Associates of, and Time to Recovery From, Eosinopenia in Severe COPD Exacerbation
Conditions: Chronic Obstructive Pulmonary Disease
Sponsor: Northumbria Healthcare NHS Foundation Trust

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Title: Associates of, and Time to Recovery from, Eosinopenia in severe 
COPD exacerbation. 
Acronym: A-TREC 
 
Key Study Information 
 
Protocol Version No/Date: Version 1.1, 8th December 2023 
IRAS Number:  
 
333785 
Sponsor: 
 
 
Northumbria Healthcare NHS Foundation Trust 
Sponsor Reference No: 
NHCT0457 
Funder: 
 
 
Northumbria Healthcare NHS Foundation Trust, Chiesi  
 
 
 
 
Limited and GlaxoSmithKline Research & Development Limited 
Funding Reference No: 
N/A 
Chief Investigator: 
 
Professor Stephen Bourke 
REC Reference: 
 
23/NW/0346 
 
 
Protocol Developers 
Professor Stephen Bourke 
Consultant Respiratory Physician 
Northumbria Healthcare NHS Foundation Trust 
Honorary Professor of Respiratory Medicine, Newcastle 
University 
Dr John Steer  
 
Consultant Respiratory Physician 
Northumbria Healthcare NHS Foundation Trust 
 
 
 
 
Associate Clinical Lecturer, Newcastle University 
Dr Arun Prasad 
 
Clinical Research Fellow 
 
 
 
 
Northumbria Healthcare NHS Foundation Trust 
Dr Peter Ireland 
 
Teaching and Research Fellow 
Northumbria Healthcare NHS Foundation Trust 
Dr Eduwin Pakpahan  
Assistant Professor in Statistics 
Northumbria University 
 
Contact Details (Northumbria Healthcare NHS Foundation Trust) 
R&D Department: 
 
Tel: 0191 2934087 
 
 
 
 
Email: Jemma.Nelson@northumbria-healthcare.nhs.uk 
 
Chief Investigator: 
 
Tel: 0191 2934026 
 
 
 
 
Email: Stephen.Bourke@nhct.nhs.uk 
 
 
 
 

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Signature page 
The undersigned confirm that the following protocol has been agreed and accepted and 
that the Chief Investigator agrees to conduct the trial in compliance with GCP guidelines, the 
Sponsor’s (and any other relevant) SOPs, and other regulatory requirements as amended. 
  
I agree to ensure that the confidential information contained in this document will not be 
used for any other purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of the Sponsor. 
 
I also confirm that I will make the findings of the trial publicly available through publication 
or other dissemination tools without any unnecessary delay and that an honest accurate 
and transparent account of the trial will be given; and that any discrepancies and serious 
breaches of GCP from the trial as planned in this protocol will be explained.  
 
 
For and on behalf of the Study Sponsor:  
Signature:  
 
..............................................................................  
Date: ....../....../......  
Name (please print):  
 
..............................................................................  
 
Position: ...............................................................  
 
 
 
Chief Investigator:  
Signature:  
 
..............................................................................  
Date: 08/ 12/ 2023  
Name (please print):  
Prof Stephen Bourke 
..............................................................................  
 
Position: Consultant Respiratory Physician..........  
 
 
 
 

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Key Study Contacts 
Chief Investigator 
 
Professor Stephen Bourke 
 
 
 
 
Consultant Respiratory Physician 
Northumbria Healthcare NHS Foundation Trust 
 
 
 
 
Tel: 0191 293 4026 
 
 
 
 
Email: Stephen.Bourke@nhct.nhs.uk 
 
Study Co-ordinator 
 
Jemma Nelson 
 
 
 
 
Research and Development 
Northumbria Healthcare NHS Foundation Trust 
 
 
 
 
Tel: 0191 293 4087 
 
 
 
 
Email: Jemma.Nelson@northumbria-healthcare.nhs.uk 
 
Sponsor 
 
 
Peta Heslop 
 
 
 
 
Head of Research and Development 
 
 
 
 
Northumbria Healthcare NHS Foundation Trust 
 
 
 
 
Tel: 0191 293 4087 
 
 
 
 
Email: Peta.Heslop@northumbria-healthcare.nhs.uk 
 
Funder s 
 
 
Jemma Nelson 
Research and Development 
Northumbria Healthcare NHS Foundation Trust 
Tel: 0191 293 4087 
Email: Jemma.Nelson@northumbria-healthcare.nhs.uk 
 
Saarah Niazi-Ali 
Chiesi Limited 
Email: s.niazi-ali@chiesi.com 
 
Rachel Tse 
GlaxoSmithKline Research & Development Limited 
Email: Rachel.w.tse@gsk.com 
 
 
Key Protocol Contributors 
Professor Stephen Bourke 
 
 
 
 
Consultant Respiratory Physician 
 
 
 
 
Tel: 0191 293 4026 
 
 
 
 
Email: Stephen.Bourke@northumbria-healthcare.nhs.uk 
 
 
 
 
 
Dr Peter Ireland 
 
 
 
 
Teaching and Research Fellow 
 
 
 
 
Email: Peter.Ireland@northumbria-healthcare.nhs.uk 
 
 
 
 

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Statistician 
 
 
Dr Eduwin Pakpahan 
 
 
 
 
Assistant Professor in Statistics 
Northumbria University 
 
 
 
 
Tel: 0191 349 5317 
 
 
 
 
Email: Eduwin.Pakpahan@northumbria.ac.uk 
 
Trial Steering Committee 
Professor Mona Bafadhel 
Chair  
 
 
Consultant Respiratory Physician 
 
 
 
 
Email: Mona.Bafadhel@kcl.ac.uk 
 
 
 
 
 

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i. 
List of Contents 
 
General Information 
Page No. 
Title Page 
1 
Key Study Information 
1 
Signature Page 
2 
Key Study Contacts 
3-4 
i. 
List of Contents 
5 
ii. 
List of Abbreviations 
6 
iii. 
Study summary 
7-8 
iv. 
Funding 
9 
v. 
Role of Study Sponsor and Funder 
10 
vi. 
Roles and Responsibilities of Trial Management Committees, 
Groups and Individuals 
11 
vii. 
Protocol Contributors 
12 
viii. 
Keywords 
13 
 
 
Section 
 
1. Background 
14-15 
2. Rationale 
15-16 
3. Objectives and Outcome Measures/Endpoints 
16-17 
4. Study Design 
17 
5. Study Setting 
17 
6. Participant Eligibility Criteria 
18-19 
7. Study Procedures 
19-24 
8. Statistics and Data Analysis 
24-26 
9. Data Management 
27 
10. Monitoring, Audit and Inspection 
27-28 
11. Ethical and Regulatory Considerations 
28-31 
12. Dissemination Policy 
32 
13. References 
33-34 
14. Appendices 
35-36 
 
 
 

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ii. 
List of Abbreviations 
 
AOT 
Ambulatory oxygen therapy 
BEC 
Blood eosinophil count 
BMI 
Body mass index 
CAT 
COPD Assessment Tool 
CI 
Chief investigator 
COPD 
Chronic Obstructive Pulmonary Disease 
CRF 
Case Report Form 
CRP 
C-reactive protein 
DECAF 
Dyspnoea, Eosinopenia, Consolidation, Acidosis, 
Fibrillation 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Record Form 
eMRCD 
Extended Medical Research Council Dyspnoea 
score 
FBC 
Full blood count 
FeNO 
Fractional exhaled Nitric Oxide 
FEV1 
Forced Expiratory Volume within 1 second 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
HRQoL  
Health-related quality of life 
ICS 
Inhaled corticosteroids 
IgE 
Immunoglobulin E 
IL 
Interleukin 
LABA 
Long-acting beta agonists 
LABD 
Long-acting bronchodilators 
LAMA 
Long-acting muscarinic antagonists 
LTOT 
Long-term oxygen therapy 
NEWS2 
National early warning score 2 
NHCT 
Northumbria Healthcare NHS Foundation Trust 
NHS 
National Health Service 
NIV 
Non-invasive ventilation 
NSECH 
Northumbria Specialist Emergency Care Hospital 
OCS 
Oral corticosteroids 
PI 
Principal Investigator 
PIS 
Patient information sheet 
PPI 
Public and Patient Involvement 
REC 
Research Ethics Committee 
SABD 
Short-acting bronchodilators 
TMG 
Trial Management Group 
TNFa 
Tumour necrosis factor alpha 
TSG 
Trial Steering Group 
 
 

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iii. 
Study Summary 
 
Study Title 
Associates of, and Time to Recovery from, Eosinopenia in severe COPD 
exacerbation 
Acronym 
A-TREC 
Trial Design 
Single centre observational cohort study 
Trial 
Participants 
Clinical diagnosis of severe exacerbation of COPD +/- eosinopenia 
Planned 
Sample Size 
200 participants 
Study Duration 
24 months of recruitment 
Follow-up 
Duration 
6 weeks follow-up from entry into study 
Planned Study 
Period 
FSFV 19/01/2024  
LSFV 01/06/2026 
Primary 
Objectives 
Outcomes 
 
Total Study Population 
1. To identify demographic, 
physiological and clinical 
factors independently 
associated with admission 
eosinopenia in patients with a 
severe exacerbation of COPD. 
 
1. Indices independently 
associated with eosinopenia 
on admission in patients with 
a severe exacerbation of 
COPD. 
 
Eosinopenia with uneventful recovery*1 
2. To assess the time to recovery 
from eosinopenia to stable 
BEC following a severe 
exacerbation of COPD. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2. The time taken for BEC to 
recover to a level equal to or 
higher than the 42-day 
assessment. 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Secondary 
Objectives 
Outcomes 
 
Total Study Population 
1. Assess the consistency of 
eosinophil phenotype during 
severe exacerbations within 
individuals. 
 
 
 
2. Compare Th1 and Th2 
cytokine levels during acute 
exacerbation of COPD and at 
the point of recovery. 
 
1. Level of agreement between 
the index admission 
eosinophil phenotype and 
prior admissions for 
exacerbations of COPD since 
May 2019*2. 
 
2. Change from baseline cytokine 
levels (Th1 and Th2) at day 28, 
stratified by intercurrent 
exacerbation or other acute 
illness status, including sub-
group analysis (eosinopenic 
cohort vs non-eosinopenic 
cohort) 
 
Eosinopenia with uneventful recovery*1 
3. To explore the time to 
recovery from admission 
eosinopenia in severe 
exacerbation of COPD, 
including the implications for 
ICS prescribing decisions at 
the GOLD 2023 threshold.  
 
 
 
 
 
3. A) The proportion of patients 
whose BEC reaches 100 cell/uL 
or higher at each visit 
 
3. B) The time taken to reach 
peak BEC following a severe 
exacerbation of COPD. 
 
3.  C) Exploratory analysis 
looking for patient and 
treatment associations with 
rate of recovery of BEC. 
 
Total Eosinopenic Cohort 
4. Assess the impact of moderate 
and severe exacerbations on 
recovery from eosinopenia.  
 
4. Comparison of the recovery of 
BEC in patients who had 
further exacerbations of COPD 
within the study period and 
patients who have not had 
further exacerbations. 
*1 Eosinopenia on admission who do not receive a further course of systemic corticosteroids 
or require emergency hospital admission for an acute illness in the six weeks following 
admission to hospital with a severe exacerbation of COPD. 
*2 May 2019 is the date that BEC measurements began to be reported to two decimal places 
at the designated research site – Northumbria Healthcare NHS Foundation Trust. 

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iv. 
Funding 
 
Funder s 
Financial Support Given 
Northumbria Healthcare NHS Foundation 
Trust 
Research and Development 
North Tyneside General Hospital 
Rake Lane 
North Shields 
NE29 8NH 
 
Email: Jemma.Nelson@northumbria-
healthcare.nhs.uk 
Essential research and laboratory costs to 
deliver the study. 
Northumbria Healthcare NHS Foundation 
Trust 
Teaching and Research Fellow Programme 
North Tyneside General Hospital 
Rake Lane 
North Shields 
NE29 8NH 
 
Email: Tracey.Hogg3@northumbria-
healthcare.nhs.uk 
Complete funding for Principal 
Investigator’s salary for 3-year period. 
Chiesi Limited 
333 Styal Road 
Manchester 
M22 5LG 
 
Email: s.niazi-ali@chiesi.com 
Desirable research and laboratory costs to 
deliver the study including statistical 
analysis 
GlaxoSmithKline Research & Development 
Limited 
980 Great West Road 
Brentford 
Middlesex 
TW8 9GS 
 
Email: Rachel.w.tse@gsk.com 
Desirable research and laboratory costs to 
deliver the study. 
 
 
 
 
 

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v. 
Role of Study Sponsor and Funder 
 
Sponsor 
The Sponsor, Northumbria Healthcare NHS Foundation Trust, assumes overall 
responsibility for the initiation and management of the trial 
 
Funder 
The study funders had no role in the study design or protocol development 
and will have no direct involvement in the study conduct, data analysis and 
interpretation, manuscript writing or dissemination of results. 
 
 
 
 

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vi. 
Roles and Responsibilities of Trial Management Committees, Groups and 
Individuals 
 
Trial Steering 
Committee 
 
A Trial Steering Committee will be formed with an independent 
Chair, and will meet at least every 12 months and send timely 
reports to the Sponsor.  
 
The independent Chair is: 
Professor Mona Bafadhel 
Consultant Respiratory Physician 
Email: Mona.Bafadhel@kcl.ac.uk 
Trial Management 
Group 
 
The Trial Management Group will meet regularly to ensure all 
practical details of the study are progressing and working well, 
and everyone within the study understands them. The Chair will 
be the Chief Investigator who assumes primary responsibility 
for the design, conduct and reporting of the study. 
 
Chief Investigator: 
Professor Stephen Bourke 
Consultant Respiratory Physician 
Tel: 0191 293 4026 
Email: Stephen.Bourke@nhct.nhs.uk 
 
 
 

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vii. 
Protocol Contributors 
 
Professor Stephen Bourke 
Conceived the study, has led the 
development of the study design and 
protocol and will ensure appropriate 
governance is in place. Professor Bourke 
will support and supervise Peter Ireland 
with all other key research activities 
including mentorship, development and 
dissemination of study results. 
Dr John Steer 
Contributed to development of the study 
design and protocol. Dr Steer will support 
and supervise Peter Ireland including 
provision of mentorship and development. 
Professor John Simpson 
Contributed to development of the study 
design and protocol. Cytokine analysis will 
occur in collaboration with Professor 
Simpson’s laboratory at Newcastle 
University. Professor Simpson will support 
and supervise Peter Ireland including 
provision of mentorship and development. 
Dr Peter Ireland 
Will be involved in all stages of the study, 
from application to final dissemination of 
results, including: developing study 
protocol, developing key study documents, 
developing the source document 
worksheet, setting up an electronic 
database, participant recruitment, 
performing baseline assessments, data 
collection, performing data validation, 
involvement in study management 
meetings, applying statistical analysis and 
involvement in preparing publication of 
results for dissemination. 
Dr Arun Prasad 
Contributed to development of the study 
design and protocol. Gathered feedback 
from patients to help inform study design. 
Dr Eduwin Pakpahan 
Statistician responsible for development of 
the initial statistical analysis plan, 
performing data analysis and assisting with 
reports and publications. 
Patient and Public Involvement 
Representative patients from the 
Northumbria Lung Research PPI group have 
been involved in the study design. 
 
 

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viii. 
Key Words 
 
Chronic Obstructive Pulmonary Disease 
(COPD) 
A lung disease causing breathlessness, 
sputum production and frequent 
exacerbations 
Blood Eosinophil Count (BEC) stable state 
Blood eosinophil count during clinical 
stability 
Eosinopenia 
Low level of eosinophils in circulating blood 
defined as < 0.05 x 109/L 
 
  
 

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1. Background 
 
Chronic obstructive pulmonary disease (COPD) is a complex and heterogenous condition 
which is characterised by persistent airflow limitation and emphysema, often contributing 
to significant and progressive respiratory symptoms. COPD is extremely prevalent with an 
estimated 391.9 million people living with the condition worldwide in 2019 (1), more than 
1.2 million of whom were living in the UK (2). COPD confers significant mortality and 
morbidity, with 3.3 million people dying from the condition in 2019 (1), making it the third-
leading cause of death worldwide. In the same year it was estimated to be the seventh-
leading cause of poor health worldwide accounting for 74.4 million disability-adjusted life 
years (1).  
  
People living with COPD are often prone to frequent exacerbations. These are characterised 
by an acute increase in breathlessness and/or cough with a change in sputum production. 
Exacerbations are often secondary to inflammation caused by infection, pollution or other 
insults to the airways (3). A severe exacerbation of COPD is commonly defined as the 
patient requiring admission to hospital for treatment. 
  
Exacerbations of COPD have a significant burden on individuals. Patients who are admitted 
to hospital with acute exacerbations of their COPD experience a substantial decrease in 
their health-related quality of life (HRQoL) and lung function (4) and have a significantly 
increased risk of mortality (5). For patients who survive to be discharged, over 40% will be 
readmitted within 90 days and over 20% of all patients who are discharged from hospital 
following an acute exacerbation of COPD will die within 1 year (6).  
  
COPD is also associated with a high burden on healthcare and the economy. There are over 
140,000 emergency hospital admissions for acute exacerbations of COPD each year in the 
UK accounting for almost 2% of all hospital admissions (2). COPD costs the NHS 
approximately £1.9 billion per year, almost 20% of the cost of all lung conditions (7). In the 
European Union respiratory disease accounts for 6% of the annual healthcare budget and 
COPD accounts for more than 50% of this (8). 
  
Inhaled corticosteroids (ICS) are of benefit in some patients with COPD. In isolation, ICS have 
not been proven to reduce the long-term decline in FEV1 or improve mortality (9) and their 
use may increase the risk of pneumonia (10). When ICS is combined with long-acting 
bronchodilators (LABD) as a triple-therapy inhaler (LABA+LAMA+ICS) there is a reduction in 
exacerbation rates plus improvement in lung function, HRQoL and survival when compared 
to mono- and dual-therapy (11, 12, 13). 
  
Blood eosinophil count (BEC) can be used as a biomarker to predict whether the addition of 
ICS to LABD will be beneficial in reducing future COPD exacerbations (14). Similarly, BEC 
informs selection for emerging biologic therapy in COPD, including Mepolizumab (15) and 
Dupilumab (16). The association between BEC and reduction in exacerbation frequency is 
based on BEC measured when the patient is clinically stable. The relationship between BEC 
and effect of ICS is continuous, with increasing effects seen as BEC rises (17). ICS have very 
little effect when the BEC is < 100 cells/uL and a post hoc risk-benefit analysis suggested 
that at lower levels of BEC the harm of ICS due to pneumonia is greater than the benefit of 

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severe exacerbation reduction (18). Patients with BEC >= 300 cells/uL are most likely to gain 
treatment benefit from the addition of ICS. Current national and international COPD 
guidelines suggest the use of BEC as a biomarker to help inform the decision of whether to 
commence or withdraw ICS (19), but do not specify measuring BEC at a time of clinical 
stability. 
  
BEC fall transiently and often profoundly during severe ECOPD (20). In the Dyspnoea, 
Eosinopenia, Consolidation, Acidaemia and atrial Fibrillation (DECAF) score developmental 
cohorts, admission eosinopenia (BEC< 50 cells/µL) was present in 1,340 of 2,645 severe 
ECOPD (21). In the recent BEC COPD study (IRAS 285200) eosinopenia was less common on 
discharge compared to admission, despite in-hospital prednisolone therapy (22), suggesting 
that it is primarily driven by factors other than corticosteroid use. BEC is also transiently 
suppressed during other acute illnesses such as sepsis (23) and in response to increases in 
adrenaline (24), further suggesting that there may be other independent factors behind 
transient eosinopenia during exacerbations of COPD.   
    
It is unclear at what point eosinopenia following an exacerbation of COPD recovers to stable 
state BEC. The timing of measuring BEC as a biomarker to inform the use of ICS as a 
maintenance therapy in COPD is integral, as measurements during an exacerbation will not 
accurately capture all patients who may benefit from this treatment. This is not recognised 
in current national and international guidelines related to COPD. 
 
 
2. Rationale 
 
Decisions regarding long-term management of COPD are often made in the acute setting. 
Given that transient eosinopenia occurs in approximately 50% of patients with severe 
exacerbations of COPD (21), measuring BEC during an acute admission or illness risks 
incorrectly identifying all patients who may benefit from the introduction of ICS. In the 
current BEC COPD study (IRAS 285200), reliance on admission and discharge BEC 
inappropriately denied ICS to 47% and 33% of patients respectively compared to a 
confirmed stable-state measure.  
  
A co-primary aim of this study is to determine when BEC will recover to stable state 
following a severe exacerbation of COPD. This will inform the optimum timing to measure 
BEC for use as a biomarker in decisions related to management escalation. Based on the 
results of BEC COPD, it is likely that an increased number of patients will be identified as 
being above the BEC threshold and therefore likely to benefit from ICS when time is allowed 
for BEC to recover to stable state. Increasing the number of patients with COPD who are 
appropriately escalated to ICS maintenance therapy should reduce the burden of COPD on 
patients and the NHS by reducing exacerbation and hospitalisation rate (11) and may also 
improve mortality (25). 
  
Eosinopenia during exacerbation of COPD is associated with increased short-term mortality 
(21). Treatment with oral corticosteroids does not fully explain the mechanisms behind the 
development of eosinopenia, with the phenomenon being less common on discharge 
compared to admission despite inpatient oral corticosteroid treatment, as seen during BEC 

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COPD. Another co-primary aim of this study is to identify demographic, physiological and 
clinical factors independently associated with admission eosinopenia in patients with a 
severe exacerbation of COPD, providing useful mechanistic information regarding the 
relationship between BEC and short-term mortality. 
  
The hypothesis for this study is that 90% of participants who are admitted to hospital with a 
severe exacerbation of COPD and eosinopenia will have recovery of their BEC to baseline 
stable state within 4 weeks. We also hypothesize that there are demographic, physiological 
and clinical factors independently associated with admission eosinopenia other than prior 
systemic corticosteroid use. 
 
 
3. Objectives and Outcome Measure/Endpoint 
 
3.1 Co-primary aims 
 
1. To identify demographic, physiological and clinical factors independently associated 
with admission eosinopenia in patients with a severe exacerbation of COPD. 
 
2. To assess the time to recovery from eosinopenia to stable BEC following a severe 
exacerbation of COPD with uneventful recovery. *1 
 
3.2 Secondary aims 
 
1. To assess the consistency of eosinophil phenotype during severe exacerbations 
within individuals. 
 
2. To compare Th1 and Th2 cytokine levels during acute exacerbation of COPD and at 
the point of recovery. 
 
3. To further explore the duration of recovery from admission eosinopenia in severe 
exacerbation of COPD, including the implications for ICS prescribing decisions at the 
GOLD 2023 threshold. *1 
 
4. To assess the impact of moderate and severe exacerbations on recovery from 
eosinopenia. *2 
 
3.3 Co-primary outcomes 
 
1. Indices independently associated with eosinopenia on admission in patients with a 
severe exacerbation of COPD. 
 
2. The time taken for BEC to recover to a level equal to or higher than the 42-day 
assessment. *1 
 
 
 

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3.4 Secondary outcomes 
 
1. Level of agreement between the index admission eosinophil phenotype and prior 
admissions for exacerbations of COPD since May 2019*3. 
 
2. Change from baseline cytokine levels (Th1 and Th2) at day 28, stratified by 
intercurrent exacerbation or other acute illness status, including sub-group analysis 
(eosinopenic cohort vs non-eosinopenic cohort) 
 
3.  
a. The time taken to reach peak BEC following a severe exacerbation of COPD. 
*1 
b. The proportion of patients whose BEC reaches 100 cells/uL or higher at each 
visit. *1 
c. Exploratory analysis looking for patient and treatment associations with rate 
of recovery of BEC. *1 
 
4. Comparison of the recovery of BEC in patients who had further exacerbations of 
COPD within the study period and patients who have not had further exacerbations. 
*2 
 
*1 Eosinopenia on admission who do not receive a further course of systemic corticosteroids 
or require emergency hospital admission for an acute illness in the six weeks following 
admission to hospital with a severe exacerbation of COPD 
 
*2 Total eosinopenic cohort 
 
*3 May 2019 is the date that BEC measurements began to be reported to two decimal places 
at the designated research site – Northumbria Healthcare NHS Foundation Trust 
 
 
4. Study Design 
 
A single-centre observational cohort study. 
 
 
5. Study Setting 
 
Patients will be recruited from a single secondary care centre within the UK. The confirmed 
recruiting site is Northumbria Healthcare NHS Foundation Trust (NHCT). Patients will be 
recruited from Northumbria Specialist Emergency Care Hospital (NSECH) and will be 
identified by daily screening of acute admissions. 
 
 
 
 
 

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6. Participant Eligibility Criteria 
 
6.1 Inclusion Criteria 
 
1. Admitted to hospital with primary clinical diagnosis of exacerbation of COPD* 
2. Age at least 35 years 
3. Smoking history of at least 10 pack years 
4. Airflow obstruction: FEV1/FVC ratio < 0.7 confirmed on historic or inpatient 
spirometry 
5. Capacity to give informed consent to participate 
6. Recruitment within 36 hours of initial full blood count following presentation to 
hospital 
 
*Primary diagnosis to be ratified by study investigator at time of eligibility review 
 
6.2 Exclusion Criteria 
 
1. Parasitic infection, systemic fungal infection (excluding infection limited to nails or 
skin), eosinophilic granulomatosis with polyangiitis, hypereosinophilic syndrome or 
other conditions associated with a high eosinophil count # 
2.  Active malignancy 
3. Maintenance oral prednisolone or other systemic steroids, anti-interleukin 5 therapy 
or other medication known to influence BEC 
4. Patients with poor venous access 
5. Investigator confirmed history of asthma in adulthood 
6. Non-COPD related health problems which in the view of the primary investigator 
may compromise the conduct and completion of the study 
 
# Patients with atopic conditions such as allergic rhinitis, allergic conjunctivitis and eczema 
will be eligible. 
 
6.3 Additional criteria for the time to recovery from eosinopenia analysis only 
 
Inclusion criteria: 
a. Eosinopenia on admission 
b. Uneventful recovery*1 
 
*1 Eosinopenia on admission who do not receive a further course of systemic corticosteroids 
or require emergency hospital admission for an acute illness in the six weeks following 
admission to hospital with a severe exacerbation of COPD 
 
 
7. Study Procedures 
 
A schedule of activities is included in the appendix of this protocol (appendix 1).  
 

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The initial assessments and investigations will be performed within 36 hours of the 
participant’s initial full blood count on presentation to hospital with a severe exacerbation 
of COPD. Length of stay as an inpatient can vary considerably for exacerbations of COPD and 
therefore the settings for the follow up assessments and investigations will vary 
considerably. These will include inpatient setting, outpatient setting or in the patient’s 
home. There will be a 1-day window for the day 3 assessment, and a 3-day window either 
side of patient follow-up assessments and investigations from day 7 of the scheduled 
activities. All visits are timed from the date and time of participant’s initial full blood count 
on presentation to hospital. 
 
Given current evidence which suggests that BEC may express a circadian rhythm in patients 
with COPD (27), blood samples will be taken between 10:00 – 18:00 as BEC are stable 
between these time points, which are also consistent with the timing of most stable state 
blood tests in clinical practice (e.g. during COPD reviews and clinic visits). The time from 
sampling to analysis will be within a 24-hour window to reduce the reduction in BEC which 
is associated with a longer time from sample collection to analysis (28). These parameters 
should reduce variability in BEC measurements which could affect the validity of our results. 
 
Reason for attrition from the time to recovery from eosinopenia analysis will be recorded 
(e.g. acute illness, steroid use) and rates of attrition will be closely monitored. We will 
introduce a procedure for participants and/or their community clinical team to contact the 
research team to provide advice on when treatment with steroids in the community is 
clinically appropriate. This may help to reduce inappropriate use of steroids and therefore 
reduce attrition rates, as well as reducing risk to participants. 
 
7.1 Recruitment 
 
Patients who may be eligible for the study (severe exacerbations of COPD) will be provided 
with a participant information sheet (PIS) on admission. This will provide basic information 
about the study to help facilitate discussions about participation in the study when 
approached by a member of the research team. 
 
Any recruitment successes or concerns will be identified by the research team and 
subsequently discussed in regular meetings with supervisors and during monthly NHCT 
respiratory research meetings. Feedback will also be obtained from participants in the study 
and shared with the Northumbria Lung Research PPI Group, the study Trial Management 
Group and the Trial Steering Group. Facilitators and barriers to recruitment identified by the 
research team and feedback obtained from study participants will be used to inform 
ongoing recruitment to improve recruitment success. 
 
We will record the details of patients with exacerbations of COPD who are not eligible or 
who decline to take part in a screening log. 
 
7.1.1 Participant Identification 
 
Participants will be identified by the usual care team based on the eligibility criteria and 
approached to discuss participation in the study. 

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Eligibility will be confirmed by the research team and recorded on the source document 
worksheet and eCRF using information obtained from historic and current electronic and 
paper clinical records. 
 
7.1.2 Screening 
 
Acute medical admissions to NSECH will be screened daily by the usual care team. Informed 
consent will need to be obtained and initial assessments and additional study specific 
baseline investigations performed within 36 hours of the participant’s initial full blood count 
on presentation to hospital with a severe exacerbation of COPD (for overnight urinary 
metanephrines, collection needs to commence within the 36-hour window). We will aim to 
discuss participation in the study with eligible patients at the earliest opportunity from time 
of initial full blood count. 
 
7.2 Consent 
 
Once identified as eligible, patients will be approached by a member of the research team. If 
not already provided, information about the study will be given in the form of the PIS and 
any initial questions will be answered. The PIS will be available in large font to aid those with 
visual impairment. We will support recruitment of patients from diverse backgrounds (e.g. 
translators and language aids to support patients with language barriers). 
 
The initial information about the study will be offered to patients in 2 formats: 
- 
Read the PIS themselves; or 
- 
Listen to the PIS being read to them 
 
Given the high incidence of exacerbations of COPD requiring hospital admission, it is 
possible that multiple eligible patients will be identified daily. All eligible patients will be 
given time to receive and understand the initial information regarding the study. The 
consent, assessment and investigation process will then be performed for all patients who 
wish to be involved in the study. Informed consent will only be taken by individuals who 
have the appropriate GCP training and prior to any study assessments or investigations 
being performed. 
 
It is likely that the consent and collection of baseline data will take approximately 90 
minutes per patient (15 minutes for initial information followed by 30 minutes for consent 
and 45 minutes for assessments and investigations). 
 
All participants in the study will be 35 years or older. 
 
7.3 Baseline Data 
 
A source document worksheet will be used to collect baseline data. Key data to be collected 
is shown below. 
 
 

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Category 
Data 
Patient demographics 
Name, NHS number, hospital number, 
Gender, Date of birth, Ethnicity, Postcode, 
Indices of Multiple Deprivation 
Admission indices 
Date and time of arrival at hospital, date 
and time of admission to ward, highest 
NEWS2 score and associated observations 
within 24 hours of presentation at hospital 
including respiratory rate, oxygen 
saturations, inspired oxygen, heart rate, 
blood pressure, temperature, DECAF score, 
requirement for invasive or non-invasive 
ventilation within 24 hours of presentation, 
worst arterial blood gas measurement 
within 24 hours of presentation, admission 
ECG (rate and rhythm), chest x-ray findings 
(including diaphragm height), height, 
weight, BMI 
Admission history 
Requirement for invasive or non-invasive 
ventilation beyond 24 hours of 
presentation, development of new chest x-
ray consolidation during admission, 
evidence of development of respiratory 
infection during admission, non-respiratory 
medical deterioration during admission, 
date of discharge 
Previous admission history 
Initial FBC for any previous admission with 
a severe exacerbation of COPD since May 
2019 
COPD History 
Smoking status, pack year history, e-
cigarette use, other inhaled recreational 
drugs, other relevant exposures notably 
occupational, exacerbation history, 
admission history, acute NIV history, 
previous spirometry, LTOT/AOT use, home 
NIV use 
Past medical history 
Various conditions 
Medication history 
Relevant long-term and acute medications 
Social history 
Home residence, Rockwood clinical frailty 
score 
Blood results 
FBC indices, CRP, albumin, procalcitonin, 
fibrinogen, lactate, copeptin, cortisol, IgE, 
pneumococcal antigen 
Urinary investigations 
Overnight urinary metanephrines 
Biofire Respiratory 2.1 Panel 
Common respiratory viruses and bacteria 

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Sputum 
Microbiological culture results and 
purulence (patient reported and 
lab/research team reported) 
Cytokine panel 
Th1 and Th2 
Spirometry and FeNO 
FEV1, FVC, VC, FeNO 
Assessments 
eMRCD, CAT Score 
 
7.4 Follow-up Data 
 
The source document worksheet will be used to collect data throughout the 6-week follow-
up period. Key data to be collected at each assessment is outlined below. 
 
Follow-up assessment 
Data 
Day 3 
Acute prednisolone and antibiotic therapy 
use, FBC indices, CRP 
Day 7 
Acute prednisolone and antibiotic therapy, 
FBC indices, CRP 
Day 14 
Clinical history, full medication history 
including acute prednisolone and antibiotic 
therapy, FBC indices, CRP, FeNO, CAT Score, 
eMRCD Score, Rockwood Clinical Fraility 
Score 
Day 21 
Acute prednisolone and antibiotic therapy, 
FBC indices, CRP 
Day 28 
Clinical history, full medication history 
including acute prednisolone and antibiotic 
therapy, FBC indices, CRP, copeptin, 
overnight urinary metanephrines, cytokine 
panel, Spirometry, FeNO, CAT Score, 
eMRCD Score, Rockwood Clinical Fraility 
Score 
Day 42 
Clinical history, full medication history 
including acute prednisolone and antibiotic 
therapy, FBC indices, CRP 
 
7.5 Study Assessments 
 
The following data will be collected during day 1 of the study once patients have met the 
inclusion/exclusion criteria and given fully informed consent: 
 
 
1) Socioeconomic details 
 
2) Full medical history 
3) COPD history (confirmation of diagnosis, exacerbation history, admission history,      
NIV history, smoking history, LTOT/AOT use and home NIV use) 
 
4) Spirometry and FeNO 
 
5) Extended Medical Research Council Dyspnoea Score (eMRCD) 
 
6) COPD Assessment Tool Score (CAT) 

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7) Rockwood Clinical Frailty Score 
 
During the 6-week follow-up period many of the above assessments will be repeated at 
certain follow-up appointments including: 
 
 
1) Clinical history 
 
2) Medication history 
 
3) Spirometry and FeNO 
 
4) Extended Medical Research Council Dyspnoea Score (eMRCD) 
 
5) COPD Assessment Tool Score (CAT) 
 
6) Rockwood Clinical Frailty Score 
 
7.6 Withdrawal criteria 
 
Participants are free to withdraw from the study at any time without giving an explanation. 
Participants will be offered an interview at the point of withdrawal to ascertain their 
reasons for withdrawing. Participants will be given the option to make requests that, if met, 
will retain them in the study. If these requests are reasonable (e.g. changing the timing or 
location of visits) then this will be sought as a solution to retain participants and reduce 
attrition. Date and time of withdrawal will be recorded on the source document worksheet 
by the research team.  
 
We will seek consent to continue to collect electronic data from any participants in the 
study who withdraw, but no further study specific assessments will occur from the point of 
participant withdrawal. Any blood sample that has been taken and stored for cytokine 
analysis, prior to participant withdrawal, will continue to be stored for subsequent analysis 
unless participants specifically withdraw consent for this. 
 
7.7 Storage and analysis of clinical samples 
 
Clinical samples collected throughout the study will include blood (plasma and serum), 
urine, sputum and nasopharyngeal swabs. Blood, urine, sputum and nasopharyngeal 
samples will be labelled with patient identifiable data on collection before being securely 
transferred to Northumbria Specialist Emergency Care Hospital, North Tyneside General 
Hospital or Wansbeck General Hospital laboratories at the earliest possible time from 
collection. This may vary slightly depending on follow-up visits as occasionally they may be 
collected in the community. Samples will be securely stored for the standard duration of 
time that each sample type are stored in the hospital laboratory. During this time only 
laboratory staff will have physical access to the samples and their security will be the 
responsibility of the laboratory manager. Following analysis, samples will be disposed of as 
per local Trust guidelines. 
 
Blood plasma samples for cytokine panel testing will be collected, labelled with an individual 
participant identification number which will be linked to personal identifiers, and 
transferred to North Tyneside General Hospital. At North Tyneside General Hospital, they 
will be centrifuged into aliquots which will be securely stored in a specialist freezer at -80C 
+/- 10C. Length of time in storage will vary depending on when the sample was taken during 

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the recruitment period but will be between 1 – 24 months. During storage the samples will 
remain labelled with individual participant identification numbers. 
 
Study samples will be transferred in batches to Newcastle University where they will 
continue to be securely stored in a specialist freezer at -80C +/- 10C to await analysis. 
During this time only laboratory staff will have physical access to the samples and their 
security will be the responsibility of the laboratory manager. Following analysis, samples will 
be disposed of as per local Newcastle University guidelines. 
 
7.8 End of the study 
 
The recruitment phase of the study will aim to end once 200 patients have been recruited, 
however the study will follow an adaptive design. We will map the number of participants 
with uneventful recovery from eosinopenia and closely monitor rates of attrition. We will 
extend recruitment if necessary to ensure that we have the required sample size for the 
time to recovery from eosinopenia analysis as per our power calculation (n = 70). The follow 
up phase of the study will end after the 6-week follow-up appointment of the last patient 
recruited. 
 
We will ensure that all participants are on optimal therapy on completion of the trial. 
 
 
8. Statistics and Data Analysis 
 
8.1 Sample size calculation 
 
There is a lack of published data on longitudinal blood eosinophils during an admission for 
exacerbation of COPD and within 6 weeks following an exacerbation. From observations 
during clinical practice, blood eosinophils often recover within 2-3 weeks after admission for 
an exacerbation of COPD. 
 
We predict that 90% of our population will have recovery of BEC to baseline within 4 weeks. 
Using a one-proportion test based on the above hypothesis, for an 80% statistical power, we 
believe a sample size of at least 69 is needed. Based on the estimated prevalence of 
admission eosinopenia (approximately 50%) and attrition including due to intercurrent 
illness or prednisolone use, we will recruit 200 patients.  
 
This will also ensure that we are adequately powered for the co-primary outcome of 
identifying independent associates of eosinopenia in the total population. We expect 100 
participants will have eosinopenia, and expect less than 10 parameters to be included in the 
regression equation, meeting the standard criterion of 10 outcomes per parameter. 
 
 
 
 
 
 

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8.2 Planned Recruitment Rate 
 
Recently, recruitment to COPD studies has been challenging due to the impact of the Covid-
19 pandemic. A-TREC requires 200 patients to be recruited from a single centre. During the 
Covid-19 pandemic 2 studies recruited 115 and 214 COPD patients respectively from our 
site. Thus, anticipated rate of recruitment will be 10-15 patients per month. Anticipated 
duration of recruitment will be 30 months. 
 
We will monitor recruitment closely and consider opening to external sites if necessary. 
 
8.3 Statistical Analysis Plan 
 
Our initial statistical analysis plan has been designed with support from Newcastle 
University and the trial statistician (Eduwin Pakpahan, Northumbria University). A full 
statistical analysis plan will be confirmed with the trial statistician prior to data hard-lock, 
and uploaded to the trial registration entry on clinicaltrials.gov. 
 
8.3.1 Baseline characteristics of population  
 
For all outcomes (both primary and secondary) we will describe baseline characteristics of 
the population and follow-up measurements using suitable measures of tendencies. For 
continuous variables, mean with the associated standard deviation and 95% confidence 
interval, or median and interquartile range, will be provided based on their distribution. For 
categorical variables (including binary variables), frequency and proportions will be given. 
To test for significance between the arms, Chi-Squared test (or Fisher’s Exact test in case of 
small number of observations), t-test, or Mann-Whitney U test will be used depending on 
whether the variable is categorical, parametric, or non-parametric. 
 
8.3.2 Primary outcome analysis 
 
Time to recovery from eosinopenia 
A 1 proportion test will be used to assess the proportion of patients who do not recover 
within 4 weeks as compared to the hypothesised proportion. 
 
A Chi-squared test will examine whether patients recover within 2, 3 and 4 weeks after 
hospital admission. 
 
Independent associates of eosinopenia 
Candidate indices will be identified by: 
• 
Univariate analysis: include indices related to eosinopenia at the 0.1 threshold. 
• 
Domain knowledge: include additional indices thought likely to be related to 
eosinopenia even if no association on univariate analysis. 
• 
Create summary indices to reduce the number of variables – e.g. evidence bacterial 
infection will include a positive blood culture, positive sputum culture or positive 
antigens. 
• 
Address collinearity. 

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• 
Independent associates of eosinopenia will be identified by logistic regression 
(backwards stepwise elimination). 
 
8.3.3 Secondary outcomes analysis 
 
To assess recovery from eosinopenia (as a binary outcome), Cochran Q test will examine 
which timepoints are significantly different from each other and compare the proportion 
that recover by a certain time period in a pairwise model. A Life table analysis will be used 
to determine probability of no recovery within specific time periods. 
 
Linear regression models will be used to identify factors that may influence recovery time, 
and a logistic regression model will assess the association between index admission 
eosinophil phenotype and separate exacerbation eosinophil phenotypes, with adjustment 
for demographic and disease characteristics. This will be summarised with odds ratios and 
95% confidence intervals. 
 
8.4 Subgroup analyses 
 
In the subgroup who attain a stable state BEC of 100 cell/uL or higher, a 1 proportion test 
will be repeated at each timepoint. 
 
8.5 Participant population 
 
Participants will be aged 35 years and over. They will have been admitted to hospital with 
an exacerbation of COPD +/- eosinopenia. We will support recruitment of patients from 
diverse backgrounds (e.g. language aids to support patients with language barriers, home 
visits for follow-up to support those patients unable to travel due to socioeconomic or 
health disability). 
 
8.6 Procedure to account for loss to follow-up or missing data 
 
We consider the tolerable level of loss to follow-up or missing data to be less than 10%. 
Every effort will be made to minimise missing baseline and outcome data. 1 in 10 
participants will undergo data verification and validation. We will allow a 2% error rate for 
objective measures (such as BEC) and a 10% error rate for subjective measures. Standard 
approaches will be used to detect patterns in missing data. The level and pattern of the 
missing data in the baseline variables and outcomes will be established by forming 
appropriate tables and the likely causes of any missing data will be investigated. This 
information will be used to determine whether the level and type of missing data has the 
potential to introduce bias into the analysis results for the proposed statistical methods. 
 
 
 
 
 
 
 

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9. Data Management 
 
9.1 Data collection 
 
Data for each participant will be collected on a paper source document worksheet that has 
been designed specifically for the study. 
 
9.2 Data handling and record keeping 
 
Paper research material will be stored within a locked filing cabinet in a key-pad secured 
office at North Tyneside General Hospital. Only the research team will have access to this 
location.  The paper research material will not contain personal data but be identified by a 
unique individual participant identification number. The file linking this to personal data will 
be held securely, separately and electronically. 
 
Data from the paper source document worksheet will be transcribed onto an electronic 
Case Report Form (eCRF). This will be stored on a secure online database (REDCap) which 
will be password protected. The REDCap database will have a security system to protect 
against unauthorised access. There will be regular data back up to prevent any loss of data. 
 
Upon completion of the study (including data analysis and publication), personal data will 
be securely destroyed including the linking files for the individual participant identification 
numbers. Anonymised, electronic research data generated by the study will be stored for 25 
years. 
 
Data will be handled and stored in accordance with the 2018 General Data Protection 
Regulation (GDPR). 
 
9.3 Access to Data 
 
Direct access to the data will be granted to the CI and PI at Northumbria Healthcare NHS 
Foundation Trust. 
 
9.4 Archiving 
 
Study data will be archived for 25 years following completion of the study. 
 
 
10. Monitoring, Audit and Inspection 
 
A Trial Steering Group (TSG) will be formed with an independent Chair and will include a 
patient representative. They will meet at least every 12 months and send timely reports to 
the Sponsor and any funders. 
 
A Trial Management Group (TMG) will also be formed which will be chaired by the CI. They 
will meet at least monthly to ensure effective day to day running of the study. 
 

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The PI will assist the CI in monitoring the study. On-site data verification and validation will 
be performed for 1 in 10 participants by an independent investigator. This will include 
participant eligibility and primary and secondary outcome data. 
 
 
11. Ethical and Regulatory Considerations 
 
11.1 Research Ethics Committee (REC) review and reports 
 
Prior to commencement of the study, approval will be sought from an NHS REC for the study 
protocol and other relevant documents e.g. participant information sheet and consent 
forms. 
 
Substantial amendments will not be implemented until the REC grants a favourable opinion 
for the study.  
 
All correspondence with the REC will be retained in the Trial Master File/Investigator Site 
File. 
 
An annual progress report (APR) will be submitted to the REC within 30 days of the 
anniversary date on which the favourable opinion was given, and annually until the trial is 
declared ended. 
 
It is the Chief Investigator’s responsibility to produce the annual reports as required. 
 
The Chief Investigator will notify the REC of the end of the study. 
 
If the study is ended prematurely, the Chief Investigator will notify the REC, including the 
reasons for the premature termination. 
 
Within one year after the end of the study, the Chief Investigator will submit a final report 
with the results, including any publications/abstracts, to the REC. 
 
The study will be registered on ClinicalTrials.gov prior to commencement. 
 
11.2 Peer review 
 
The study has been reviewed by 2 independent experts. 
 
11.3 Public and Patient Involvement 
 
We have sought the views of patients with COPD on the planned research. Participants from 
the Northumbria Lung Research Patient and Public Involvement (PPI) group (expert patients 
with COPD and experience taking part in and reviewing research proposals) and from an 
existing clinical COPD study were contacted via the telephone to obtain their feedback on 
the proposed study.  
 

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Questions which were asked of these patients included: 
 
1. Is the study of an interest to you? 
2. Do you think it is important for the NHS? 
3. Is the study design clear? 
4. Are the number of study visits appropriate for you? 
5. Is there anything that would put you off taking part? 
 
All participants thought the study was interesting and useful. They felt it would be 
important to the NHS and potentially answer important clinical questions. They thought the 
study design was clear and not too complicated, with none of the participants 
recommending any changes to the study design. 75% of participants thought the number of 
study visits were appropriate and the number of tests were not too high. 
 
Feedback on the A-TREC PIS was obtained from two members of the Northumbria Lung 
Research PPI Group. The PIS was sent out via post and then a focussed telephone interview 
was performed with each member.  
 
Both members felt that the language used in the PIS was understandable and appropriate 
for patients with COPD. They also felt that there was an appropriate amount of information 
within the PIS, and neither member felt that there should be additional information added. 
One member thought that additional information would likely lead to information overload 
for patients who were considering taking part in the study. 
 
Both members felt that the information relayed in the PIS was clear and that there were no 
areas which required further clarity. One member stated that they found the PIS more 
understandable than previous information sheets that they have read related to clinical 
research. They described the A-TREC PIS as ‘inclusive’ for participants, as it was easy to 
understand and did not contain any jargon. The other member described the A-TREC PIS as 
‘impressive’ and thought that it was straightforward to read and understand.  
 
One member stated that they thought patients would find it reassuring to be followed up in 
the study after an admission to hospital with an exacerbation of COPD, as often patients are 
discharged without future follow up plans. They also thought that some patients would 
welcome additional blood tests for further reassurance and did not see these as an extra 
burden.  
 
Overall, both members thought that the PIS was suitable for the study. They also thought 
that the study was worthwhile and important. One member specifically stated that they 
would want to be involved in the study if they were admitted to hospital with an 
exacerbation of their COPD. They were both supportive of research that sought to improve 
care for patients with COPD.   
 
 
 
 
 

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11.4 Regulatory Compliance 
 
The study will not commence until a favourable REC opinion is obtained. The anticipated 
start date for recruitment is 19th January 2024. 
 
For any amendment to the study, the CI, in agreement with the sponsor will submit 
information to the appropriate body for them to issue approval for the amendment. 
 
11.5 Protocol Compliance 
 
A protocol non-compliance is a departure from the ethically approved study protocol, study 
process (e.g. consent) or from Good Clinical Practice or other applicable regulatory 
requirements. Any protocol deviations will be documented on a protocol deviation form, 
filed in the study master file, and reported to the CI and sponsor immediately. 
 
11.6 Notification of Serious Breaches to GCP and/or the protocol 
 
A serious breach of the GCP and/or protocol will be immediately notified to the CI and 
sponsor. 
 
11.7 Data protection and patient confidentiality 
 
All members of the research team will comply with the requirements of the Data Protection 
Act 1998 with regards to the collection, storage, processing and disclosure of personal 
information and will uphold the Act’s core principles. 
 
Participant’s personal identifiable information will be replaced with an unrelated sequence 
of characters, with the data and the linking code secured in separate locations. Access to 
this data will be limited a to a need only basis. Personal data, including the linking files, will 
be destroyed upon completion of the study. 
 
All electronic data will be transferred via the secure database (REDCap). Anonymised, 
electronic research data generated by the study will be stored for 25 years. 
 
11.8 Financial and other competing interests for the chief investigator, PIs and committee 
members for the overall study management 
 
Funding for the Teaching and Research Fellowship has been secured which will cover the PI 
expenses for the entirety of the study. 
 
Essential laboratory costs will be covered by available funds from the Respiratory Medicine 
research budget within the Research and Development department at Northumbria 
Healthcare NHS Foundation Trust. 
 
External funding applications have been made to Chiesi Limited and GlaxoSmithKline for 
additional desirable research costs. 
 

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None of the funders have had, or will have, any influence on the design or conduct of the 
study, and none of the participant data will be shared with funders. 
 
11.9 Indemnity 
 
Northumbria Healthcare NHS Foundation Trust (NHCT) has liability for clinical negligence. 
NHS Indemnity covers NHS staff and medical academic staff with honorary contracts for 
potential liability in respect of negligent harm arising from the conduct of the study. 
 
As Sponsor, NHCT will provide indemnity in respect of potential liability and negligent harm 
arising from study management. 
 
Indemnity in respect of potential liability arising from negligent harm related to study design 
is provided by NHCT. 
 
11.10 Amendments 
 
All amendments will be discussed with the Chief Investigator who will be responsible for the 
final decision to make an amendment and whether the amendment is substantial or non-
substantial. 
 
When necessary, approval for amendments to the study protocol and/or original supporting 
documents will be obtained from an appropriate Research Ethics Committee. 
 
An amendment history will be recorded and the most up to date versions of protocols and 
supporting documents, and previous versions, will be stored and available for audit 
purposes. 
 
11.11 Post study care 
 
This study will be conducted in accordance with relevant regulations, Good Clinical Practice 
and the principles of the Declaration of Helsinki. 
 
11.12 Access to the final study dataset 
 
The CI, PI, host organisation and statistician will have access to the full dataset, for the 
duration of the trial. 
 
 
 
 
 
 
 
 
 
 

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12. Dissemination Policy 
 
12.1 Dissemination Policy 
 
Upon completion of the study, and with the PPI representatives, we will facilitate 
dissemination of the results to people with COPD. Results will be fully anonymised and 
shared with study participants, presented at conferences, and published in medical journals. 
We will engage the relevant British Thoracic Society Specialist Advisory Groups, British Lung 
Foundation and the National Institute for Health and Care Excellence to share the impact of 
the study. 
 
12.2 Authorship Eligibility Guidelines 
 
The CI and NHCT will be writing manuscripts, abstracts, press releases and any other 
publications arising from the study. Authorship will be determined in accordance with the 
International Committee of Medical Journal Editors guidelines and other contributors will be 
acknowledged. 
 
 
 
 

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13. References 
 
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of Chronic Obstructive Pulmonary Disease Exacerbations: The Rome Proposal. Am J 
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significant impact on health-related quality of life, utility, and lung function in 
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8. Forum of International Respiratory Societies (FIRS). The global impact of respiratory 
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14. Bafadhel M, Peterson S, De Blas MA, Calverley PM, Rennard SI, Richter K, Fagerås M. 
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obstructive pulmonary disease: a post-hoc analysis of three randomised trials. 
Lancet Respir Med. 2018 Feb;6(2):117-126. 
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Papi A, Singh D, Laws E, Mannent LP, Patel N, Staudinger HW, Yancopoulos GD, 
Mortensen ER, Akinlade B, Maloney J, Lu X, Bauer D, Bansal A, Robinson LB, Abdulai 
RM; BOREAS Investigators. Dupilumab for COPD with Type 2 Inflammation Indicated 
by Eosinophil Counts. N Engl J Med. 2023 Jul 20;389(3):205-214. 
17. Singh D, Agusti A, Martinez FJ, Papi A, Pavord ID, Wedzicha JA, Vogelmeier CF, Halpin 
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A-TREC Protocol 
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IRAS 333785 
35 
 
14. Appendices 
 
1. Schedule of Activities 
 
 
Admission 
Day 1 
(EC & NEC) 
Day 3 
 
(EC) 
Day 7 
 
(EC) 
Day 14 
(EC) 
Day 21 
(EC) 
Day 28 
(EC) 
Day 28 
(NEC) 
Day 42 
(EC) 
Screening 
X 
 
 
 
 
 
 
 
Consent 
X 
 
 
 
 
 
 
 
Eligibility review 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Co-Morbidities 
X 
 
 
 
 
 
 
 
Admission 
indices 
X 
 
 
 
 
 
 
 
COPD History 
X 
 
 
 
 
 
 
 
Clinical History 
X 
 
 
X 
 
X 
X 
X 
Full medication 
history 
X 
 
 
X 
 
X 
X 
X 
Prednisolone 
and antibiotic 
therapy 
X 
X 
X 
X 
X 
X 
X 
X 
FBC within 2 
years during 
severe ECOPD 
X 
 
 
 
 
 
 
 
FBC 
X 
X 
X 
X 
X 
X 
X 
X 
CRP 
X 
X 
X 
X 
X 
X 
X 
X 
Procalcitonin 
X 
 
 
 
 
 
 
 
Fibrinogen 
X 
 
 
 
 
 
 
 
Lactate 
X 
 
 
 
 
 
 
 
Copeptin 
X 
 
 
 
 
X 
X 
 
Cortisol 
X 
 
 
 
 
 
 
 
IgE 
X 
 
 
 
 
 
 
 
Overnight 
urinary 
metanephrines 
X 
 
 
 
 
X 
X 
 
Biofire 
Respiratory 2.1 
Panel 
X 
 
 
 
 
 
 
 
Streptococcal 
antigen 
X 
 
 
 
 
 
 
 
Sputum 
microbiology 
and purulence 
X 
 
 
 
 
 
 
 
Cytokine panel 
X 
 
 
 
 
X 
X 
 
Spirometry 
X 
 
 
 
 
X 
 
 

A-TREC Protocol 
v1.1 08/12/2023 
IRAS 333785 
36 
 
FeNO 
X 
 
 
X 
 
X 
 
 
CAT Score 
X 
 
 
X 
 
X 
X 
 
eMRCD Score 
X 
 
 
X 
 
X 
X 
 
Rockwood 
clinical frailty 
scale 
X 
 
 
X 
 
X 
X 
 
EC = Eosinopenic cohort (n = 100) 
 
NEC = Non-eosinopenic cohort (n = 100)