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COPD STARR
Studying the different characteristics of chronic obstructive pulmonary disease in primary care using
near-patient testing and relating this to treatment responses during an acute exacerbation
Internal Reference Number / Short title:
COPD: STudying Acute exaceRbations and Responses (COPD STARR)
IRAS:151240
Ethics Ref: 15 SC 0025
Date and Version No: 19th December 2014. Version 1.0
Chief Investigator:
Dr Mona Bafadhel, University of Oxford
[email protected]
01865 612898
Sponsor:
University of Oxford
Funder:
National Institute for Health Research
Chief Investigator Signature:
Confidentiality Statement There are no conflicts of interest to declare
This document contains confidential information that must not be disclosed to anyone other than the
Sponsor, the Investigator Team, host organisation, and members of the Research Ethics Committee, unless
authorised to do so.
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TABLE OF CONTENTS
1.
SYNOPSIS ............................................................................................................................................... 5
2.
ABBREVIATIONS..................................................................................................................................... 6
3.
BACKGROUND AND RATIONALE ............................................................................................................ 7
3.1.
Current treatment strategies using corticosteroids and antibiotics ............................................. 7
3.2.
Characterising COPD phenotypes.................................................................................................. 8
3.3.
Directed treatment using near-patient testing ............................................................................. 9
3.4.
Study Rationale.............................................................................................................................. 9
Figure 1. Study rationale ..................................................................................................................... 10
4.
OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS ........................................................................ 11
4.1.
Study Aims ................................................................................................................................... 11
4.2.
Study Objectives .......................................................................................................................... 11
4.3. Study Outcomes............................................................................................................................... 11
4.3.
5.
Hypothesis ................................................................................................................................... 11
STUDY DESIGN ..................................................................................................................................... 12
Figure 2. Study schedule...................................................................................................................... 12
Figure 3. Project timelines and Gantt chart ........................................................................................ 13
6.
7.
PARTICIPANT IDENTIFICATION ............................................................................................................ 13
6.1.
Study Participants ........................................................................................................................ 13
6.1.
Inclusion Criteria.......................................................................................................................... 13
6.2.
Exclusion Criteria ......................................................................................................................... 14
STUDY PROCEDURES ........................................................................................................................... 14
7.1.
Recruitment ................................................................................................................................. 14
7.2.
Informed Consent ........................................................................................................................ 15
7.3.
Screening and Eligibility Assessment........................................................................................... 15
7.3.1 Pre Screening assessment .......................................................................................................... 15
7.3.2. Screening assessment ............................................................................................................... 15
7.4.
Study Assessments ...................................................................................................................... 15
7.4.1 Scheduled baseline visit 1 .......................................................................................................... 16
7.4.2. Unscheduled exacerbation visit 2 (day 0) ................................................................................. 17
7.4.3. Unscheduled exacerbation visit 3 (day 30) ................................................................................... 18
7.4.4. Unscheduled exacerbation visit 4 (day 90) ............................................................................... 19
Figure 4. Study scheduled and unscheduled visit assessments .......................................................... 19
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7.5.
Discontinuation/Withdrawal of Participants from Study ............................................................ 19
7.6.
Definition of End of Study ........................................................................................................... 20
8.
SAFETY REPORTING ............................................................................................................................. 20
8.1.
Definition of Serious Adverse Events .......................................................................................... 20
8.2.
Reporting Procedures for Serious Adverse Events ...................................................................... 20
9.
STATISTICS AND ANALYSIS................................................................................................................... 21
9.1.
Statistical Plan ............................................................................................................................. 21
9.2.
Health Economic Analysis Plan .................................................................................................... 21
10.
DATA MANAGEMENT ...................................................................................................................... 22
10.1.
Access to Data ......................................................................................................................... 22
10.2.
Data Recording ........................................................................................................................ 22
10.3.
Data Storage ............................................................................................................................ 22
10.4.
Data protection ....................................................................................................................... 22
11.
QUALITY ASSURANCE PROCEDURES ............................................................................................... 22
12.
ETHICAL AND REGULATORY CONSIDERATIONS............................................................................... 23
12.1.
Declaration of Helsinki............................................................................................................. 23
12.2.
Guidelines for Good Clinical Practice ...................................................................................... 23
12.3.
Approvals ................................................................................................................................. 23
12.4.
Reporting ................................................................................................................................. 23
12.5.
Participant Confidentiality ....................................................................................................... 23
12.6.
Expenses and Benefits ............................................................................................................. 23
13.
FINANCE AND INSURANCE .............................................................................................................. 24
13.1.
Funding .................................................................................................................................... 24
13.2.
Insurance ................................................................................................................................. 24
14.
PUBLICATION POLICY....................................................................................................................... 24
15.
REFERENCES .................................................................................................................................... 25
16.
APPENDIX A: Charlson Co-morbidity index ..................................................................................... 28
17.
APPENDIX B: MRC Dyspnoea Scale.................................................................................................. 29
18.
APPENDIX C: Visual Analogue Scale (VAS) ....................................................................................... 30
19.
APPENDIX D: COPD Assessment Tool (CAT) .................................................................................... 31
20.
APPENDIX E: Hospital and Anxiety Depression Scale (HADS) .......................................................... 32
21.
APPENDIX F: EuroQol 5D ................................................................................................................. 33
22.
APPENDIX G: Standard Operating Procedures ................................................................................ 35
23.
Appendix H: 30 day VAS diary card ................................................................................................. 36
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COPD STARR
APPENDIX I: AMENDMENT HISTORY .............................................................................................. 40
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1. SYNOPSIS
Studying the different characteristics of chronic obstructive pulmonary disease in
primary care using near-patient testing and relating this to treatment responses
during an acute exacerbation
Internal ref. no. / COPD: STudying Acute exaceRbations and Responses (COPD STARR)
short title
Study Title
Study Design
Prospective observational cohort study
Study Setting
Primary & Community Care
Study Participants
Adults, aged >40 with COPD
Planned Sample Size
300
Planned Study Period
12 months – Projected anticipated start date Jan 2015
Objectives
Primary
Characterise COPD during stable
state and exacerbations in
primary care
Outcomes
1. Measure the incidence of
eosinophilic and non-eosinophilic
COPD phenotypes in primary care
using near-patient testing (blood
eosinophil count and C reactive
protein)
2. Quantify the proportion of patients
that respond (treatment
responders) and do not respond
(treatment failures) to
standard/usual treatment for a
COPD exacerbation in primary care
and relate to phenotypes of COPD
3. Measure patient reported outcomes
(symptoms, health status and
healthcare utilisation) following
treatment of an exacerbation of
COPD
4. Derive pilot data quantifying
treatment response following
standard treatment of an
exacerbation of COPD in primary for
a future randomised clinical trial
Secondary
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2. ABBREVIATIONS
CAT
COPD assessment tool
COPD
chronic obstructive pulmonary disease
CRF
case record form
CRP
c reactive protein
FEV1
forced expiratory volume in 1 second
FENO
fraction exhaled nitric oxide
FVC
forced vital capacity
GMP
good medical practice
GP
general practitioner
HADS
hospital anxiety and depression scale
MRC
Medical research council dyspnoea scale
MRSA
methicillin resistant staphylococcus aureus
NNH
number needed to harm
PI
principal investigator
PRO
patient reported outcome
QA
quality assurance
QC
quality control
QP
quality persons
RCT
randomised control trial
SAE
serious adverse event
SI
sub-investigator
TSC
trial steering committee
VAS
visual analogue scale
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3. BACKGROUND AND RATIONALE
Chronic obstructive pulmonary disease (COPD) is associated with significant morbidity and mortality1,2
affecting quality of life and associated with lung function decline3. It is predicted to be the 3rd leading cause
of death by 2020 affecting over 200 million people worldwide4. The natural progression of COPD is
characterised by progressive airflow obstruction and often punctuated by periods of worsening in
respiratory symptoms and function associated with significant impact on quality of life. These episodes are
termed exacerbations or lung attacks and represent a large burden on healthcare, accounting for 15% of
all U.K acute hospital admissions, 1 million hospital bed days and an estimated annual NHS expenditure of
approximately £500 million2. In the U.K, more than 1.4 million GP consultations annually are attributable
to COPD exacerbations. It is estimated that there are 130,000 hospitalised exacerbations of COPD annually
and approximately 75% of these have been treated by the GP within 4 weeks of admission2. A single acute
episode of COPD requiring hospitalisation costs £1,5005 and projected treatment failure costs can
accumulate to over £145 million annually. At present there is limited evidence to understand why patients
seen and treated by the GP fail treatment within 30 days and require further treatment and admission.
There are no primary care studies which have examined whether this sub-group of treated COPD patients
have a new or prolonged re-exacerbation event, whether there are detectable prognostic features of
worsened outcomes identifying a higher risk of patient or whether there are simple bedside tools that can
be used to recognise and predict an adequate or inadequate response to treatment. Current COPD
exacerbation treatment strategies rely on oral corticosteroids and antibiotics albeit in an inferior ‘one size
fits all’ approach. Furthermore the evidence for the use of corticosteroids and antibiotics during COPD
exacerbations is weak6,7 and not without harm8-10. There is currently no guidance available to identify
treatment responders in primary care, where the largest proportions of exacerbations are initially and
often singly managed.
3.1. Current treatment strategies using corticosteroids and antibiotics
The clinical response to treatment varies considerably and is associated with significant side effects. Our
current inability to target therapy means some patients are inappropriately treated placing a vulnerable
population at further risk. A review of the evidence, in a Cochrane systematic review6, supporting systemic
corticosteroids and antibiotics during exacerbations of COPD determined marginal short term
improvements without mortality benefits6,7. This Cochrane review showed significant heterogeneity with
respect to study protocols, patient attrition and study outcomes. Corticosteroid use is associated with
multiple risks including osteoporosis, fractures and hyperglycaemia. The use of corticosteroids in COPD
exacerbations is associated with significant harm (number needed to harm (NNH) of 5) and a 5 fold risk of
hyperglycaemia; for every 13 persons treated, 1 will develop hyperglycaemia6; with additional costs to the
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NHS related to diabetes and osteoporosis.
The widespread use of antibiotic therapy is associated with
the production of ‘super bugs’ such as Methicillin Resistant Staphylococcus aureus (MRSA) in addition to
antibiotic associated infection (C difficile) and antibiotic related diarrhoea. C difficile rates and detected
MRSA bacteraemia (accounting for 22 million and 37 million bed days respectively) is directly related to
this blanket use of antibiotics. A 15% reduction in antibiotic usage in 1 year is associated with a 70%
reduction in MRSA rates11. Many of the studies, providing the evidence for treatment have focussed on
severe or hospitalised exacerbations of COPD. Despite the widespread use of corticosteroid and antibiotic
therapy there are no studies investigating outcomes in exacerbations presenting to the GP in primary care.
Pathogens such as bacteria and viruses are believed to be the major underlying cause of COPD
exacerbations12,13. In primary care, sampling for virus or bacteria at the onset of an exacerbation is not
performed and guidance for the prescription of antibiotics is based on symptoms and sputum purulence14
although confounded by the presence of bacterial colonisation15. At present, there is a paucity of
randomised antibiotic placebo control studies in mild or moderate primary care exacerbations of COPD to
support the practice of withholding antibiotic or therapy.
3.2. Characterising COPD phenotypes
Recent trends have advocated the characterisation of COPD phenotypes which relate to clinically
meaningful outcomes such as symptoms, exacerbations and responses to treatment in the management
of COPD16. The presence of a sputum eosinophilia in stable COPD has been repeatedly associated with a
positive clinical response (FEV1 and symptoms) following treatment with oral corticosteroids17-19. A sputum
eosinophilia is detected in up to 40% of COPD20, but sputum processing is time consuming and requires
specialist skills21. In previous work our research group have determined and validated that the blood
eosinophil count is the best surrogate for a sputum eosinophilia during COPD exacerbations22. In a recent
biomarker-driven randomised placebo control trial our research group has determined that a high
peripheral blood eosinophil count during an exacerbation of COPD (approximately occurring in 50%) was
associated with marked clinical and statistically significant improvement in after 14 days of prednisolone
therapy compared to non-eosinophilic COPD exacerbation prescribed prednisolone23. Furthermore in a
study investigating prognosticators for COPD exacerbations the DECAF index has recently been shown to
be a strong predictor of mortality in hospitalised exacerbations of COPD. Importantly, this study confirmed
that a low peripheral eosinophil count was an independent predictor of COPD exacerbation mortality 24.
Eosinopenia accompanies the acute response to infection and inflammation25. These studies would
suggest that the blood eosinophil count may be identifying a treatment responsive and prognostic COPD
exacerbation phenotype and may be a simple and useful tool to use in the management of COPD
exacerbations in primary care.
It is well recognised that antibiotic therapy should be given to bacterial
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infections. In previous work we have also shown that the C reactive protein level (CRP) is the best bedside
test to determine whether antibiotics should and should not be prescribed in admissions to hospital with
symptoms suggestive of an acute respiratory illness26. In further validation studies, it has been observed
that a CRP of above 50 has been found to be associated with the most benefit following antibiotic
treatment in hospitalised exacerbations of COPD 27 and is also predictive of a treatment failure in mild to
moderate exacerbations28. The combination of these independent findings suggests that the blood
eosinophil count and CRP can be used as biomarkers to determine treatment with oral steroids and
antibiotics.
3.3. Directed treatment using near-patient testing
Near-patient testing in primary care using the peripheral blood eosinophil count and the CRP could be
used to guide effective and personalised treatment in patients with COPD. Currently available systems
include the Hemocue® 5-point differential cell count system and the QuikRead-go CRP analyser
(OxfordBiosystems) which accurately and rapidly (within 2 minutes) determine the peripheral blood
eosinophil count and CRP from finger-prick sampling. Hemocue® a leading provider of automated
haematology diagnostics, manufacture a portable analyser which provides accurate and rapid (within
minutes) cell counts from finger-prick sampling. This diagnostic is currently used in neonatology, A&E and
at Mount Everest Base Camp29-31. The fraction of exhaled Nitric Oxide (NiOX MINO®, Aerocrine) is a
surrogate measure of eosinophilic airway inflammation and is an approved tool in the management of
asthma32. The test requires little skill, is automated and similar to a breathalyser. Children as young as 5
years old have been effective at using it in the paediatric respiratory clinic. However, little is known about
its effectiveness in patients with COPD and during an exacerbation and its accuracy as a surrogate marker.
Identification of COPD exacerbation phenotypes in primary care using the application of near-patient
testing could deliver improvement and targeted antibiotic and corticosteroid therapy.
3.4. Study Rationale
It is recognised that the majority of exacerbations that are hospitalised have been seen by their general
practitioner in the previous 30 days and received treatment with oral steroids and antibiotics 2. These
hospitalisations are effectively treatment failures. Hospitalisations of COPD are associated with increased
mortality33, worsened health status34, lung function decline35 and further exacerbations36,37. Eosinophilic
COPD exacerbations have greatest improvement with oral steroid therapy23 and severe hospitalised
exacerbations have most benefit with antibiotic therapy38. It remains unknown what proportion of
inflammatory phenotypes occur in patients attending primary care with an exacerbation of COPD and how
many are treatment successes or treatment failures (figure 1).
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Figure 1. Study rationale
Near-patient testing in primary care at the initial COPD exacerbation consultation could guide effective
and personalised treatment and reduce treatment failures associated with eosinophilic and noneosinophilic exacerbations. To investigate this, an observational study to quantify the proportion of COPD
exacerbation phenotypes (eosinophilic and non-eosinophilic exacerbations) and the proportion that have
treatment failures with current standard therapy according to eosinophilic and non-eosinophilic
phenotypes will be performed. Characterisation of these patients in primary care using questionnaires
that relate to the exacerbation (COPD assessment tool39, CAT), the symptoms (visual analogue scale40,
VAS), the degree of anxiety or depression (Hospital and anxiety depression score41, HADS) and quality of
life (EuroQol 5D42), and simple finger-prick sampling of blood for measurement of eosinophils and CRP can
facilitate understanding these treatment failures. This work will then derive pertinent data for a future
randomised controlled trial to determine if a personalised stratified medicine approach using near-patient
testing could be used to deliver therapy for patients with COPD exacerbations in primary care leading to
strategies to aid the right treatment for the right patient at the right time.
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4. OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS
4.1. Study Aims
To study and understand the characteristics of patients with COPD exacerbations in a primary care setting.
4.2. Study Objectives
Characterise COPD during stable state and exacerbations in primary care
4.3. Study Outcomes
1. Measure the incidence of eosinophilic and non-eosinophilic COPD phenotypes in primary care using
near-patient testing (blood eosinophil count and CRP)
2. Quantify the proportion of patients that respond (treatment responders) and do not respond
(treatment failures) to standard/usual treatment for a COPD exacerbation in primary care and relate
to phenotypes of COPD
3. Measure patient reported outcomes (symptoms, health status and healthcare utilisation) following
treatment of an exacerbation of COPD
4. Derive pilot data quantifying treatment response following standard treatment of an exacerbation of
COPD in primary for a future randomised clinical trial
4.3. Hypothesis
We hypothesise that the non-selective non-phenotype specific treatment of an exacerbation leads to a
failure to respond to standard treatment of a COPD exacerbation (also called a treatment failure).
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5. STUDY DESIGN
Study design: Prospective observational cohort study
Setting: This will be conducted in a single centre large primary care practice and in the community. The
recorded number of patients registered within the GP surgery geographical area is approximately 24,000
and the practice has 367 COPD registered patients. The community based nursing team are in charge of
admission avoidance for COPD patients in the geographical area of the primary care practice.
Study duration: 12 months data collection and 3 months analyses
Data collection: Demographic and full medical history, including smoking history, exacerbation history and
medication history. Clinic based spirometry, pulse oximetry, quality of life questionnaires (CAT, VAS, HADS,
EuroQoL) and inflammatory phenotype based on finger-prick sampling and lung function.
Study schedule: Baseline stable visit to record demographic, severity, symptom and inflammatory
measurements. Exacerbation visit as defined by GP or Community Nursing Team. Medical history and
management as per usual treatment by responsible team; research review thereafter for inflammation
phenotype and symptomology. Telephone visit consultation for symptomology and treatment failure
episodes (figure 2).
Figure 2. Study schedule
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Project timelines
It is anticipated that subject recruitment, follow up and data cleaning will be completed over 15 months.
The timeline for the project is outlined in the Gantt figure 3.
Figure 3. Project timelines and Gantt chart
Time (months)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Ethics Application and Approval
Subject recruitment
Subject follow up
Data Cleaning and Data Lock
Data Analysis
Dissemination & Public engagement
6. PARTICIPANT IDENTIFICATION
6.1. Study Participants
Adults (age > 40) with a diagnosis of COPD attending primary care or Community respiratory nurse review
at stable state or with an acute exacerbation of COPD necessitating a course of systemic corticosteroids
and/or antibiotic therapy will be recruited to enter the study. Patients with COPD having an annual review
with their general practitioner for reasons other than a COPD exacerbation will also be invited for nearpatient testing and characterisation by the study staff which will also include inhaler technique, smoking
cessation advice and as an aide-mémoire to enrich the exacerbation population. The participant
population, inclusion and exclusion criteria in this observational study are listed below.
6.1. Inclusion Criteria

Participant is willing and able to give informed consent for participation in the study

Male or Female, aged 40 years or above.

Known diagnosis of COPD (either diagnosis made in primary or secondary care) as per national and
international guidelines1,2, irrespective of severity

Current or Ex-Smoker

Smoking pack year history >10

Spirometry confirming fixed airflow obstruction (FEV1/FVC ratio <0.7)
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6.2. Exclusion Criteria

History of atopic childhood asthma

Current history of primary lung malignancy or current active pulmonary TB

HIV, hepatitis B or C positive (will be part of initial screening eligibility from medical notes)

Clinically relevant disease or disorder (past or present) which in the opinion of the investigator may
either put the subject at risk because of participating in the study or may influence the results of the
study or the subject’s ability to participate in the study.

Any clinically relevant lung disease, other than COPD considered by the investigator to be the primary
diagnosis. For example mild-to-moderate bronchiectasis is acceptable in addition to COPD unless the
bronchiectasis is considered to be the primary diagnosis.

An alternative cause for the increase in symptoms of COPD that are unrelated to an exacerbation such
as i) suspicion or clinical evidence of pneumonia; ii) high probability and suspicion of pulmonary
embolism; iii) suspicion or clinical evidence of a pneumothorax; iv) primary ischaemic event – ST or
Non ST elevation myocardial infarct and left ventricular failure [i.e. not an exacerbation of COPD]
7. STUDY PROCEDURES
7.1. Recruitment
Within primary care, as part of the quality and outcomes framework (QOF) for managing long term
common and chronic conditions, GP’s annually perform spirometry and identify patients with respiratory
disease. Within this identification procedure, all primary care practices nationally have COPD registers. At
the selected practice, there are 367 patients with COPD on the register. This will identify COPD participants
immediately, with invitation letters joint directly from the study team and the GP surgery. In addition to
this, the community respiratory admission avoidance team, funded by both the local NHS hospital and the
Clinical Commissioning Group for the relevant area, are also responsible for 350 patients with COPD who
have direct access to the nursing team (including home visits and referrals locally) during periods of
worsening of their symptoms. These patients can also be identified immediately and invited to take part
in the research via invitation letters. Screening for suitability will be available directly from GP medical
records for the primary care COPD registered patients and from the community care nursing team notes.
Study specific adverts will be left in the primary care practice.
All patients suitable for observation will be invited to take part. Assuming a recruitment response of 50%
from screening we will aim to recruit 300 patients.
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7.2. Informed Consent
The participant must personally sign and date the latest approved version of the Informed Consent form
before any trial specific procedures are performed.
Written and verbal versions of the Participant Information and Informed Consent will be presented to the
participants detailing no less than: the exact nature of the trial; what it will involve for the participant; the
implications and constraints of the protocol; the known side effects and any risks involved in taking part.
It will be clearly stated that the participant is free to withdraw from the trial at any time for any reason
without prejudice to future care, and with no obligation to give the reason for withdrawal.
The participant will be allowed as much time as wished to consider the information and the opportunity
to question the Investigator, their GP or other independent parties to decide whether they will participate
in the trial. Written Informed Consent will then be obtained by means of participant dated signature and
dated signature of the person who presented and obtained the Informed Consent. The person who
obtained the consent must be suitably qualified and experienced, and have been authorised to do so by
the Chief/Principal Investigator. A copy of the signed Informed Consent will be given to the participant.
The original signed form will be retained at the trial site.
7.3. Screening and Eligibility Assessment
7.3.1 Pre Screening assessment
Primary care GP and community nursing records will be used to identify eligible participants including
confirmation of diagnosis, inclusion and exclusion criteria (during the participant stable state of disease).
7.3.2. Screening assessment
At the screening visit participants will be given the opportunity to ask the research staff any questions they
have about the study prior to providing informed written consent. Participants will be informed that they
can withdraw from the research project at any time without prejudice to further care. No pre-specified
screening procedures are required for subject recruitment in this observational study and upon provision
of consent participants will be asked to confirm eligibility and study assessments will be undertaken.
7.4. Study Assessments
Study assessments will be performed within the primary care practice by the research team or within the
community (at home) by the community respiratory nursing staff.
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7.4.1 Scheduled baseline visit 1
Demographic history: Participant demographics including age, smoking history and past COPD medical
history will be collected.
Medication history: Full medication history will be collected, including the use of as required and over the
counter medication. Any drug allergy will be documented and dates of flu vaccination, S. pneumoniae and
H. influenzae B vaccinations will be recorded from medical records.
Past medical history: Full medical history will be collected from the participant and from the medical notes.
The Charlson Comorbidity Index43 (CCI) will be calculated [detailed in appendix A] .
COPD diagnosis history: The age of onset and age of diagnosis of COPD symptoms will be recorded from
the participant and from the medical records.
Past exacerbation history: The frequency of exacerbations, including those requiring hospitalisation in the
previous 12 months will be captured from participant recollection and from the medical records.
Medication prescribed at each exacerbation event (if available) from medical records will be captured.
Questionnaires: Patient reported outcome measures (PRO’s) will be sought to specifically test symptoms,
health status, quality of life and any associated depression and anxiety. This will utilise the use of the
Medical Research Council dyspnoea scale (MRC, Appendix B); Visual analogue score (VAS, Appendix C) 40;
COPD Assessment Tool (CAT, Appendix D) 44; the Hospital Anxiety and Depression Scale (HADS, Appendix
E)41 and the EuroQol 5D (Appendix F)42. Instructions to use these questionnaires will be given to all
participants. Each of these questionnaires are validated to be self-completed for ease of use.
Near-patient point of care testing procedures:
Lung Function: Spirometry will be performed to determine the forced expiratory volume in 1 second (FEV1)
and the forced vital capacity (FVC) according to standard ATS/ERS criteria45.
Exhaled Nitric Oxide: FENO will be used to determine airway inflammation. Participants are instructed to
blow into a machine for 10 seconds at tidal volume (normal breathing). The FENO will be available
immediately.
Pin prick testing: Using a fully sterile technique, a pin-prick blood test will be performed to determine the
inflammatory phenotype. Approximately 5 drops of blood (up to a maximum of 10 drops) will be taken for
measurement of peripheral blood eosinophil counts and CRP levels.
Sputum Collection: If the participant produces any sputum during the visit it will be collected into a sterile
container and processed the same day for measurement of sputum cell differential counts and
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microbiology. Any cell free supernatants will be stored for cell mediator analysis. These samples will be
stored and used in a number of analytical ways not limited to but including cell isolation for functional
assays, cell differential counts, and preparation of supernatants for mediator analysis. The samples will
also be used in microbiological analysis for assessment of pathogens which may include bacteriology,
virology and mycology. Development of analytical methods will be devised. Methods will include, but will
not be restricted to, immunocytochemistry, flow cytometry, ELISA, radioimmunoassay, LC/MS and
proteomics.
Pulse Oximetry: Oxygen saturations at rest will be recorded on all participants and available immediately.
This is performed by putting a non-invasive probe on the participants’ finger and recording the reading at
30 seconds.
Standard operating procedures for the near-patient point of care testing is presented in Appendix G. All
research staff undertaking any assessments and procedures will be trained to use the equipment and
perform the questionnaires to determine patient reported outcomes. Anticipated duration of visit is 30 to
45 minutes.
7.4.2. Unscheduled exacerbation visit 2 (day 0)
Study assessments will be performed on participants attending to see their GP or community respiratory
team for management of an exacerbation of COPD after medical assessment and treatment as per usual
care with medication dispensed or prescribed as per standard guidelines. After this healthcare review,
participants will be invited and seen by the research team. The anticipated duration will be 30 minutes.
Exacerbation history: Collection of data specific to the exacerbation with respect to symptom type,
duration and severity and details regarding which medication has been prescribed and its duration. During
an exacerbation the Anthonisen criteria14 with increased symptoms of breathlessness, sputum production
and sputum purulence will be used as per GOLD1 definition. The Anthonisen criteria for severity of an
exacerbation will be used as follows: Type 1 – Three major symptoms; Type 2 - two major symptoms; Type
3 – One major and one minor symptom. The major symptoms are i) Increased breathlessness; ii) increased
sputum production; or iii) increased sputum purulence. The minor symptoms are iv) Upper respiratory
tract infection in the previous 5 days; v) fever without apparent cause; vi) increased wheeze; vii) increased
cough; viii) increase in respiratory or heart rate 20% above baseline.
Questionnaires: This will utilise the use of the Visual analogue score (VAS, Appendix C)40; COPD Assessment
Tool (CAT, Appendix D) 44; and the EuroQol 5D (Appendix F)42. Instructions to use these questionnaires will
be given to all participants. Each of these questionnaires are validated to be self-completed for ease of
use.
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Diary Card: Participants will be asked to complete a 30-day daily diary (using the VAS tool, for the
symptoms of cough, breathlessness, and sputum volume and purulence) for assessment of symptoms and
recovery following treatment (Appendix H). Guidance will be given on how to complete this and a selfaddressed envelope addressed to the research centre.
Lung Function: If possible spirometry will be performed to determine the forced expiratory volume in 1
second (FEV1) and the forced vital capacity (FVC) according to standard ATS/ERS criteria45.
Exhaled Nitric Oxide: If possible FENO will be used to determine airway inflammation. Participants are
instructed to blow into a machine for 10 seconds at tidal volume (normal breathing). The FENO will be
available immediately.
Pin prick testing: Using a fully sterile technique, a pin-prick blood test will be performed to determine the
inflammatory phenotype. Approximately 5 drops of blood (up to a maximum of 10 drops) will be taken for
measurement of peripheral blood eosinophil counts and CRP levels.
Sputum Collection: If the participant produces any sputum during the visit it will be collected into a sterile
container and processed the same day for measurement of sputum cell differential counts and
microbiology and assessed as described above.
Pulse Oximetry: Oxygen saturations at rest will be recorded on all participants and available immediately.
This is performed by putting a non-invasive probe on the participants’ finger and recording the reading at
30 seconds.
7.4.3. Unscheduled exacerbation visit 3 (day 30)
This is a telephone consultation to ascertain any history of a treatment response or treatment failure
following the exacerbation event utilising PRO’s and medical records. A treatment failure is defined as the
need for re-treatment, further use of standby home packs, emergency attendances, hospitalisation or the
event of death of any cause. The telephone consultation will have an anticipated duration of 15 minutes.
All participants will be encouraged to post back their completed 30-day VAS diary at this telephone
consultation. Medical notes, prescription dispensing and hospitalised episode data will be interrogated for
collection of any treatment failure episodes.
Questionnaires: Participants will be interviewed using the following PRO’s; Visual analogue score (VAS,
Appendix C)40; COPD Assessment Tool (CAT, Appendix D) 44; and the EuroQol 5D (Appendix F)42.
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7.4.4. Unscheduled exacerbation visit 4 (day 90)
A final telephone consultation with PRO’s to ascertain any history of a treatment response or treatment
failure will be conducted with an anticipated duration time of 15 minutes. Medical notes, prescription
dispensing and hospitalised episode data will be again interrogated for collection of any treatment failure
episodes.
Questionnaires: Participants will be interviewed using the following PRO’s; Visual analogue score (VAS,
Appendix C)40; COPD Assessment Tool (CAT, Appendix D) 44; and the EuroQol 5D (Appendix F)42.
Participants who have a further exacerbation within 30 days of the index exacerbation event will be
categorised as a treatment failure episode and recorded as such. Participants that have an exacerbation
between days 30 to 90 of the index exacerbation event will be invited to attend and have data captured
as a new exacerbation event and the visit schedule is then restarted as per figure 2.
The planned study assessments and study schedule is presented in figure 4.
Figure 4. Study scheduled and unscheduled visit assessments
Scheduled
Unscheduled
Unscheduled
Unscheduled
Visit 1
Visit 2
Visit 3
Visit 4
X
X
X
X
X
X
Demographics
X
Medical history
X
Exacerbation history
X
X
Medication history
X
X
Treatment response history
Questionnaires
X
X
Exhaled NO
X
X
Spirometry
X
X
Pin prick blood test
X
X
Sputum
X
X
Symptom Diary
X
7.5. Discontinuation/Withdrawal of Participants from Study
Participants are free to withdraw consent and may be discontinued from study assessments at any time,
at the discretion of the investigator. Reasons for withdrawal/exclusion by researcher are specified as noncompliance with study requirements or health issues that compromise ongoing involvement. Participants
will be asked on withdrawal from any of the interventions whether they are still willing to provide follow-
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up information at day 30 and day 90. If they decline, no further information will be collected. The reason
for withdrawal will be recorded in the CRF.
If the participant is withdrawn due to an adverse event, the Investigator will arrange for follow-up visits or
telephone calls until the adverse event has resolved or stabilised. No further procedures or observations
will be necessary following study withdrawal and withdrawn participants will not be replaced. Data from
withdrawn participants will not be excluded from study analysis. The reason for withdrawal will be
recorded in the CRF.
7.6. Definition of End of Study
The end of trial participation is the day 90 (visit 4) which will be a final telephone consultation. The study
duration will be 12 months data collection with an additional 3 month period for data analysis.
8. SAFETY REPORTING
8.1. Definition of Serious Adverse Events
A serious adverse event is any untoward medical occurrence that:

results in death

is life-threatening

requires inpatient hospitalisation or prolongation of existing hospitalisation

results in persistent or significant disability/incapacity

consists of a congenital anomaly or birth defect.
Other ‘important medical events’ may also be considered serious if they jeopardise the participant or
require an intervention to prevent one of the above consequences.
NOTE: The term "life-threatening" in the definition of "serious" refers to an event in which the participant
was at risk of death at the time of the event; it does not refer to an event which hypothetically might have
caused death if it were more severe.
8.2. Reporting Procedures for Serious Adverse Events
Exacerbations of COPD requiring treatment, admission to hospital or resulting in death are anticipated
occurrences during the disease course and one of the outcomes of investigation in this study. Thus serious
adverse events (SAEs) or adverse events causing discontinuation in the study will be only recorded. These
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SAE’s will be reported to the chief investigator or a designated clinician and assessed for any causal link
between the intervention delivered within the clinical trial and the serious adverse event. All SAE’s will be
reported using the NRES Serious Adverse Event form.
9. STATISTICS AND ANALYSIS
In this observational study, we will be collecting data to characterise COPD phenotypes. All participant
data will be used. Listwise or pairwise deletion will be used for missing data in these analysis, thereby the
data analysis will be complete case analysis. The planned number of participants for this study is 300. There
are 367 COPD patients at the selected primary care practice and 350 COPD patients under the community
respiratory team. Assuming a retention of 50%, from the pool of 717 patients we will recruit approximately
300 patients over a 12 month period.
9.1. Statistical Plan
Descriptive statistics will be used to summarise the baseline characteristics of participants and parametric
or non-parametric t-tests (including Mann Whitney) will be used to compare outcomes between the
inflammatory phenotypes in relation to disease severity, exacerbation history, treatment history, patient
reported outcomes and results of near patient inflammation. Fisher’s exact test and logistic regression
modelling will be applied to study the treatment failure episodes and relate this to inflammatory
phenotypes. Length of recovery of exacerbation visits will be analysed using a Kaplan Meier survival
analysis estimator.
9.2. Health Economic Analysis Plan
Patient-level resource use data, including associated treatment costs (such as physician and nurse time,
oral corticosteroids, antibiotics, other medications, finger-prick tests), all additional health and personal
social service costs (such as visits to emergency walk-in centres, A&E and hospital admissions) as well as
leisure and productivity loss due to ill health for participants, will be collected and analysed. Unit costs
from the UK, will be derived from national published sources and unit cost schedules and the impact of
their use in valuing resource utilization in the economic analyses will be explored.
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10. DATA MANAGEMENT
10.1.
Access to Data
Direct access will be granted to authorised representatives from the Sponsor or host institution for
monitoring and/or audit of the study to ensure compliance with regulations.
10.2.
Data Recording
All participants will be provided with a unique identifier, which is anonymised on all CRF’s and the
electronic database. All data collected will be stored on CRF’s and then entered onto a password protected
computer. CRF data will be held in a secure site separate to the unique identifier code issued on
recruitment. Any collected sputum samples will be stored anonymously, identified by the unique identifier
only. A link between the unique identifiers and personal information will be held in secure conditions in a
separate file at the research center, and only the CI will have access to this.
10.3.
Data Storage
Study data will be carefully reviewed and, before any final analysis, clean file/database lock must be
documented. The reason for any excluded data will be described in detail in the report. Any changes in the
database after clean file/database lock will be documented.
10.4.
Data protection
Documents will be stored securely as per ethical consideration and only study staff and authorised
personnel will be granted access to data. The study will comply with relevant data protection and privacy
legislation. As part of study consent, participants will authorise the anonymous collection, use and
disclosure of their study data by the Investigator and by those persons who need that information for the
purposes of the study.
11. QUALITY ASSURANCE PROCEDURES
The study may be monitored, or audited in accordance with the current approved protocol, ICH GCP,
relevant regulations and standard operating procedures.
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12. ETHICAL AND REGULATORY CONSIDERATIONS
12.1.
Declaration of Helsinki
The Investigator will ensure that this study is conducted in accordance with the principles of the
Declaration of Helsinki.
12.2.
Guidelines for Good Clinical Practice
The Investigator will ensure that this study is conducted in accordance with relevant regulations and with
Good Clinical Practice.
12.3.
Approvals
The protocol, informed consent form, participant information sheet and any proposed advertising material
will be submitted to an appropriate Research Ethics Committee (REC), and host institution(s) for written
approval. The Investigator will submit and, where necessary, obtain approval from the above parties for
all substantial amendments to the original approved documents.
12.4.
Reporting
The CI shall submit once a year or on request, an Annual Progress Report to the REC, host organisation and
Sponsor. In addition, an End of Trial notification and final report will be submitted to the REC, host
organisation and Sponsor.
12.5.
Participant Confidentiality
The trial staff will ensure that the participants’ anonymity is maintained. The participants will be identified
only by initials and a participants ID number on the CRF and any electronic database. All documents will
be stored securely and only accessible by trial staff and authorised personnel. The trial will comply with
the Data Protection Act, which requires data to be anonymised as soon as it is practical to do so.
12.6.
Expenses and Benefits
Reasonable travel expenses for any visits additional to normal care will be reimbursed on production of
receipts, or a mileage allowance provided as appropriate.
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13. FINANCE AND INSURANCE
13.1.
Funding
This study is funded by the National Institute of Health Research via a personal fellowship award to Dr
Mona Bafadhel, the Chief and Principal Investigator. The award from the NIHR is to fund the observational
study and then to undertake a multi-centre randomised primary care based clinical trial utilising the pilot
data obtained from the observational study necessary to adequately power the clinical trial.
13.2.
Insurance
The University of Oxford has a specialist insurance policy in place which would operate in the event of any
participant suffering harm as a result of their involvement in the research (Newline Underwriting
Management Ltd, at Lloyd’s of London). NHS indemnity operates in respect of the clinical treatment which
is provided.
14. PUBLICATION POLICY
The final results of the study will be submitted for publication in peer-reviewed scientific journals for
publication and dissemination. Authorship will be determined in accordance with the ICMJE guidelines and
other contributors will be acknowledged. All data will be anonymised for publication. Public dissemination
of the study results will be via patient led organisations such as the British Lung Foundation and the
Breathe Easy groups. Patient and Public Involvement (PPI) will be specifically sought to address
dissemination of results and compilation of an end of study newsletter to the participants.
Contractual stipulation for the funding body is that the NIHR will be notified prior to publication (oral,
written or other form) of the research data. The CI shall send one draft copy of the proposed publication
to the NIHR Authority’s Representative at the same time as submission for publication or at least 28 days
before the date intended for publication whichever is earlier. The CI shall ensure that the outcome of the
Research is prepared for publication in a suitable peer-reviewed journal and shall ensure that it, and any
other publication, including patent applications, of or resulting from research carried out under this
Contract shall acknowledge the Authority’s financial support and carry a disclaimer as the Authority may
require or in the absence of direction from the Authority a notice as follows:
“This report is independent research supported by the National Institute for Health Research (PostDoctoral Fellowship, Dr Mona Bafadhel, PDF-2013-06-052). The views expressed in this publication are
those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or
the Department of Health.”
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15. REFERENCES
1.
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4.
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Andersson F, Borg S, Jansson SA, et al. The costs of exacerbations in chronic obstructive pulmonary
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Aaron SD, Vandemheen KL, Hebert P, et al. Outpatient oral prednisone after emergency treatment of
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Rothberg MB, Pekow PS, Lahti M, Brody O, Skiest DJ, Lindenauer PK. Antibiotic therapy and treatment
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Molstad S, Erntell M, Hanberger H, et al. Sustained reduction of antibiotic use and low bacterial
resistance: 10-year follow-up of the Swedish Strama programme. The Lancet infectious diseases 2008;8:12532.
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Sethi S, Murphy TF. Infection in the pathogenesis and course of chronic obstructive pulmonary disease.
The New England journal of medicine 2008;359:2355-65.
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Papi A, Bellettato CM, Braccioni F, et al. Infections and airway inflammation in chronic obstructive
pulmonary disease severe exacerbations. American journal of respiratory and critical care medicine
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14.
Anthonisen NR, Manfreda J, Warren CP, Hershfield ES, Harding GK, Nelson NA. Antibiotic therapy in
exacerbations of chronic obstructive pulmonary disease. Annals of internal medicine 1987;106:196-204.
15.
Soler N, Ewig S, Torres A, Filella X, Gonzalez J, Zaubet A. Airway inflammation and bronchial microbial
patterns in patients with stable chronic obstructive pulmonary disease. The European respiratory journal :
official journal of the European Society for Clinical Respiratory Physiology 1999;14:1015-22.
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Han MK, Agusti A, Calverley PM, et al. Chronic obstructive pulmonary disease phenotypes: the future of
COPD. American journal of respiratory and critical care medicine 2010;182:598-604.
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Shim C, Stover DE, Williams MH, Jr. Response to corticosteroids in chronic bronchitis. The Journal of
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smokers with chronic obstructive bronchitis. American journal of respiratory and critical care medicine
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Brightling CE, Monteiro W, Ward R, et al. Sputum eosinophilia and short-term response to prednisolone
in chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2000;356:1480-5.
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Saha S, Brightling CE. Eosinophilic airway inflammation in COPD. International journal of chronic
obstructive pulmonary disease 2006;1:39-47.
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Pavord ID, Sterk PJ, Hargreave FE, et al. Clinical applications of assessment of airway inflammation
using induced sputum. The European respiratory journal Supplement 2002;37:40s-3s.
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Bafadhel M, McKenna S, Terry S, et al. Acute exacerbations of chronic obstructive pulmonary disease:
identification of biologic clusters and their biomarkers. American journal of respiratory and critical care
medicine 2011;184:662-71.
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Bafadhel M, McKenna S, Terry S, et al. Blood eosinophils to direct corticosteroid treatment of
exacerbations of chronic obstructive pulmonary disease: a randomized placebo-controlled trial. American
journal of respiratory and critical care medicine 2012;186:48-55.
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Steer J, Gibson J, Bourke SC. The DECAF Score: predicting hospital mortality in exacerbations of chronic
obstructive pulmonary disease. Thorax 2012.
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Bass DA, Gonwa TA, Szejda P, Cousart MS, DeChatelet LR, McCall CE. Eosinopenia of acute infection:
Production of eosinopenia by chemotactic factors of acute inflammation. The Journal of clinical investigation
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Bafadhel M, Clark TW, Reid C, et al. Procalcitonin and C-reactive protein in hospitalized adult patients
with community-acquired pneumonia or exacerbation of asthma or COPD. Chest 2011;139:1410-8.
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Daniels JM, Snijders D, de Graaff CS, Vlaspolder F, Jansen HM, Boersma WG. Antibiotics in addition to
systemic corticosteroids for acute exacerbations of chronic obstructive pulmonary disease. American journal of
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Exacerbations of Mild to Moderate COPD. American journal of respiratory and critical care medicine 2012.
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Hobbs FD, Delaney BC, Fitzmaurice DA, et al. A review of near patient testing in primary care. Health
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Casey JR, Pichichero ME. A comparison of 2 white blood cell count devices to aid judicious antibiotic
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Grocott MP, Martin DS, Levett DZ, et al. Arterial blood gases and oxygen content in climbers on Mount
Everest. The New England journal of medicine 2009;360:140-9.
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Network BTSSIG. British guideline on the management of asthma. Thorax 2014;69:i1-i192.
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Suissa S, Dell'Aniello S, Ernst P. Long-term natural history of chronic obstructive pulmonary disease:
severe exacerbations and mortality. Thorax 2012;67:957-63.
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Seemungal TA, Donaldson GC, Paul EA, Bestall JC, Jeffries DJ, Wedzicha JA. Effect of exacerbation on
quality of life in patients with chronic obstructive pulmonary disease. American journal of respiratory and
critical care medicine 1998;157:1418-22.
35.
Donaldson GC, Seemungal TA, Bhowmik A, Wedzicha JA. Relationship between exacerbation frequency
and lung function decline in chronic obstructive pulmonary disease. Thorax 2002;57:847-52.
36.
Hurst JR, Donaldson GC, Quint JK, Goldring JJ, Baghai-Ravary R, Wedzicha JA. Temporal clustering of
exacerbations in chronic obstructive pulmonary disease. American journal of respiratory and critical care
medicine 2009;179:369-74.
37.
Hurst JR, Vestbo J, Anzueto A, et al. Susceptibility to exacerbation in chronic obstructive pulmonary
disease. The New England journal of medicine 2010;363:1128-38.
38.
Puhan MA, Vollenweider D, Latshang T, Steurer J, Steurer-Stey C. Exacerbations of chronic obstructive
pulmonary disease: when are antibiotics indicated? A systematic review. Respiratory research 2007;8:30.
39.
Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Kline Leidy N. Development and first validation of
the COPD Assessment Test. The European respiratory journal 2009;34:648-54.
40.
Brightling CE, Monterio W, Green RH, et al. Induced sputum and other outcome measures in chronic
obstructive pulmonary disease: safety and repeatability. Respiratory medicine 2001;95:999-1002.
41.
Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983;67:361-
70.
42.
EuroQol--a new facility for the measurement of health-related quality of life. The EuroQol Group. Health
policy 1990;16:199-208.
43.
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in
longitudinal studies: development and validation. Journal of chronic diseases 1987;40:373-83.
44.
Mackay AJ, Donaldson GC, Patel AR, Jones PW, Hurst JR, Wedzicha JA. Usefulness of the Chronic
Obstructive Pulmonary Disease Assessment Test to evaluate severity of COPD exacerbations. American journal
of respiratory and critical care medicine 2012;185:1218-24.
45.
Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. The European respiratory
journal 2005;26:319-38.
46.
Fletcher CM, Elmes PC, Fairbairn AS, Wood CH. The significance of respiratory symptoms and the
diagnosis of chronic bronchitis in a working population. British medical journal 1959;2:257-66.
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16. APPENDIX A: Charlson Co-morbidity index
Serum Albumin (g/dL)
☐ Age <40 years
0 points
☐ Age 41‐50 years
1 points
☐ Age 51‐60 years
2 points
☐ Age 61‐70 years
3 points
☐ Age 71‐80 years
4 points
1 Point
☐
☐
☐
☐
☐
☐
☐
☐
☐
☐
Myocardial Infarction (history, not ECG changes only)
Congestive Heart Failure
Peripheral Vascular Disease
Cerebrovascular Disease: CVA with mild or no residua TIA
Dementia
COPD
Connective Tissue Disease
Peptic Ulcer Disease
Mild Liver Disease (without portal hypertension, includes chronic hepatitis)
Diabetes without end-organ damage (excludes diet-controlled alone)
2 Points
☐
☐
☐
☐
☐
☐
Hemiplegia
Moderate to Severe Chronic Kidney Disease
Diabetes with end-organ damage (retinopathy, neuropathy, nephropathy, or brittle diabetes)
Tumor without metastasis (exclude if > 5yrs from diagnosis)
Leukemia
Lymphoma
3 Points
☐ Moderate or severe liver disease
6 Points
☐ Metastatic solid tumor
☐ AIDS (not just HIV positive)
Calculating Charlston’s co-morbidity
1. Calculate Charlson Score or Index (i)
1. Add Comorbidity score to age score
2. Total denoted as 'i' below
2. Calculate Charlson Probablity (10 year mortality)
1. Calculate Y = e^(i * 0.9)
2. Calculate Z = 0.983^Y
3. where Z is the 10 year survival
Online calculator of the Charlson score - http://touchcalc.com/calculators/cci_js
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17. APPENDIX B: MRC Dyspnoea Scale
The MRC dyspnoea scale is a standardised instrument to quantify the disability associated with
breathlessness 46. Respondents are asked what degree of breathlessness they have related to a set if
standardised exercises.
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18. APPENDIX C: Visual Analogue Scale (VAS)
The visual analogue scale is a standardised tool
40
to quantify the degree of symptoms specified from a
scale of no symptoms to the worst ever symptoms.
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19. APPENDIX D: COPD Assessment Tool (CAT)
The CAT is a validated short (8-item) patient completed questionnaire to measure health status specifically
in patients with COPD 39
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20. APPENDIX E: Hospital and Anxiety Depression Scale (HADS)
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21. APPENDIX F: EuroQol 5D
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The EQ-5D is a standardised instrument for the measurement of health utility and used for health
economic applications
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22. APPENDIX G: Standard Operating Procedures
Exhaled Nitric Oxide (NO)
Nitric oxide is widely distributed in the body. Relevant to the lung is the production of nitric oxide in the
presence of eosinophilic airway inflammation. Exhaled NO is only produced when inflammation is present
and can be measured within the clinic in a few minutes. Participants have to inhale deeply and then exhale
through a disposable filter for 10 seconds. The results are available within 2 minutes, with normal values
ranging between 5 and 25 parts per billion (ppb). The following factors can cause an increase in the FeNO:
airway viral infection, allergic rhinitis and recent consumption of nitrate rich food (beetroot, strawberries,
gooseberries and raspberries). A decrease in FeNO can be caused by repeated spirometric measures (thus
FeNO is performed before lung function), exercise and smoking.
Spirometry
The forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and slow vital capacity (SVC)
will be measured at each visit using standard spirometry. Spirometry measurements will be obtained using
spirometry equipment that meets or exceeds the minimal performance recommendations of the American
Thoracic Society45. For FEV1 and FVC determinations, at least 3 acceptable spirometry efforts (with no
more than 8) should be obtained. Acceptable spirometry efforts should have a satisfactory start of test
and end of test (i.e. a plateau in the volume-time curve) and be free from artefacts due to cough, early
termination, poor, obstructed mouthpiece, equipment malfunction, or other reasons. Calibration records
will be kept as source documentation. At stable visits whenever possible both pre and post-bronchodilator
data measurements will be recorded. At exacerbation only post-bronchodilator measurements of FEV1
and FVC will be captured.
Near patient pin-prick blood sampling
Near patient test analysis will be performed using the HemoCue WBC DIFF® and QuikRead® CRP analyser.
This provides the blood differential cell count and CRP within a few minutes from a very small amount of
blood (10μL, equivalent to 1 finger-prick blood spot for each test). Using a completely sterile technique,
prick the lateral edge of the proximal third of the digit for sampling and sample according to the
manufacturer’s recommendations.
COPD Assessment Tool (CAT)
The COPD Assessment is a validated, short and simple patient completed questionnaire which has been
developed for use in routine clinical practice to measure the health status of patients with COPD 39. The
CAT is an 8-item questionnaire suitable for completion by all patients diagnosed with COPD. When
completing the questionnaire, subjects rate their experience on a 6-point scale, ranging from 0 (maximum
impairment) to 5 (no impairment) with a scoring range of 0-40. Higher scores indicate greater disease
impact.
Visual Analogue Scale (VAS)
The VAS is a 100 mm length line where patients will simply mark on the line how they feel from no
symptom to worst ever. This will be measured using a ruler and recorded in the eCRF. VAS will be measured
for dyspnoea, cough, and sputum production (volume) and sputum purulence (colour) and has been
validated for use in COPD patients40.
EuroQoL 5D (EQ-5D-5L)
The EQ-5D-5L is a standardised instrument for use as a measure of health utility. It is designed for selfcompletion and is cognitively simple, taking only a few minutes to complete. The EQ-5D-5L is a two-part
self-assessment questionnaire. The first part consists of five items covering five dimensions (mobility, selfcare, usual activities, pain/discomfort, and anxiety/depression). Each dimension is measured by a fivepoint Likert scale (no problems, slight problems, moderate problems, severe problems, and extreme
problems). Respondents are asked to choose one level that reflects their "own health state today" for each
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of the five dimensions. Respondents can be then classified into one of 243 distinct health states. The
second part is a 20-cm visual analogue scale (EQ-VAS) that has endpoints labelled "best imaginable health
state" and "worst imaginable health state "anchored at 100 and 0, respectively. Respondents are asked to
indicate how they rate their own health by drawing a line from an anchor box to that point on the EQ-VAS
which best represents their own health on that day. EQ-5D-5L health states are converted to a single
summary index by applying a formula that essentially attaches weights to each of the levels in each
dimension. The formula is based on the valuation of EQ-5D health states from general population samples.
Modified Medical Research Council Dyspnoea Scale (mMRC)
The MRC dyspnoea scale is a simple method used to assess the severity of breathlessness46. Graded 0 to 4
patients are asked to choose one of 4 statements relating to the severity of breathlessness. The higher the
score the worse the breathlessness.
Charlson Co-Morbidity Index (CCI)
The Charlson comorbidity index43 is a tool used to predict the ten-year mortality for a patient who may
have a range of comorbid conditions, such as heart disease or cancer (a total of 22 conditions). Each
condition is assigned a score and a total score is allocated to provide a total score to predict mortality.
23. Appendix H: 30 day VAS diary card
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ID:______Initials:
Date Started:
A Visual Analogue Scale (VAS) is an instrument used to try to measure a characteristic or attitude
that cannot easily be directly measured, e.g. how you feel.
This questionnaire is to be taken each day and should only take approximately 5 minutes of your
time.
There are four sections, each with a different symptom – Cough, Breathlessness, amount of sputum
you produce and how discoloured your sputum is.
We would like to know how good or bad you feel that symptom are on each day after your treatment
has started. For example, if on day 1 your cough is not bad, place a mark on the line towards the
left hand side or if was really bad then place the mark towards the right hand side. Do this for each
symptom each day.
Once the 30 days has finished please pop the diary in the envelope provided and place it in your
local post box.
We would like to say thank-you for taking the time to fill in this questionnaire
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Worst Cough Imaginable
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Worse Sputum
Production Imaginable
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24. APPENDIX I: AMENDMENT HISTORY
Amendment
Protocol
No.
Version No.
Date issued
Author(s)
of Details of Changes made
changes
Protocol amendments must be submitted to the Sponsor for approval prior to submission to the REC
committee or MHRA.
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