Procalcitonin-guided Treatment Regarding Antibiotic Use for Acute COPD Exacerbations: a Prospective Randomised Controlled Trial
Phase: NA
Conditions: COPD Exacerbation, COPD, Acute Copd Exacerbation
Sponsor: Erasmus Medical Center

 
1 
 
 
 
 
 
 
Procalcitonin-guided treatment regarding antibiotic use for acute COPD 
exacerbations: a prospective randomised controlled trial  
 
 
 
 
 
 
 
 
 
 
 
 
 
Version 12, August 23rd 2022  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
2 
 
 
PROTOCOL TITLE: Procalcitonin-guided treatment regarding antibiotic use for acute COPD 
exacerbations: a prospective randomised controlled trial 
Protocol ID 
Xx 
Short title 
PRECISION study 
EudraCT number 
Xx
Version 
Xx 
Date
Xx
Coordinating investigator/project 
leader 
 
Menno M. van der Eerden, MD, PhD 
 
Erasmus MC,  
's-Gravendijkwal 230 
3015 CE Rotterdam 
e-mail: m.vandereerden@erasmusmc.nl 
Principal investigator(s)  
 
Menno M. van der Eerden, MD, PhD 
 
Erasmus MC,  
's-Gravendijkwal 230 
3015 CE Rotterdam 
e-mail: m.vandereerden@erasmusmc.nl 
 
Co-investigator 
 
 
 
 
 
 
Research centre 
 
J.W.K. van der Berg, MD, PhD 
Isala clinics 
Dokter van Heesweg 2 
8025 AB Zwolle 
Email: j.w.k.van.den.berg@isala.nl 
 
A. Geel, research coordinator trial unit., Erasmus MC 
Rotterdam, Dep. of Pulmonology, Postbus 2040, 3000 CA 
Rotterdam, tel: +31107030323, email: 
a.geel@erasmusmc.nl 
 
 
Sponsor 
ZonMW 
 
 
Subsidising party 
 
Independent expert (s)
Paul van Daele
 
Erasmus MC,  
's-Gravendijkwal 230 
3015 CE Rotterdam 
 
 
 
Laboratory sites <if applicable>
Amphia Hospital, Breda 
Groene Hart, Gouda 
Isala clinics, Zwolle  
North West Hospital Group, Alkmaar 
OLVG Oost, Amsterdam 
Sint Franciscus Gasthuis, Rotterdam 
Erasmus MC, Rotterdam 
 
Bravis hospital, Bergen op Zoom/Roosendaal 
Zuyderland hospital, Heerlen 
MST, Enschede 
Catharina hospital, Eindhoven 
Pharmacy <if applicable>
N.A
 
 

 
3 
 
PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Head of Department: 
Prof. Dr. J.G.J.V. Aerts 
 
 
 
[Coordinating Investigator/Project 
leader/Principal Investigator]: 
Dr. M.M. van der Eerden 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
4 
 
Synopsis 
 
Title
Procalcitonin-guided treatment regarding antibiotic use for acute 
COPD exacerbations: a prospective randomized controlled trial 
Short title
PRECISION study
Clinical study phase
IV
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
5 
 
Summary 
Study objectives
The primary objective of this study is to show that at hospitalization for a severe 
exacerbation of COPD, PCT-guided treatment regarding antibiotic use is non-
inferior to usual care consisting of prednisolone and or antibiotics, in terms of 
treatment failure at day 30 for patients hospitalized because of an acute 
exacerbation of COPD (AECOPD). Treatment failure is defined as disease-related 
mortality, endotracheal intubation, vasopressors, renal failure, lung 
abcess/empyema, pneumonia development or hospital readmission within 30 days 
after inclusion of the study.  
 
The secondary objectives of this study are to assess the following secondary 
endpoints: 
 Treatment failure defined as an incomplete resolution of the clinical 
signs and symptoms associated with the AECOPD at day 30 after 
inclusion of the study (i.e not reaching the baseline condition prior to 
the AECOPD) scored using the modified Anthonisen criteria. 
 
Change in Quality of Life on day 1, 10, and after 30 days using the  COPD 
Assessment Test (CAT) 
 
Start of antibiotic therapy after an initial opposite decision (after 48 hours) 
 
Side effects (gastro-intestinal complaints, allergic reactions)  
 
Cumulative antibiotic consumption 
 
Cumulative prednisolone consumption 
 
Length of hospitalization  
 
Time to complete resolution of symptoms according to daily symptom 
diaries evaluating the modified Anthonisen criteria 
 
Re-exacerbation within 30 days 
 
PROM symptom score: EXACT – Respiratory symptoms scale (at 
admission, at day 10 and at day 30 after admission) 
 
Non-Invasive ventilation after 72 hours of admission 
 
  
Test drug 
   Name of active ingredient 
 
   Dose 
 
   Route of administration 
 
   Duration of treatment 
 
 
Amoxicillin-clavulanic acid or doxycycline (in case of a bètalactam or penicillin 
allergy) 875/125mg three times a day and 100mg once daily  (200 mg on the first 
day), respectively 
 
Oral 
 
5 days 
 
 
Indication
Severe acute exacerbation of COPD (i.e. with hospitalization) 
 
 
 
Diagnosis and main criteria for 
inclusion 
Inclusion criteria 
- 
COPD, according to GOLD 2018 definition 
- 
Hospitalization because of severe acute exacerbation of COPD 
- 
Post-bronchodilator FEV1/FVC < 0,70 and FEV1% < 80%pred. within last 5 
years 
- 
At least 40 years of age 
- 
Smokers or ex-smokers with > 10 packyears 

 
6 
 
- 
Written informed consent 
- 
Start of symptoms within 7 days before admission 
- 
Presence of at least 2 major symptoms of the modified Anthonisen criteria 
(acute deterioration in sputum volu11me, sputum purulence and dyspnea) or the 
presence of 1 major symptom and 1 minor symptom (coughing, wheeze, nasal 
discharge, sore throat, fever) 
 
Exclusion criteria 
- Indication for ICU and or non-invasive ventilation < 72h of admission 
-    Pneumonia, radiologically confirmed  
- Infection at another site and/or sepsis according to the SIRS criteria (with 
tachycardia and tachypnea not being caused by the exacerbation).  
- COPD before age 40. 
- Asthma, without presence of COPD. 
o Patients with COPD , with or without a history of asthma (in 
childhood or as an adolescent) will NOT be excluded/are allowed 
to participate. 
o Patients with Asthma/COPD overlap syndrome (with current 
asthma AND COPD) will NOT be excluded/are allowed to 
participate.  
- Clinically relevant heart failure or myocardial ischemia 
- Chronic use of immunosuppressants, including prednisolone (prednisone 
equivalent of 10mg or less is NOT an exclusion criterion). 
- Known bronchiectasis as a primary diagnosis 
- Colonisation with Pseudomonas spp. or other micro-organisms in recent cultures 
(last 60 days) not susceptible to amoxicillin-clavulanic acid 
- Pregnancy 
- Recent exacerbation (last 28 days) 
 
Study design
Prospective randomized controlled trial
Methodology
Hospital based clinical trial 
Type of control
Usual care, in which the physician decides on clinical reasons to prescribe 
prednisolone and or antibiotics 
Number of subjects
678 
Primary variabel
Treatment failure at day 30 
Plan for statistical analysis
Primary analysis 
The primary endpoint is defined as 30-day treatment failure. The per protocol (PP) 
population is the main analysis population. The difference and corresponding 95% 
confidence interval (two-sided) in the incidence of the primary endpoint between 
the randomly allocated strategies (biomarker-guided antibiotic use minus usual 
care) will be determined. Non-inferiority will be concluded if the upper limit of this 
confidence interval does not exceed the prespecified non-inferiority margin of 5%.  
 
Secondary analyses 
Differences in the incidence of these secondary endpoints between randomly 
allocated strategies will be analyzed by chi-square tests and logistic regression.
 
 
 
 
 
 
 
 

 
7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
8 
 
TABLE OF CONTENTS 
 
1. INTRODUCTION AND RATIONALE ...................................................................................  
2. OBJECTIVES  
3. STUDY DESIGN .................................................................................................................  
4. STUDY POPULATION ........................................................................................................  
4.1 
Population (base)................................................................................................................. 11 
4.2 
Inclusion criteria ......................................................................................................................  
4.3 
Exclusion criteria .....................................................................................................................  
4.4 
Sample size calculation ..........................................................................................................  
5. TREATMENT OF SUBJECTS ............................................................................................  
5.1 
Investigational product/treatment..........................................................................................  
5.2 
Use of co-intervention (if applicable) ....................................................................................  
5.3 
Escape medication (if applicable) ..........................................................................................  
6. INVESTIGATIONAL PRODUCT .........................................................................................  
6.1 
Name and description of investigational  product(s) ..........................................................  
6.2 
Summary of findings from non-clinical studies ...................................................................  
6.3 
Summary of findings from clinical studies ...........................................................................  
6.4 
Summary of known and potential risks and benefits ..........................................................  
6.5 
Description and justification of route of administration and dosage ................................  
6.6 
Dosages, dosage modifications and method of administration .........................................  
6.7 
Preparation and labelling of Investigational Medicinal Product .........................................  
6.8 
Drug accountability .................................................................................................................  
7. NON-INVESTIGATIONAL PRODUCT ................................................................................  
7.1 
7.1 Name and description of non-investigational product(s)…………………… 
7.2 
Summary of findings from non-clinical studies ...................................................................  
7.3 
Summary of findings from clinical studies ...........................................................................  
7.4 
Summary of known and potential risks and benefits ..........................................................  
7.5 
Description and justification of route of administration and dosage ................................  
7.6 
Dosages, dosage modifications and method of administration .........................................  
7.7 
Preparation and labelling of Non Investigational Medicinal Product .................................  
7.8 
Drug accountability .................................................................................................................  
8.  METHODS 
8.1 
Study parameters/endpoints ..................................................................................................  
8.1.1 
Main study parameter/endpoint ..........................................................................  
8.1.2 
Secondary study parameters/endpoints (if applicable) .......................................  
8.1.3 
Other study parameters (if applicable) ................................................................  
8.2 
Randomisation, blinding and treatment allocation ..............................................................  
8.3 
Study procedures ....................................................................................................................  
8.4 
Withdrawal of individual subjects..........................................................................................  
8.4.1 
Specific criteria for withdrawal (if applicable) ......................................................  
8.5 
Replacement of individual subjects after withdrawal ..........................................................  
8.6 
Follow-up of subjects withdrawn from treatment ................................................................  
8.7 
Premature termination of the study .......................................................................................  
9. SAFETY REPORTING ........................................................................................................  
9.1 
Section 10 WMO event ............................................................................................................  
9.2 
AEs, SAEs and SUSARs .........................................................................................................  
9.2.1 
Adverse events (AEs) .........................................................................................  
9.2.2 
Serious adverse events (SAEs) ..........................................................................  
9.2.3 
Suspected unexpected serious adverse reactions (SUSARs) ............................  
9.3 
Annual safety report ................................................................................................................  
9.4 
Follow-up of adverse events ..................................................................................................  
9.5 
[Data Safety Monitoring Board (DSMB) / Safety Committee] ..............................................  
10. 
STATISTICAL ANALYSIS .............................................................................................  
10.1 
Primary study parameter(s) ....................................................................................................  
10.2 
Secondary study parameter(s) ...............................................................................................  
10.3 
Other study parameters ..........................................................................................................  

 
9 
 
10.4 
Interim analysis (if applicable) ...............................................................................................  
11. 
ETHICAL CONSIDERATIONS ......................................................................................  
11.1 
Regulation statement ..............................................................................................................  
11.2 
Recruitment and consent .......................................................................................................  
11.3 
Objection by minors or incapacitated subjects (if applicable) ...........................................  
11.4 
Benefits and risks assessment, group relatedness.............................................................  
11.5 
Compensation for injury .........................................................................................................  
11.6 
Incentives (if applicable) .........................................................................................................  
12. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION ............................  
12.1 
Handling and storage of data and documents .....................................................................  
12.2 
Monitoring and Quality Assurance ........................................................................................  
12.3 
Amendments ............................................................................................................................  
12.4 
Annual progress report ...........................................................................................................  
12.5 
End of study report .................................................................................................................  
12.6 
Public disclosure and publication policy ..............................................................................  
13. 
STRUCTURED RISK ANALYSIS..................................................................................  
13.1 
Potential issues of concern ....................................................................................................  
13.2 
Synthesis ..................................................................................................................................  
14. 
REFERENCES .............................................................................................................  
 
 
 
 
 
 
 

 
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1. INTRODUCTION AND RATIONALE 
 
Chronic obstructive pulmonary disease (COPD) is a prevalent disease, worldwide, and in the 
Netherlands with approximately 600.000 patients. COPD is currently the 4th leading cause of 
death worldwide and it is estimated to be the 3rd leading cause in 2020 (1-3). It is also a 
leading cause of disability-adjusted life years and with increasing prevalence the loss will 
also increase. The burden on health-care system is therefore impressing: COPD accounts for 
just over 3% of the total health care budget in the European Union. The majority of these 
costs are attributed to acute exacerbations of COPD (AECOPD) (4).  
Reducing the burden of disease for patients (mortality and disability adjusted life years) and 
for society (costs) of this leading chronic disease is therefore of paramount importance. 
Given the contribution of exacerbations both to loss in quality of life and to costs, it is of 
major importance to improve the current treatment of exacerbations. Treatment of AECOPD 
generally consists of corticosteroids to reduce airway inflammation and antibiotics to treat 
bacterial infections, mostly in one-size fits all fashion. 
 
Pulmonary physicians are well aware of overuse of both antibiotics and of prednisolone, but 
lack the tools to decide which medication to give on in the clinical setting. As a consequence, 
in the Netherlands 65% of patients hospitalized for COPD receive antibiotics (Landelijk 
Zorgpad COPD 2018). This overuse is important not only for the costs incurred for giving 
useless therapy, but there are also major side effects, the more frequent ones being 
gastrointestinal complaints. Finally, the overuse of antibiotics results in induction of 
antibiotic resistance, a worldwide grave concern.  
Biomarkers may aid towards a more personalized treatment of AECOPD by identifying which 
patient would benefit from antibiotics. Procalcitonin (PCT) is the precursor of calcitonin and 
is released in response to a bacterial infection within 6-12 hours by many tissues under 
stimulation of several cytokines. Procalcitonin levels are minimally raised in viral infections 
(5), making it a relative specific diagnostic tool for bacterial infections. Several trials have 
shown a reduction in antibiotic consumption in AECOPD when using a PCT-guided treatment 
algorithm (6-9). One meta-analysis about the use of PCT to guide antibiotic administration in 
AECOPD suggested that PCT-based protocols may be superior to standard care in a mixed 
group of patients and indications (10). In this meta-analysis 7 of the 8 included trials, 
including trials performed by Stolz et al. (Chest 2007), Verduri et al. (PLoS ONE 2015) and 
Corti et al. (Int J of COPD 2016) recommended starting antibiotic therapy for procalcitonin 
levels > 0.25ug/L (or 0.25ng/mL), (6a,b,c) This meta-analysis included  the before mentioned 
study by Schuetz et al.  (6). To be able to compare our results to these important 
international studies we decided to use the same cut-off value.  The quality of the data of 
the meta-analysis was judged low to moderate, necessitating appropriately powered 
confirmatory trials before recommending introducing such strategies in daily clinical practice 
(10). 
In summary, PCT has not been tested in a clinical setting in a treatment algorithm specifically 
in COPD with the primary outcome measure being treatment failure. 
 
2. OBJECTIVES 
We hypothesize that at hospitalization for a severe acute exacerbation for COPD, biomarker-
guided treatment based on procalcitonin level to guide antibiotic administration is non-

 
11 
 
inferior to usual care consisting of prednisolone and or antibiotics, which is based on a 
clinical decision, in terms of treatment failure at day 30. 
The secondary objectives are to establish that a biomarker-guided decision algorithm results 
in an improvement in quality of life, a decrease in consumption of antibiotics, and a 
reduction of important side effects. 
 
3. STUDY DESIGN 
 
Study design: prospective randomized controlled trial. 
 
 
Patients will be randomized to biomarker-guided treatment (based on blood procalcitonin 
level) or to usual care. In the usual care arm, and in the biomarker guided-arm in case of high 
procalcitonin, patients will receive amoxicillin-clavulanic acid. 
Prednisolone will be given during 5 days and with a dose of 40mg/day in a single dose as 
recommended by the Dutch National Guideline (16). 
 
Usual care 
Physician’s choice 
Prednisolone ± antibiotics  
PCT level guided care 
PCT ≤ 0.25ug/L  
Prednisolone  
PCT > 0.25ug/L  
Prednisolone + amoxicillin-
clavulanic acid 
 
The procalcitonin will be measured in both groups but will only be reported for the patients 
randomised to the PCT group and not for patients in the usual care group during the study period. 
The measurement will be performed in the usual care group but this will be blinded until the study is 
completed. 
 
 
 
 
 
 
 
 
 
4. STUDY POPULATION 
 
4.1 Population (base)  
Patients with a severe exacerbation of COPD, defined according to the GOLD criteria (3) and 
modified Anthonisen criteria (13,14), for which they need to be hospitalized. 
 
4.2  Inclusion criteria 
 
COPD, according to GOLD 2018 definition 
 
Indication for hospitalization because of acute severe exacerbation of COPD, as 
defined by GOLD 2018 and modified Anthonisen criteria (13,14) 
 
Presence of at least 2 major symptoms of the modified Anthonisen criteria (acute 
deterioration in sputum volume, sputum purulence and dyspnea) or the presence of 
1 major symptom and 1 minor symptom (coughing, wheeze, nasal discharge, sore 
throat, fever) 
 
Post-bronchodilator FEV1/FVC < 0,70 and FEV1% < 80%pred. within last 5 years 
 
At least 40 years  
 
Smokers or ex-smokers with > 10 packyears 
 
Written informed consent 
 
Start of symptoms no more than 7 days before admission 
 
 
 

 
12 
 
4.3  Exclusion criteria 
 Indication for ICU and or non-invasive ventilation < 72h of admission 
 Pneumonia, radiologically confirmed 
  Infection at another site and/or sepsis according to the SIRS criteria (with 
tachycardia and tachypnea not being caused by the exacerbation). 
 COPD before age 40. 
 Asthma, without presence of COPD. 
- 
Patients with COPD , with or without a history of asthma (in childhood or as 
an adolescent) will NOT be excluded/are allowed to participate. 
- 
Patients with Asthma/COPD overlap syndrome (with current asthma AND 
COPD) will NOT be excluded/are allowed to participate.  
 Clinically relevant heart failure or myocardial ischemia 
 Chronic use of immunosuppressants, including prednisolone (a prednisone 
equivalent of 10mg or less is allowed/is NOT an exclusion criterion) 
 Known bronchiectasis as a primary diagnosis 
 Colonisation with Pseudomonas spp. or other micro-organisms in recent cultures 
(last 60 days) not susceptible to amoxicillin-clavulanic acid 
 Pregnancy 
 Recent exacerbation (last 28 days) 
 
4.4 Sample size calculation 
In international literature there is scarce information about the percentages of treatment 
failure in patients admitted with an AECOPD receiving usual care. Therefore, we have 
performed a further search on PCT studies with a primary outcome of 30-day treatment 
failure. In the study by Schuetz et al. (JAMA 2009), who studied patients with lower 
respiratory tract infection, 30-day treatment failure was observed in 15.5% of the patients 
randomised to biomarker-based treatment, as compared to 18.9% in those randomised to 
usual care. This implies a relative risk of 0.82 in favour of the biomarker-based strategy. The 
study by Schuetz et al. was designed as a non-inferiority study, using a non-inferiority 
boundary of 7.5%. In view of these data we decided to design our study as a non-inferior 
study, whereas we choose a non-inferiority boundary of 5.0%. We based the primary 
outcome on the study of Huang et al. (NEJM 2018) (15). The incidence of the primary 
outcome was 20.4%. Using the relative risk of 0.82 in favour of the PCT-guided treatment 
group we expect the incidence of the primary outcome to be 16.7% in the PCT-guided 
treatment group. Then a total sample size of 626 is required (313 per treatment arm) to 
demonstrate non-inferiority with a power of 80%, and applying a one-sided alpha error of 
0.025. We aim to enroll a total of 690 patients, accounting for a 10% drop-out rate. Because 
of an interim-analysis this number of patients will increase to 693 (as detailed below in 
section 10.4). 
 
5. TREATMENT OF SUBJECTS 
Patients will be randomized into: 
- 
biomarker-guided treatment based on blood procalcitonin level to receive 
amoxicillin-clavulanic acid  875/125 mg three times a day for 5 days or no antibiotic 
treatment depending on the serum PCT-level 
or alternatively to   

 
13 
 
- 
usual care depending on the clinical decision of the physician to start or to withhold 
antibiotic treatment consisting of amoxicillin-clavulanic acid three times a day  
875/125mg. The duration of treatment will also be by physician’s choice.  
 
In case of a bètalactam or penicillin allergy: 
- 
doxycycline 100mg (200 mg on the first day) once daily for 5 days  
 
All patients will receive prednisolone 40mg once a day during 5 days, following the Dutch 
national guideline (16). 
Next to antibiotics and prednisolone allocation as detailed above, all patients will 
additionally receive all standard care according to the Global Initiative for Chronic 
Obstructive Lung Disease (GOLD) 2018 guidelines and the Dutch guideline for care for 
patients with an acute exacerbation of COPD (16). 
 
5.1 Investigational product/treatment 
Patients will receive amoxicillin-clavulanic acid or no antibiotic therapy 
 
5.2 Use of co-intervention (if applicable) 
N.A. 
 
5.3 Escape medication (if applicable) 
5.3.1 N.A. 
 

 
14 
 
6. INVESTIGATIONAL PRODUCT  
 
 
 
 
 
  
6.1 Name and description of investigational product(s) 
N.A.  
 
6.2 Summary of findings from non-clinical studies 
N.A.  
 
6.3 Summary of findings from clinical studies 
N.A. 
   
6.4 Summary of known and potential risks and benefits 
N.A. 
 
6.5 Description and justification of route of administration and dosage 
N.A. 
 
6.6 Dosages, dosage modifications and method of administration 
N.A. 
 
6.7 Preparation and labelling of Investigational Medicinal Product 
N.A. 
 
6.8 Drug accountability 
N.A. 
 

 
15 
 
7. NON-INVESTIGATIONAL PRODUCT 
 
7.1 
Name and description of non-investigational product(s) 
Not applicable: it is standard of care in all guidelines to administer prednisolone and 
antibiotics in the majority of patients. Our drugs and dosing are within registration label and 
adhere to the Dutch guideline for in-hospital treatment of COPD exacerbations (16) (in line 
with GOLD 2018). 
 
7.2 
Summary of findings from non-clinical studies 
These are not presented here: it is standard of care in all guidelines to administer 
prednisolone and antibiotics in the majority of patients. Our drugs and dosing are within 
registration label and adhere to the Dutch guideline for in-hospital treatment of COPD 
exacerbations (16) (in line with GOLD 2018). 
 
7.3 
Summary of findings from clinical studies 
Appendix 1 
 
7.4 
Summary of known and potential risks and benefits 
Appendix 1 
 
7.5 
Description and justification of route of administration and dosage 
Appendix 1 
 
7.6 
Dosages, dosage modifications and method of administration 
Appendix 1 
 
7.7 
Preparation and labelling of Non Investigational Medicinal Product 
Appendix 1 
 
7.8 
Drug accountability 
N.A. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
16 
 
8. METHODS 
 
8.1 Study parameters/endpoints 
8.1.1 Main study parameter/endpoint 
The primary objective of this study is to show that at hospitalization for a severe 
exacerbation of COPD, PCT-guided treatment regarding antibiotic use is non-inferior  to 
usual care consisting of prednisolone and or antibiotics, in terms of treatment failure at day 
30 for patients hospitalized because of an acute exacerbation of COPD (AECOPD). Treatment 
failure is defined as disease-related mortality, need for endotracheal intubation or 
vasopressors, renal failure*, lung abcess/empyema, development of pneumonia or 
rehospitalization within 30 days after inclusion.  
 
*renal failure is defined as Kidney Disease: Improving Global Outcomes (KDIGO) stage 3 – 
new renal replacement therapy, tripling of baseline creatinine, or serum creatinine ≥ 350 
umol/L.  
 
8.1.2 Secondary study parameters/endpoints 
The secondary objectives of this study are to assess the following secondary endpoints:-  
 
The key secondary objective is: 
- Treatment failure defined as an incomplete resolution of the clinical signs and symptoms 
associated with the AECOPD at day 30 after inclusion of the study (i.e not reaching the 
baseline condition prior to the AECOPD) scored using the modified Anthonisen criteria.  
 
The other secondary objectives are: 
 
Change in Quality of Life on day 1, 10, and after 30 days using the COPD Assessment 
Test (CAT) 
 
Decision to start antibiotic therapy after an initial opposite decision (after 48 hours) 
 
Side effects (gastro-intestinal complaints, allergic reactions)  
 
Cumulative antibiotic consumption 
 
Cumulative prednisolone consumption 
 
Length of hospitalization  
 
Time to complete resolution of symptoms according to daily symptom diaries 
evaluating the modified Anthonisen criteria 
 
Re-exacerbation within 30 days 
 
PROM symptom score: EXACT – Respiratory symptoms scale (at admission, at day 10 
and at day 30 after admission) 
 
Non-Invasive ventilation after 72 hours of admission 
 
8.1.3 Other study parameters (if applicable) 
Demographics 
Vital signs 
Sputum for routine bacterial cultures 
Serum sample for storage at -80 degrees Celsius 
Sputum sample for storage at -80 degrees Celsius 
Charlson Comorbidity Index 
 

 
17 
 
Cost-effectiveness analysis (CEA): 
 
 General considerations 
Alongside the clinical trial, an economic evaluation will be performed conform the guidelines  
of the Health Care Institute Netherlands (17). This evaluation will be conducted from a 
societal and payer’s perspective. When adopting the societal perspective, costs will include 
30-day inpatient and outpatient (emergency room, specialist visits) hospital costs, primary 
care costs (visits to GP and nurse practitioner), medication costs, ambulance costs, 
productivity costs, informal care costs and travel costs. 
 
 Cost analysis 
The resource utilization underlying these costs will be obtained from a combination of 
sources, including case report forms, hospital administrative systems and a patient’s self-
reported questionnaire, which is based on an adapted version of the iMTA Medical 
Consumption Questionnaire (iMCQ) (18). When adopting the payer’s perspective only the 
costs covered by the Health Insurance Act will be included. Unit costs will be based on 
reference prices obtained from the costing manual (19). In a sensitivity analysis we will 
adjust the unit cost of a hospital day to reflect ward-specific and hospitalization-day-specific 
costs instead of average costs based on all patients in a hospital. Productivity costs will be 
based on the Friction Cost method (20). 
Savings in health care costs are expected to result from a reduction in antibiotics use, a 
reduced length of stay and a reduction in the incidence of side-effects from antibiotics. 
These savings will be compared to the additional costs of adopting the procalcitonin-guided 
treatment, including the costs of additional lab tests. 
 
 Patient outcome analysis 
The difference in total costs between the two groups will be related to the difference in the 
following outcomes: QALYs, treatment failures and CAT (COPD Assessment Test). This will 
result in the following incremental cost-effectiveness ratios (ICER): costs per QALY, costs per 
treatment failure avoided and costs per additional patient with at least one MCID 
improvement in CAT. The utilities to calculate QALYs will be measured with the EQ-5D-5L 
with and without the respiratory bolt-on (21). The ICER’s will be estimated using a decision 
tree model that synthesizes the evidence collected during the clinical trial. The uncertainty 
around the ICER will be estimated in probabilistic sensitivity analysis, the results of which will 
be graphically shown in a CE-plane and Cost-Effectiveness Acceptability Curve. 
 
Budget impact analysis (BIA): 
 
 General considerations 
A budget impact model to estimate the impact of large-scale implementation of the 
intervention will be developed. This model will be a transparent cost calculator that includes 
nation-wide estimates of the size of the COPD population that is hospitalized for 
exacerbations, scenarios on the proportion and speed of uptake of the procalcitonin-guided 
AECOPD treatment, and changes in costs as a result of this.  
 
 
 

 
18 
 
o Cost analysis 
These analyses will be conducted in accordance with the ISPOR and Dutch guidelines of 
ZONMW, for time horizons between 1 and 5 years (22, 23). 
 
8.2 Randomisation, blinding and treatment allocation 
Upon presentation at the emergency department, patients will be clinically judged for in- 
and exclusion criteria, among which indication for hospitalization. When eligible the patient 
will be notified about the study. When the patient is interested in participating, the patient 
information form will be discussed by the treating physician. The participation being 
voluntarily and the opportunity to discontinue participation will be made clear by the 
treating physician. Informed consent will be requested with at least two hours of time to 
decide. Randomisation will occur by a computer-based program. We will use a block-
randomisation with randomly alternating blocks of 4 or 6 patients (random permuted block 
randomisation) and with stratification by center and with stratification by pre-treatment 
with antibiotics. The patient will not be blinded for the treatment received (prednisolone 
with or without antibiotic therapy) but the patient will be blinded for the treatment strategy 
(usual care or PCT-guided treatment). The participating centers will appoint two physicians 
that will be outcome assessors. The outcome assessors will be blinded for the treatment 
strategy.  
 
8.3 Study procedures 
Study period: 
All the assessments will be done at baseline, at day 10 and day 30.  
Patients diary cards will be reviewed at each visit for symptoms and exacerbations 
 
Day 1
Day 3
Day 5
Day 10
Day 30
Initiation procedures
Informed consent 
X 
 
 
 
 
Medication history 
X
Vital signs 
X 
 
 
 
 
Check for eligibility
X
Sputum collection
X
Blood sampling, including 
procalcitonin* 
X 
 
 
 
 
Blood sampling CRP, 
eosinophils 
x 
 
 
 
 
Serum for storage
X
Sputum for storage 
X 
 
 
 
 
Modified Anthonisen 
criteria 
X 
X 
X 
X 
X 
Clinical assessment for 
treatment failure 
 
X 
X 
X 
X 
CAT
X
X
X
E-RS 
X 
 
 
X 
X 
EQ-5D-5L
X
X
X
iMCQ
X
Randomization 
X 
 
 
 
 

 
19 
 
Antibiotic consumption
X
X
X
X
X
Diary cards according to 
modified Anthonisen 
criteria** 
X 
X 
X 
X 
X 
Assessment of adverse 
effects 
x 
X 
X 
X 
X 
 
* (PCT will only be reported for the randomised PCT group and not for the usual care group 
during the study period. The measurement will be performed in the usual care group but 
this will be blinded until the study ends.) 
** This symptom card will be evaluated on the given days by the patient 
 
8.4 Withdrawal of individual subjects 
After signing the informed consent, patients still are allowed to withdraw from the study. 
Every attempt will be made to collect the primary end-point. Withdrawal by the investigator 
will mainly be because of safety reasons and mostly constitute a treatment failure. 
 
8.4.1. Specific criteria for withdrawal (if applicable)  
N/A 
 
8.5 Replacement of individual subject after withdrawal 
No subjects will be replaced in the study as soon as the quotum is reached of randomised 
subjects. 
 
8.6 Follow-up of subjects withdrawn from treatment 
Patients who are withdrawn from the study will be invited for a follow up visit as detailed 
above, and otherwise it will be attempted to collect data on the primary end-points as long 
as this is within the agreement of the informed consent. 
 
8.7 Premature termination of the study  
N/A 
 
9. 
SAFETY REPORTING  
9.1 
Section 10 WMO event 
In accordance to section 10, subsection 1, of the WMO, the investigator will inform the 
subjects and the reviewing accredited METC if anything occurs, on the basis of which it 
appears that the disadvantages of participation may be significantly greater than was 
foreseen in the research proposal. The study will be suspended pending further review by 
the accredited METC, except in so far as suspension would jeopardise the subjects’ health. 
The investigator will take care that all subjects are kept informed. 
 
 
9.2 
AEs, SAEs and SUSARs 
9.2.1 Adverse events (AEs)  
In a clinical study, an AE is any untoward medical occurrence (i.e. any unfavourable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject 
or clinical investigation subject after providing written informed consent for participation in 

 
20 
 
the study. Therefore, an AE may or may not be temporally or causally associated with the 
use of a medicinal (investigational) product.  
 
In the following differentiation between medical history and AEs, the term ‘condition’ may 
include abnormal e.g. physical examination findings, symptoms, diseases, laboratory, 
pulmonary function test (PFT). 
 
All adverse events reported spontaneously by the subject or observed by the investigator or 
his staff will be recorded.  
 
Common expected adverse events are: 
- 
Diarrhoea 
- 
Gastric complaints 
 
9.2.2 Serious adverse events (SAEs) 
 
An SAE is classified as any untoward medical occurrence that, at any dose, meets any of the 
following criteria (a-f): 
a) Results in death; 
b) In life-threatening: 
The term ‘life-threatening’ in the definition refers to an event in which the subject 
was at risk of death at the time of the event, it does not refer to an event, which 
hypothetically might have caused death if it were more severe 
c) Requires inpatient hospitalization or prolongation of existing hospitalization 
A hospitalization or prolongation of hospitalization will not be regarded as an SAE if 
at least one of the following exception is met: 
o The admission results in a hospital stay of less than 12 hours 
o The admission is pre-planned (i.e., elective or scheduled surgery arranged 
prior to the start of the study); 
o The admission is not associated with an AE (e.g., social hospitalization for 
purposes of respite care).  
However, it should be noted that invasive treatment during a hospitalization may 
fulfil the criterion of ‘medically important’ and as such may be reportable as an SAE 
dependent on clinical judgment. In addition, where local regulatory authorities 
specifically require a more stringent definition, the local regulation takes 
precedence. 
d) Results in persistent or significant disability / incapacity 
Disability means a substantial disruption of a person’s ability to conduct normal life’s 
functions 
e) Is a congenital anomaly / birth defect; 
f) Is another medically important serious advent as judged by the investigator 
 
When a SAE is reported spontaneously by the subject or observed by the principal 
investigator or his staff it will be reported to the coordinating investigator in the 
ErasmusMC.  
The coordinating investigator will report the SAEs through the web portal ToetsingOnline to 
the accredited METC that approved the protocol, within 15 days after the sponsor has first 
knowledge of the serious adverse reaction.  

 
21 
 
SAEs that result in death or are life threatening should be reported expedited. The expedited 
reporting will occur not later than 7 days after the responsible investigator has first 
knowledge of the adverse reaction. This is for a preliminary report with another 8 days for 
completion of the report.  
 
9.2.3 Suspected unexpected serious adverse reactions (SUSARs) 
 
Adverse reactions are all untoward and unintended responses to an investigational product 
related to any dose administered. 
 
Unexpected adverse reactions are SUSARs if the following three conditions are met: 
1. 
the event must be serious (see chapter 9.2.2); 
2. 
there must be a certain degree of probability that the event is a harmful and an 
undesirable reaction to the medicinal product under investigation, regardless of 
the administered dose; 
3. 
the adverse reaction must be unexpected, that is to say, the nature and severity 
of the adverse reaction are not in agreement with the product information as 
recorded in: 
a) Summary of Product Characteristics (SPC) for an authorised medicinal product; 
b) Investigator’s Brochure for an unauthorised medicinal product. 
The coordinating investigator in the ErasmusMC will report expedited the following SUSARs 
through the web portal ToetsingOnline to the METC: 
- SUSARs that have arisen in the clinical trial that was assessed by the METC; 
- SUSARs that have arisen in other clinical trials of the same sponsor and with the same 
medicinal product, and that could have consequences for the safety of the subjects involved 
in the clinical trial that was assessed by the METC. 
The remaining SUSARs are recorded in an overview list (line-listing) that will be submitted 
once every half year to the METC. This line-listing provides an overview of all SUSARs from 
the study medicine, accompanied by a brief report highlighting the main points of concern.  
The expedited reporting of SUSARs through the web portal ToetsingOnline is sufficient as 
notification to the competent authority. 
 
The coordinating investigator will report expedited all SUSARs to the competent authorities 
in other Member States, according to the requirements of the Member States.  
 
The expedited reporting will occur not later than 15 days after the sponsor has first 
knowledge of the adverse reactions. For fatal or life threatening cases the term will be 
maximal 7 days for a preliminary report with another 8 days for completion of the report.  
 
9.3 
Annual safety report  
In addition to the expedited reporting of SUSARs, the coordinating investigator will submit, 
once a year throughout the clinical trial, a safety report to the accredited METC, competent 
authority, and competent authorities of the concerned Member States. 
This safety report consists of: 
- 
a list of all suspected (unexpected or expected) serious adverse reactions, along with 
an aggregated summary table of all reported serious adverse reactions, ordered by 
organ system, per study; 

 
22 
 
- 
a report concerning the safety of the subjects, consisting of a complete safety 
analysis and an evaluation of the balance between the efficacy and the harmfulness 
of the medicine under investigation. 
 
9.4 
Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been reached. 
Depending on the event, follow up may require additional tests or medical procedures as 
indicated, and/or referral to the general physician or a medical specialist. 
SAEs need to be reported till end of study within the Netherlands, as defined in the protocol 
 
9.5 
[Data Safety Monitoring Board (DSMB) / Safety Committee] 
 
An interim analysis will be performed at 50% of patient accrual, analysing the primary 
outcome and safety data. The safety data consists of observed adverse events and SAE. A 
DSMB will assess this interim analysis. The members of the DSMB will be dr. Gert-Jan 
Braunstahl (pulmonologist Franciscus Gasthuis & Vlietland), dr. Mireille van Westreenen 
(medical microbiologist Erasmus Medical Center) and prof. dr. ir. Eric (H.) Boersma 
(Professor of Clinical Epidemiology of Cardiovascular Diseases Erasmus Medical Center).  
The advice(s) of the DSMB will only be sent to the principal investigator of the study. Should 
the principal investigator decide not to fully implement the advice of the DSMB, the principal 
investigator will send the advice to the reviewing Ethical Committee (in Dutch: METC), 
including a note to substantiate why (part of) the advice of the DSMB will not be followed. 
 
Criteria on which the DSMB may decide to terminate the trial prematurely are: 
1. Any serious adverse event related to the treatment under investigation has occurred. 
2. A significant evidence of benefit  
 
10. 
STATISTICAL ANALYSIS 
 
 
There will be two analysis populations for this study: 
 
1. The Intention-to-Treat (ITT) population is defined as all randomised patients who took at 
least one dose of study drug. 
 
2. The Per-Protocol (PP) population is defined as a subset of ITT population constituted by 
those patients who: a) met all inclusion/exclusion criteria, b) attained a sufficient compliance 
to the treatment received,  treatment with prednisolone and/or antibiotics, when prescribed 
on admission for at least 5 days, and c) did not present serious deviations from the protocol. 
 
The analysis of all the efficacy variables will be performed on both the ITT and the PP 
populations in order to assess the robustness of the findings from the ITT population. 
All the demographic and baseline patients’ characteristics and safety outcomes will be 
analysed using the ITT population. 
All efficacy variables will be analysed for ITT and the PPS, and the PP population will be 
considered the primary population for assessing efficacy.  
 
 
 

 
23 
 
10.1 
Primary study parameter(s)  
The primary objective of this study is to show that at hospitalization for a severe 
exacerbation of COPD, PCT-guided treatment regarding antibiotic use is non-inferior  to 
usual care consisting of prednisolone and or antibiotics, in terms of treatment failure at day 
30 for patients hospitalized because of an acute exacerbation of COPD (AECOPD). Treatment 
failure is defined as disease-related mortality, need for endotracheal intubation or 
vasopressors, renal failure*, lung abcess/empyema, development of pneumonia or 
rehospitalization within 30 days after inclusion.  
 
*renal failure is defined as Kidney Disease: Improving Global Outcomes (KDIGO) stage 3 – 
new renal replacement therapy, tripling of baseline creatinine, or serum creatinine ≥ 350 
umol/L.  
  
10.2 
Secondary study parameter(s) 
Key secondary outcome: 
- Treatment failure defined as an incomplete resolution of the clinical signs and symptoms 
associated with the AECOPD at day 30 after inclusion of the study (i.e not reaching the 
baseline condition prior to the AECOPD) scored using the modified Anthonisen criteria.  
 
Other secondary outcomes: 
 
Change in Quality of Life on day 1, 10, and after 30 days using the COPD Assessment 
Test (CAT)Start of antibiotic therapy after an initial opposite decision (after 48 hours) 
 
Side effects (gastro-intestinal complaints, allergic reactions)  
 
Cumulative antibiotic consumption 
 
Cumulative prednisolone consumption 
 
Length of hospitalization  
 
Time to complete resolution of symptoms according to daily symptom diaries 
evaluating the modified Anthonisen criteria 
 
Re-exacerbation within 30 days 
 
PROM symptom score: EXACT – Respiratory symptoms scale (at admission, at day 10 
and at day 30 after admission) 
 
ICU admission after 72 hours of admission 
 
Non-Invasive ventilation after 72 hours of admission 
 
10.3 
Other study parameters 
 
Demographics 
Vital signs 
Sputum for routine bacterial cultures 
Serum sample for storage at -80 degrees Celsius 
Sputum sample for storage at -80 degrees Celsius 
Charlson comorbidity index 
Cost effectiveness analysis, as detailed above in section 8.1.3 
 
Statistical and analytical plans 
Primary analysis 
The primary endpoint is defined as 30-day treatment failure. The per protocol (PP) 
population is the main analysis population. An analysis will be performed for the randomly 

 
24 
 
allocated antibiotic strategy (i.e. usual care versus antibiotics in patients with PCT >0.25 
µg/L). The difference and corresponding 95% confidence interval (two-sided) in the 
incidence of the primary endpoint between the randomly allocated strategies (biomarker-
guided drug use minus drug-in-all) will be determined. Non-inferiority will be concluded if 
the upper limit of the 95% confidence interval does not exceed the prespecified non-
inferiority margin of 5%.  
 
Secondary analyses 
The minimal clinically important difference (MCID) of the COPD Assessment Test (CAT) is 
considered to be a decrease of 2 to 3 points (after rehabilitation) and a decrease of 2 points 
according to Kon et al. who conducted 3 trials, in patients who underwent rehabilitation, 
paients who were admitted to the hospital because of an exacerbation and outpatient who 
were stable (24, 25). We will consider a decrease of 2 points as a minimal clinically important 
difference. The definition of symptomatic improvement of the E-RS is RS-total ≥ -2.0 (scale 
range 0-40) (26). Adverse events will be compared by total number of adverse events, of 
serious adverse events, and separately for gastro-intestinal complaints. Differences in the 
incidence of these secondary endpoints between randomly allocated strategies will be 
analyzed by chi-square tests and logistic regression. Secondary endpoints consisting of 
continuous variables will be analyzed either using the unpaired t-test (for variables with 
normal distribution) or the Man-Whitney-U test (for variables with a skewed distribution). 
The distribution will be analyzed when the results are complete.  
 
 
10.4 
Interim analysis (if applicable) 
An interim analysis will be performed after 50% of the participants needed has been 
accrued/included. The analysis will focus on the primary outcome and on safety. The non-
inferiority design of the study means that a clear disadvantage of the PCT-guided treatment 
arm or in other words a clear benefit of the usual care arm will lead to discontinuation of the 
trial. The p-value at the interim analysis will be 0.0054 according to the O’Brien-Fleming 
method, and the p-value at final analysis will be 0.0492 (27). The safety data consists of 
observed adverse events and SAE. The change of the p-value at final analysis will lead to an 
increase of 2 patients per treatment arm. The number of patients per treatment arm will be 
315. Using a 10% drop-out rate this will lead to a total number of patients of 693. 
 
11. 
ETHICAL CONSIDERATIONS  
11.1 
Regulation statement 
 
The study will be conducted according to the principles of the Declaration of Helsinki (59th 
WMA General Assembly, Seoul, Korea, October 2008) and in accordance with the Medical 
Research Involving Human Subjects Act (WMO). 
 
11.2 
Recruitment and consent 
This study will include 693 patients during a 48-month period. Annually, there are around 
23,000 hospital admissions for AECOPD in the Netherlands (28). Nine centers will participate 
in the study: Amphia hospital (Breda), Erasmus MC (Rotterdam) Groene Hart (Gouda), Isala 
clinics (Zwolle), North West Hospital Group (Alkmaar), OLVG Oost (Amsterdam), the Sint 
Franciscus Gasthuis (Rotterdam), Zuyderland (Heerlen), Bravis Hospital (Bergen op 
Zoom/Roosendaal) , MST (Enschede) and Catharina hospital (Eindhoven).  
 

 
25 
 
Informed consent forms will be presented before start of the study. Only patients that 
signed the informed consent will be entered in the study. Subject’s written informed 
consent will be obtained prior to any study-related procedures. At any time patients have 
the right to withdraw from the study without any consequences for their ongoing treatment. 
For further details, see 8.4. 
 
11.3 
Objection by minors or incapacitated subjects (if applicable) 
N/A 
 
 
11.4 
Benefits and risks assessment, group relatedness  
Benefits: The main problem is the worldwide overuse of antibiotics contributing to the 
induction of global antibiotic resistance. We expect that a biomarker-based intervention 
using PCT to guide antibiotic treatment next to being non-inferior regarding treatment 
failure, will decrease the number of adverse effects and improve quality of life.  
 
Risks assessments: Common side effects of antibiotics are diarrhoea and other gastro-
intestinal complaints.  
 
 
11.5 
Compensation for injury  
The sponsor/investigator has a liability insurance which is in accordance with article 7, 
subsection 6 of the WMO. The sponsor (also) has an insurance which is in accordance with 
the legal requirements in the Netherlands (Article 7 WMO and the Measure regarding 
Compulsory Insurance for Clinical Research in Humans of 23th June 2003). This insurance 
provides cover for damage to research subjects through injury or death caused by the study. 
 
11.6 
Incentives (if applicable) 
N.A. 
 
12. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
 
12.1 
Handling and storage of data and documents 
 
Data will be handled and collected in compliance with ICH-GCP (Good Clinical Practice) and 
in accordance with prevailing national and international regulations, principles and 
guidelines such as VSNU code, NFU, WGBO and WMO and Erasmus MC policy on clinical 
trials (“Richtlijn wetenschappelijke integriteit Erasmus MC”, “Erasmus MC 
Onderzoeksbeleid”) 
 
Database 
For randomization, clinical data collection and central data management, Castor® will be 
used. Castor® is a web-based software tool designed to capture clinical study data. Castor® is 
hosted by an external party (Castor EDC), which is validated for conducting clinical trials in 
the Erasmus MC and meets all requirements to be ICH-GCP compliant.  
 
The standard way to capture data in clinical studies is via e-CRFs which are specifically 
designed to collect study data in a structured format. Castor® allows sponsors (or their 
delegates) to design, manage and complete study specific e-CRFs. The e-CRFs can be 
completed for all participating subjects and can be reached from various locations in the 
world, allowing Castor® to be used for multicenter studies. 

 
26 
 
CRF design 
The sponsor of the study will design CRFs that accurately represent the protocol of the 
clinical study. The study specific CRFs will be designed in such a way that they accurately 
capture the required data for addressing the study objectives as outlined in the protocol of 
the clinical study. They should be parsimoniously (i.e. only collect what is needed to know, 
not what is nice to know) while at the same time being complete (i.e. no critical omissions 
leading to incomplete data). 
 
Audit trail and data back-up 
One of Castor®’s prime features is that it keeps an audit trail, i.e. provides documentary 
evidence of the sequence of activities by user that have affected at any time a specific 
operation, procedure, or event. Data cannot be permanently deleted, ensuring proper 
backing-up of data. With regard to data entry, each change after submission will need to be 
accompanied by a reason for change.  
 
Data entry 
Data entry will be done according to Standard Operating Procedures. Besides, study specific 
data entry guidelines will be provided to local datamanagers, promoting a uniform and 
standardized way of data entry and providing ways of working in case of exceptions (i.e. 
missings, unknowns etc). The local datamanagers will be trained in using the eCRF system 
Castor®  prior to data entry start. All trainings will be documented conform GCP 
requirements.  
 
12.2 
Monitoring and Quality Assurance  
A study specific monitoring plan, compliant with NFU guidelines and the Erasmus MC 
requirements for the METC approved monitoring risk (i.e. minimal, medium or high, will be 
written. This study specific monitoring plan will focus both on quality assurance and cost 
efficiency.  
Throughout the trial, a trained, qualified and independent monitor will periodically visit each 
participating site in order to, among other things, randomly check compliance with the 
protocol, compliance with in- and exclusion criteria, proper implementation and conduct of 
Informed Consent procedures, Source Data Verification (i.e. cross-check data in Castor® with 
patient dossier and vice versa) and SAE reporting. 
Findings will be discussed with the Local Investigator and reported in a standard monitor 
report that will be shared with and filed by the Sponsor. The monitor will also feed any 
relevant findings back to the person(s) responsible for data validation (central data 
management). 
 
Data validation/ Central Data management 
For critical data, i.e. data prone to errors, front-end validation checks (i.e. error messages) 
may be applied, preventing users from incorrect or illogical data entry.   
Advanced back-end data consistency checks, focusing on missings, inconsistencies and 
outliers will be applied as batch cleanings to filter affected records. Affected records (i.e. 
missings, outliers) will be dealt with appropriately. That is, data queries will be generated 
and sent to the respective participating site. The participating site will have to address these 
queries until they are resolved satisfactory. 
Timely data entry will be monitored throughout and reminders will be sent in case of delays.  

 
27 
 
 
A comprehensive study specific data management, detailing which data should be handled 
when, how, and by whom until they are deemed validated for data analyses, will be written 
prior to study commencement and reviewed/edited throughout the trial if so needed.  
 
12.3 
Amendments  
A ‘substantial amendment’ is defined as an amendment to the terms of the METC 
application, or to the protocol or any other supporting documentation, that is likely to affect 
to a significant degree: 
- 
the safety or physical or mental integrity of the subjects of the trial; 
- 
the scientific value of the trial; 
- 
the conduct or management of the trial; or 
- 
the quality or safety of any intervention used in the trial. 
 
All substantial amendments will be notified to the METC and to the competent authority. 
 
Non-substantial amendments will not be notified to the accredited METC and the competent 
authority, but will be recorded and filed by the sponsor.  
< Examples of non-substantial amendments are typing errors and administrative changes like 
changes in names, telephone numbers and other contact details of involved persons 
mentioned in the submitted study documentation.> 
 
12.4 
Annual progress report 
 
The sponsor/investigator will submit a summary of the progress of the trial to the accredited 
METC once a year. Information will be provided on the date of inclusion of the first subject, 
numbers of subjects included and numbers of subjects that have completed the trial, serious 
adverse events/serious adverse reactions, other problems, and amendments.  
 
12.5 
End of study report  
The sponsor will notify the accredited METC and the competent authority of the end of the 
study within a period of 180 days. The end of the study is defined as the last patient’s last 
visit.  
 
In case the study is ended prematurely, the sponsor will notify the accredited METC and the 
competent authority within 15 days, including the reasons for the premature termination. 
 
Within one year after the end of the study, the investigator/sponsor will submit a final study 
report with the results of the study, including any publications/abstracts of the study, to the 
accredited METC and the Competent Authority.  
 
12.6 
Public disclosure and publication policy 
 
This study is an investigator-initiated study. Therefore, arrangements concerning the public 
disclosure and publication between the sponsor and the investigator are not applicable. 
Results of this study will be disclosed to the public without any restrictions.  
 

 
28 
 
13. 
STRUCTURED RISK ANALYSIS 
 
 
13.1 
Potential issues of concern 
Patients in both groups will either receive amoxicillin-clavulanic acid 875/125mg three times 
a day during five days or no antibiotic therapy. Common expected adverse events are: 
diarrhoea and other gastro-intestinal complaints. Patients will receive diary cards, these 
diary cards will be reviewed at each visits for symptoms, adverse events and exacerbations. 
In case of an adverse event measures will be taken to treat the existing adverse event. 
 
13.2 
Synthesis 
 
It is standard of care in all guidelines to administer prednisolone and antibiotics in the 
majority of COPD patients. Our drugs and dosing are within registration label and adhere to 
the Dutch guideline for treatment of COPD exacerbations in the hospital (15) (in line with 
GOLD 2018). We expect that risks of experiencing adverse events are acceptable for the 
subjects participating in the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
29 
 
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