Clinical trial NCT03999203
Conditions: Asthma Cough
Sponsor: Queen's University, Belfast
Start date: 2017-10-04; Completion date: 2019-12-30
Enrollment: 61 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This study aims to characterise cough in severe asthma through an observational cross-sectional analysis of patients stratified by inflammatory biomarker profile using a number of subjective and objective cough measurement tools.

Detailed description:
This study will use a combination of subjective and objective cough measures to assess the frequency of cough as well as its related morbidity in severe asthmatics. Comparisons will be made between T2-High, T2-Low and T2-intermediate patients defined using a composite biomarker profile (blood eosinophil count and FeNO) to assess the role of cough in each and these results will be compared to the transcriptomic and proteomic measurements in the RASP-UK where the same biomarker profiling is being used to define clinical sub-groups of severe asthma. This study aims to also improve characterisation of the T2-Low population and identify possible mechanisms for the pathophysiology of this group.

60 patients are expected to be recruited to the study. Patients will be provided with an information sheet and have a telephone follow-up after at least 24 hours to ask if they remain interested in participation and if so, they will then be asked back for a baseline visit.

Three groups of severe asthmatics will be recruited (as described in appropriate section) and undergo the following procedures:

* Demographic details, height, weight, spirometry, FeNO and vital signs
* Patient reported outcomes:

  * Asthma Mini-Asthma Quality of Life Questionnaire (mini-AQLQ) - abbreviated version of Juniper AQLQ
  * Asthma Control Questionnaire (ACQ-5 (5 questions);
  * Leicester Cough Questionnaire, the Cough-specific quality-of-life Questionnaire and Cough Hypersensitivity Questionnaire will be used to assess the impact of cough;
  * Visual analogue scales (VAS) for cough (VASc) and urge to cough (VASu) will be used as a measure of cough severity.
* Blood samples - a sample of blood will be taken for whole blood transcriptomic and serum analyses
* Citric acid cough challenge test will be used to measure cough reflex sensitivity in each phenotype.
* Spontaneous sputum sample - if patients produce a sputum sample during spirometry or citric acid challenge, this will be recorded and the sample will be retained for sputum differential cell count and storage of processed soluble components.
* On completing the above procedures, patients will be asked to wear a validated ambulatory cough monitor (Leicester Cough Monitor) for a 24-hour period to assess the frequency of cough and if they agree, will be fully instructed in its use.

Patients will be asked to attend a follow-up visit 2 weeks after baseline. The study procedures will remain the same as visit 1 with the exception of collection of clinical samples.

A mild/moderate population will be recruited and undergo the same procedures as the severe group in a baseline visit. No mild/moderate asthmatics will be asked to attend for a follow-up visit.

Arms: arm 1: Severe asthmatic patients with eosinophil count ≥ 0.15x10\^9/mL andhigh FeNO levels ≥20 ppb.

Interventions include 24 hour ambulatory cough monitoring (Leicester Cough Monitor), citric acid cough challenge, fractional exhaled nitric oxide (FeNO) testing, patient reported outcome measures and blood, urine and sputum sampling arm 2: Severe asthmatic patients with eosinophil count ≤ 0.15x10\^9/mL and low FeNO levels \<20 ppb.

Interventions include 24 hour ambulatory cough monitoring (Leicester Cough Monitor), citric acid cough challenge, fractional exhaled nitric oxide (FeNO) testing, patient reported outcome measures and blood, urine and sputum sampling arm 3: mild/moderate severe asthmatics (defined as step 2/3 using the GINA classification of severity) recruited from general respiratory clinics in the Belfast HSC Trust Interventions include 24 hour ambulatory cough monitoring (Leicester Cough Monitor), citric acid cough challenge, fractional exhaled nitric oxide (FeNO) testing, patient reported outcome measures and blood, urine and sputum sampling arm 4: Severe asthmatic patients with eosinophil count ≥ 0.15x10\^9/mL OR high FeNO levels ≥20 ppb.

Interventions include 24 hour ambulatory cough monitoring (Leicester Cough Monitor), citric acid cough challenge, fractional exhaled nitric oxide (FeNO) testing, patient reported outcome measures and blood, urine and sputum sampling
Interventions: intervention 1: Citric acid intervention 2: Leicester Cough monitor intervention 3: fractional exhaled nitric oxide testing (FeNO) intervention 4: Patient reported outcome measures
Intervention descriptions: intervention 1: Citric Acid cough challenge to be administered to assess the cough reflex sensitivity in patients intervention 2: Ambulatory cough monitor to assess cough frequency over a 24 hour period intervention 3: Measurement of exhaled nitric oxide to give an indication of airway inflammation intervention 4: A number a patient reported outcome measures will be administered including: Asthma control questionnaire (ACQ-5), mini Asthma Quality of Life Questionnaire (mini AQLQ), Leicester Cough Questionnaire (LCQ), Cough Quality of Life Questionnaire (CQLQ), Cough Hypersensitivity Questionnaire (CHQ) and visual analogue scales for severity og cough (VASc) and Urge to Cough (VASu)

Protocol documents:
Prot_SAP_001.pdf: 
Page 1 
 
 
 
CLINICAL STUDY PROTOCOL 
 
 
A  CROSS-SECTIONAL STUDY TO MEASURE COUGH IN 
SEVERE ASTHMA. 
 
Sponsors:  
Queen’s University Belfast 
Version of Protocol: 
11 
Date of Protocol: 
12/12/2018 
 


Page 2 
 
 
 
Protocol Approval – Principal/Coordinating Investigator 
 
Study Title            
  
A cross-sectional study to measure cough in severe asthma 
Protocol Number 
11 
Protocol Date 
12/12/2018 
 
 
 
Principal Investigator  
Professor Liam G Heaney 
Professor of Respiratory Medicine 
 
School of Medicine, Dentistry and Biomedical Sciences, Queen's University 
Belfast Address: Centre for Experimental Medicine, 97 Lisburn Road Belfast, 
Northern Ireland. BT9 7BL 
 
Telephone: 028 9097 5850 
Email: l.heaney@qub.ac.uk 


Page 3 
 
 
Abbreviations 
 
 
Abbreviation 
Definition 
ACQ 
Asthma Control Questionnaire 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATS 
American Thoracic Society 
BMI 
body mass index 
BTS 
British Thoracic Society 
CCL 
chemokine ligand 
CQLQ 
Cough specific quality of life questionnaire 
CT 
computed tomography 
CRF 
case report form 
ERS 
European Respiratory Society 
FAS 
Full-analysis set 
FeNO 
fractional exhaled nitrous oxide 
FEV1 
forced expiratory volume in 1 second 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
GINA 
Global Initiative for Asthma 
ICF 
informed consent form 
ICS 
inhaled corticosteroids 
LCM 
Leicester Cough Monitor 
LCQ 
Leicester Cough Questionnaire 
MiniAQLQ 
Mini asthma quality of life questionnaire 
EC 
Ethics committee 
Ig 
immunoglobulin 
IL 
interleukin 
LABAs 
long-acting β-2 agonists 
OCS 
oral corticosteroids 
OTC 
over the counter 
PRO 
patient-reported outcome 
SABAs 
short-acting β-2 agonists 
SAP 
Statistical analysis plan 
T2 
Type-2 eosinophilic inflammation 
TB 
tuberculosis 
 
 
 


Page 4 
 
 
1.0     Background 
1.1 Cough and Asthma 
Asthma is a respiratory disease that affects 1-18% of the worldwide population. It is 
characterised by a collection of symptoms which include shortness of breath, chest 
tightness, wheeze and cough and by variable expiratory airflow limitation. These usually 
tend to vary over time and in intensity and can be triggered by a range of stimuli.(1) The 
condition is typically recognised as one that consists of periodic exacerbations coupled 
with chronic inflammation of the airways with or without structural airway changes. This 
may also be associated with persistent symptoms and a reduced lung function.(2)  
Asthma has been traditionally ‘stratified’ on the basis of response to ‘step-wise’ incremental 
treatment with inhaled corticosteroid (ICS) therapy forming the cornerstone of this approach 
(1,3). However, more recently, asthma has been stratified on the basis of inflammatory 
phenotype to better understand disease heterogeneity with a view to developing biomarkers 
of therapeutic response and for the better targeting of both new and existing treatments (4,5). 
Using sputum analysis (5,6), and more recently whole genome expression profiling (4), it is 
clear that even in mild steroid-naive asthma, approximately 50% of patients do not have a 
typical Type 2 (T2)-driven eosinophilic inflammation, and are called ‘T2-low asthma’. Perhaps 
more significantly, based on the normal diagnostic criteria for asthma, this T2 low group is 
indistinguishable from the typical ‘T2-high’/eosinophilic group. In the context of therapeutic 
response, the T2-low patients have a minimal response to ICS therapy (5,6). In severe 
disease, the T2-low profile is also prevalent (7,8), and in case series of difficult-to-treat 
patients with asthma, there is evidence that inappropriate escalation of corticosteroid 
treatment is frequent, with significant morbidity due to systemic corticosteroid exposure (9-
11). The RASP-UK programme is exploiting the use of composite biomarkers of T2 biology to 
define patient sub-groups using easily measurable biomarkers (blood eosinophil count, 
fractional exhaled nitric oxide (FeNO) and serum periostin) (http://www.rasp.org.uk/) 
 
Despite its troublesome occurrence in disease, cough is important in normal human 
health in maintenance of the respiratory system. Its role in removal of foreign material 
and in enhancing mucociliary clearance helps to protect the airways when stimulated by 
extrinsic factors or in the presence of disease.(12) Cough becomes disordered in asthma 
and is thought to be due to the associated inflammation in the lungs, which causes 
sensitisation of cough reflexes and can lead to upsetting attacks of cough due to minimal 
stimulation or changes in the environment.(13) 
 
Cough is one of the main reported symptoms in asthma. Although symptoms such as 
wheeze and shortness of breath may be more prevalent in the condition, cough in 
asthmatic patients is often described as the most problematic.(14) It is therefore 
surprising that although there are a number of tools available to aid in management of 
cough (15), there has been little consideration given to the assessment how severe a 
patient’s cough is in asthma.  
 
When a patient’s cough is poorly controlled, it tends to drive escalation of corticosteroid 
therapy. This is not always appropriate and often fails to achieve adequate disease 
control and often unnecessarily exposes patients to the unacceptable side effects of high 
dose corticosteroid therapy. A novel approach has been developed to manage patients 


Page 5 
 
 
and their treatment based on individual inflammatory biomarker profiles. Only half of 
patients with asthma have typical eosinophilic airway inflammation driven by ’Type 2’ 
cytokines (interleukin IL-4, IL-5 and IL-13). In severe asthma, this proportion drops to 
between 25-50%. For the remainder of patients there is little evidence that T2 cytokines 
play a major role in their condition and so respond less well to steroid therapy. These 
patients have been termed ‘T2-Low’.  
 
Therefore, it is important to accurately define how cough is related to the clinical and 
biological phenotypes in asthma. 
 
 
1.2 Study Rationale  
 
We hypothesise that cough represents a significant burden in severe asthma which can be 
defined using subjective and objective cough measures. It is also hypothesised that cough 
morbidity is over-represented in the T2-low severe asthma population and this may represent 
mechanistic pathways that are suitable for exploitation for novel anti-tussive drug discovery. 
 
This study will use a combination of subjective and objective cough measures to assess 
the frequency of cough as well as its related morbidity in severe asthmatics. Comparisons 
will be made between T2-High, T2-Low and T2-intermediate patients defined using a 
composite biomarker profile (blood eosinophil count and FeNO) to assess the role of 
cough in each and these results will be compared to the transcriptomic and proteomic 
measurements in the RASP-UK where the same biomarker profiling is being used to 
define clinical sub-groups of severe asthma. This study aims to also improve 
characterisation of the T2-Low population and identify possible mechanisms for the 
pathophysiology of this group. 
 
A population of patients will be assessed after screening at a single visit to enable the 
summary of clinical characteristics and allow these data to be related to the biomarkers 
measured in serum, plasma and sputum. 
 
Four patient groups will be investigated in the study and will be defined as follows: 
 
Group A 
T2-High Severe Asthmatics 
- 
Persistent blood eosinophil count ≥0.3x109/mL and 
- 
Persistent high FeNO levels ≥30 ppb) and 
- 
Adherence to inhaled and oral corticosteroid therapy 
Group B 
T2-Low Severe Asthmatics 
- 
Persistent blood eosinophil count ≤0.2x109/Ml and 
- 
Persistent low FeNO levels (<30ppb) 
These measurements are undertaken routinely at each clinic visit at the Difficult Asthma 
Service in Belfast HSC Trust. 
 
 


Page 6 
 
 
Group C 
Mild/moderate Asthmatics 
- 
mild/moderate severe asthmatics (defined as step 2/3 using the GINA classification of 
severity) recruited from general respiratory clinics in the Belfast HSC Trust 
Group D 
T2 – intermediate 
- Persistent blood eosinophil count ≥ 0.3x109/mL OR 
- Persistent FeNO levels ≥ 30 ppb 
 
 
We believe that these patient groups will show differences in their cough frequency and 
severity and this novel research may provide information that will help to further characterize 
these phenotypes in the future. We believe that cough as a symptom in asthma is 
independent of Type-2 inflammation pathways and so further research into this symptom may 
help to uncover alternative pathways driving the condition. We aim to understand cough in 
relation to specific biomarkers in this population and how differences in cough frequency and 
severity relates to them. It is important to understand the nature of cough in these patients 
and how it changes in response to treatment.  
 
 
2.0     Objectives 
2.1 Primary Objectives 
The primary objectives for this study are as follows: 
 
 To objectively measure cough frequency in different phenotypes of severe asthma 
(T2-high, T2-low and T2-intermediate) and a mild/moderate asthma control group 
using a validated ambulatory cough monitor (Leicester Cough Monitor) 
 
 To objectively measure cough reflex sensitivity in different phenotypes of severe 
asthma and a mild/moderate asthma control group using citric acid cough 
challenge testing  
 
 To subjectively measure cough severity and quality of life in different phenotypes of 
severe asthma and a mild/moderate asthma control group using the Leicester 
cough questionnaire (LCQ), Cough Quality of life Questionnaire (CQLQ) and visual 
analogue scales 
 
 
2.2  Exploratory Objectives 
The exploratory objectives for this study are as follows: 
 
 To determine the relationship between objective and subjective measures of cough 
and established biomarkers of asthma severity and symptom control including sputum 
eosinophils (as defined by % eosinophils), blood eosinophil count, FeNO (ppb), lung 


Page 7 
 
 
function (FEV1), and Asthma Control Questionnaire (ACQ-5). 
 Exploratory analysis will be undertaken to determine the relationship between the 
objective and subjective cough measures, biomarker profile and transcriptomic and 
proteomic measurements in blood and urine samples from severe asthma patients 
using learning from the RASP-UK programme in relevant stored samples. 
 Reproducibility of objective and subjective measures of cough in a severe asthma 
population will also be explored. 
 
2.3  Description of Study 
This is a cross-sectional study, in patients aged 18 to 75 years (inclusive), with severe 
asthma, as defined by the GINA step 4/5 classification of asthma severity (1). Prior to 
screening, patients will have been assessed using a systematic protocol to exclude other 
causes of apparently uncontrolled asthma (16). It is expected that approximately 60 patients 
will be enrolled at the study centre. Following review after clinical attendance, patients will 
be invited to take part in the study and attend for a screening visit. Patients will be provided 
with an information sheet and have a telephone follow-up after at least 24 hours to ask if 
they remain interested in participation and if so, they will then be asked back for a baseline 
visit. 
 
 
3.0     Patient and Methods 
3.1 Patients with severe asthma (Groups A, B and D) 
The study will recruit patients aged 18 to 75 years, inclusive, with severe OCS-
dependent asthma (GINA step 5 classification of asthma severity). 
 
 
3.1.1 Inclusion Criteria 
Patients must meet the following criteria for study entry: 
 
1. Ability and willingness to comply with the study procedures 
2. Age ≥18 to ≤75 years at the time of informed consent 
3. Severe asthma (as defined by GINA step 4/5 classification of asthma severity) after 
a detailed systematic assessment 
4. History of asthma treatment with high doses of ICS (≥1000 µg beclomethasone 
dipropionate daily, or equivalent) and an additional controller 
 
5. Three patient groups with severe asthma will be investigated in the study and will be 
defined as follows: 
 
 
T2-High Severe Asthmatics (Group A) 
- 
Persistent blood eosinophil count ≥0.3x109/mL and 
- 
Persistent high FeNO levels ≥30 ppb and 


Page 8 
 
 
- 
Adherence to inhaled and oral corticosteroid therapy 
T2-Low Severe Asthmatics (Group B) 
- 
Persistent blood eosinophil count ≤0.2x109/Ml and 
- 
Persistent low FeNO levels (<30ppb) 
T2 – Intermediate Severe Asthmatics (Group D) 
- Persistent blood eosinophil count ≥ 0.3x109/mL OR 
- Persistent FeNO levels ≥ 30 ppb 
 
 
As stated above, these measurements are made at each clinic visit as part of routine care 
and will be available on all subjects prior to Inclusion 
6. A chest x-ray or CT scan obtained within 12 months before the time of informed 
consent and showing no new pathology requiring investigation as a potential cause 
for their cough 
 
 
3.1.2 Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
 
1. Baseline FEV1 ≤50% of predicted or ≤ 1.0L 
2. Asthma exacerbation within 28 days before the time of informed consent or during 
Screening 
3. Major episode of infection requiring any of the following: 
 
Admission to hospital for ≥24 hours within the 28 days before the time of 
informed consent  
 
Treatment with intravenous antibiotics within the 28 days before the time of 
informed consent or during Screening 
 
Treatment with oral antibiotics within the 14 days before the time of 
informed consent or during Screening 
4. For adults: Active tuberculosis (TB) requiring treatment within the 12 months 
before the time of informed consent (patients are also required to have no 
recurrence of symptoms in the 12 months following completion of TB treatment), 
or 
5. Known history of severe clinically significant immunodeficiency, including, but 
not limited to, human immunodeficiency virus infection and/or currently receiving 
or have historically received intravenous Ig for treatment for immunodeficiency 
Note: Immunodeficiency encompasses a wide spectrum of human conditions 
and/or diseases. A relative IgG deficiency that is thought, but not proven, to be a 
feature of severe asthma would not be exclusionary for the study.  
6. Diagnosis or history of malignancy, or current investigation for possible 
malignancy 
7. Other clinically significant medical disease that is uncontrolled despite 


Page 9 
 
 
treatment or that is likely, in the opinion of the investigator, to require a 
change in therapy or affect the ability to participate in the study


Page 10 
 
 
 
 
8. History of alcohol, drug, or chemical abuse that would impair or risk the 
patient’s full participation in the study, in the opinion of the investigator 
9. Current smoker or former smoker with a smoking history of >15 pack-years 
A current smoker is defined as someone who has smoked one or more 
cigarettes per day (or marijuana or pipe or cigar) for ≥30 days within the 
24 months before the time of informed consent and for whom cotinine testing is 
positive. 
A former smoker is defined as someone who has smoked one or more cigarettes 
per day (or marijuana or pipe or cigar) for ≥30 days in his or her lifetime (as long as 
the 30-day total did not include the 24 months before the time of informed consent) 
and for whom cotinine testing is negative. 
A pack-year is defined as the average number of packs per day times the 
number of years of smoking. 
10. Initiation of or change in allergen immunotherapy within three months before the 
time of informed consent 
11. Treatment with an investigational agent within 30 days of informed consent or 5 
half-lives of the investigational agent, whichever is longer 
12. Female patients who are pregnant or lactating 
 
 
3.2 Control Population (Group C) 
Mild/moderate severe asthmatics (who have received a diagnosis of asthma from a physician 
and are defined as step 2/3 using the BTS/SIGN classification of severity and ACQ<1.5) aged 
18-75 years inclusive will be recruited from general respiratory clinics in the Belfast HSC 
Trust. Patients must have the ability and willingness to comply with study procedures.  
 
Patients within this population will also be recruited through selected General Practice 
surgeries. Patients attending general asthma review clinics within their surgery will be 
approached by practice nurses and informed about the study and given the appropriate study 
information (patient information sheet, invitation letter from GP surgery etc). Patients may 
then contact the study coordinator if interested in taking part in the study.  
 
Exclusion criteria for this group is as detailed in section 3.1.2.  
 
3.3 Study Assessments 
3.3.1 Baseline study visit 
Following written informed consent participants will undergo the following baseline 
study procedures: 
- 
Demographic details, height, weight, spirometry, FeNO and vital signs 


Page 11 
 
 
- 
Patient reported outcomes: 
o Asthma Mini-Asthma Quality of Life Questionnaire (mini-AQLQ) - 
abbreviated version of Juniper AQLQ 
o Asthma Control Questionnaire (ACQ-5 (5 questions); 
o Leicester Cough Questionnaire, the Cough-specific quality-of-life 
Questionnaire and Cough Hypersensitivity Questionnaire will be used to 
assess the impact of cough; 
o Visual analogue scales (VAS) for cough (VASc) and urge to cough 
(VASu) will be used as a measure of cough severity. 
 
- 
Blood samples – a sample of blood will be taken for whole blood 
transcriptomic and serum analyses (see section 4.3.6.1 below) 
- 
Citric acid cough challenge test will be used to measure cough reflex 
sensitivity in each phenotype. 
- 
Spontaneous sputum sample - if patients produce a sputum sample during 
spirometry or citric acid challenge, this will be recorded and the sample will be 
retained for sputum differential cell count and storage of processed soluble 
components. 
- 
On completing the above procedures, patients will be asked to wear a 
validated ambulatory cough monitor (Leicester Cough Monitor) for a 24-hour 
period to assess the frequency of cough and if they agree, will be fully 
instructed in its use. 
 
All assessments to be performed during the study are summarised in Table 3.1. 
 
3.3.2 Follow-up visit 
The follow-up visit will be performed 2 weeks after the baseline visit and is to assess 
reproducibility of cough measurements (objective and subjective) in this patient group. 
The following procedure will be performed: 
- 
FeNO 
- 
Patient reported outcomes: 
o Asthma Mini-Asthma Quality of Life Questionnaire (mini-AQLQ) - 
abbreviated version of Juniper AQLQ 
o Asthma Control Questionnaire (ACQ-5 (5 questions 1 minute); 
o Leicester Cough Questionnaire, Cough-specific quality-of-life 
Questionnaire and Cough Hypersensitivity Questionnaire will be used to 
assess the impact of cough; 
o Visual analogue scales (VAS) for cough (VASc) and urge to cough 
(VASu) will be used as a measure of cough severity. 
- 
Citric acid cough challenge test will be used to measure cough reflex 


Page 12 
 
 
sensitivity in each phenotype. 
On completing the above procedures, patients will be asked to wear a validated 
ambulatory cough monitor (Leicester Cough Monitor) for a 24-hour period to assess 
the frequency of cough and if they agree, will be fully instructed in its use. 
All assessments to be performed during the study are summarised in Table 1. 
 
            Table 1 Schedule of Assessments 
 
 
Visit 1a 
(N=60) 
Visit 2 
(N=25) 
 
DAY 
 
0 
15 
Informed consent 
X 
 
Patient eligibility (inclusion/exclusion criteria) 
X 
 
Demographic data 
X 
 
General medical history and baseline conditions 
X 
 
Weight 
X 
 
Height 
X 
 
AE assessments 
X 
X 
Pregnancy test b, where appropriate 
X 
 
Concomitant medications 
X 
 
Patient-reported outcomes 
ACQ-5 
Mini AQLQ 
LCQ 
CQLQ 
VASc and VASu 
Cough Hypersensitivity Questionnaire 
  
X 
X 
X 
X 
X 
X 
  
X 
X 
X 
X 
X 
X 
Objective measurements 
FeNO 
Cough Frequency (LCM) 
Citric acid cough challenge 
  
X 
X 
X 
  
X 
X 
X 
Physical Examination 
X 
 
Vital sign measurements 
X 
 
Serum for periostin 
X 
 
Serum for biomarkerc 
X 
 
Plasma for biomarkerd 
X 
 
Heamatology (blood eosinophil and neutrophil 
count) 
X 
 
Serum Chemistry 
X 
 
Urine Sample 
X 
 
Plasma and serum sample for storage  
X 
 
Spontaneous sputum sample 
X 
 
 


Page 13 
 
 
a Baseline visit should not take place on a Friday 
b After informed consent 
c including but not limited to asthma related biomarkers described in the body of the 
protocol i.e. CCL13, CCL17, CCL18, IgE, IL17A) 
dAsthma related biomarkers that cannot be measured in serum or are better 
measured in plasma (eg CXCL13, CXCL1) 
 
3.4 Medical History, Concomitant Medications and Demographic Data 
Medical history is defined as clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), smoking history, and use of alcohol 
and drugs of abuse within the past year. All medications (e.g. prescription drugs, over-
the-counter (OTC) drugs, herbal/homeopathic remedies, nutritional supplements) 
used by the patient within 90 days before the screening visit will be recorded as part of 
the patient’s medical history. Medical history will include specific information pertaining 
to diseases commonly associated with asthma such as but not limited to the following: 
allergic rhinitis, atopic dermatitis, type 2 diabetes mellitus, arthritis osteoporosis, and 
heart disease. Demographic data will include age (date of birth), sex, and self-
reported race/ethnicity. 
 
3.4.1 Vital Signs 
Vital signs will include measurements of oral body temperature, respiratory rate, pulse rate, 
and systolic and diastolic blood pressure while the patient is in a seated position having 
rested for approximately 10 minutes before measurements are performed. All 
measurements completed with standard clinical procedures. Vital signs will be measured at 
the time points shown in Table 3.1. 
 
3.4.2 Physical Examinations 
A complete physical examination at Screening and Visit 1 will include, but is not necessarily 
limited to, the following: an evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, and 
neurological systems. Any abnormality identified during screening should be recorded on 
the general medical history and baseline conditions page in a paper CRF which will then be 
transferred onto a study database. 
 
3.4.3 Height and Weight Measurements 
Height and weight measurements will be recorded at the time points shown in Table 4–1. 
Patients will be asked to remove their shoes and coats before measurements are taken. 
 
 
 


Page 14 
 
 
3.5 Asthma-Related Assessments 
 
3.5.1 Spirometry 
Spirometry, including the procedure for bronchodilator testing, will be conducted as per the 
BTS registry standards and according to the ATS/European Respiratory Society (ERS) 
Consensus Statement (Clausen and Wanger 2003). Spirometric measurements to be 
collected will include FEV1 and FVC values (volume, L) and peak expiratory flow values 
(L/min) in addition to the flow-volume and volume-time curves. The percent-predicted FEV1 
and FVC will be derived from these volume measurements using the equations derived from 
the National Health and Nutrition Examination Survey data set (Hankinson et al 1999). 
 
3.5.2 Fractional Exhaled Nitric Oxide 
Measurement of FeNO will be performed with a standard device in accordance with 
guidelines published by the ATS. Patients will be assessed with the same system at each 
visit. 
 
3.5.3 Spontaneous Sputum 
Sputum induction will be performed according to the individual routine protocol at the study 
centre. The following is a description of the procedure; the patient will have an FEV1 
measurement as per ATS guidelines (this will be the Baseline measurement). All patients will 
be asked to blow their noses and rinse their mouths thoroughly prior to being asked to cough 
into a sputum jar. If spontaneous expectoration results in a good quality sputum sample, the 
procedure is considered complete. Inability to provide a spontaneous sputum sample is not 
an exclusion criterion. Sputum will be processed (ideally within 1 hour) according to standard 
procedures as described in the study manual provided and a differential count will be 
obtained.  
 
3.5.4 Laboratory Assessments 
Laboratory assessments will be completed at the time points shown in Table 4–1.  
 
3.5.4.1 Blood Sample 
A blood sample will be taken on study visit 1 for exploration of the biomarkers listed below. A 
total of 70ml (approximately 4 tablespoons) of blood will be taken at study visit 1 and will not 
be repeated at any follow up visit. These samples will be stored for a maximum of 10 years 
after all study data has been collected and may be used in the future for more research 
related to asthma. The data resulting from the stored samples will be kept confidential. 
 
3.5.4.2 
Samples for Biomarkers 
The following dynamic biomarker specimens will be collected for exploration of biomarkers. 
These biomarkers can include, but are not limited to, biomarkers related to asthma, IL13, 
periostin, eosinophilic airway inflammation, corticosteroid signaling and putative inflammatory 
pathways in severe steroid dependent asthma and cough hypersensitivity 


Page 15 
 
 
 
Serum (e.g. CCL-13, CCL-17, CCL-18, IgE, IL 17A) 
 
Plasma (e.g. CXCL1), serum Interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF)-
alpha, IL-8, 
 
neurotrophins e.g. brain derived neurotrophic factor (BDNF), nerve growth factor 
(NGF)  (e.g. BDGF, NGF) 
 
sputum Interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF)-alpha, IL-8, and  
 
Samples will be transferred to Queen's University Belfast under the standard BSHCT MTA. 
Specimens will be taken and stored in line with the authorised use of specimens as 
specified in this protocol and in the informed consent form. 
  
Samples will be destroyed no later than 10 years after the date of final closure of the 
associated clinical database. The storage period will be in accordance with applicable laws 
(e.g., health authority requirements). 
 
3.5.5 Objective Cough Measurement 
Cough frequency will be measured in patients using a validated ambulatory cough frequency 
monitor. This will allow comparisons of cough frequency to be made between different asthma 
phenotypes based on objective measurements. The monitor will be distributed to patients 
following other study assessments and patients will be asked to wear the monitor for a set 
period of time in order to gather the relevant data. 
 
3.5.5.1 Leicester Cough Monitor (LCM) 
The LCM is a validated ambulatory cough frequency monitor that will allow the measurement 
of cough frequency in distinct asthma phenotypes over a period of 24-hours. Distribution of 
the LCM will take place as per the schedule of assessments (Table 4–1). 
 
3.5.5.2 Citric Acid Cough Challenge 
The Citric Acid Cough Challenge will be used to assess the cough reflex sensitivity in each 
phenotype and will be performed as per the study centre’s protocol. The cough challenge will 
take place as per the schedule of assessments (Table 4–1). 
 
3.5.6 Patient-Reported Outcomes 
Patient-reported outcome (PRO) data will be requested from the patients to assess the level 
of asthma control and the impact of cough. The PRO instruments, translated as required in 
the patient’s primary language, will be distributed by the asthma study staff and completed 
in their entirety by the patient. To ensure instrument validity and that data standards meet 
health authority requirements, PRO questionnaires should be self-administered at the study 
before the completion of other study assessments. 
 
3.5.6.1 Mini Asthma Quality of Life Questionnaire 
The mini-AQLQ (Appendix 8.1) will be used to assess the patients’ asthma-
specific health-related quality of life (Juniper et al 2005). The 


Page 16 
 
 
questionnaire contains four domains: activity limitations, symptoms, emotional function, and 
environmental stimuli. The mini-AQLQ has been validated for use in this study population and 
has a recall specification of 2 weeks. The mini-AQLQ will be administered to the patient 
before all other non-PRO assessments and before the patient receives any disease-status 
information during that assessment. The mini-AQLQ will be completed as per the schedule of 
assessments (Table 4–1). 
 
 
3.5.6.2 Asthma Control Questionnaire - 5 
Asthma control will be measured by the ACQ-5 (Appendix 8.2) (Juniper et al 1999).This 
is a fully validated measurement tool that can detect small differences between patients 
with different levels of asthma control. The ACQ-5 will be completed before the Mini-
AQLQ 
 
3.5.6.3 Leicester Cough Questionnaire (LCQ) 
The Leicester Cough Questionnaire (Appendix 8.3) is a valid, repeatable 19 item self-
completed QOL measure of chronic cough that is responsive to change. This tool assesses 
cough related QOL in three domains: Physical, Psychological and Social. This will allow for 
the measurement of QOL in relation to cough and for comparisons to be made between 
asthma phenotypes. The LCQ will be administered to the patient before all other non-PRO 
assessments and before the patient receives any disease-status information during that 
assessment. The LCQ will be completed as per the schedule of assessments (Table 4–1). 
 
3.5.6.4 The Cough Specific Quality of Life Questionnaire 
The Cough-Specific Quality of life Questionnaire (Appendix 8.4) is a valid, repeatable 19 item 
self-completed QOL measure of chronic cough that is responsive to change. This tool 
assesses cough related QOL in three domains: Physical, Psychological and Social. This will 
allow for the measurement of QOL in relation to cough and for comparisons to be made 
between asthma phenotypes. The LCQ will be administered to the patient before all other 
non-PRO assessments and before the patient receives any disease-status information during 
that assessment. The LCQ will be completed as per the schedule of assessments (Table 4–
1). 
 
3.5.6.5 Visual Analogue Scale for Cough (VASc) 
The VASc (Appendix 8.5) is a 100mm scale on which patients indicate the severity of cough. 
The scale ranges from no cough (0mm) to worst cough ever (100mm) and patients can mark 
the severity of their cough on the scale as appropriate. The VASc will be administered to the 
patient before all other non-PRO assessments and before the patient receives any disease-
status information during that assessment. The VASc will be completed as per the schedule 
of assessments (Table 4–1). 
  
 
3.5.6.6 Visual Analogue Scale for Urge to Cough (VASu) 
The VASu (Appendix 8.6) is a 100mm scale on which patients indicate their urge to cough. 
The scale ranges from no urge (0mm) to severe urge (100mm) and patients can mark the 


Page 17 
 
 
severity of their urge to cough on the scale as appropriate. The VASu will be administered to 
the patient before all other non-PRO assessments and before the patient receives any 
disease-status information during that assessment. The VASu will be completed as per the 
schedule of assessments (Table 4–1). 
 
3.5.6.7 Cough Hypersensitivity Questionnaire (CHQ) 
The Cough Hypersensitivity Questionnaire (Appendix 8.7) is a 23 item questionnaire that 
evaluates the presence of cough triggers, urge to cough and laryngeal symptoms suggestive 
of neuropathic paraesthesia. The CHQ will be administered to the patient before all other non-
PRO assessments and before the patient receives any disease-status information during that 
assessment. The CHQ will be completed as per the schedule of assessments (Table 4–1). 
 
4.0 Statistical Considerations and Analysis Plan 
4.1 Determination of Sample Size 
No formal sample size calculation has been performed as the study is exploratory  
 
4.2 Analysis Sets 
The full-analysis set (FAS) will be used in all statistical analyses. The FAS will consist of all 
patients who meet the criteria for entering the study. 
 
4.3 Statistical Analysis 
Demographic, baseline, and outcome data will be listed and summarised using descriptive 
statistical methods. Baseline weight, height, BMI, bronchodilator reversibility, spontaneous 
sputum results will be summarised. General medical history and baseline conditions will 
be listed. Patient disposition will be presented accompanied by the number and 
percentage of patients entering and completing the study. Reasons for withdrawal will be 
summarised. Concurrent medications and rescue medications will be listed and 
summarised. 
 
4.4 Exploratory Analysis 
Exploratory outcome measures will be listed and summarised appropriately by patient group 
and visit. The relationship of cough with each exploratory outcome will be investigated by 
presenting scatterplot matrices for each patient group and visit, or other appropriate methods 
with appropriate between group comparison. 
 
5.0 Ethics and Confidentiality 
5.1 Patient Information and Consent 
It is the responsibility of the investigator, or a person designated by the investigator to obtain 
signed informed consent from patients prior to participating in this study after adequate 
explanation of the aims, methods, anticipated benefits, and potential hazards of the study. 
The Consent Forms must be signed and dated by the patient before his or her participation 
in the study. 


Page 18 
 
 
 
Before recruitment and enrolment, each prospective patient will be given a full explanation 
of the study and be allowed to read the approved Patient Information Sheet (PIS). Once 
the investigator is assured that the patient understands the implications of participating in 
the study, the patient will be asked to give consent to participate in the study by signing the 
ICF. 
 
The investigator shall retain the signed original informed consent(s) and give a copy of the 
signed original to the patient  
 
5.2 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain patient confidentiality. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without written 
permission from the patient, except as necessary for monitoring and auditing. 
 
The investigator and all employees and coworkers involved with this study may not disclose 
or use for any purpose, other than performance of the study, any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 
study. Prior written agreement from the sponsor or its designee must be obtained for the 
disclosure of any said confidential information to other parties. 
 
6.0   Safety Reporting 
  
6.1    Definition of Adverse Events 
The definitions of adverse events is given in Table 2. 
  
  
Table 2. Terms and Definitions for Adverse Events 
  
Term 
Definition 
Adverse Event 
(AE) 
Any untoward medical occurrence in a participant resulting 
from administration of any of the research procedures 
Serious Adverse 
Event (SAE) 
  
Any adverse event that 
 
results in death, 
 
is life-threatening 
 
requires hospitalisation or prolongation of existing 
hospitalisation*, 
 
results in persistent or significant disability or incapacity 
or is otherwise considered medically significant by the 
investigator 
  
  
6.2    AE Reporting 
The Chief Investigator or their delegated investigator is responsible for recording adverse 
events observed during the study period.  Both adverse events and serious adverse events, 
will be recorded in the CRF. 


Page 19 
 
 
  
The investigator should attempt, if possible, to establish a diagnosis based on the subject’s 
signs and symptoms. The investigator must be follow all adverse events observed during the 
study until they are resolved or stabilized, or the events are otherwise explained. All adverse 
events must be treated appropriately. The action taken to treat the adverse event will be 
recorded in the CRF. The CI will report all related and unexpected SAEs to the REC and 
Sponsor within 15 days. 
  
The investigator must record the adverse events, seriousness as well as duration (start and 
end dates).  All adverse events must be included in the annual progress report submitted to the 
sponsor and Research Ethics Committee. 
 
 
 
7.0 References 
(1) Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention. 
2016. 
(2) American Thoracic Society / European Thoracic Society. An Official American Thoracic 
Society/European Respiratory Society Statement: Asthma Control and Exacerbations. - Am J Respir 
Crit Care Med 2009;180:1-59. 
(3) British Thoracic Society Scottish Intercollegiate Guidelines Network. British guideline on the 
management of asthma. 2016. 
(4) Woodruff PG, Modrek B, Choy DF, Jia G, Abbas AR, Ellwanger A, et al. T-helper Type 2ΓÇôdriven 
Inflammation Defines Major Subphenotypes of Asthma. American Journal of Respiratory and Critical 
Care Medicine 2009 05/27;180(5):388-395. 
(5) McGrath KW, Icitovic N, Boushey HA, Lazarus SC, Sutherland ER, Chinchilli VM, et al. A Large 
Subgroup of Mild-to-Moderate Asthma Is Persistently Noneosinophilic. American Journal of 
Respiratory and Critical Care Medicine 2011 12/16;185(6):612-619. 
(6) Pavord ID, Brightling CE, Woltmann G, Wardlaw AJ. Non-eosinophilic corticosteroid unresponsive 
asthma. Lancet 1999 Jun 26;353(9171):2213-2214. 
(7) Butler CA, McQuaid S, Taggart CC, Weldon S, Carter R, Skibinski G, et al. Glucocorticoid receptor 
Î² and histone deacetylase 1 and 2 expression in the airways of severe asthma. Thorax 2012 
May;67(5):392-398. 
(8) Shikotra A, Choy DF, Ohri CM, Doran E, Butler C, Hargadon B, et al. Increased expression of 
immunoreactive thymic stromal lymphopoietin in patients with severe asthma. J Allergy Clin Immunol 
2012 1;129(1):104-111.e9. 
(9) Sweeney J., Brightling C.E., MenziesGow A., Niven R., Patterson C.C., Heaney LG. Clinical 
management and outcome of refractory asthma in the UK from the British Thoracic Society Difficult 
Asthma Registry. Thorax 2012 August 2012;67(8):754-756. 
(10) Sweeney J., Patterson C.C., MenziesGow A., Niven R.M., Mansur A.H., Bucknall C., et al. 
Comorbidity in severe asthma requiring systemic corticosteroid therapy: Cross-sectional data from the 
optimum patient care research database and the british thoracic difficult asthma registry. Thorax 2016 
April 2016;71(4):339-346. 
(11) Heaney L.G., Brightling C.E., MenziesGow A., Stevenson M., Niven RM. Refractory asthma in the 
UK: Cross-sectional findings from a UK multicentre registry. Thorax 2010 September 2010;65(9):787-
794. 


Page 20 
 
 
(12) Chang AB. Cough, cough receptors, and asthma in children. Pediatr Pulmonol 1999;28(1):59-70. 
(13) McGarvey L. Seeing Is Believing. Sensing Real Progress in the Study of Human Airway Nerves. 
Am J Respir Crit Care Med 2015 07/01; 2016/10;192(1):1-2. 
(14) Osman L, McKenzie L, Cairns J, Friend J, Godden D, Legge J, et al. Patient weighting of 
importance of asthma symptoms. Thorax 2001 02;56(2):138-142. 
(15) Raj AA, Birring SS. Clinical assessment of chronic cough severity. Pulm Pharmacol Ther 2007 
8;20(4):334-337. 
(16) Heaney L.G., Conway E., Kelly C., Johnston B.T., English C., Stevenson M., et al. Predictors of 
therapy resistant asthma: Outcome of a systematic evaluation protocol. Thorax 2003 01 Jul 
2003;58(7):561-566. 
 


Page 21 
 
 
8.0 
Appendices 
8.1 
Appendix: Mini Asthma Quality of Life Questionnaire 
 
 


Page 22 
 
 


Page 23 
 
 
 
 
8.2 
Appendix: Asthma Quality of Life Questionnaire – 5 


Page 24 
 
 
 
8.3 
Appendix: Leicester Cough Questionnaire 
 
LEICESTER COUGH 
QUESTIONNAIRE 
 
 
This questionnaire is designed to assess the impact of 
cough on various aspects of your everyday life.  Read 
each question carefully and answer by SELECTING the 
response that best applies to you.  On the next page, 
there is an example from a completed questionnaire.  
Please answer ALL questions, as honestly as you can.  
This questionnaire is confidential.  
 
 
Name………………….. 
Date of Birth…./…/…… 
Date...…………….…… 
 
 
 
Developed 2001


Page 25 
 
 
EXAMPLE PAGE 
(Not to be completed) 
 
1.  In the last 2 weeks, have you had chest or stomach pains as a result 
of your cough?    
1. 
All of the time 
2. 
Most of the time 
3. 
A good bit of the time 
4. 
Some of the time 
5. 
A little of the time 
6. 
Hardly any of the time 
7. 
None of the time 
 
 
2.  In the last 2 weeks, my cough has made me feel frustrated. 
 
1. 
All of the time 
2. 
Most of the time 
3. 
A good bit of the time 
4. 
Some of the time 
5. 
A little of the time 
6. 
Hardly any of the time 
7. 
None of the time 
 
 
3. In the last 2 weeks, my cough has interrupted conversation or 
telephone calls. 
1. 
All of the time 
2. 
Most of the time 
3. 
A good bit of the time 
4. 
Some of the time 
5. 
A little of the time 
6. 
Hardly any of the time 
7. 
None of the time 
 
 


Page 26 
 
 
LEICESTER COUGH 
QUESTIONNAIRE 
 
1. In the last 2 weeks, have you had chest or stomach pains as a result of your cough?  
1. 
All of the time 
2. 
Most of the time 
3. 
A good bit of the time  
 
 
4. 
Some of the time 
5. 
A little of the time 
6. 
Hardly any of the time 
7. 
None of the time 
 
 
2. In the last 2 weeks, have you been bothered by sputum (phlegm) production 
when you cough? 
 
1. 
Every time 
2. 
Most times 
3. 
Several times 
4. 
Sometimes 
5. 
Occasionally 
6. 
Rarely  
7. 
Never 
 
 
3. In the last 2 weeks, have you been tired because of your cough? 
 
1. 
All of the time 
2. 
Most of the time 
3. 
A good bit of the time 
4. 
Some of the time 
5. 
A little of the time 
6. 
Hardly any of the time 
7. 
None of the time 
 
4. In the last 2 weeks, have you felt in control of your cough? 
 
1. 
None of the time 
2. 
Hardly any of the time 
3. 
A little of the time 
4. 
Some of the time 
5. 
A good bit of the time 
6. 
Most of the time 
7. 
All of the time 
 
 
5. How often during the last 2 weeks have you felt embarrassed by 
your coughing? 
1. 
All of the time 
2. 
Most of the time 
3. 
A good bit of the time 


Page 27 
 
 
4. 
Some of the time 
5. 
A little of the time 
6. 
Hardly any of the time 
7. 
None of the time 
 
 
6. In the last 2 weeks, my cough has made me feel anxious. 
 
1. 
All of the time 
2. 
Most of the time 
3. 
A good bit of the time 
4. 
Some of the time 
5. 
A little of the time 
6. 
Hardly any of the time 
7. 
None of the time 
 
7. In the last 2 weeks, my cough has interfered with my job, or other daily tasks. 
 
1. 
All of the time 
2. 
Most of the time 
3. 
A good bit of the time 
4. 
Some of the time 
5. 
A little of the time 
6. 
Hardly any of the time 
7. 
None of the time 
 
8. In the last 2 weeks, I felt that my cough interfered with the overall enjoyment of 
my life. 
 
1. 
All of the time 
2. 
Most of the time 
3. 
A good bit of the time 
4. 
Some of the time 
5. 
A little of the time 
6. 
Hardly any of the time 
7. 
None of the time 
 
9. In the last 2 weeks, exposure to paints or fumes has made me cough. 
 
1. 
All of the time 
2. 
Most of the time 
3. 
A good bit of the time 
4. 
Some of the time 
5. 
A little of the time 
6. 
Hardly any of the time 
7. 
None of the time 
 
10. In the last 2 weeks, has your cough disturbed your sleep? 
 
1. 
All of the time 
2. 
Most of the time 
3. 
A good bit of the time 
4. 
Some of the time 


Page 28 
 
 
5. 
A little of the time 
6. 
Hardly any of the time 
7. 
None of the time 
 
 
 
11. In the last two weeks, how many times a day have you had coughing bouts? 
 
1. 
All the time (continuously) 
2. 
Most times during the day 
3. 
Several times during the day 
4. 
Sometimes during the day 
5. 
Occasionally through the day 
6. 
Rarely 
7. 
None 
 
 
12. In the last 2 weeks, my cough has made me feel frustrated. 
 
1. 
All of the time 
2. 
Most of the time 
3. 
A good bit of the time 
4. 
Some of the time 
5. 
A little of the time 
6. 
Hardly any of the time 
7. 
None of the time 
 
 
13. In the last 2 weeks, my cough has made me feel fed up. 
 
1. 
All of the time 
2. 
Most of the time 
3. 
A good bit of the time 
4. 
Some of the time 
5. 
A little of the time 
6. 
Hardly any of the time 
7. 
None of the time 
 
 
14. In the last 2 weeks, have you suffered from a hoarse voice as a result of your 
cough? 
 
1. 
All of the time 
2. 
Most of the time 
3. 
A good bit of the time 
4. 
Some of the time 
5. 
A little of the time 
6. 
Hardly any of the time 
7. 
None of the time 
 
 
15. In the last 2 weeks, have you had a lot of energy? 
 


Page 29 
 
 
1. 
None of the time 
2. 
Hardly any of the time 
3. 
A little of the time 
4. 
Some of the time 
5. 
A good bit of the time 
6. 
Most of the time 
7. 
All of the time 
 
 
16. In the last 2 weeks, have you worried that your cough may indicate a serious 
illness? 
 
1. 
All of the time 
2. 
Most of the time 
3. 
A good bit of the time 
4. 
Some of the time 
5. 
A little of the time 
6. 
Hardly any of the time 
7. 
None of the time 
 
 
17. In the last 2 weeks, have you been concerned that other people think 
something is wrong with you, because of your cough? 
 
1. 
All of the time 
2. 
Most of the time 
3. 
A good bit of the time 
4. 
Some of the time 
5. 
A little of the time 
6. 
Hardly any of the time 
7. 
None of the time 
 
 
18. In the last 2 weeks, my cough has interrupted conversation or telephone 
calls. 
 
1. 
Every time 
2. 
Most times 
3. 
A good bit of the time 
4. 
Some of the time 
5. 
A little of the time 
6. 
Hardly any of the time 
7. 
None of the time 
 
 
19. In the last 2 weeks, I feel that my cough has annoyed my partner, family or 
friends. 
 
1. 
Every time I cough 
2. 
Most times when I cough 
3. 
Several times when I cough 
4. 
Sometimes when I cough 
5. 
Occasionally when I cough 


Page 30 
 
 
6. 
Rarely 
7. 
Never 
 
 
Thank you for completing this questionnaire. 


 
 
 
8.4 
Appendix: Cough Specific Quality of Life Questionnaire 
The Cough-Specific Quality-of-Life Questionnaire (CQLQ) 
 
NAME (OPTIONAL): ________________________________          STUDY RECORD #: _________________                        
DATE: ________  
 
Please indicate below how your cough affects you. Circle the answer that best describes your agreement 
with each item. Please respond to every item. Thank you for your help. 
 
1.  
Family and or close friends can’t tolerate it 
any more.  
STRONGLY DISAGREE 
DISAGREE 
AGREE 
STRONGLY AGREE 
2.  
I have experienced prolonged absences from 
important activities such as work, school, or 
volunteer services.  
STRONGLY DISAGREE 
DISAGREE 
AGREE 
STRONGLY AGREE 
3.  
I have been completely prevented from 
engaging in important activities such as 
work, school, or volunteer services.  
STRONGLY DISAGREE 
DISAGREE 
AGREE 
STRONGLY AGREE 
4.  
I have lost my appetite.  
STRONGLY DISAGREE 
DISAGREE 
AGREE 
STRONGLY AGREE 
5.  
I am sick to my stomach and vomit.  
STRONGLY DISAGREE 
DISAGREE 
AGREE 
STRONGLY AGREE 
6.  
I cough and it makes me retch (dry heaves).  
STRONGLY DISAGREE 
DISAGREE 
AGREE 
STRONGLY AGREE 
7.  
I have a fear that I might have AIDS or 
tuberculosis.  
STRONGLY DISAGREE 
DISAGREE 
AGREE 
STRONGLY AGREE 
8.  
I have headaches.  
STRONGLY DISAGREE 
DISAGREE 
AGREE 
STRONGLY AGREE 
9.  
I am concerned that I have cancer.  
STRONGLY DISAGREE 
DISAGREE 
AGREE 
STRONGLY AGREE 
10.  
I am dizzy.  
STRONGLY DISAGREE 
DISAGREE 
AGREE 
STRONGLY AGREE 
11.  
I wet my pants.  
STRONGLY DISAGREE 
DISAGREE 
AGREE 
STRONGLY AGREE 
12.  
I soil my pants.  
STRONGLY DISAGREE 
DISAGREE 
AGREE 
STRONGLY AGREE 
13.  
I sweat.  
STRONGLY DISAGREE 
DISAGREE 
AGREE 
STRONGLY AGREE 
 


 
 
 
 
 
 
 
 
 
 
 
14.  
I am hoarse.  
STRONGLY DISAGREE 
DISAGREE 
AGREE 
STRONGLY AGREE 
15.  
It hurts when I breathe.  
STRONGLY DISAGREE 
DISAGREE 
AGREE 
STRONGLY AGREE 
16.  
I broke a rib.  
STRONGLY DISAGREE 
DISAGREE 
AGREE 
STRONGLY AGREE 
17.  
I cannot sleep at night.  
STRONGLY DISAGREE 
DISAGREE 
AGREE 
STRONGLY AGREE 
18.  
I have difficulty speaking on the phone.  
STRONGLY DISAGREE 
DISAGREE 
AGREE 
STRONGLY AGREE 
19.  
I can no longer sing, for instance in church.  
STRONGLY DISAGREE 
DISAGREE 
AGREE 
STRONGLY AGREE 
20.  
I have stopped going to social activities such 
as movies, plays, town meetings.  
STRONGLY DISAGREE 
DISAGREE 
AGREE 
STRONGLY AGREE 
21.  
I have had to change my lifestyle.  
STRONGLY DISAGREE 
DISAGREE 
AGREE 
STRONGLY AGREE 
22.  
I ache all over.  
STRONGLY DISAGREE 
DISAGREE 
AGREE 
STRONGLY AGREE 
23.  
I am exhausted.  
STRONGLY DISAGREE 
DISAGREE 
AGREE 
STRONGLY AGREE 
24.  
I am embarrassed.  
STRONGLY DISAGREE 
DISAGREE 
AGREE 
STRONGLY AGREE 
25.  
I am upset by people thinking that I have  
something wrong with me.  
STRONGLY DISAGREE 
DISAGREE 
AGREE 
STRONGLY AGREE 
26.  
I want to be reassured that I do not have 
anything seriously the matter with me.  
STRONGLY DISAGREE 
DISAGREE 
AGREE 
STRONGLY AGREE 
27.  
I am self-conscious.  
STRONGLY DISAGREE 
DISAGREE 
AGREE 
STRONGLY AGREE 
28.  
I am concerned that I have something 
seriously the  
matter with me.  
STRONGLY DISAGREE 
DISAGREE 
AGREE 
STRONGLY AGREE 
The Cough Quality of Life Questionnaire©2000 by Richard S. Irwin, Cynthia T. French, and Kenneth E. Fletcher 
 CQLQ - United States/English - Mapi ID050905 / CQLQ_AU2.0_eng-USori.doc 
The Cough Quality of Life Questionnaire©2000 by Richard S. Irwin, Cynthia T. French, and Kenneth E. Fletcher 
 CQLQ - United States/English - Mapi ID050905 / CQLQ_AU2.0_eng-USori.doc 


Page 33 
 
 
Worst cough ever (100mm) 
No Cough (0mm) 
 
8.5 
Appendix: Visual Analogue Scale for Cough 
 
 
 


Page 34 
 
 
 
 
8.6 
Appendix: Visual Analogue Scale for Urge to Cough
Worst urge to cough ever (100mm) 
 
No Urge to Cough (0mm) 


Page 35 
 
 
8.7 
Appendix: Cough Hypersensitivity Questionnaire (CHQ)  
 
 
 
Cough Hypersensitivity Questionnaire: assessing triggers of cough  
 
 
This questionnaire assesses the sensations, urges and triggers associated 
with your cough.  
Please answer all questions.  
Have you experienced any of the following in relation to your cough within 
the last 2 weeks? 
Noticeable urge to cough before coughing starts  
 
 
Y/N 
 
 
Tickle in throat  
 
 
 
 
 
 
Y/N 
 
 
Itchy throat 
 
 
 
 
 
 
 
Y/N 
 
 
Dry throat  
 
 
 
 
 
 
 
Y/N 
 
 
Irritation in throat 
 
 
 
 
 
 
Y/N 
 
 
Throat clearing  
 
 
 
 
 
 
Y/N 
 
 
Sensation in the chest before you cough  
 
 
 
Y/N 
 
Do any of the following trigger your cough? 
Cold air  
 
 
 
 
 
 
 
Y/N 
Hot air  
 
 
 
 
 
 
 
Y/N 
Dry air  
 
 
 
 
 
 
 
Y/N 
Damp conditions 
 
 
 
 
 
 
Y/N 
Perfumes or scents 
 
 
 
 
 
 
Y/N 
Smoke or smoky atmosphere 
 
 
 
 
 
Y/N 
Talking  
 
 
 
 
 
 
 
Y/N 
Laughing 
 
 
 
 
 
 
 
Y/N 
 
 
Eating  
 
 
 
 
 
 
 
Y/N 
Heartburn 
 
 
 
 
 
 
 
Y/N 
Indigestion 
 
 
 
 
 
 
 
Y/N 
Change in body position (for example lying down)  
 
 
Y/N 
Exercise 
 
 
 
 
 
 
 
Y/N 
Brushing teeth  
 
 
 
 
 
 
Y/N 
Sputum (phlegm) 
 
 
 
 
 
 
Y/N 
Post-nasal drip (dripping sensation in back of the throat)  
 
Y/N 
 
 
 
 
 
 
 
 
©King’s College Hospital 2010. KK Lee & SS Birring.