additional 3 items are included to asses overall QoL, and QoL during different 
months of the year [13].  

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EQ-5D-5L (Appendix 3) 
This is a 5-item scale, with a final question which asks patients to use a category rating scale to rate 
their quality of life on the day of completion. This scale is commonly used in clinical trials to determine 
improvement in patients’ perceived quality of life. The correlations between EQ-5D-5L scores and SAQ 
scores will be explored [14].  
Routine Clinic Questionnaires  
The Mini Asthma Quality of Life Questionnaire (MiniAQLQ) (Appendix 4) 
This 15-item scale is commonly used as the quality of life scale in asthma studies [15]. For the purpose 
of validation, we wish to show that this scale correlates with the burden of symptoms but not, or with a 
much lower correlation, with the burden of treatment. 
Asthma Control Test (ACT) (Appendix 5) 
This 5-item scale is commonly used as a measure of asthma control in asthma studies [16]. For the 
purpose of validation, we wish to show that this scale correlates with the burden of symptoms but not, 
or with a much lower correlation, with the burden of treatment. 
OR (depending on the preference of centres) 
Asthma Control Questionnaire (Asthma Control Questionnaire) (Appendix 6) 
Another questionnaire of asthma control.  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) [17] 
2.4.2 Clinic Data to be collected:  
Data to describe patient characteristics 
Patient demographics:  
Age 
Sex 
Ethnicity  
Clinical data: 
Spirometry: absolute Forced Expiratory Volume (FEV1) (litres) and percentage of predicted 
FEV1 (FEV1%)  
Forced Vital Capacity (FVC) (litres)  
Weight (Kg), Body Mass Index (BMI)  
Asthma severity: Treatment level by drug class classified by GINA step 
Health care utilisation:  
Emergency Department, attendance in the last 12 months 
Hospital admissions in the last 12 months  
Clinic Data Outcome Measures: 
Number of exacerbations in the last 12 months requiring OCS 

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Prednisolone dose mg / day if on maintenance OCS 
Note: The three UK specialist centres are part of the BTS severe asthma network, and contribute to a 
shared database.  Except for the two study questionnaires (SAQ and EQ-5D-5L) the above data are 
part of routine data collection. 
Permissions will be obtained following procedures appropriate for each centre. 
2.5 Patient Invitation Letter and Patient Information Leaflet 
As this study is taking place at multiple sites, the Patient Invitation Letter and Information Leaflet will 
need to be adapted for use by each centre.  The anticipated adaptations will include: letter heading; 
and a change of the centres PI and research nurse contact details in the case that a participant has 
questions. 
2.6 Recruitment and consent. 
Patient eligible to participate in the study will be identified by a health care professional familiar with 
them. When possible, a Patient Invitation Letter (Appendix 7) and a Patient Information Leaflet 
(Appendix 8) will be posted to eligible patients two weeks before their scheduled clinic appointment. The 
Invitation Letter and Information Leaflet will provide patients with instruction to read the information 
carefully and to decide if they wish to participate in the study. The Information Leaflet will contain contact 
details for the patients clinical care team, as well as the SAQ development team in case the patient has 
questions. If they understand the information they have read and wish to participate, the Information 
Leaflet asks patients to sign the consent form and bring it with them to their next scheduled clinic 
appointment.  
Alternatively, patients will be approached by a member of their clinical care team and asked if they wish 
to participate in the study during a clinic appointment. Patients will be provided with a Patient Information 
Leaflet at this time and given time to read through it and have any questions answered by either a 
healthcare professional responsible for their care before consenting or a member of the SAQ 
development team. When ready, the patient will be asked to sign the Consent Form.  
The right of the participant to refuse to participate without giving reasons will be respected.  All 
participants are free to withdraw at any time from without giving reasons and without prejudicing further 
treatment. 
2.6.1 Inclusion Criteria 
All patients must have a diagnosis of severe asthma, be taking high dose inhaled corticosteroids 
(GINA step 4 & 5), and be aged 16 years or over. 
2.6.2 Exclusion Criteria 
Patients that are unwilling to participate will be excluded from the study. 

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In the opinion of the physician responsible for the care of the patient, the patient has a condition, other 
than asthma, which is significantly contributing to their respiratory symptoms, e.g. lung cancer, heart 
failure or severe COPD. 
The SAQ is currently only translated into British English. Therefore, if the participant is unable to read 
in English, they will be unable to participate.  
2.6.3 Sample size calculation  
Sample size determination is based on the analysis where the greatest number of patients is needed, 
namely factor analysis.  For exploratory factor analysis the number of participants needed per item 
varies but ranges between 15 and 20 participants per item [18, 19]. There are 16 items in the SAQ. 
Thus, data from 240 – 320 participants is needed for any factor analysis, (80 – 107 participants from 
each centre.) 
2.7 Data Collection Method 
After providing written informed consent, participants will be provided with a pack consisting of a consent 
form, and the following questionnaires: (a) SAQ, (b) MiniAQLQ, and (c) EQ-5-5L (d) ACT/ACQ. 
All clinic data will be input onto the Baseline Case Report Form (CRF) (Appendix 9) by a research nurse.  
This data and the completed pseudonymised questionnaires will be emailed to the Plymouth RA (JL) 
via NHS email.  This data will utilise a participant number system.  Each site will place a copy of the 
completed questionnaires into the patient’s notes as they may contain relevant clinical information for 
current and future treatment. 
2.8 Analysis  
Factor analysis of the SAQ A trial principal axis factor analysis with scree plot will be calculated.  On 
the basis of factor loadings on the first factor, it will be decided whether it is legitimate to provide an 
overall score for the questionnaire.  Using the scree plot to determine factor number, an oblique rotation 
will be carried out and interpretation of emerging factor loadings (from the pattern matrix) determined.  
Correlations between questionnaires 
Correlations between questionnaires will be calculated using Pearson Correlations. 
Discriminant validity  We will test for significant differences between the SAQ and other scales using 
a mixed design analysis of variance (one within and one between) where groups are defined in two 
ways (a) maintenance dose oral corticosteroids and (b) cumulative dose oral corticosteroids.  The aim 
of this analysis is to investigate whether the SAQ has better discriminant validity than other scales.  First 
the interaction term of the analysis of variance will be used to determine whether sensitivity differs across 
all groups.  Second, because the SAQ is expected to be more sensitive to discrimination at the top end 
of prednisolone use, a mixed design analysis of variance will be conducted on the two highest doses of 
prednisolone only.  

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3.0 Sensitivity to Change Study 
3.1 Aim 
To assess the sensitivity to change of the SAQ, for patients who initiate a new biologic treatment for 
their asthma.  
To determine the SAQ’s minimal clinically important difference (MCID).  
3.2 Study Design 
Type of study: A multi-centre sensitivity to change study, using the SAQ, other questionnaire measures 
and clinic data  
Duration of the study: 18 months. 
Sample size: Between 30 and 50 participants per each of the five participating sites: 
1. University Hospitals Plymouth, NHS Foundation Trust, Plymouth, UK 
2. Royal Brompton and Harefield NHS Foundation Trust, London, UK 
3. University Hospital of South Manchester, Manchester University NHS Foundation Trust, 
UK 
4. Birmingham Heartlands Hospital NHS Foundation Trust, Birmingham, UK 
5. Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, UK 
Baseline questionnaire data from participants recruited for this part of the study will be added to the 
dataset for part 1. 
3.3 Study outcome measures 
3.3.1 Investigation questionnaires: 
1. Severe Asthma Questionnaire (SAQ) (Appendix 2)  
2. Global Rating of Change Questionnaire (Appendix 10) 
This scale will be used by participants to indicate how much better they feel since commencing 
a biologic treatment for asthma.  The 11-point scale ranges from -5 (a great deal worse) to 5 (A 
great deal better) [20]. 
3. EQ-5D-5L (Appendix 3) 
3.3.2 Clinic Data to be collected:  
Baseline characteristics: 
Age 
Sex 
Spirometry: absolute FEV1 (litres) and percentage of predicted FEV1 (FEV1 %)  
Forced Vital Capacity (FVC) (litres)  
Body Mass Index (BMI)  

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Asthma severity: Treatment level by drug class classified by GINA step 
Maintenance OCS dose (mg/day)Health care utilisation:  
Emergency Department attendance in the last 12 months 
Hospital admissions in the last 12 months  
Clinic Data Outcome Measures to be recorded at each treatment visit: 
Weight (Kg) 
Maintenance OCS dose (mg/day) 
Number of exacerbations since last clinic visit requiring OCS Health care utilisation, the 
number of:  
Emergency Department attendances since last clinic visit  
Hospital admissions since last clinic visit. 
Must be recorded on the follow-up CRF at the final study visit (16 weeks), (weeks 4, 8 and 12 
are optional):  
FEV1 (litres) 
FEV1 (% predicted) 
3.4 Recruitment and Consent 
Patients will be identified as eligible to participate by a health professional familiar with them.  When 
possible, these patients will be contacted by a health professional two weeks before they are due to 
attend for their asthma treatment, and invited to participate.  This contact will be made by posting a 
Patient Invitation Letter (Appendix 11) and Patient Information Leaflet with a consent form (Appendix 
12) out to the patient.  
The Invitation Letter and Patient Information Leaflet will include instructions to read the material 
carefully.  Contact details for the centres PI, and researcher will be included on the Patient Information 
Leaflet, and can be contacted if the patient has questions.  If they wish to participate after reading this 
information, patients may complete the consent form and bring it with them to their next asthma clinic 
appointment.  
Alternatively, when attending their appointment, patients who have been identified as eligible to 
participate in this study, will be asked if they are interested in participating.  If so, a health professional 
will brief and consent the patient or alternatively, will introduce the patient to a researcher who will 
facilitate this.  The participant will be provided with a Patient Information Leaflet.  The patient will be 
assigned a participant number at this time.  
The researcher will be available to answer detailed question about the research project.  In addition, as 
this is a clinic setting, multiple health professionals will also be present, who will be aware of this project, 
and be able to answered questions, or refer the patient to the researcher if necessary.  Patients will 
have all questions answered, before they sign a consent form, and will be aware that they can withdraw 
at any time if they choose. 

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3.4.1 Inclusion Criteria  
Patients commencing a biologic treatment for their severe asthma (GINA step 4 & 5), as per NICE 
guidelines 
3.4.2 Exclusion Criteria  
Patients will be excluded from the study if they are unwilling to participate 
In the opinion of the physician responsible for the care of the patient, the patient has a condition, other 
than asthma which is significantly contributing to their respiratory symptoms, e.g. lung cancer, heart 
failure or severe COPD. 
3.4.3 Sample size calculation  
Three types of analysis are planned.  Sample size is based on analysis 2 (see below where the sample 
is divided into quartiles and we test whether there are significant differences between quartiles.  Four 
groups of 25 patients will detect an effect size of 0.3 with a power of 70% at a significance level 5%. The 
total sample is therefore 100 participants. The addition of a fifth site with the aim of also recruiting 25 
patients will mean this analysis remains sufficiently powered even if one of the other sites under-recruits.  
3.5 Data collection methods  
After providing written informed consent, patients commencing a new biologic treatment for their severe 
asthma will be asked to complete the SAQ (Appendix 2) and the EQ-5D-5L (Appendix 3) at the time of 
their first treatment. This is in addition to the Mini Asthma Quality of Life questionnaire (Mini-AQLQ) 
(Appendix 4) and Asthma Control Test (ACT) (Appendix 5) or Asthma Control Questionnaire (ACQ) 
(Appendix 6), which are normally completed as part of an appointment. 
As this is a new biologic treatment, patients will be expected to attend a hospital appointment every 2 
or every 4 weeks for subsequent treatments.  The frequency of these visits is dependent on the biologic 
treatment that is prescribed. 
In total there are five questionnaires.  Participants will not be asked to complete all five at every visit.  At 
4, 8, 12 and 16 weeks participants will be asked to complete the Severe Asthma Questionnaire (SAQ) 
and the Global Rating of Change Questionnaire (GRCQ).  At sixteen weeks participants will be asked 
to complete the EQ-5D-5L again in addition to the SAQ and GRCQ. 
Once completed, the pseudonymised questionnaires will be scanned and sent to the Plymouth RA (JL) 
via NHSmail after each appointment. 
Demographic Information and clinic data from week 0 (baseline) will be entered into the Baseline CRF 
(Appendix 9).  Once completed, the Baseline CRF will then be scanned and sent to the Plymouth RA 
(JL) via NHSmail.  Data collection from appointments at 0, 4, 8, 12 and 16 weeks will be entered into 
the Follow-up CRF (appendix 13).  Once complete, the Follow-up CRF will be scanned and sent to the 
Plymouth RA (JL) via NHSmail.  

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Participant data from week 0 (baseline) will be added to the validation dataset.  This will be explained 
to the patient on the Patient Information Leaflet (Appendix 12).  
Copies of the questionnaires will also be placed in the patients’ medical file at the participating site. 
3.6 Analysis  
The SAQ  provides two scores, the SAQ score which is the mean of all 16 domain specific items, and 
the SAQ-global score which is a single item score based on the SAQ-Global, which itself is based on a 
Borg scale [21].  Borg scales use multiple quantifiers at empirically derived points along the scale with 
the aim of achieving a ratio scale.  In this analysis plan, the term SAQ will refer to both the SAQ score 
and the SAQ global score.  Separate analyses will be carried out on the SAQ score and SAQ-global.  
Several analyses will be carried to ensure that the MCID concept is fit for purpose.   
Data from 4, 8, 12 and 16 weeks will be compared to the data collected at week 0 (baseline), providing 
4 change scores per patient.  Patients can indicate any one of 5 levels of improvement in any of the four 
weeks, or, if there is no change or deterioration, up to 11 types of change.  If patients report the same 
level of global rating of change at each of the four time points (e.g., they record ‘a little better’ at week 4 
and ‘a little better at week 8), the average SAQ change score will be calculated for that patient.  This 
average will then be used as the SAQ change for that particular level of global rating of change.  This 
procedure is followed so that each patient can contribute just one value to the population average of the 
SAQ change score at any level of global change, and which, in the case of the level of ‘a little better’ is 
used to calculate the MCID.  We shall carry out three analyses to check on the validity of the MCID 
concept.  If the checks come out positive, then the existing method of calculating the MCID (i.e., as the 
change in the SAQ that maps on to the global rating of change criterion of ‘a little better) will be adopted. 
If the checks are negative – i.e., suggesting some revision to the way the MCID concept is employed – 
then we will adapt the methodology in accordance with our findings.  
What degree of change on the SAQ is associated with each of the 5 levels of improvement and 5 levels 
of deterioration on the global rating of change score? 
The mean, confidence intervals, and standard deviation of change of the SAQ will be calculated for each 
level of change in the GRCQ.  These means will then be plotted (change in SAQ on x axis, global change 
on y axis) to show the relationship between change and perceived change at different degrees of 
change.  These results should show that the change in the SAQ increases with increase in global change 
scores, and will be tested for by analysis of variance.  This analysis is needed to show that the MCID is 
specific to the level of change of ‘a little better’ or ‘a little worse’ rather than any other level of global 
rating of change.  The analysis will also check whether ‘a little better’ is equivalent in terms of ‘a little 
worse’ in terms of SAQ change. 
Is the MCID transitive– i.e., is the MCID independent of level of deficit of quality of life? 

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Patients will be allocated to quartiles based on severity of the SAQ score at week 0.  The mean, 
confidence intervals and standard deviation of change scores for change at ‘a little better’ will be 
calculated.  Analysis of variance will be calculated for the four quartiles to test of transitivity.  Effect size 
(eta) will be calculated.  This analysis is needed to show that the MCID level can be applied across the 
full range of deficit of quality of life. 
Are items in the SAQ equivalent with regard to the MCID – i.e., is change in all the 16 SAQ items 
equivalent in terms of their relationship with the global rating of change? 
To test for equivalence, change in each of the 16 items of the SAQ and the SAQ-global will be correlated 
against the global rating of change score.  These correlations will be examined and interpreted.  
Regression will be explored, but may be ruled out due to co-linearity.  This analysis is needed to show 
whether weighting of items is needed when calculating the MCID, or whether the MCID is based simply 
on the mean of all items. 
Demographic information analyses 
In addition, we will also test whether baseline characteristics are similar across the four quartile groups 
and investigate whether the change in SAQ is related to the collected demographic and clinical data. 
If the above show no problems with the existing methodology, then the MCID will be calculated from the 
average SAQ change for the rating of ‘a little better’.  That is, any patient who has provided a global 
rating of change of ‘little better’ will contribute an initial and final SAQ score to produce a SAQ difference 
score for each patient, and the average of the SAQ difference scores across patients will be then form 
the MCID.  If there are problems, then we shall modify the MCID, for example, having different values 
for different levels of quality of life deficit (see 2 above) or by using a weighting of items (see 3 above).  
4.0 Withdrawal Criteria for study programme 
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.  If the participant no longer 
meets the eligibility criteria, their data may be removed from the database.  The patient will be thanked 
for their time, and told not to expect to be asked to participate further. 
5.0 Data Management for study programme 
The study incorporates the following types of data, which will only be accessed by the research team: 
Quantitative data: Anonymised questionnaires, validating clinic data information; 
Routinely recorded clinic data and service use in the last 12 months; 
Recruitment data (proportions of uptake, completion and attrition). 
In accordance with the Data Protection Act (2018), UHPNT information governance 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.  
Each centre will be given a different participant number pre-fix to use (see the table below).  All data will 

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be password protected, stored securely and will only be accessible by researchers and authorised 
personnel from Plymouth University and UHPNT. 
Table of participant numbers 
Site 
Participant number pre-fixes 
Derriford Hospital 
1.xxx 
The Royal Brompton Hospital 
2.xxx 
University Hospital of South Manchester 
3.xxx 
Birmingham Heartlands Hospital 
4.xxx 
Royal Devon and Exeter Hospital 
5.xxx 
Anonymised electronic will be transferred to Plymouth University for analysis.  It will be transferred from 
UHPNT to UoP by NHS email. 
The sender will ensure that the NHS email encryption service is used.  The University uses a secure 
shared drive which the study team will use to store electronic data.  Printed anonymised data will be 
kept in project specific folders, stored in a locked cupboard in a locked room, under the responsibility of 
the Investigators. 
After coding, the source questionnaires will be added to the patients’ notes because they contain 
information which may be helpful to the clinical team.  Patients’ records are stored securely on UHPNT 
premises in accordance with UHPNT information security policy. 
A document linking research IDs with clinical identification numbers will be created and stored within 
each of the patients’ respective centres, anonymised data will be analysed by the SAQ team (RJ, MM, 
MH, JL and YW).  
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. 
5.1 Procedure for Accounting for Missing, Unused, and Spurious Data. 
Questionnaires where the completion rate is < 10% will be defined as invalid, but the level of invalid data 
will be used to inform the development of the questionnaire (for example, individual items with large 
amounts of missing data will be scrutinised closely and may be amended or excluded from the future 
drafts of the scale).  Data entry will be checked for 1 in 5 cases and more frequently if errors are found.  
5.2 Procedures for Reporting any Deviation(s) from the Original Statistical Plan 
Our study is not a trial.  However, 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 GCP. 

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5.3 Archiving 
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 5 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 5 years after the last participant’s final study visit. 
6.0 Regulatory Issues 
The Investigator will ensure that this study is conducted in full conformity with relevant regulations, the 
UK Policy Framework for Health and Social Care Research (2017) and in accordance with the principles 
of the Declaration of Helsinki. 
6.1 Ethics Approval 
The CI will obtain a positive opinion from a Health Research Authority (HRA) Research Ethics 
Committee (REC) for the study.  
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 NHS 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 investigator 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. 
6.2 Ethical Issues 
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 

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not there as clinicians, but as researchers.  Should any patient appear distressed as a result of 
completing the questionnaires, 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 PALS, which will appear on the Patient Invitation Letter.  
We appreciate the number of questionnaires patients are being asked to complete as part of the study 
and are keen to limit the burden of data collection.  There are 41 questions in the four questionnaires 
taken together for part 1 of the study.  Participants enrolled in part 2 of the study will not be asked to 
complete all five at their questionnaires at one occasion.  At most they will be asked to complete three 
questionnaires.  As part of their treatment for their asthma, patients on biologic treatments are asked to 
stay for at least 30 minutes following each injections so they can be monitored.  The questionnaires can 
be completed during this time.  This should take about 20 minutes.   
6.3 Confidentiality 
The Chief Investigator will preserve the confidentiality of participants taking part in the study and will 
comply with the Data Protection Act (2018).  Research teams at all sites will ensure that participants’ 
anonymity is maintained on all documents in compliance with national regulations.  A privacy notice 
explaining how patient research data is used will be included in the Participant Information Sheet. 
6.4 Indemnity 
This is an NHS-sponsored research study.  If an individual suffers negligent harm as a result of 
participating in the study, NHS indemnity covers NHS staff and those people responsible for conducting 
the trial who have honorary contracts with the relevant NHS Trust.  In the case of non-negligent harm, 
the NHS is unable to agree in advance to pay compensation, but an ex-gratia payment may be 
considered in the event of a claim. 
6.5 Sponsor 
The study Sponsor is University Hospitals Plymouth NHS Trust (UHPNT).  Selected sponsorship tasks 
will be formally delegated to the SAQ Team and study sites according to an agreed task allocation 
matrix. 
6.6 Monitoring, Audit & Inspection 
The study may be subject to monitoring by Universities Hospitals Plymouth NHS Trust under their 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 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 before forms are sent to the SAQ Team.  Data will be monitored centrally for quality and 
completeness by the SAQ Team and every effort will be made to recover data from incomplete forms 

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where possible.  The SAQ Team will oversee data tracking and data entry and initiate processes to 
resolve data queries where necessary.  The SAQ Team trial manager will devise a risk-based monitoring 
plan specific to the study which will include both central monitoring strategies and study site visits as 
appropriate. 
7.0 Study Management 
The CI will be responsible for the overall running of the trial and for the local conduct of the trial at the 
Plymouth site.  The PI at each of the other participating sites will be responsible for the conduct of the 
study at his/her trial site.  The sponsor will coordinate trial-related activities and assist with overall trial 
management, monitoring and production of progress reports. 
The roles and responsibilities of each member of the research team are as follows: 
Chief Investigator 
Matthew Masoli – clinical and difficult asthma advice, use of questionnaire in clinical practice lead for 
dissemination at conferences etc. 
Co-Investigators 
Michael Hyland – questionnaire design and adaptations, and translations 
Rupert Jones – study management and co-ordination, communications lead to GSK and wider 
communications strategy, advice on use of questionnaire in clinical practice, conference presentations 
Statistician 
Yinghui Wei 
Study coordinator 
Joseph Lanario 
The research group is further supported by the Research Development and Innovation team of 
Universities Hospitals Plymouth NHS Trust including governance, and logistic support.  
7.1 Study Management Group  
A Study Management Group (SMG) including the CI, SAQ Team, trial statistician and other personnel 
relevant to the study (e.g. clinicians,  patient and Sponsor representatives) will meet regularly (usually 
monthly) throughout the duration of the trial to monitor progress, resolve day-to-day problems, oversee 
development of study documentation, monitor participant recruitment and retention, assess data quality, 
review budgetary issues, discuss analysis, interpret study findings, draft reports and plan dissemination 
of results. 
8.0 Dissemination and Publication Policy 
A website for the Severe Asthma Questionnaire has been established, www.saq.org.uk.  This website 
includes various pages containing versions of the questionnaire, information about how the SAQ was 
developed, advice on use and scoring, publications, contact details and translation etc.  

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After publication, the study team will prepare a plain English summary of the study results which will be 
posted on a website and each PI will be notified.  As soon as practicable, patients at sites involved in 
the study will be informed of the results. 
A formal worldwide communications strategy will be developed to promote the use of the SAQ including 
submissions to the FDA and other regulatory bodies.  We will plan to ensure that key opinion leaders 
are well informed and will provide resources for promotion such as slide sets. 
9.0 Funding 
An unrestricted non promotional grant from GlaxoSmithKline 
10.0 Impact 
The proposed studies will produce the SAQ which will be validated furtherfor use in the UK: 
The educational value for clinicians of understanding the impact of severe asthma on patients.  The 
outputs of the research will demonstrate the differences in health issues for patients with mild-moderate 
asthma versus those with severe asthma.  This will allow clinicians to ensure that the specific problems 
faced by patients with severe asthma are identified and can then be addressed and help patients to be 
referred appropriately. 
In routine clinical practice in severe asthma services, having questionnaires to measure both the severe 
symptom burden and the burden of treatment will allow rational choices in the use of newer biological 
agents in severe asthma. 
The choices will better reflect the patients’ perspective.  As this is a multi-centre study, the new 
questionnaire will get significant exposure to a large number of key severe asthma specialists and this 
will help its dissemination and adoption in clinical practice. 
For research, especially in clinical trials of newer drugs, the questionnaire will allow better assessment 
of impacts which affect patients with severe asthma. 
The questionnaire is expected to be more responsive to change.  For example, if a drug allows a 
reduction in OCS exposure, the benefits can be more accurately measured particularly from a patient-
centred perspective.  In turn, if more accurate measurement of the burden of severe asthma and its 
treatment is performed in clinical trials, regulatory bodies such as NICE are better able to assess the 
true value of newer, but expensive, drugs (indeed, NICE has called for such measures to facilitate 
rational decisions on the use of relatively expensive therapies for patients who may benefit). 
While the initial emphasis of this research proposal has been in the United Kingdom, the questionnaires 
are applicable to patient populations around the world as the issues confronting patients with severe 
asthma are similar.  Where they can be afforded, novel biological agents may be used extensively 
globally.  The questionnaires will help to identify those people who are likely to benefit from steroid 
sparing medications and measure the impact such medicines have on improving patient-related 

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outcomes.  Given the enormous burden of severe asthma, it is imperative that the right measures are 
available to assess treatments for this group of patients. 
 
 

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11.0 References 
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http://www.globalasthmareport.org/resources/Global_Asthma_Report_2014.pdf  
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2. Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, 
evaluation and treatment of severe asthma. European Respiratory Journal 2014;43:343–373 
3. Judd LL, Schettler PJ, Brown ES, et al. Adverse consequences of glucocorticoid medication: 
psychological, cognitive, and behavioral effects. American Journal of Psychiatry 2014; 
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4. Hyland ME, Whalley B, Halpin D, et al. Frequency of non-asthma GP visits predicts asthma 
exacerbations: an observational study in general practice. Primary Care Respiratory Journal: 
journal of the General Practice Airways Group 2012;21(4):405-11. 
5. Gamble J, Stevenson M, McClean E, et al. The prevalence of nonadherence in difficult asthma. 
American Journal of Respiratory and Critical Care Medicine 2009;180:817-22. 
6. Osman LM, Hyland ME. Adherence and self management. Evidence-based Respiratory 
Medicine 2005:91. 
7. Cooper V, Metcalf L, Versnel J, et al. Patient-reported side effects, concerns and adherence to 
corticosteroid treatment for asthma, and comparison with physician estimates of side-effect 
prevalence: a UK-wide, cross-sectional study. NPJ Primary Care Respiratory Medicine 
2015;25:15026. 
8. Hyland ME, Whalley B, Jones RC, et al. A qualitative study of the impact of severe asthma and 
its treatment showing that treatment burden is neglected in existing asthma assessment 
scales. Quality of Life Research 2015;24:631-39. 
9. Hyland ME, Lanario JW, Pooler J, Masoli M, Jones RC. How patient participation was used to 
develop a questionnaire that is fit for purpose for assessing quality of life in severe asthma. 
Health and quality of life outcomes. 2018; 16(1):24.  
10. Hyland ME, Jones RC, Lanario JW, Masoli M. The construction and validation of the Severe 
Asthma Questionnaire (SAQ). Eur Respir J 2018 in press  
11. National Institute for Health and Clinical Excellence. Omalizumab for treating severe persistent 
allergic asthma. Technology Appraisal Guidance, 2013. 
12. U.S. Department of Health and Human Services Food and Drug Administration. Guidance for 
Industry Patient-Reported Outcome Measures: Use in Medical Product Development to 
Support Labeling Claims. 2000 
13. Hyland ME, Jones RC, Lanario JW, Masoli M. The construction and validation of the Severe 
Asthma Questionnaire (SAQ). European Respiratory Journal. 2018 Jan 1:1800618. 
14. Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new five-level 
version of EQ-5D (EQ-5D-5L). Qual Life Res 2011; 20: 1727–1736. 
15. Juniper E, Guyatt G, Cox F, et al. Development and validation of the mini asthma quality of life 
questionnaire. European Respiratory Journal 1999;14(1):32-38. 
16. Nathan RA, Sorkness CA, Kosinski M, et al. Development of the asthma control test: a survey 
for assessing asthma control. Journal of Allergy and Clinical Immunology 2004;113(1):59-65. 
17. Juniper EF, O’Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a 
questionnaire to measure asthma control. Eur Respir J 1999; 14: 902-7 
18. Costello AB, Osborne JW. Best practices in exploratory factor analysis: Four recommendations 
for getting the most from your analysis. Practical assessment, research & evaluation 2005; 
10(7):1-9. 

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19. Osborne JW. Best practices in exploratory factor analysis. CreateSpace Independent 
Publishing Platform; 2014. 
20. Kamper, S.J., Maher, C.G. and Mackay, G., 2009. Global rating of change scales: a review of 
strengths and weaknesses and considerations for design. Journal of Manual & Manipulative 
Therapy, 17(3), pp.163-170. 
21. Borg, G. A. Psychophysical bases of perceived exertion. Med Sci Sports & Exerc; 14(5): 377-
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