Antibiotic Stewardship Through CRP-guided Antibiotic Treatment for Patients With Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD)
Phase: NA
Conditions: Acute Exacerbation of COPD, Lung Diseases, Lung Diseases, Obstructive, Pulmonary Disease, Chronic Obstructive, Respiratory Tract Disease
Sponsor: The University of Hong Kong

 
 
PROTOCOL TITLE  
 
Antibiotic stewardship through CRP-guided 
antibiotic treatment for patients with Acute 
Exacerbation of Chronic Obstructive Pulmonary 
Disease (AECOPD) 
 
 
 
Protocol Number 
 
AECOPD-WAI-21200182 
 
 
 
 
 
Version 1.1 
 
 
 
 
Date 
31 October 2021 
 
 

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Contents 
1. 
List of Abbreviations ......................................................................................................... 2 
2. 
Study Summary ................................................................................................................. 3 
3. 
Investigators ...................................................................................................................... 4 
                     3.1 Principal investigator .................................................................................................................... 4 
                     3.2 Co-investigator ............................................................................................................................. 4 
4. 
Introduction ........................................................................................................................ 5 
5. 
Aims and Objectives of the study .................................................................................... 8 
                     5.1 Clinical Question .......................................................................................................................... 8 
                     5.2 Aims and Hypotheses to be Tested: ............................................................................................. 8 
6. 
Study design ...................................................................................................................... 9 
                     6.1 Design……… ............................................................................................................................... 9 
                     6.2 Study sites .................................................................................................................................... 9 
                     6.3 Subjects recruitment ..................................................................................................................... 9 
                     6.4 Selection of Subjects .................................................................................................................... 9 
6.4.1 
The inclusion criterion:……………………………………………………………9 
6.4.2 
The exclusion criteria:…………………………………………………………….9 
                     6.5 Intervention ................................................................................................................................ 10 
                     6.6 Procedures .................... ………………………………………………………………………………..11 
6.6.1 
Subject Eligibility assessment…………………………………………………..11 
6.6.2 
Randomization……………………………………………………………………11 
6.6.3 
Allocation concealment and blinding…………………………………………...11 
6.6.4 
Communication with Receiving Ward Staffs .………………………..………..12 
6.6.5 
Data collection…………………………………………………………..………..12 
6.6.6 
Procedure…………………………………………………………………………12 
6.6.7 
Microbiological assessment…………………………………………………….13 
6.6.8 
Follow up………………………………………………………………………….13 
7. 
Assessment of Efficacy .................................................................................................. 14 
8. 
Assessment of Safety ..................................................................................................... 14 
9. 
Statistics and Data Analysis........................................................................................... 14 
10. 
Outcomes and measures ................................................................................................ 15 
11. 
Direct Access to Source Data/ Documents ................................................................... 16 
12. 
Ethics ................................................................................................................................ 16 
13. 
Data Handling and Record Keeping .............................................................................. 16 
14. 
Financing and Insurance ................................................................................................ 16 
15. 
Publication Policy ............................................................................................................ 17 
16. 
References ....................................................................................................................... 18 
Appendix 1 ……………………………………………………………………………………………………..20 
Appendix 2 ……………………………………………………………………………………………………..21 
Appendix 3…………………………………………………………………………………………………….. 22 
Appendix 4 ……………………………………………………………………………………………………..23 
Appendix 5 ……………………………………………………………………………………………………..24 
Appendix 6 ……………………………………………………………………………………………………..25 
Appendix 7 ……………………………………………………………………………………………………..26 
Appendix 8…………………………………………………………………………………………………….. 27 
 
 
 

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1. List of Abbreviations  
 
AE 
Adverse event  
A&E 
Accident and Emergency 
AECOPD 
Acute Exacerbation of Chronic Obstructive Pulmonary Disease 
AIDS 
Acquired immunodeficiency syndrome 
BA 
blood agar 
CCQ 
Clinical COPD Questionnaire (Appendix 1) 
CI 
Confidence Interval 
COPD 
Chronic obstructive pulmonary disease 
CONSORT 
Consolidated Standards of Reporting Trials  
CRP 
C-reactive protein 
CRQ-SAS 
Chronic Respiratory Disease Questionnaire, self-administered, 
standardized (Appendix 2) 
ED 
Emergency Department 
EQ-5D 
EuroQoL 5-dimension 
EQ-5D-5L 
EuroQoL 5-dimension 5-level (Appendix 3) 
GOLD 
Global Initiative for Chronic Obstructive Lung Disease 
HA 
Hospital Authority 
HOKLAS 
Hong Kong Laboratory Accreditation Scheme 
ICU 
Intensive Care Unit 
IQR 
Interquartile range  
ISO 
International Organization for Standardization 
ITT 
Intention-to-treat  
MALDI-ToF-MS 
Matrix Assisted Laser Desorption Ionising Time of Flight Mass 
Spectrometry 
NEWS2 
National Early Warning Score 2 
PCT 
Procalcitonin 
OR 
Odds ratio 
QALY 
Quality-adjusted life year  
QMH 
Queen Mary Hospital  
RCT 
Randomized Controlled Trial 
RT-PCR 
Reverse transcription polymerase chain reaction 
SAE 
Serious adverse event 
UTI 
Urinary Tract Infection 

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2. Study Summary 
Title 
Antibiotic stewardship through CRP-guided antibiotic treatment for 
patients with Acute Exacerbation of Chronic Obstructive Pulmonary 
Disease (AECOPD) 
Short Title 
Antibiotic stewardship in AECOPD 
Protocol Number 
AECOPD-WAI-21200182 
Methodology 
Patient-level, multi-centre, single-blind, open-label, randomized, 
combined superiority (antibiotic duration) and non-inferiority (COPD 
health status) trial. 
Study Duration 
36 months 
Study Centre 
Multiple centres 
Objectives 
To determine whether the addition of serial CRP levels (with advice on 
interpretation) to usual care for managing AECOPD leads to a reduction 
in antibiotic exposure (defined as the total number of antibiotic days by 
Day 28) for AECOPD without negatively impacting on COPD health 
status, compared with usual care alone. 
Number of Subjects 
N=1,184 
Diagnosis and Main 
Inclusion Criteria 
1. Being diagnosed with active AECOPD; AND  
2. Known COPD in their medical records; AND 
3. Age 40 years or older; AND 
4. Able to provide informed consent in Cantonese, Mandarin, or English; 
AND 
5. Able to complete the questionnaires during the study period  
Participation 
Duration  
One year 
Interventions 
The intervention group will be recommended to test for CRP at 
randomization and every day during the stay. Antibiotics are considered 
for discontinuation when CRP reduces below 5mg/dL, on top of existing 
clinical judgment. The control group will not be tested for CRP and 
antibiotics will be discontinued according to clinical judgment. 
Main outcome 
measures and study 
instruments 
The antibiotic exposure (total number of antibiotic days) and recovery in 
terms of COPD health status (Clinical COPD Questionnaire total scores) 
within 28 days from randomization.  
The secondary outcomes include prevalence of potentially pathogenic 
bacteria and commensal organisms and their proportion of drug-
resistant strain, antibiotics prescribed and total antibiotics consumption 
(doses), adverse effects potentially attributable to antibiotics prescribed 
for the exacerbation, general health status, disease-specific, health-
related quality of life over time measured using the CRQ-SAS 
(dyspnoea, fatigue, emotion function, mastery and total scores) and 
costs (total HA cost) and cost-effectiveness. 
Statistical 
Methodology 
- Baseline subject characteristics: descriptive statistics.  
- COPD-related health status, general health status, and duration of 
antibiotics: Fisher exact tests. 
- Adverse effects and number of events: Chi squared tests.  
- Between-group difference, CCQ score, and EQ-5D: Students’ t-test.  
- Group comparison for categorical variables: Fisher ‘s Exact test  
- All analyses will be performed using Stata software  
- For missing data handling: multiple imputation methods.  
- Cost evaluations: the healthcare provider using standard methods.  
- Cost-effectiveness analysis during the RCT: ITT principle.  
- Health economic outcomes: QALY. 
 
 
 

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3. Investigators 
3.1  Principal investigator 
Dr. WAI Ka Chung, Abraham  
Clinical Assistant Professor, Emergency Medicine Unit, 
LKS Faculty of Medicine, The University of Hong Kong, Hong Kong 
 
3.2  Co-investigator 
Dr. CHOO Kah Lin 
Consultant & Chief of Service, Department of Medicine,  
North District Hospital, Hong Kong  
 
Dr. CHEUNG Lap Woon 
Associate Consultant, Department of Accident & Emergency, 
Princess Margaret Hospital, Hong Kong 
 
Dr. SO Lok Tsun Jerome 
Associate Consultant, Department of Accident & Emergency, 
Tseung Kwan O Hospital, Hong Kong 
 
Dr. POON Kin Ming 
Associate Consultant, Department of Accident & Emergency, 
Tin Shui Wai Hospital, Hong Kong 
 
Dr. TONG Chak Kwan 
Clinical Associate Professor, Department of Medicine, 
LKS Faculty of Medicine, The University of Hong Kong, Hong Kong 
 
Dr. WONG King Ho, Carlos 
Assistant Professor, Department of Pharmacology and Pharmacy,  
LKS Faculty of Medicine, The University of Hong Kong, Hong Kong 
 
Prof. Timothy H. RAINER 
Clinical Professor, Emergency Medicine Unit,  
LKS Faculty of Medicine, The University of Hong Kong, Hong Kong 
 
Prof. HUI Shu Cheong, David 
Stanley Ho Professor of Respiratory Medicine and Chair Professor,  
Department of Medicine & Therapeutics, The Chinese University of Hong Kong 
 
 

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4. Introduction 
Multiple small successes against antimicrobial resistance are urgently needed. The 
Global Action Plan in 2015 reiterated the importance of tackling antimicrobial abuse and 
bacterial resistance, which is jeopardizing our ability to manage infectious diseases.1 
Antimicrobial resistance is predicted to cause catastrophic economic impacts in the next 10 
years by putting 24 million people into extreme poverty, and will lead to an estimated 10 million 
deaths annually by 2050.2 Evidence has shown that an extended course of antibiotics is by 
no means superior to a shorter one.3 The over-prescription of broad-spectrum antibiotics in 
both hospitals and primary care has become a global concern and has driven initiatives to 
safeguard patient safety through the responsible use of antibiotics as treatments and 
prophylaxis. In our recent analysis, 55% of pathogenic bacteria identified in sputum culture 
from AECOPD patients in Hong Kong has demonstrated resistance to at least one antibiotic. 
(A Wai, personal communication) Even relatively small changes in prescribing are likely to 
have beneficial effects on resistance at a population level.4  
There is a need for improved decision-making for antibiotic prescription in AECOPD. 
International Guideline (GOLD strategy)5 recommends empirical broad-spectrum antibiotics 
covering common respiratory pathogens for acute management,5 based on self-reported 
subjective AECOPD features, and the risk of bacterial infection. Evidence for the optimal 
duration of antibiotic treatment is unclear.6  Antibiotics are reportedly used in 87% of AECOPD 
patients in US, 7 74% in UK,8 and 96% in Hong Kong (A Wai, Personal communication). 
AECOPD contributes 21,000 episodes of local hospital admission and readmission in 2019 
(A Wai, personal communication). AECOPD is triggered by infectious and non-infectious 
precipitants, although 30% are undetermined.9 Bacterial infection accounts for only 35%-57% 
among the infected. Inappropriate antibiotic usage may increase the risks of adverse events 
such as Clostridioides difficile colitis.10 Moreover, this confers a predisposition to airway 
colonization by multidrug-resistant bacteria, increasing COPD patients’ risk of carrying 
resistant organisms in their lungs and then exacerbation or progression of pneumonia.10 We 
have found that 55% of pathogenic bacteria identified from sputum culture among AECOPD 
patients were resistant to 1 or more antibiotics. (A Wai, personal communication) 
C-Reactive Protein (CRP) may help physicians make more appropriate antibiotic 
decisions. C-Reactive Protein (CRP) is an acute-phase reactant secreted by the liver in 
response to bacterial infections. It is synthesized within 4 to 6 hours after tissue 
injury/inflammation, and levels double every 8 hours, peaking at about 36 hours.11 CRP is 
significantly elevated in patients with bacterial infection, representing better treatment effect 
with antibiotics at elevated CRP values.12 CRP has been shown to be highly selective for 
AECOPD and it has excellent diagnostic accuracy when interpreted together with AECOPD 
symptomatology.13 Elevated CRPs (>5 mg/dL) in hospitalised AECOPD patients are 

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associated with chest infections, implying a treatment role for antibiotics in this group. Yet 
antibiotics did not offer higher benefit over placebo among those with normal CRP level.14 
Work done by others 
CRP-guided antibiotic prescription is effective and safe. In hospitalised AECOPD patients 
with CRP-guided prescriptions (antibiotic treatment if CRP ⩾50 mg/L, i.e. 5mg/dL) versus a 
control group with standard GOLD treatment fewer patients in the CRP group were prescribed 
with antibiotics compared to the GOLD group (31.7% versus 46.2%, p=0.028; adjusted odds 
ratio (OR) 0.178, 95% CI 0.077–0.411, p=0.029), without a significant difference in the 
treatment effects between both groups. Yet, the discontinuation of antibiotics in both groups 
was guided by clinical judgment. The 30-day treatment failure rate was nearly equal in CRP 
and control groups (44.5% vs. 45.5%, p=0.881), the time to next exacerbation was 
comparable (32 days vs. 28 days, p=0.713), and the length of hospital stay was also similar 
(7 days vs. 6 days, p=0.206). On day 30, there was no difference in the symptoms score and 
quality of life, and no serious adverse events were detected.  
CRP-guided antibiotic discontinuation is also safe. Whether antibiotic therapy with CRP-
guided duration or fixed 7-day duration were clinically non-inferior to fixed 14-day duration in 
patients with uncomplicated gram-negative bacteraemia was determined in a multicentre trial 
involved 504 adults.15 The main outcome was the rate of clinical failure at 30 days, which was 
2.4% in CRP-guided patients who experienced recurrent bacteraemia, local suppurative 
complications, distant complications, re-initiation of antibiotic therapy due to clinical 
deterioration, or any-cause mortality, compared with a failure rate of 6.6% in the 7-day group 
and 5.5% in the 14-day group. The CRP-guided treatment met the 10% margin for inferiority. 
Work done by us 
The team is experienced to conduct trials on antibiotic stewardship with AECOPD. 
Butler et al. studied whether point-of-care CRP laboratory testing could be used to safely 
guide (and perhaps reduce) antibiotic prescribing for AECOPD in primary care practices in 
the UK.16 In this multi-centre, open-label, randomised controlled trial, 653 AECOPD patients 
were randomised to either the CRP-guided treatment group or the usual (GOLD strategy) care 
group.5 The results showed that patients in the CRP group reported less antibiotic use within 
28 days of randomisation (57.0% vs. 77.4%, adjusted OR 0.31, 95% CI 0.20 to 0.47) and 
mildly lower (better) clinical COPD questionnaire scores at 2 weeks (adjusted mean difference 
−0.19 points, 90% CI −0.33 to −0.05). Antibiotics were prescribed less frequently at the initial 
consultation in the CRP-guided group compared with the usual care group (47.7% vs. 69.7%, 
adjusted OR 0.31, 95% CI 0.21 to 0.45). There was no evidence of harm to patients, including 
no differences in diagnosis of pneumonia at the 4-week follow-up and no differences in 
adverse events related to antibiotics. Both Prins et al. and this study provide evidence of the 

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benefits of CRP-guided antibiotic prescription in regard to less antibiotic use, and non-
inferiority on the clinical outcomes in AECOPD patients including 30-day treatment failure, 
length of stay, symptoms score, diagnosis of pneumonia, quality of life, and adverse events.  
In the previous study antibiotics were found to be prescribed in 33% of patients who had low 
CRP levels, even though guidance indicated that antibiotics likely would not be of benefit.16 
Patient factors such as expectations for antibiotics, access to antibiotics before consultation 
with the clinician, and lack of clear guidelines can influence clinicians’ antibiotics prescribing 
behaviour for acute respiratory symptoms. Previous reports also suggested that risk aversion 
and long turnaround time for CRP resulted in driving them to prescribe antibiotics.17  
Local situation has been well studied. Hui (co-applicant) and Ko (our collaborator) found 
that an infectious aetiology could be established in only 48.7% of the AECOPD patients.18 
40.8% of sputum culture was positive. The commonest bacteria identified were Streptococcus 
pneumoniae, Pseudomonas aeruginosa, and Haemophilus influenzae.  
A&E is an ideal location to start antibiotic stewardship for AECOPD. Prior work has also 
been conducted by our team in Hong Kong to ensure the significance of the problem, the 
feasibility of data collection, and the preliminary results relevant to AECOPD patients with 
available CRP levels. 21,129 patients were admitted to emergency medicine wards and 
medical wards through A&E in 2019 (mean age 79 years (IQR 71-86)). Elevated CRP was 
associated with doubled odds ratio of ICU admission or death (Odds ratio 2.06, 95%CI 1.75 
– 2.43). Analysis reveals that 96% of patients with a normal CRP were given antibiotics. 
Among those with normal CRP, unadjusted statistics suggested those without antibiotics did 
not have lower odds ratios for deterioration requiring ICU admission and for death (p<0.01) 
(Appendix 4, Table 1). Overall, AECOPD patients were prescribed antibiotics for a mean of 
9.4 days (SD 10.3) but the mean duration of an elevated CRP was 6.4 days (SD 6.8). There 
is an opportunity to shorten antimicrobial regimen for some AECOPD patients. Further details 
of the results can be found in Appendix 4, Figure 1 and Figure 2. As personalised antibiotic 
treatments may reduce healthcare resource utilisation, we sought to determine the optimal 
antibiotics therapy duration for AECOPD patients based on clinical decision-making and CRP 
results. 
Research Gaps 
1. Antibiotic 
stewardship 
involves 
both 
appropriate 
prescription 
and 
timely 
discontinuation of an antibiotic treatment. Limited evidence informs antibiotic 
prescription practice for AECOPD in A&E. Information on CRP-guided antibiotic 
discontinuation is absent.   
2. Previous studies with hospitalized AECOPD patients with severe symptoms and severe 
outcomes was insufficient in power.  

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3. Cost-effectiveness analyses on CRP-guided antibiotic treatment in AECOPD patients 
are lacking.  
 
 
5. Aims and Objectives of the study 
5.1  Clinical Question 
In adult AECOPD patients in Emergency Departments, does CRP-guided antibiotic treatment, 
compared with usual care, lead to shorter antibiotic duration without negatively impact on 
clinical COPD-health status? 
 
5.2  Aims and Hypotheses to be Tested: 
This study seeks to establish whether serial CRP level guided clinical judgment can safely 
and cost-effectively be used to better target antibiotic treatment (include both treatment and 
discontinuation) for AECOPD in emergency departments to those that are most likely to 
benefit, so that overall antibiotic exposure duration is decreased without compromising 
COPD-related health status. 
The primary objective is to determine whether the addition of a serial CRP levels to usual 
care for AECOPD leads to shorter antibiotic duration,  
The co-primary objective is to determine whether the addition of a serial CRP levels to usual 
care for AECOPD is non-inferior to usual care alone, on COPD health status as measured by 
CCQ  
The secondary objectives are the effectiveness of the addition of serial CRP levels to usual 
care in AECOPD patients on: 
• 
General health status as measured by EQ-5D-5L  
• 
Adverse effects of antibiotics  
• 
Cost-effectiveness of individualised CRP-guided antibiotic treatments. 
Primary and secondary objectives and outcome measures are listed in Appendix 5. 
We hypothesise that: 
(i) 
antibiotic duration (defined as ‘the number of days of antibiotic treatment’) in 28 days 
among AECOPD patients will be significantly lower for CRP-guided antibiotic 
treatment (including prescription and discontinuation) than usual care  
(ii) 
COPD health status as measured by the Clinical COPD Questionnaire (CCQ) has no 
statistically significant difference between two groups;   

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(iii) 
general health status of AECOPD patients as measured by EQ-5D-5L will not be 
significantly different between the two groups 
(iv) 
adverse effects of antibiotic treatment in AECOPD patients will not be significantly 
different between the two groups 
(v) 
CRP-guided antibiotic treatment will be more cost-effective than usual care 
 
6. Study design 
6.1  Design 
Patient-level, multi-centre, single-blind, open-label, randomized, combined superiority 
(antibiotic duration) and non-inferiority (COPD health status) trial. 
 
6.2  Study sites 
Eligible patients will be recruited via the A&E and relevant departments (e. g. medical wards) 
of 8 hospitals in 5 hospital clusters in Hong Kong. 
 
6.3  Subjects recruitment 
Eligible patients will be recruited via the A&E of 8 hospitals in 5 hospital clusters in Hong Kong. 
Patients will be screened on arrival in A&E for inclusion and exclusion criteria. Delegated 
trained personnel will explain the study to the potential subjects and obtain their written 
consent before joining the study. 
 
6.4  Selection of Subjects  
6.4.1 
The inclusion criterion: 
The inclusion criteria are ALL of the below: 
1. 
Being diagnosed with active AECOPD (AECOPD is defined as an event in the natural 
course of a disease characterized by a change in baseline dyspnoea, cough, and/or 
sputum that is beyond the normal day-to-day variations with acute onset, which may 
warrant a change in regular medication in patients with underlying COPD).5 
2. 
Known COPD in their medical records. 
3. 
Age 40 years or older. 
4. 
Able to provide informed consent in Cantonese, Mandarin, or English 
5. 
Able to complete the questionnaires during the study period (i.e. 6 months after 
randomisation) 
 
6.4.2 
The exclusion criteria: 
Patients will be excluded if any ONE of the following are present: 
1. 
Pre-treatment with systemic corticosteroids for the present exacerbation. 

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2. 
Pre-treatment with any antibiotics for the present exacerbation, any concurrent infection 
or prophylaxis. 
3. 
Known clinical stroke in past 6 months 
4. 
Patients with high suspicion of active AECOPD mimics: 
1) Pneumonia 
2) Congestive heart failure 
3) Bronchiectasis 
4) Pulmonary embolism 
5) Pneumothorax 
6) Atrial fibrillation / flutter 
5. 
Lung comorbidities: 
1) Cystic fibrosis 
2) Tuberculosis 
3) Unresolved lung malignancy 
6. 
Progression or new radiographic abnormalities on the chest X-ray. 
7. 
Immunodeficiency disorders such as AIDS, humoral immune defect, ciliary dysfunction 
etc., and the use of immunosuppressive drugs for more than 28 days. 
8. 
Active inflammatory condition (e.g. flare up of rheumatoid arthritis, gout or polymyalgia 
rheumatica) or concurrent infection at another site (e.g. UTI, cellulitis) that is likely to 
produce a systemic response 
9. 
Currently pregnant 
10. 
NEWS2 score19 of ≥3 
 
6.5  Intervention 
This is a two-arm, open, single-blind, single-centred, individually randomised controlled trial 
involving emergency physicians in ED. This trial will evaluate the addition of serial CRP levels 
to usual care to guide antibiotics management decisions for patients presenting in ED with 
AECOPD, which is the first in the world. Patients presenting with AECOPD will be randomised 
to clinical management based on usual care alone or usual care with the addition of a serial 
CRP levels.  
 
Control arm 
Patients in the control arm will be treated with usual care (GOLD initiative). No CRP would be 
measured. 
 
Intervention arm 
Training in CRP interpretation will help to guide decisions about the use of antibiotic treatment 
for AECOPD. All serum CRP tests will be conducted by the local pathology laboratory in each 

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participating hospital. These laboratories have been accredited by Hong Kong Laboratory 
Accreditation Scheme (HOKLAS) based on ISO standards.  
 
The attending doctor will use the CRP level to inform their decision to continue antibiotics 
around 3 hours from blood taking. These doctors will be provided pre-study training on CRP 
interpretation.  
 
Every day from randomization, serum CRP testing will be encouraged to take. Once CRP has 
declined to <5mg/dL and the patient has remained afebrile for past 48 hours, antibiotic 
treatment will be reviewed for discontinuation. Otherwise, antibiotic treatment will be 
continued. A switch on the administration route, or a change of antibiotics due to adverse 
effect, allergy, or suggestion from culture result, is permitted according to in-patient 
physician’s decisions. CRP will continue to be monitored daily upon discharge from that 
hospital (up to 28 days).   
 
6.6 Procedures 
Patients This trial will be taken place in the emergency departments and wards from 5 
hospitals in 5 hospital clusters in Hong Kong.  
 
6.6.1 
Subject Eligibility assessment 
An attending emergency physician who assesses and cares the patient with active AECOPD 
shall assess the eligibility for recruitment. That patient will be eligible for the trial if inclusion 
criteria are fulfilled, without any exclusion criteria. After consent, that patient will be given a 
participant identity code as the identifier in the trial. 
 
6.6.2 
Randomization 
Patients will be randomized at ED (Day 1). They are randomised in a 1:1 ratio to receive 
either usual care alone (control), or usual care with addition of CRP trend monitoring for 
discontinuation of antibiotics. The randomization sequence will be centralised. Computer-
generated and randomly permuted blocks allocations will be used. Exacerbation 
classification suggested by GOLD Initiative is adopted as a minimisation variable so that 
balance is achieved with respect to differing levels of COPD exacerbation severity. 
 
6.6.3 
Allocation concealment and blinding 
Once the subjects sign the consent form, the research nurse will open an opaque, sealed 
envelope to assign the patients in a 1:1 ratio into the two different groups: (1) intervention 
arm: usual care (GOLD strategy) with addition of serial CRP levels or (2) control arm: usual 
care (GOLD strategy) only. The outcome assessors (who will be the research nurses) and 
data analysts will be blinded throughout the study. The A&E / ward physicians cannot be 
blinded as they will follow our protocol for ordering serum CRP testing and for antibiotic 

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treatments for patients in the intervention group. All staff involved in the recruitment, consent, 
data collection and clinical evaluation will be trained with a standard Good Clinical Practice 
(GCP)-compatible programme, which covers the aims and rationale of this trial, the 
management of AECOPD recommended in GOLD initiative, and the interpretation of CRP 
results. A diagram detailing the data collection time points for intervention group and control 
group is shown in Appendix 5.  A participant flow diagram is available at Appendix 6. The 
CONSORT diagram is listed as Appendix 7. 
 
6.6.4 
Communication with Receiving Ward Staffs 
Participants in the study may transfer to another departments after treatment/ care in A&E. 
The following communication would be conducted: 
- 
A handover note that informs the receiving ward staffs about patients' enrolment to the 
trial, group assignment, and previous treatments given in A&E. The note would also 
suggest the investigations for the receiving ward staffs. 
- 
Telephone handover about intervention group and investigations of the study, and 
treatments given in A&E to ward. 
 
6.6.5 
Data collection 
Trained physicians and nurses may help patient recruitment and data collection in busy 
emergency departments.  
 
6.6.6 
Procedure 
The attending emergency physician who sees the patient will report the duration of AECOPD 
symptoms, medication history, and physical findings (temperature, pulse, oxygen saturation, 
respiratory rate, abnormal lung sounds and peak expiratory flow rate before and after 
bronchodilators). The patient was treated according to GOLD initiative, including 
bronchodilator, and systemic steroid. A sputum sample, a throat swab sample (for bacterial 
culture) and a nasopharyngeal swab (for respiratory virus – pneumonia panel) are collected. 
The attending physician will assess and record the sputum colour using the Bronkotest chart 
(Appendix 8). That patient will be interviewed for CCQ an EQ-5D-5L questionnaire. 
 
Patients randomised to the intervention group will be recommended to have CRP tested and 
the result will be recorded in the proforma. Medication (including antibiotics) prescription and 
other management plan will be recorded. 
 
Trial team members will collect healthcare service utilization data, spirometry result, 
laboratory results and antibiotics prescribed for 12 months before randomization. 
 

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6.6.7 
Microbiological assessment 
Sputum, throat swab and nasopharyngeal swab samples, which are obtained in the initial 
encounter and in week-4 follow up, are sent to local hospital laboratories. Sputum sample 
is not necessarily available, depending on the symptomatology.  
 
All samples will be prepared and tested according to hospital standard operation 
procedure. Bacteria found in the sputum sample will be identified using the Matrix 
Assisted Laser Desorption Ionising Time of Flight Mass Spectrometry (MALDI-ToF-MS) 
and semi-quantitative counts recorded. The throat swab for bacterial culture & sensitivity 
should be collected using sterile swabs and placed into Amies transport medium (+/- 
charcoal). A sheep blood agar plate (BA) is inoculated and incubated at 35 – 37 ̊C for 20 
- 24h in 5 – 10% CO2. Nasopharyngeal swab sample is collected with flexible wire shaft 
swab and transported in viral transport media. The sample will be tested for RT-PCR for 
respiratory viruses. 
 
 
6.6.8 
Follow Up 
The trial team will aim to contact all participants through telephone call, or audio / video call 
with instant messaging software and application service such as WhatsApp, WeChat, or 
Instant Messenger, every week after randomization to follow up CCQ and EQ-5D 
questionnaires. The patient will be met on video call at 4-weeks post randomization. A copy 
of Chronic Respiratory Disease Questionnaire, self-administered, standardized (CRQ-SAS) 
and EQ-5D will be sent to patients for completion and return at 6 months. 
 
 Week 1 & Week 3 
Follow-up call for week 1 and 3 (±1 working day): The patient will be interviewed for the 
symptomatology, CCQ and EQ-5D questionnaires. 
 
  Week 4 
Clinical follow up at week 4 (±2 working days) by research clinician for medication 
consumption, adverse effects, sick leave, diagnosis of pneumonia since the initial encounter, 
any further CRP tests since the initial encounter, health care consultations, CCQ and EQ-5D. 
The patient will be required to return to the emergency department to undergo fresh sputum 
collection, throat swab and nasopharyngeal swab anytime during the day of weekdays before 
end of week 5.  The colour of the sputum specimen will be examined. If the patient defaults 
the follow up at week 4, the team will contact the patient again and collect as many data items 
as possible. If the patient is unable to present, follow up call will be performed. 
 

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  Month 6 
At 6-months post randomisation, the trial team member will examine the patient’s medical 
record for any spirometry results, prescription, and healthcare service utilization. The patient 
will also be sent a copy of CRQ-SAS and EQ-5D then for self-completion. A text reminder 
message will be sent through with instant messaging software and application service 
application. Defaulted patients will be called for interview to collect their responses.  
 
7. Assessment of Efficacy  
Mean antibiotic duration (in days) within 28-days for AECOPD after randomization. 
 
 
8. Assessment of Safety 
Adverse Event 
Events fulfilling the definition of a serious adverse event (SAE), including death, emergency 
hospitalization for conditions other than AECOPD, life-threatening medical conditions, 
(required preventive intervention for) disability or permanent damage, or other serious medical 
events that occur between randomization and 4-week post randomization will be reported to 
the trial team as soon as it is detected. 
 
9. Statistics and Data Analysis 
Trained physicians and nurses will help with patient recruitment and data collection in the 
busy emergency departments.  
 
Baseline subject characteristics will be reported using descriptive statistics such as 
percentage, medians, and interquartile ranges. COPD-related health status, general health 
status, and duration of antibiotics use will be compared among groups by Fisher exact tests. 
Adverse effects and number of events in the intervention group compared to control group 
will be noted and compared by Chi squared tests.  
 
To estimate the between-group difference on primary outcome of antibiotic duration, two 
sample T test will be used to the analysis. The other continuous variables including the co-
primary outcome (CCQ score) and secondary outcome (EQ-5D) will be analyzed in the same 
manner.  
 
Fisher ‘s Exact test will be used to make group comparison for categorical variables such as  
COPD Severity (GOLD grading), COPD exacerbation severity (Anthonisen criteria) and 
microbiological pathogen. All available data will be summarized descriptively by tables and 
figures. All analyses will be performed using Stata software (version 16 or updated version) 
and considered significant at p<0.05.  

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For missing data handling, multiple imputation methods will be used to assess the sensitivity  
of primary outcome results to missing data. Assuming at random, generalised linear models 
will used for the multiple imputations.  
 
Cost evaluations of the intervention group versus control group among AECOPD patients 
attending EDs will be conducted according to the healthcare provider using standard 
methods. For the cost-effectiveness analysis during the RCT, empirical data from RCT will 
be used to estimate the effects and proportions of antibiotic use in each group following the 
ITT principle within the trial period. An ingredient approach will be used to estimate the cost 
of the individualised CRP-guided groups including antibiotics, CRP testing, and culture 
testing. The healthcare resource use with respect to length of hospital stay in the general 
ward, intensive care unit, and high dependency unit, and investigations, procedures, 
vasopressors, and drugs will be measured for all patients in the two groups. The EQ-5D-5L 
utility scores at baseline and at the follow-up assessments will be used to estimate quality-
adjusted life years (QALY) using the area under the receiver operating characteristic curve 
approach. Health economic outcomes will be assessed as incremental cost-effectiveness 
ratios in the form of incremental cost per incremental QALY gained from the intervention 
relative to the control group over the trial period. Both deterministic and probabilistic sensitivity 
analyses will be conducted to test the robustness and uncertainty in the costs and health 
economic outcomes. 
 
10.  Outcomes and measures  
Based on our Co-I's prior experience 20, co-primary outcomes will be proposed in this study 
because including both antimicrobial use and patients’ relevant clinical outcomes can ensure 
adequate power and effect size to simultaneously answer both research questions.  
The primary outcome is mean antibiotic duration (in days) within 28-days for AECOPD after 
randomization, measured at the end of each week, using audio/video call until 28 days post 
randomization. Medication record is also reviewed at 4-weeks post randomization to capture 
prescription of antibiotics related or unrelated to AECOPD.  
The co-primary outcome is the CCQ score which will be collected via audio/video call at 14 
days, as this is the time most AECOPD patients recover and helps inform if that patient is 
suffering from delayed recovery. The CCQ is a patient-centred health status measure that 
has been well validated and is widely used in patients with COPD.21 
Secondary outcome measures include adverse effects potentially attributable to antibiotics 
prescribed for the exacerbation, general health status measured by EuroQol-5D (EQ-5D), 

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Costs (total HA cost) and cost-effectiveness, Disease-specific, health-related quality of life 
over time measured using the CRQ-SAS (dyspnoea, fatigue, emotion function, mastery and 
total scores). 
 
 
11.  Direct Access to Source Data/ Documents 
The investigators and the research assistants in the research team will be responsible for 
data collection of the project. The investigators will permit trial-related monitoring, audits, IRB 
review, and regulatory inspection(s), providing direct access to source data and documents. 
 
 
12.  Ethics 
The trial will be conducted in accordance with the principles originating in the Declaration of 
Helsinki, and those in Good Clinical Practice. After patients (or relatives/legal representatives) 
are assessed as suitable for the Trial, all subjects for this study will be provided a consent 
form describing this study and providing sufficient information for subjects to make an 
informed decision about their participation in this study. This consent form is submitted with 
the protocol for review and approval by the Institutional Review Board (IRB) for the study. The 
formal consent of a subject, using the IRB-approved consent form, must be obtained before 
that subject is submitted to any study procedure. This consent form must be signed by the 
subject or legally acceptable surrogate, and the investigator-designated research 
professional obtaining the consent. The trial will be conducted in accordance with the 
information and consent forms.  
 
 
13.  Data Handling and Record Keeping 
We will collect baseline and follow up data as appropriate. The principal investigator will be 
responsible for data safekeeping. We will use a bespoke case report form and an audit trail 
to ensure that the data captured are consistent, reliable and fully compliant with Good Clinical 
Practice/regulatory requirements. Information about study subjects will be kept confidential, 
and managed according to the laws of the Hong Kong Special Administrative Region and, in 
particular, the Personal Data (Privacy) Ordinance, Cap 486. The name, address or any other 
identifying information will not be passed on to anyone and data will be assigned an 
anonymous identification code. The hospital inpatient and specialist clinic outpatient paper 
medical records are retained for six years and general outpatient paper medical records are 
kept for three years after the last follow up of a patient. Radiological films are stored only for 
one to four years. These documents should be retained for a longer period if required.   
 
14.  Financing and Insurance 

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The study would apply for the Health and Medical Research Fund (HMRF).  
The study would apply for HKU Master Clinical Trial Insurance Policy. 
 
15.  Publication Policy 
The research findings will be published in international peer reviewed journals and reports.  
Individual subjects will not be directly identifiable from the results. 
 
 
 

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16.  References 
1. Mendelson M, Matsoso MP. The World Health Organization global action plan for 
antimicrobial resistance. SAMJ: South African Medical Journal. 2015;105(5):325-325.  
2. Strathdee SA, Davies SC, Marcelin JR. Confronting antimicrobial resistance beyond the 
COVID-19 pandemic and the 2020 US election. The Lancet. 2020;396(10257):1050-1053.  
3. Tansarli GS, Mylonakis E. Systematic review and meta-analysis of the efficacy of short-
course antibiotic treatments for community-acquired pneumonia in adults. Antimicrobial 
agents and chemotherapy. 2018;62(9) 
4. Goossens H, Ferech M, Vander Stichele R, Elseviers M, Group EP. Outpatient antibiotic 
use in Europe and association with resistance: a cross-national database study. The 
Lancet. 2005;365(9459):579-587.  
5. Halpin DM, Criner GJ, Papi A, et al. Global initiative for the diagnosis, management, and 
prevention of chronic obstructive lung disease: The 2020 GOLD science committee report 
on COVID-19 & COPD. American journal of respiratory and critical care medicine. 2020;(ja) 
6. Stolbrink M, Bonnett LJ, Blakey JD. Antibiotics for COPD exacerbations: does drug or 
duration matter? A primary care database analysis. BMJ open respiratory research. 
2019;6(1):e000458.  
7. Mathioudakis AG, Janssens W, Sivapalan P, et al. Acute exacerbations of chronic 
obstructive pulmonary disease: in search of diagnostic biomarkers and treatable traits. 
Thorax. 2020;75(6):520-527.  
8. Pouwels KB, Dolk FCK, Smith DR, Robotham JV, Smieszek T. Actual versus 
‘ideal’antibiotic prescribing for common conditions in English primary care. Journal of 
Antimicrobial Chemotherapy. 2018;73(suppl_2):19-26.  
9. Sapey E, Stockley RA. COPD exacerbations· 2: Aetiology. Thorax. 2006;61(3):250-258.  
10. Al-Jaghbeer MJ, Justo JA, Owens W, et al. Risk factors for pneumonia due to beta-lactam-
susceptible and beta-lactam-resistant Pseudomonas aeruginosa: a case–case–control 
study. Infection. 2018;46(4):487-494.  
11. Hu L, Shi Q, Shi M, Liu R, Wang C. Diagnostic value of PCT and CRP for detecting serious 
bacterial infections in patients with fever of unknown origin: a systematic review and meta-
analysis. Applied immunohistochemistry & molecular morphology. 2017;25(8):e61-e69.  
12. Ding X, Wu X, Yu C, Hu S. Value of C-reactive protein measurement in hospitalized 
patients with acute exacerbations of chronic obstructive pulmonary disease. Med J Wuhan 
University. 2006;27(5):660-3.  
13. Hurst JR, Donaldson GC, Perera WR, et al. Use of plasma biomarkers at exacerbation of 
chronic obstructive pulmonary disease. American journal of respiratory and critical care 
medicine. 2006;174(8):867-874.  
14. Llor C, Moragas A, Hernández S, Bayona C, Miravitlles M. Efficacy of antibiotic therapy for 
acute exacerbations of mild to moderate chronic obstructive pulmonary disease. American 
journal of respiratory and critical care medicine. 2012;186(8):716-723.  

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15. Von Dach E, Albrich WC, Brunel A-S, et al. Effect of C-reactive protein–guided antibiotic 
treatment duration, 7-day treatment, or 14-day treatment on 30-day clinical failure rate in 
patients with uncomplicated gram-negative bacteremia: a randomized clinical trial. Jama. 
2020;323(21):2160-2169.  
16. Butler CC, Gillespie D, White P, et al. C-reactive protein testing to guide antibiotic 
prescribing for COPD exacerbations. New England Journal of Medicine. 2019;381(2):111-
120.  
17. Huddy JR, Ni MZ, Barlow J, Majeed A, Hanna GB. Point-of-care C reactive protein for the 
diagnosis of lower respiratory tract infection in NHS primary care: a qualitative study of 
barriers and facilitators to adoption. BMJ open. 2016;6(3) 
18. Ko FW, Ip M, Chan PK, Ng SS, Chau S, Hui DS. A one-year prospective study of infectious 
etiology in patients hospitalized with acute exacerbations of COPD and concomitant 
pneumonia. Respiratory medicine. 2008;102(8):1109-1116.  
19. Physicians RCo. National Early Warning Score (NEWS)2: Standardising the assessment 
of acute-illness severity in the NHS. Updated report of a working party . . Royal College of 
Physicians. 2020. https://www.rcplondon.ac.uk/projects/outputs/national-early-warning-
score-news-2 
20. Gillespie D, Francis NA, Carrol ED, Thomas-Jones E, Butler CC, Hood K. Use of co-
primary outcomes for trials of antimicrobial stewardship interventions. The Lancet 
Infectious Diseases. 2018;18(6):595-597.  
21. Kocks JW, Tuinenga MG, Uil SM, Van den Berg J, Ståhl E, Van Der Molen T. Health status 
measurement in COPD: the minimal clinically important difference of the clinical COPD 
questionnaire. Respiratory research. 2006;7(1):1-8.  
22. Offen W, Chuang-Stein C, Dmitrienko A, et al. Multiple co-primary endpoints: medical and 
statistical solutions: a report from the multiple endpoints expert team of the Pharmaceutical 
Research and Manufacturers of America. Drug information journal. 2007;41(1):31-46.  
23. Moher D, Chan AW. SPIRIT (standard protocol items: recommendations for interventional 
trials). Guidelines for Reporting Health Research: a user’s manual. 2014:56-67.  
24. Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guidelines for 
reporting parallel group randomised trials. Trials. 2010;11(1):1-8.  
 
 

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Appendix 1 
Clinical COPD Questionnaire 
 

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Appendix 2  
 
CRQ-SAS 
 
 
 
Source: Wijkstra P, TenVergert E, Van Altena R, Otten V, et al. Reliability and validity of the Chronic 
Respiratory Questionnaire (CRQ). Thorax. 1994; 49(5):465-7.  
 
 
 

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Appendix 3 
EQ-5D-5L 
 
Under each heading, please tick the ONE box that best describes your health 
TODAY.  
 
 
MOBILITY  
 
 
I have no problems in walking about                                
 
 
I have slight problems in walking about                            
 
 
I have moderate problems in walking about                     
 
 
I have severe problems in walking about                         
 
 
I am unable to walk about                                                
 
 
 
SELF-CARE  
 
 
I have no problems washing or dressing myself              
 
 
I have slight problems washing or dressing myself          
 
 
I have moderate problems washing or dressing myself   
 
 
I have severe problems washing or dressing myself        
 
 
I am unable to wash or dress myself                                
 
 
 
USUAL ACTIVITIES (e.g. work, study, housework, family or leisure activities) 
 
I have no problems doing my usual activities                   
 
 
I have slight problems doing my usual activities               
 
 
I have moderate problems doing my usual activities        
 
 
I have severe problems doing my usual activities             
 
 
I am unable to do my usual activities 
 
 
 
PAIN / DISCOMFORT  
 
 
I have no pain or discomfort 
 
 
I have slight pain or discomfort 
 
 
I have moderate pain or discomfort 
 
 
I have severe pain or discomfort 
 
 
I have extreme pain or discomfort 
 
 
 
ANXIETY / DEPRESSION  
 
 
I am not anxious or depressed 
 
 
I am slightly anxious or depressed 
 
 
I am moderately anxious or depressed 
 
 
I am severely anxious or depressed 
 
 
I am extremely anxious or depressed 
 
  
 
Source: HERDMAN, Michael, et al. Development and preliminary testing of the new five-level version 
of EQ-5D (EQ-5D-5L). Quality of life research, 2011, 20.10: 1727-1736. 
 
 

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Appendix 4 
 
Prior work on AECOPD in Hong Kong  
 
Table 1  
Outcomes of AECOPD patients 
  
No Antibiotics 
Antibiotics 
  
  
Not ICU / 
death 
ICU / death 
Not ICU / 
death 
ICU / death 
Total 
 p-value 
 OR (95%CI) 
Normal CRP 
200 
2 
4898 
318 
5418 
0.001 
0.15 (0.02, 0.57) 
High CRP 
12 
0 
2422 
312 
2746 
0.382 
0 (0, 2.49) 
 
Figure 1  
Density graph for duration of CRP elevation for AECOPD patients by different 
pathogens 
 
 
Figure 2 
Density graph for duration of antibiotics for AECOPD patients by different pathogens 
 
 
 
 

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Appendix 5 
 
Primary and secondary objectives and outcome measures. 
 
 
Objective 
Outcome measures 
Time point of evaluation 
(from Randomization) 
Primary 
To determine whether the 
addition of a serial CRP 
levels (with advice on 
interpretation) to usual care 
for managing AECOPD 
leads to a reduction in 
antibiotic exposure for 
AECOPD compared to 
usual care alone. 
Antibiotic duration  
4 week 
Primary 
To determine whether the 
addition of a serial CRP 
levels (with advice on 
interpretation) to usual care 
for managing AECOPD 
leads to a reduction in 
antibiotic exposure for 
AECOPD without negatively 
impacting on COPD health 
status compared to usual 
care alone. 
Recovery in terms of COPD health status 
as assessed using the Clinical COPD 
Questionnaire (CCQ) total scores 
2 week 
Secondary 
To evaluate the effect of 
serial CRP levels for 
AECOPD in emergency 
department on: 
Prevalence of potentially pathogenic 
bacteria cultured from sputum at 4 weeks 
and the proportion of bacteria that are 
resistant  
4-week 
Prevalence of commensal organisms 
cultured from sputum at 4 weeks and the 
proportion of bacteria that are resistant  
4-week 
Adverse effects potentially attributable to 
antibiotics prescribed for the exacerbation 
Weekly for 4 weeks 
All-cause antibiotic consumption 
During the first 4 weeks post 
randomisation 
Antibiotic prescribing 
At index consultation & 4-
week 
Use of other COPD treatments including 
orally administered steroids 
4-week 
General health status measured by 
EuroQol-5D (EQ-5D) 
Weekly for 4 weeks 
Primary and secondary care consultations, 
including hospitalisations 
4-week & 6-month 
Costs (total HA cost) and cost-
effectiveness 
6 month 
Incidence of pneumonia (measured by 
patient and medical record) 
4-week & 6-momnth 
Disease-specific, health-related quality of 
life over time measured using the CRQ-
SAS (dyspnoea, fatigue, emotion function, 
mastery and total scores) 
6-month 
 
 
Key: AECOPD acute exacerbation of chronic obstructive pulmonary disease, CCQ Clinical COPD Questionnaire, 
CRP C-reactive protein point-of-care test, CRQ-SAS Chronic Respiratory Disease Questionnaire, self-
administered, standardised 

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Appendix 6 
 
Participant Flow Diagram 
 
 
 
 

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Appendix 7 
 
CONSORT 2010 Flow Diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Excluded (n= 296) 
   Not meeting inclusion criteria  
   Declined to participate   
   Other reasons   
Analysed (n= 473) 
Follow up at 1 week (T1), 
2 weeks (T2), 3 weeks 
(T3), 4 weeks (T4) and 6 
months (T5) 
Allocated to Intervention arm (n= 
592) 
 Received individualized CRP-
guided antibiotic treatment  
Allocated to control group (n= 592) 
 Received treatment with GOLD 
strategy  
Allocation 
Follow-Up 
Randomized (n= 1,184) 
Enrolment 
Lost to follow-up (n= 119) 
Analysed (n= 473) 
Follow up at 1 week (T1), 
2 weeks (T2), 3 weeks 
(T3), 4 weeks (T4) and 6 
months (T5) 
Lost to follow-up (n= 119) 
Assessed for eligibility (n= 1,480) 
Analysis 

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Appendix 8 
 
BRONKOTEST 
 
 
 
Source: https://www.ersnet.org