Standard vs Targeted Oxygen Therapy Prehospital for Chronic Obstructive Pulmonary Disease
Phase: PHASE4
Conditions: COPD Exacerbation, COPD Exacerbation Acute
Sponsor: Central Denmark Region

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Standard vs Targeted Oxygen Therapy Prehospital  
for Chronic Obstructive Pulmonary Disease 
Acronym: STOP-COPD 
Project name 
Standard vs Targeted Oxygen Therapy 
Prehospital for Chronic Obstructive 
Pulmonary Disease 
Project Acronym 
STOP-COPD Standard vs Targeted Oxygen 
Therapy Prehospital for Chronic Obstructive 
Pulmonary Disease 
Sponsor-Investigator 
Martin Faurholdt Gude, MD 
Prehospital Emergency Medical Services, Olof 
Palmes Allé 34 1. sal, 8200 Aarhus N 
Sponsor-Investigator signature 
 
 
Study coordinator
Arne Sylvester Rønde Jensen, Paramedic 
Universal trial number
U1111-1278-2162 
Danish Medicines Agency ref. 
number 
2021070942 
EU CTIS number
2022-502003-30-00 
Protocol Version
4.3.2 
Website (not active until trial start)
www.STOP-COPD.com 
This version (4.3.2 ClinicalTrials.gov submission version) includes minor editorial changes, 
including the removal of appendices containing Danish-language material (Appendices 2–7), 
to comply with ClinicalTrials.gov language requirements. No changes were made to the 
study design or content. The original version: https://www.stop-copd.com/protocol  
 

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Content 
Abbreviations..................................................................................................................................................... 6 
0 List of modifications ....................................................................................................................................... 8 
1 Summary ....................................................................................................................................................... 11 
2 Project overview ........................................................................................................................................... 15 
3 Background ................................................................................................................................................... 16 
3.1 Incidence and mortality ......................................................................................................................... 16 
3.2 Pathophysiology .................................................................................................................................... 16 
3.2.1 Hypoxic Pulmonary Vasoconstriction ............................................................................................. 16 
3.2.2 The Haldane effect ......................................................................................................................... 17 
3.2.3 Impaired respirator-drive in patients with COPD ........................................................................... 17 
3.3 Current evidence ................................................................................................................................... 18 
3.4 Guidelines .............................................................................................................................................. 19 
3.5 Standard of care in Denmark ................................................................................................................. 20 
4 Trial objectives .............................................................................................................................................. 20 
5 Trial Design ................................................................................................................................................... 21 
5.1 Overview ................................................................................................................................................ 21 
5.1.1 Study procedures ............................................................................................................................ 21 
5.2 Setting .................................................................................................................................................... 22 
5.3 Rollout ................................................................................................................................................... 22 
5.4 Outcomes .............................................................................................................................................. 23 
5.4.1 Primary Outcome ........................................................................................................................... 23 
5.4.2 Secondary outcomes ...................................................................................................................... 23 
5.5 Allocation ............................................................................................................................................... 24 
5.6 Randomization ....................................................................................................................................... 24 

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5.7 Blinding .................................................................................................................................................. 24 
5.8 Study drugs ............................................................................................................................................ 24 
5.8.1 Investigational medicinal products ................................................................................................ 25 
5.8.2 Auxiliary medicinal product ............................................................................................................ 26 
5.9 Trial phases ............................................................................................................................................ 26 
5.10 Termination ......................................................................................................................................... 27 
5.10.1 Termination of allocated treatment ............................................................................................. 27 
5.10.2 Termination of the trial ................................................................................................................ 27 
5.11 Co-enrolment....................................................................................................................................... 27 
5.12 Medical responsibility .......................................................................................................................... 28 
5.13 Recruitment ......................................................................................................................................... 28 
5.14 End of trial ........................................................................................................................................... 28 
6 Inclusion and exclusion ................................................................................................................................. 28 
6.1 Screening and enrolment ...................................................................................................................... 28 
6.2 Inclusion criteria .................................................................................................................................... 29 
6.3 Exclusion criteria .................................................................................................................................... 29 
7 Intervention .................................................................................................................................................. 30 
7.1 Standard treatment ............................................................................................................................... 30 
7.2 Intervention treatment ......................................................................................................................... 31 
7.3 Clinical treatment .................................................................................................................................. 31 
7.4 Clinical personnel .................................................................................................................................. 32 
8 Data collection .............................................................................................................................................. 32 
8.1 Process ................................................................................................................................................... 32 
8.2 Variables ................................................................................................................................................ 33 
8.2.1 Baseline characteristics .................................................................................................................. 33 
8.2.2 Pre-intervention characteristics ..................................................................................................... 34 

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8.2.3 Post-intervention characteristics.................................................................................................... 34 
8.2.4 Outcomes ....................................................................................................................................... 35 
8.2.5 Safety .............................................................................................................................................. 35 
8.2.6 ABG ................................................................................................................................................. 35 
8.3 Patient-experienced dyspnoea .............................................................................................................. 36 
8.4 Data quality and validity ........................................................................................................................ 36 
8.4.1 Protocol violations .......................................................................................................................... 36 
9 Safety ............................................................................................................................................................ 37 
9.1 Standard treatment ............................................................................................................................... 37 
9.2 Intervention treatment ......................................................................................................................... 37 
9.3 Adverse events and reactions ............................................................................................................... 37 
9.3.1 Definitions ...................................................................................................................................... 37 
9.3.2 Reporting ........................................................................................................................................ 38 
9.4 Specific adverse reactions ..................................................................................................................... 39 
9.4.1 Medical Oxygen ”Air Liquide” ......................................................................................................... 39 
9.4.2 Compressed Atmospheric Air ”Air Liquide” ................................................................................... 39 
9.4.3 Salbutamol ...................................................................................................................................... 39 
9.4.4 Berodual ......................................................................................................................................... 40 
9.5 Assessment of adverse events .............................................................................................................. 40 
9.5.1 Timing ............................................................................................................................................. 40 
9.5.2 Classification of an event ................................................................................................................ 40 
10 Sample size and statistical analysis plan .................................................................................................... 40 
10.1 Sample size calculation ........................................................................................................................ 40 
10.2 Feasibility ............................................................................................................................................. 41 
10.2.1 Patients ......................................................................................................................................... 41 
10.2.2 Clinician’s enrolment rate ............................................................................................................ 42 

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10.3 Stopping criteria .................................................................................................................................. 42 
10.4 Statistical analysis plan ........................................................................................................................ 42 
10.4.1 Outcomes and statistics ............................................................................................................... 42 
10.4.2 Subgroup analysis ......................................................................................................................... 43 
10.5 Missing data ......................................................................................................................................... 44 
11 Data ............................................................................................................................................................ 44 
11.1 Storage ................................................................................................................................................. 44 
11.2 Data access .......................................................................................................................................... 45 
11.3 Data sharing ......................................................................................................................................... 45 
12 Quality and monitoring .............................................................................................................................. 45 
12.1 Good Clinical Practice monitoring ....................................................................................................... 45 
12.2 Data monitoring committee ................................................................................................................ 45 
13 Ethical Considerations ................................................................................................................................ 46 
13.1 Risk/benefit assessment ...................................................................................................................... 46 
13.1.1 Potential benefits ......................................................................................................................... 46 
13.1.2 Potential harms ............................................................................................................................ 46 
13.1.3 Risk/benefit ratio .......................................................................................................................... 47 
13.2 Consent in emergency situations ........................................................................................................ 47 
13.2.1 Regulations from the European Parliament ................................................................................. 48 
13.2.2 Obtaining informed consent......................................................................................................... 49 
13.2.3 Responsibilities regarding consent ............................................................................................... 51 
13.2.4 Decline of consent ........................................................................................................................ 52 
13.3 Summary of ethical considerations ..................................................................................................... 52 
13.4 Insurance ............................................................................................................................................. 52 
13.5 Approval from authorities ................................................................................................................... 52 
14 Funding ....................................................................................................................................................... 52 

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15 Timeline ...................................................................................................................................................... 54 
16 Publication .................................................................................................................................................. 55 
17 Division of tasks .......................................................................................................................................... 55 
18 References .................................................................................................................................................. 56 
Appendices ...................................................................................................................................................... 59 
Appendix 1 CONSORT flow diagram ............................................................................................................ 59 
Appendix 2: [Removed from the ClinicalTrials.gov submission version] This appendix contained an SOP in 
Danish and was removed to comply with ClinicalTrials.gov language requirements. ................................ 60 
Appendix 3: [Removed from the ClinicalTrials.gov submission version] .................................................... 60 
Appendix 4: [Removed from the ClinicalTrials.gov submission version] .................................................... 60 
Appendix 5: [Removed from the ClinicalTrials.gov submission version] .................................................... 60 
Appendix 6: [Removed from the ClinicalTrials.gov submission version] .................................................... 60 
Appendix 7: [Removed from the ClinicalTrials.gov submission version] .................................................... 60 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Abbreviations 
ABG: Arterial Blood Gas 
ACS: Acute Coronary Syndrome 
AECOPD: Acute Exacerbation of Chronic Obstructive Pulmonary Disease  
AHF: Acute Heart Failure  
EMDC: Emergency Medical Dispatch Center 
BTS: British Thoracic Society   
CI: Confidence Interval 
COPD: Chronic Obstructive Pulmonary Disease 
CRN: Civil Registration Number  
CTR: REGULATION (EU) No 536/2014 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 16 
April 2014 on clinical trials on medicinal products for human use, and repealing  Directive 
2001/20/EC 
DMC: Data monitoring committee  
eCRF: electronic Case Report Form 
ED: Emergency department 
EMS: Emergency Medicine Services 
EMT: Emergency Medical Technician  
EPR: Electronic patient Record 
GCP: Good Clinical Practice  
Hb: Haemoglobin 
HEMS: Helicopter Emergency Medical Services 
ICU: Intensive Care Unit  
IQR: Inter Quartile Range 
MacCAT-CR: MacArthur Competence Assessment Tool for Clinical Research 
MAT: Medical Laboratory Technologist 
NIV: Non-Invasive Ventilation 
PaCO2: partial pressure of arterial dissolved carbon dioxide  
PaO2: Arterial Partial pressure of oxygen 
PEMSCDR: Prehospital Emergency Medical Service of Central Denmark Region 
PDSA: Paln-Do-Study-Act 
PPR: Prehospital Patient Record  

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PRU: The physician response unit (rapid response emergency service, staffed by a senior          
anesthesiologist) 
RedCAP: Research Electronic Data Capture 
RCT: Randomized Controlled Trial 
SD: Standard Deviation 
SmPC: Summary of product characteristics (DK: Produktresume) 
SOP: Standard operating procedure 
SpO2: Blood saturation 
TMF: Trial master file 
V/Q ratio: Ventilation/Perfusion ratio 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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0 List of modifications  
Date of modification
Protocol version 
Summary of modification
Explanation 
21-08-2023 
4.2 
 New trial steering 
committee members p. 
9-10 
To strengthen the trial 
steering committee and 
the conduct of the trial 
21-08-2023 
4.2 
 Missing objective added 
p. 18 
There was an error 
between the secondary 
outcomes and the trial's 
secondary objectives. It 
has now been corrected.
21-08-2023 
4.2 
 Specification of standard 
treatment p. 27-28 
The reason for the 
change in the protocol, is
that we realized that we 
would change the 
standard operating 
procedure used for 
treatment in the control 
arm if we specified the 
flow of oxygen used to 
correct a low blood 
oxygen saturation 
<88%. Several local 
guidelines describe 
treatment of patients 
with a low blood 
saturation in the 
prehospital setting in the 
Central Denmark Region. 
By specifying a specific 
flow target, a high risk of
changing the current 
management would be 
introduced. 
21-08-2023 
4.2 
 Exclusion criteria in 
"Summary" updated p. 
11 
There was an error 
between the exclusion 
criteria in the summary 
and the rest of the 
protocol. It has now 
been corrected. 

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21-08-2023 
4.2 
 Sex added as 
stratification factor p. 21 
It is the sponsors goal to 
ensure an equal gender 
distribution in all areas 
in this trial. This applies 
both to the composition 
of the trial steering 
committee, personnel 
employed in the trial and 
to the allocation of 
participants. We will 
however, not make an 
equal distribution of sex 
among the participants 
because it would 
introduce bias and we 
would lose external 
validity as it would not 
represent the true 
distribution. However, by 
introducing stratification 
on sex, we simply 
ensure an equal 
distribution of gender 
between the two groups 
(the intervention and the 
comparator arm). 
21-08-2023 
4.2 
 Name of GCP monitor 
added p. 10 
The monitor has firstly 
been designated now. 
21-08-2023 
4.2 
 Statistical analysis 
method added for 
"Patient experienced 
dyspnoea" p. 40 
Due to unknown reasons 
the statistical method for 
analysing "Patient 
experienced dyspnoea" 
was missed in the 
original protocol. 
21-08-2023 
4.2 
 Change in reporting of 
SUSARs p. 35-36 
The update refers to the 
new procedure 
applicable for the Central 
Denmark Region. This is 
standard procedure for 
the entire region. 
21-08-2023 
4.2 
 New funder added p. 54 
Application for funding of 
the trial will be ongoing.
21-08-2023 
4.2 
 New exclusion criteria 
"Prior decline to consent 
in the trial" has been 
added to the list of 

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exclusion criteria due to 
technical challenges with 
the automatic exclusion.
Section 13.2.4 has been 
updated to reflect this 
change. 
21-08-2023 
4.2 
 Updated logo and project 
overview 
N/A 
21-08-2023 
4.2 
 New exclusion criteria 
"Prior decline to consent 
in the trial" has been 
added to the list of 
exclusion criteria due to 
technical challenges with 
the automatic exclusion.
21-08-2023 
4.2 
 New supplier of 
investigational medical 
products 
Due to new regional 
supplier of medical 
gasses the supplier and 
name of products has 
been changed. The 
content of the products 
is the same as the prior.
21-08-2023 
4.2 
 Appendix 6 & 7 pictures 
of labelling changed 
reflecting the new 
supplier 
Due to new regional 
supplier 
21-08-2023 
4.2 
 SmPC, in appendix 3 & 4, 
for investigational 
medical products 
updated to reflect the 
new supplier 
Due to new regional 
supplier 
21-08-2023 
4.2 
 Inclusion criteria added 
For clarification "Need of 
inhaled bronchodilators" 
has been added as an 
inclusion criterion. The 
need of inhaled 
bronchodilators has all 
the time been the focus 
of the trial and a part of 
the description of the 
targeted patient 
population. 
21-08-2023 
4.2 
 
 
 
 Blinding of in-hospital 
staff 
Knowledge of patient 
allocation might 
influence in-hospital staff 
in the post-trial care, to 
account for this, in-

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hospital staff will be 
blinded for allocation. 
Section 5.7 has been 
updated. 
08-12-2023 
4.3 
 Updated time plan 
Planned study period, 
updated. 
Timeline, updated. 
21-05-2025 
4.3.1 
 Removal of Danish text 
for ClinicalTrials.gov 
submission 
 No scientific or 
procedural changes 
Minor editorial revision 
to remove residual 
Danish text in 
preparation for 
ClinicalTrials.gov 
submission 
24-05-2025 
4.3.2 
 Final removal of residual 
Danish text for 
ClinicalTrials.gov 
submission, including 
removal of Appendices 
2–7 containing Danish-
language material 
 No scientific or 
procedural changes   
Minor editorial revision 
to ensure full 
compliance with 
ClinicalTrials.gov 
language requirements 
1 Summary 
Sponsor-Investigator: 
Martin Faurholdt Gude 
Prehospital Emergency Medical Services 
 
Olof Palmes Allé 34 1. sal 
8200 Aarhus N 
Title of study: 
STOP-COPD Standard vs Targeted Oxygen Therapy Prehospital for Chronic Obstructive 
Pulmonary Disease 
Trial Steering Committee  
Sponsor-Investigator: 
Martin Faurholdt Gude, MD, Prehospital Emergency Medical Services,  
Olof Palmes Allé 34 1. sal, 8200 Aarhus N 
 
Study coordinator: 
Arne Sylvester Rønde Jensen, Prehospital Emergency Medical Services,  
Olof Palmes Allé 34 1. sal, 8200 Aarhus N 

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Phone: 0045 22396968 
Mail: arjens@rm.dk 
 
Members: 
Ulla Væggemose, Head of research, academic coordinator, associate professor, PhD, 
Prehospital Emergency Medical Services, Olof Palmes Allé 34 1., 8200 Aarhus N 
 
Søren Helbo Skaarup, MD, consultant, PhD, Department of Respiratory Diseases and 
Allergy. Aarhus University Hospital. 
 
Søren Paaske Johnsen, MD, PhD, clinical professor University of Aalborg 
 
Sophie-Charlott Seidenfaden, MD, PhD, Post Doc, Prehospital Emergency Medical Services  
 
Michael Drevland, Clinical Prehospital Specialist, Prehospital Emergency Medical Services  
 
Tina Haahr Nørgaard, Department Manager, Department of Education and Quality, 
Prehospital Emergency Medical Services  
Data monitoring committee:  
 
Anders Gade Kjærgaard, MD, PhD, department of anaesthesiology and intensive care
Aarhus University Hospital, Denmark  
 
Mikkel Brabrand, MD, PhD, FRCP(Ed), FESEM, clinical professor (University of 
Southern Denmark), Consultant – Department of Emergency Medicine Odense 
University Hospital  
 
Tim Alex Lindskou, Senior researcher, PhD, Centre for Prehospital and Emergency 
Research, Aalborg University and Aalborg University Hospital, Denmark 
Good Clinical Practice monitoring: 
Birgitte Horst Andreasen, The GCP-unit, Aarhus and Aalborg University hospitals,  
Olof Palmes Allé 15, 
8200 Aarhus N 
Study center: 
Prehospital Emergency Medical Services, Central Denmark Region 
Planned study period: 
Planning 2020-2025 
Enrolment 2025-2027 

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End of trial: 2027 
Reporting 2028 
Patient population: 
Prehospital patients with suspected Acute Exacerbation of Chronic Obstructive Pulmonary 
Disease treated with inhaled bronchodilators 
Intervention: 
Titrated oxygen strategy - a mix of supplemental oxygen and compressed atmospheric air 
as driver for inhaled bronchodilators 
Comparator: 
Standard care using compressed oxygen (100%) as driver for inhaled bronchodilators 
Methods:  
Interventional, prospective, randomized 1:1, parallel groups, patient blinded, prehospital, 
single center, acute, superiority trial  
Inclusion: 
Patients over the age of 40 
EMT or Paramedic suspected AECOPD 
Confirmed suspicion of COPD 
Need of inhaled bronchodilators 
Exclusion: 
Non-chronic obstructive pulmonary disease (COPD) bronchospasm 
Known or suspected pregnancy  
Prehospital Non-invasive, invasive or assisted bag mask ventilation 
Allergy to inhaled bronchodilators (Salbutamol) 
Transfer between hospitals  
More than 2 doses (5 mg salbutamol) inhalation drug, acute treatment by EMS personnel, 
before allocated treatment is initiated 
Readmission within 30 days from a previous randomisation 
Suspicion of acute coronary syndrome 
Prior decline to participate in the trial 
Sample size: 
Intervention group: 944 patients 
Comparator group: 944 patients 
Primary Outcome:  
30-day mortality  

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Secondary outcomes: 
Mortality, (24-hour) 
Mortality, (7-day) 
Length of hospital stay  
ICU admission rate 
Length of ICU stay 
In-hospital need for NIV within 24 hours, 7 days and 30 days 
Time to NIV 
In-hospital need for invasive ventilation within 24 hours, 7 days and 30 days 
Time to invasive ventilation 
Acidosis on arrival to hospital 
The degree of acidosis based on the pH-value 
Patient experienced dyspnoea on a scale 0-10 (see section 8.3) 
Readmission rate 
Time to readmission 

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2 Project overview 
 

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3 Background 
 
3.1 Incidence and mortality 
COPD is a widespread condition, the third leading cause of death worldwide, and affecting 
around 328 mill. people[1, 2]. In Denmark, estimated 200.000-400.000 people live with 
COPD[3, 4]. An acute exacerbation of chronic pulmonary disease (AECOPD) is frequently 
encountered in the prehospital setting, and the Prehospital Emergency Medical Services of the 
Central Denmark Region (PEMSCDR) dispatches 2000-3000 ambulances each year to patients 
with suspected AECOPD and need for inhaltiondrugs. AECOPD have a high in-hospital mortality 
varying from around 5% to 10%[5, 6]. Based on 2020 data from the Danish COPD registry the 
30-day mortality in the CDR was 13% (95%CL 11-14) without significant variance between 
hospitals[7]. COPD patients with respiratory failure that require invasive or non-invasive 
ventilator (NIV) support have an even higher in-hospital mortality ranging from 11% and up to 
31%[7, 8]. This emphasizes the importance of a prehospital treatment that seeks to prevent 
the development of respiratory failure. 
 
3.2 Pathophysiology 
In patients with COPD the pathophysiological cornerstone is an impaired ability to exhale 
carbon dioxide (CO2) at a given minute ventilation reflecting an enlarged physiological dead 
space[9]. 
It has been long known that inspired high oxygen concentrations might exaggerate poor CO2 
excretion causing respiratory acidosis and subsequently a higher mortality in AECOPD [10]. 
The underlying mechanisms are several and the following have been described: attenuation of 
“hypoxic pulmonary vasoconstriction”, the Haldane effect[11-13], and impaired respiratory 
drive.  
 
3.2.1 Hypoxic Pulmonary Vasoconstriction 
To maintain an optimal ventilation/perfusion (V/Q) ratio for pulmonary gas exchange, the 
pulmonary vasculature constricts in response to a decreasing alveolar O2 concentration. This 
ensures a normal V/Q ratio redirecting the blood flow to lung areas with good ventilation. 
COPD patients have an altered V/Q ratio because of destruction of alveolar septa resulting in 
large air pockets with only peripheral gas exchange (emphysema). This leads to dead space 
ventilation with increasing pCO2 in the blood[9].  
If the O2 concentration increases in the poorly ventilated alveoli, as with oxygen therapy 
(based on supra-normal oxygen fractions with unchanged poor ventilation), the associated 

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capillaries will dilate and increase blood flow (inhibition of the pulmonary vasoconstriction), to 
maintain the normal V/Q ratio[11-13]. In the case of COPD patients, capillary blood is now led 
through poorly ventilated alveoli, which prevents effective excretion of CO2, and lowers the 
amount of blood led through the well-ventilated alveoli, hence further lowers the excretion of 
CO2. On the other hand, the inhibition of the pulmonary vasoconstriction caused by 
supplemental oxygen therapy lowers pulmonal vascular resistance which is beneficial for COPD 
patients who has COPD associated pulmonal hypertension.  
 
3.2.2 The Haldane effect  
CO2 produced by metabolism is mainly transported in the blood from the tissue to the lung 
after a chemical reaction with H2O. This process is catalysed by the enzyme carbonic 
anhydrase where CO2 and H2O react (fuses) and subsequently separates into H+ that binds to 
haemoglobin (Hb) and to HCO3- that dissolves in plasma. In the pulmonary capillaries, the 
O2 level is high and Hb begins to bind O2 because of a higher affinity. This increases free H+ 
and the high level of H+ turn the reaction chain around where H+ reacts with HCO3- to form 
CO2 and H2O. The CO2 diffuses into the air in the alveoli (if the alveoli is well ventilated and 
have a normal structure) and then CO2 gets excreted with ventilation. This is known as the 
Haldane effect[11-13]. 
This means that more CO2 can be excreted in an oxygen-rich environment, which is found in 
the pulmonary capillaries, and accentuated during oxygen therapy if ventilation is increased. 
However, in AECOPD patients the ventilation is already near maximum capacity (still inefficient 
because the enlarged physiological dead space) and therefore, when the fraction of inspired 
oxygen (FiO2) is increased with oxygen therapy, ventilation cannot compensate for the excess 
amounts of free CO2. This, together with the consequences of the inhibited pulmonary 
vasoconstriction, leads to a further increase in the arterial blood measured partial pressure of 
carbon dioxide (PaCO2) and associated acidosis. 
 
3.2.3 Impaired respirator-drive in patients with COPD  
The well-known theory describing a shift from normal CO2-based respiratory drive to hypoxic 
drive in patients with severe COPD has been questioned[12, 14]. Still, an association between 
hyperoxia and low minute ventilation exists originating from both decreased tidal volume and 
respiratory frequency. The effect from hyperoxia on minute ventilation is greatest within the 
first 5 minutes hereafter the ventilation increases to a sub-normal level near the pre-oxygen 
state[11].    
 
 

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All the above-mentioned mechanisms resulting in increased PaCO2 and acidosis both 
representing physiological changes worsening overall homeostasis and pulmonary arterial 
hypertension and in general a comorbid COPD–heart failure that are common in many patients 
with COPD. 
In addition to the mechanisms described above increasing PaCO2 and acidosis in AECOPD 
treated with supplemental oxygen delivery, the AECOPD condition results in an extensive 
increased work of breathing that eventually can lead to exhaustion, decreasing minute 
ventilation and worsening CO2 retention creating a viscous spiral.    
 
3.3 Current evidence 
A Cochrane systematic review from 2020[15] found only one randomized clinical trial (RCT) on 
titrated oxygen for prehospital COPD patients, and concluded that "More evidence is required 
to optimise the management of people with AECOPD and provide increased generalisability to 
the findings of this review". To date, Austin et al. (2010) [16] conducted the only RCT on 
oxygen treatment of prehospital suspected AECOPD patients including 405 patients. In an 
intention to treat analysis, a decrease in mortality was found (9% to 4%) when changing a 
"high flow" oxygen protocol with a "titrated" oxygen protocol in patients with suspected 
AECOPD. The finding was statistically significant and the scale of the mortally reduction was 
highly clinically relevant. In a subgroup analysis only based on the confirmed AECOPD a 
significant decreasing mortality from 9% to 2% was seen. A reduction in mortality was also 
seen for AECOPD suspected patients with a final diagnosis of a non-COPD respiratory condition 
(9% to 4%). 
A review on patients admitted to an emergency department (ED) with AECOPD patients with 
hyperoxia (PaO2 >100 mmHg /13,3 kPa) had an odds ratio (OR) of 8.51 of having serious 
adverse outcome with normoxia (PaO2 60-100 mmHg / 8,0-13,3kPa) as the referent group. In 
addition, the OR was 1.45 for a serious adverse outcome in the hypoxia (PaO2 <60 mmHg / 
8,0 kPa) group also compared to the reference group[17]. An observational study found that 
serious adverse outcomes were associated with a OR of 1.1 pr. 10 mmHg (1.33 kPa) rise in 
PaO2 [18].  
Among prehospital patients with a final discharge diagnose of AECOPD, a decrease in 30-day 
mortality (19,6% to 4,6%) was observed between periods with two different treatment 
protocols -  a period with "high flow oxygen" and a period with "titrated oxygen", in [6].  
The proportion of patients with AECOPD arriving at hospital by ambulance receiving 
inappropriate oxygen therapy is as high as 88.7% of whom 33.3% had respiratory acidosis[5].  
The need of another prehospital RCT's to investigate the optimal oxygen therapy to AECOPD 
patients have been identified several times [5, 6, 15, 18]. 

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For in-hospital AECOPD patients, Bardsley et al.[19] found that a titrated oxygen strategy 
during bronchodilator inhalation, resulted in a lesser increase in the amount of PtCO2 in blood 
(subcutaneous measured) compared to standard oxygen strategy with high oxygen fractions. 
Unfortunately, no patient related outcomes were investigated. 
Edwards et al.[20] reported similar finding in a similar study on COPD patients in stable 
chronical period of COPD.  
Gunawarden et al. [21] only found a rise in CO2 in admitted COPD patients in "relatively 
stable" condition when making a subgroup analysis of patients defined as CO2 retainers. 
 
3.4 Guidelines 
British Thoracic Society's "Guideline for oxygen use in adults in healthcare and emergency 
settings"[22], the British NICE guidelines[23] and the "Thoracic Society of Australia and New 
Zealand oxygen guidelines for acute oxygen use in adults"[24] all recommend COPD patients 
to be treated with oxygen targeting SpO2 at 88-92%. They also recommend the use of non-
oxygen driven nebulizers, and if not available the use of oxygen driven nebulizers to be limited 
to 6 minutes. Finally; they recommend ambulance services to implement non-oxygen driven 
nebulizers[22]. The 2019 national guideline on emergency oxygen published by the Danish 
Health Authority and The Danish Society of Respiratory Medicine also recommends the 
targeted SpO2 at 88-92%[25, 26]. Danish Health Authority's national clinical guideline on 
oxygen therapy for critically ill patients, recommends oxygen treatment in adults, without risk 
of hypercarbia, to be initiated if SpO2 is less than 94%. However, the specific recommendation 
to maintain the blood saturation above 93% is noted as a weak recommendation and is based 
on a single systematic review with "serious risk of bias and low external validity" quoted from 
the 2019 Danish guideline[25]. Also, the systematic review was based on 25 randomize clinical 
trials of which 4 regarded surgical patients, 9 regarded STROKE or traumatic brain injury (TBI) 
patients, 8 on post-ROSC or myocardial infarction and 4 on sepsis or ICU patients. 
Furthermore, 8 of the randomized studies did either not report any results or were pilot 
studies. Most studies did not use oxygen levels relevant to the STOP-COPD trial. In conclusion, 
the 2019 Danish guideline on oxygen therapy for acute patients has a low generalizability to 
prehospital patients in general and specifically to the hypoxic prehospital patients. Noted as a 
final remark “patients with a risk of hypercapnia should be treated with titrated oxygen with 
aiming at a saturation SpO2 88-92%” according to the Danish guideline. 
  

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3.5 Standard of care in Denmark 
The PEMSCDR system delivers treatment to patients with suspected AECOPD regularly. The 
treatment consists primarily of inhaled nebulized bronchodilators (Salbutamol see https://stop-
copd.com/protocol), where the nebulizer is driven by compressed oxygen despite the local 
prehospital standard operating procedure (SOP) recommending a SpO2 target of 88-92%. 
The EMT's and paramedics in Denmark work under delegation from a medical doctor, the 
delegating doctor. The delegating doctor develops treatment SOP's which the EMT's and 
paramedics adopts. In the case of COPD and Salbutamol treatment, the indication mentioned 
in the SOP is bronchospasm (see https://stop-copd.com/protocol). In severe cases the 
patients are also treated with IV steroids prehospitally.  
The PRU will in some cases be dispatched simultaneous with the ambulance based on the 
emergency call or on request from the ambulance personnel. The PRU unit provides the option 
for advanced treatment: e.g., Beta-2-agonists for systemic administration; combined inhaled 
drug (Fenoterol and Ipratropium); and ventilator treatment (NIV or intubation-based 
ventilation).  
In the Danish EMS, patients with AECOPD are widely (88.7%) treated with inappropriately high 
fractions of supplemental oxygen evident by high PaO2 in arterial gas analysis at admission[5]. 
This is in line with Susanto et al.[27] who found a widespread use of supplemental oxygen 
despite COPD patients having SpO2 >92%.    
 
4 Trial objectives 
The objectives of this trial are: 
 
Primary objective: To determine whether prehospital titrated oxygen strategy in patients 
with suspected AECOPD will decrease 30-day mortality compared to patients receiving 
standard care. 
 
Secondary objectives: 
 
To determine whether a prehospital titrated oxygen strategy for AECOPD patients will 
have a positive effect on experienced dyspnoea, rated on a scale from 0-10 compared 
to patients receiving standard care (see section 8.3)  
 
To determine whether a prehospital titrated oxygen strategy for AECOPD patients will 
reduce the in-hospital need for NIV or invasive ventilation compared to patients 
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 
To determine whether a prehospital titrated oxygen strategy for AECOPD patients will 
result in a reduced 24-hour and 7-day mortality compared to patients receiving 
standard care. 
 
To determine whether a prehospital titrated oxygen strategy for AECOPD patients will 
reduce the proportion of patients with respiratory acidosis (PaCO2 >6,3 kPa AND pH 
<7,35[6]) and the degree of acidosis measured on arrival to hospital compared to 
patients receiving standard care. 
 
To determine whether a prehospital titrated oxygen strategy for AECOPD patients 
reduces mortality (24 hours, 7 days, 30 days), acidosis, intensive care unit (ICU) 
admission rate and need of assisted ventilation compared to patients receiving standard 
care analyzed on a subgroup level based on prehospital transport time.  
 
To determine whether a titrated oxygen strategy has an effect on time to intensive care 
admission, non-invasive ventilation or endotracheal assisted ventilation events 
compared with standard care 
 
To determine if a titrated oxygen strategy will lower the readmission rate compared 
with standard care 
 
To determine whether a prehospital titrated oxygen strategy for patients with AECOPD 
will result in reduced length of hospital and ICU stay compared with patients receiving 
standard care 
 
5 Trial Design 
5.1 Overview 
The STOP-COPD trial is a patient blinded, randomized, parallel group, superiority trial 
investigating titrated oxygen strategy on prehospital suspected AECOPD patients compared to 
standard care. The trial will take place in the PEMSCDR, which has both public and private 
(contractual based) services. The trial will be performed as an acute trial, see section 13. 
 
5.1.1 Study procedures  
Procedure/ Intervention 
Description 
Pre intervention  
Acute treatment 
All patients are treated acutely according to standard, if not 
in the ambulance. 
Randomization 
All patients eligible for inhalation treatment are screened 
using the TrialPartner/ REDCap randomization site 

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Enrolment 
All patients fulfilling inclusion and exclusion criteria are 
enrolled 
Per-intervention 
Intervention treatment 
Targeted oxygen therapy SpO2 88-92% during treatment 
and transport. 
Standard treatment 
Standard treatment during treatment and transport 
Post intervention 
Consent gaining 
Informed consent is gained from patient or relative and legal 
guardian as soon as possible after hospital arrival. 
Follow up 
Follow up in PPR are made on first normal working day after 
enrolment and follow up in EPR are made on day 30 after 
enrolment.  
 
5.2 Setting 
The trial will take place in the Central Denmark Region EMS system. All EMS units are 
dispatched from the same regional emergency medical dispatch center (EMDC), which is 
staffed with an emergency medical doctor in daytime from 8 AM to 8 PM. From 8 PM to 8 AM, 
this function is outsourced to the PRU units. An emergency can be allocated one or more from 
a total of five levels of care: a lying transport with no treatment possibilities; an ambulance 
staffed with an EMT team, an ambulance staffed with a paramedic team, PRU and helicopter 
emergency medical service (HEMS) units. This trial will only take place in the ambulances 
staffed with either a EMT or a paramedic team. In some cases, one of the physician manned 
units (PRU or HEMS) will be dispatched together with an EMT or paramedic ambulance, in 
these cases the patient will be enrolled if no NIV or invasive ventilation is initiated, this last 
rule is believed to introduce very limited introduction of selection bias due to the very limited 
use of NIV prehospitally. Pre excluding patients seen by PRU will introduce significant selection 
bias where patients with the most severe AECOPD gets excluded. Sensitivity analysis regarding 
PRU involvement will be made on all outcomes See section 5.10. 
 
5.3 Rollout 
The trial will use a stepwise implementation over 4-8 weeks according to the iterative 
principles described by the plan-do-study-act (PDSA) circles for implementation processes[28]. 
The region has 6 hospitals, ranging from small local hospitals to a large university hospital, all 
capable of receiving COPD patients. The region's EMS system manage a total of 69 
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and geography. The implementation process will happen in 4 steps and include evaluating 
meetings in the study group according to the PDSA model. If significant changes to the study 
setup are made the relevant authorities will be notified.  
5.4 Outcomes 
5.4.1 Primary Outcome 
Outcome 
Assessment 
Mortality, 30-day 
EPR – by study personnel 
 
   
5.4.2 Secondary outcomes 
Outcome 
Assessment 
Mortality, 24-hour 
EPR – by study personnel 
Mortality, 7-day 
EPR – by study personnel 
Length of hospitalization 
EPR – by study personnel 
ICU admission rate 
EPR – by study personnel 
Length of ICU stay 
EPR – by study personnel 
In-hospital need for NIV within 24 hours, 
7 days and 30 days 
EPR – by study personnel 
Time to NIV 
EPR – by study personnel 
In-hospital need for invasive mechanical 
ventilation within 24 hours, 7 days and 30 
days 
EPR – by study personnel 
Time to invasive ventilation 
EPR – by study personnel 
Proportion of patients with respiratory 
acidosis on arrival to hospital 
EPR – by study personnel 
The degree of acidosis based on the pH-
value 
EPR – by study personnel 
Patient experienced dyspnoea on a verbal 
rating scale 0-10 (see section 8.3) 
PPR – by study personnel 
Readmission rate 
EPR – by study personnel 
Time to readmission 
EPR – by study personnel 
 
 

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5.5 Allocation 
Patients will be randomized in a 1:1 ratio to either titrated oxygen strategy or standard 
treatment. 
 
5.6 Randomization 
The patient will be randomized to standard treatment or titrated treatment according to 
section 7 by EMTs or paramedics using TrialPartner (an ad-on to REDCap) supported by The 
Clinical Trail Unit Aarhus University, Denmark. This site will be accessible by smartphone or 
tablet and require no log in information. A randomized block design will be utilized using 
receiving hospital, sex and age group (above/below 70 years of age) as blocking factors. Each 
block will be of random size comprising 4, 6 or 8 patients. The randomization site will need 
information about receiving hospital, age, CRN and inclusion/exclusion criteria – all data will be 
uploaded encrypted. The EMTs and paramedics participating in the STOP-COPD trial will be 
trained and informed about the randomization process before enrolment starts. If a patient has 
been included previously and withdrawn, for any reason, the TrialPartner randomization site 
will deem the patient not eligible for inclusion. 
 
5.7 Blinding 
The trial will be single blinded. The patients will be blinded to treatment allocation. The EMTs 
or paramedics will not be blinded because of practical, ethical and security problems with 
carrying compressed gas without known content in an ambulance. As part of study informed 
and training, the EMT's and paramedics will be attentive to keep all AECOPD suspected 
patients blinded to the treatment allocated.  
To account for the risk of different in-hospital post-trial care, in-hospital staff will be blinded 
for allocation. If adverse events occur, the EMT or paramedic will be able to provide 
information on allocation. Additionally, the trial personnel can offer information about patient 
allocation if such information becomes necessary. Thus, a protocol for emergency unblinding is 
not necessary. 
 
5.8 Study drugs 
All drugs in the study are used according to the marketing authorisation. Thus, the study can 
be defined as a "Low-intervention clinical trial"[29].  
 

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5.8.1 Investigational medicinal products 
5.8.1.1 Oxygen (Medical Oxygen ”Air Liquide”) 
Oxygen (Medical Oxygen ”Air Liquide”) will be used in both treatment groups. Oxygen (Medical 
Oxygen ”Air Liquide”) consists of 100% O2 compressed in 2 or 10 l. pressure cylinders, stored 
in the ambulance or in the airway bag.  In the standard care group oxygen will be used as the 
only driver for the inhaled bronchodilator. In the intervention group oxygen will be used to 
titrate the SpO2 level to 88-92% but the driver for inhaled bronchodilators will be compressed 
atmospheric air (see section 5.7.1.2). In both study groups the opportunity exists to escalate 
the oxygen levels if the patient remains hypoxic. The duration of treatment will be dictated by 
the patient’s clinical presentation (the presence of bronchoconstriction) and can be applied if 
needed from patient contact until hospital admission. The use is in accordance with the SmPC. 
The Oxygen (Medical Oxygen ”Air Liquide”) will be labelled from the manufacturer. Oxygen 
(Medical Oxygen ”Air Liquide”) will be produced, managed, and stored according to standard 
procedures for oxygen. Oxygen (Medical Oxygen ”Air Liquide”) will be used in any other setting 
than the STOP-COPD trial according to standard procedures. Oxygen (Medical Oxygen ”Air 
Liquide”) is labelled in accordance with European regulations and therefore, additional labelling 
is not necessary[30]. See appendix 3 for SmPC and appendix 7 for labelling. 
 
5.8.1.2 Compressed air (”Air Liquide”) 
Compressed air (”Air Liquide”) will be used in the intervention group only. Compressed air (”Air 
Liquide”)consists of 21% O2 + 79% N2 compressed in 10 L pressure cylinders, stored in the 
ambulance, due to logistical reasons it is not practical to carry a 2 l. cylinder of compressed air 
in the airway bag.  In the intervention group Compressed air (”Air Liquide”) will be used as the 
only driver for the inhaled bronchodilator. Treatment can be ongoing, if indicated, from patient 
contact and until hospital admission. Compressed air (”Air Liquide”) will be labelled from the 
manufacturer. The use is in accordance with the SmPC. 
Compressed air (”Air Liquide”) will be produced, managed, and stored according to the same 
SOP as for oxygen. When stored in ambulances, the compressed air outlet and inlet will be 
clearly marked with “Only for use in the STOP-COPD trial” (translated from Danish), see 
Appendix 6. Compressed air (Air Liquide) is labelled in accordance with European regulations 
and therefore, additional labelling is not necessary[30]. See Appendix 4 for SmPC and 
Appendix 8 for labelling. 
 
5.8.1.3 Procedures 
The investigational medicinal products, oxygen (Medical Oxygen ”Air Liquide”) and compressed 
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gasses to PEMSCDR (Air Liquide Denmark A/S, Høje Taastrup Vej 42, 2630 Taastrup, 
Denmark). The supplier will register batch numbers as usual. Expiration date will be part of the 
daily control of the ambulances. Because this is the usual supplier, procedures for delivery and 
storage will follow the SOP for oxygen delivery in PEMSCDR. When an ambulance needs 
resupply of oxygen or compressed air it will follow the SOP for oxygen resupply. 
The study coordinator will monitor consumption of oxygen and compressed air and make 
orders when needed. Registration of consumption on patient level is not possible.  
At the end of the trial, the compressed air cylinders will be returned to manufacture according 
to standard procedure. 
 
5.8.2 Auxiliary medicinal product 
5.8.2.1 Salbutamol 
Salbutamol (a pure β2 agonist) liquid for nebulization is used in all ambulances in the region as 
bronchodilator for treatment of bronchospasm, this includes AECOPD, asthma and allergy. The 
Salbutamol is used in according to the regional SOP (see https://stop-copd.com/protocol). 
Information about the product can be found in the investigator’s brochure. The use is in 
accordance with the SmPC. 
 
5.8.2.2 Berodual 
Berodual (a combined β2 agonist and anticholinergic drug) liquid for nebulization is used in the 
region as bronchodilator for treatment of bronchospasm by the PRU units. The EMT's and 
paramedics does not routinely use Berodual but in case of PRU unit support Berodual might be 
used on the discretion of the PRU doctor. Information about the product can be found in the 
investigator’s brochure. The use is in accordance with the SmPC. 
   
5.8.2.3 Procedures 
The auxiliary medicinal product will be delivered through the ordinary supplier of medicinal 
products to the ambulances of the PEMSCDR, and follow the SOPs for delivery, storage and 
resupply. Expiration date will be part of the daily control of the ambulances 
 
5.9 Trial phases 
The trial procedures will be divided into three phases. First the intervention phase, this will be 
in the prehospital setting as described in section 3.3 this phase will take around 0,5-2 hours 
depending on geographical location. The second phase is the consent phase, this could take up 
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up, here data to the CRF's are collected from prehospital patient record (PPR) system and the 
in-hospital electronic patient record (EPR), this phase will last 30 days because of the primary 
outcome, there will be no patient contact in this period. The total duration of all phases will be 
around 31 days. To ensure that late registered outcomes are also discovered and registered in 
the eCRF, a safety follow up will be made on day 100 from inclusion. 
There will be no blood draws, interventions, or additional procedures regarding this study in-
hospital, meaning that in-hospital treatment will be according to treatment as usual. 
 
5.10 Termination 
5.10.1 Termination of allocated treatment 
In both treatment groups the standard procedure regarding requesting PRU unit support is 
applicable. This means that in case of worsening, treatment failure or adverse reactions EMDC 
or PRU units are contacted for treatment guidance or requested for advanced treatment 
support. This also means that the EMDC or PRU doctor can terminate the allocated treatment 
and treatment on discretion by the EMDC or PRU doctor can be initiated. Termination and 
reason for termination of treatment will be registered and used in the data analysis.  
 
5.10.2 Termination of the trial 
Rules for termination of the trial will be available in section 10.3 and mentioned in the data 
monitoring committee (DMC) charter (see section 12.2). 
 
5.10.3 Withdrawal of treatment 
Due to the acute design of the trial, withdrawal of subjects from treatment is suspected to be a 
rare occurring event. However, if occurring all data already collected will be deleted, except in 
the TrialPartner randomization site, and the patient registered in the consort diagram as 
decline to participate under follow-up. This also applies to patients not giving consent (see 
section 13.2) and patients withdrawn by the EMDC or PRU (see section 5.9.1). 
The sample size calculation includes a 4% lost to follow up, this makes a procedure for 
replacement needless (see section 10.1). A current prehospital RCT shows a withdrawal rate 
around 2% (ClinicalTrials.gov identifier (NCT number): NCT03481777). 
 
5.11 Co-enrolment 
The STOP-COPD trial is the only prehospital trial investigating COPD patients in the PEMSCDR 
currently. If other trials end up enrolling at the same time, measures to ensure consecutive 
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5.12 Medical responsibility 
EMT's and paramedics work under delegation from the medical director of the PEMSCDR. The 
STOP-COPD trial will have no impact on this distribution of responsibility. The trial is approved 
by the medical director and the management of the PEMSCDR. 
 
5.13 Recruitment  
The STOP-COPD trial will be approved as an acute trial. This means that the EMT's and 
paramedics will be responsible for recruiting patients to the trial before patient consent is 
obtained. The process will be as follow; all patients in whom the treating EMT or paramedic 
finds indication for inhalation drug therapy will be screened for participation in the STOP-COPD 
trial. The screening will be using the randomization site as mentioned in section 5.5. In this 
process the EMT or paramedic will evaluate the patient for all inclusion and exclusion criteria. 
If all inclusion criteria and no exclusion criteria are fulfilled the randomization site will tell the 
EMT or paramedic to start intervention or standard treatment as applicable. If the patient is 
not included in the trial the randomization site will tell the EMT or paramedic to treat the 
patient as usual. 
After arrival to hospital and stabilisation, consent is sought from the patient as stated in 
section 13.2.  
 
5.14 End of trial  
Last day of patient enrolment is the 30th of September 2025. Followed by the 30-day follow up 
period and the 100-day safety follow up period as mentioned in section 5.8 making the date 
08/01/2026.     
 
6 Inclusion and exclusion  
 
6.1 Screening and enrolment 
All patients, for which the treating EMT or paramedic finds indication for inhalation treatment, 
will be screened for eligibility using the TrialPartner randomization site. Patients who fulfil all 
inclusion criteria and none of the exclusion criteria will be considered eligible for 
randomization.  
If the patient is not declared eligible for randomization by the REDCap randomization site an 
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later reporting according to the CONSORT guidelines. No further registration of non-included 
patients will be made. 
 
Give the that the STOP-COPD trial is an acute trial, no informed consent will be sought in the 
prehospital setting (see section 13) given the need for prompt intervention. However, some 
patients may experience the treatment a little different than they are used to and other might 
not detect any difference. To accommodate this the following short sentence will be a part of 
the enrolment process and should be said right before initiation of trial treatment: 
 
English: "You will receive an experimental treatment which, we expect, will help during your 
hospitalization. You will be contacted during your hospitalization and be further informed about 
the treatment." 
 
6.2 Inclusion criteria 
 
 
Patients over the age of 40 years 
35 or 40 years of age has been used in multiple other studies as a cut off to find COPD 
patients because of the relatively small number of COPD patients under the age of 
35/40 and the relatively large group of asthma patients under the age of 35/40 [4, 16, 
31-33]. The STOP-COPD trial will use an age of 40 as cut off. 
 
The treating EMS provider (EMT or Paramedic) suspicion of AECOPD 
The local SOP only states bronchospasm as an indicator for inhalation treatment see 
https://stop-copd.com/protocol. To fulfil this inclusion criteria in the STOP-COPD trial 
the treating EMT or Paramedic must also suspect AECOPD. 
 
Confirmation of the EMS provider suspicion of COPD  
Confirmation of COPD after the initial EMS provider suspicion of AECOPD can be 
obtained from one of the following four sources: the patient, relatives present at the 
scene, caretakers present at the scene, from discharge letter or text from medical 
records confirming COPD with the patient’s ID, medication list with COPD listed and 
with the patient’s ID. 
 
Need of inhaled bronchodilators  
All four listed criteria must be present for inclusion in the STOP-COPD trial 
 
6.3 Exclusion criteria 
 
Non-COPD bronchospasm  

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 
Known or suspected pregnancy  
 
Prehospital NIV, invasive or bag mask assisted ventilation 
 
Allergy to inhalation drug (Salbutamol) 
 
Transfer between hospitals 
 
More than 2 doses (5 mg salbutamol) inhalation drug, acute treatment by EMS 
personnel, before allocated treatment is initiated 
 
Readmission within 30 days from last randomization 
 
Suspicion of acute coronary syndrome (ACS) (based on symptoms, ECG, TnT biomarker 
and medical consult. In concordance to the local SOP[34]) 
 
Prior decline to participate in the trial 
7 Intervention 
 
The enrolment and randomization will start at first patient contact. If acute treatment is 
needed patients will receive oxygen or inhalation drugs while the randomization is being 
processed. After randomization the patient is transported to the ambulance where the 
allocated treatment is initiated. If the patient receives more than 2 doses (5 mg salbutamol) of 
inhalation drug, given by the EMT or paramedic (acute treatment), before allocated treatment 
is initiated this will exclude the patient from participating in the trial. 
 
Rationale: Need of acute treatment of a critical patient in their home (or where the patient 
might be at first contact) should not be an exclusion from the trial. Start of allocated treatment 
outside the ambulance would not be practically possible because of the extra gas cylinder for 
compressed atmospheric air. Furthermore, it would be unethical to withhold treatment until 
the patient was in the ambulance physically.  
Acute treatment is defined as urgent need for oxygen, inhalation drugs or assisted ventilation 
on first patient encounter, on the discretion of the treating EMT or paramedic, and only when 
deployed outside the ambulance.  
 
7.1 Standard treatment 
The treatment will be according to standard treatment. If the treating EMT or paramedic finds 
indication for inhaled bronchodilators, this will be done with Oxygen (Medical Oxygen ”Air 
Liquide”) 6-8 l/min. as the driver for the nebulizer. The patient will have a Bi-nasal EtCO2 
meter placed under the nebulizer. This will measure the EtCO2 during the treatment and at the 
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of the treating EMT or paramedic according to local guidelines (see https://stop-
copd.com/protocol).  
Following scenarios regarding SpO2 can occur during treatment: 
SpO2 <88%: Supplemental oxygen via the EtCO2 -meter if needed. If the patient remains 
hypoxic the patient is consulted with the EMDC doctor or the PRU unit. 
SpO2 88-92%: No intervention. 
SpO2 >92%: No intervention. 
If repeated treatment is not indicated the patient receives supplemental oxygen according to 
the local SOP. 
At arrival to hospital the patient will have an ABG analysed within 30 minutes after handover, 
by hospital staff. The ABG analysis is standard in-hospital treatment and not a part of the trial. 
 
7.2 Intervention treatment 
The intervention treatment will be titrated oxygen strategy based on blood oxygenation 
(SpO2). If the treating EMT or paramedic finds indications for inhaled bronchodilators, this will 
be done with compressed air (Atmospheric Air ”Air Liquide”) 6-8 l/min. as the driver for the 
nebulizer. The patient will have a Bi-nasal EtCO2 meter placed under the nebulizer. This will 
measure the EtCO2 during the treatment and at the same time Oxygen (Medical Oxygen ”Air 
Liquide”) can be titrated through this to a target SpO2 of 88-92%. Repeated treatment will be 
at the discretion of the treating EMT or paramedic according to local guidelines (see 
https://stop-copd.com/protocol). 
Following scenarios regarding SpO2 can occur during treatment: 
SpO2 <88%: Supplemental oxygen via the EtCO2-meter up to 10 l/min, if higher oxygen 
levels are needed oxygen will be used as driver for the nebulizer. If the SpO2 remains under 
88% additional oxygen can be added via the EtCO2-meter. If the patient remains hypoxic the 
patient is consulted with the EMDC doctor or the PRU unit. 
SpO2 88-92%: No intervention. 
SpO2 >92%: No intervention. 
If repeated treatment is not indicated the patient receives oxygen to achieve SpO2 88-92%. 
At arrival to hospital the patient will have an ABG analysed within 30 min of handover by 
hospital staff. The ABG analysis is standard in-hospital treatment and not a part of the trial. 
 
7.3 Clinical treatment 
Patients in both treatment arms will receive the usual prehospital and in-hospital treatment, 
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7.4 Clinical personnel  
Prior to the beginning of patient enrolment EMTs and paramedics involved in the STOP-COPD 
study will be informed about the trial and educated in the procedures. This includes the trial’s 
background, objectives, the inclusion/exclusion criteria, the randomization process, the 
intervention treatment, and the trial procedures they are involved in. The education will consist 
of educational videos and e-learning materials, this will be made in collaboration with the 
education department of the PEMSCDR. This educational procedure has been used in multiple 
other prehospital studies in the region with success[35, 36]. Documentation on completed 
education for the EMT's and paramedics will be available in the trial master file (TMF).  
Throughout the enrolment period the clinical personnel participating in the trial, other health 
professionals and the public will be informed through the website www.STOP-COPD.com about 
the study status.  
8 Data collection 
8.1 Process 
Enrolment and randomization will be performed by the treating EMT or paramedic directly in 
the trial specific REDCap site via link on smartphone or tablet. The treating EMT or paramedic 
will register limited data in REDCap including CRN number, admission hospital and 
inclusion/exclusion criteria. The EMT or paramedic presses the "Randomiser" button, and the 
specific REDCap site will tell the EMT or paramedic to which treatment arm the patient is 
randomized and what the treatment consists of. REDCap automatically notifies the coordinator 
about the enrolment of the patient by text message or e-mail. For those not randomized, a 
specific reason for non-inclusion/exclusion will be documented in the eCRF according to the 
documentation in the PPR. 
To obtain patient consent, trained personnel will contact the patient at the hospital department 
where the patient is admitted.  
If the patient is dead, has a GCS<15 or otherwise unable to give consent, then mandatory 
consent will be obtained by a close relative (next of kin) and a physician (legal guardian) 
independent of investigator’s interests according to "REGULATION (EU) No 536/2014 OF THE 
EUROPEAN PARLIAMENT AND OF THE COUNCIL of 16 April 2014 on clinical trials on medicinal 
products for human use, and repealing Directive 2001/20/EC" which has been active since 31 
January 2022 and the Danish Act on Clinical Trials of Medicinal Products [29, 37]. 
The PPR and EPR – systems are used to collect data for the eCRF. This is done by the study 
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group member) after consent is gained from a patient or surrogate. The eCRF will be 
developed, tested and validated in REDCap before initiation of the trial to optimize the use and 
ensure high data quality. 
Prehospital variables are collected using the ZOLL X series defibrillator (ZOLL Medical 
Corporation, Chelmsford, Massachusetts, USA). Data from the Zoll x series is automatically 
transferred to the PPR system and the data collection will happen from there.  
Data collection stops 30 days after last patient (patient number 1.988) has been enrolled. 
    
8.2 Variables 
A detailed data dictionary that clearly defines all included variables in the eCRF will be created 
prior to patient enrolment. The data dictionary will provide the name of the variable 
including the code used in the database, a definition of the variable, categories for categorical 
variables, and units and ranges for continuous variables. All variables are collected from either 
PPR or EPR, the data dictionary specifies where to collect each variable. 
 
8.2.1 Baseline characteristics  
 
CRN number  
 
Event number 
 
Dansk Index number 
 
Video call to EMDC 
 
Ambulance ID 
 
Receiving hospital 
 
Age 
 
Sex 
 
Known COPD 
 
Home oxygen supplement 
 
Home NIV 
 
Earlier AECOPD  
 
Current smoking 
 
Limited treatment level (do-not-resuscitate (DNR), no ICU, no intubation) 
 
Comorbidities  
 
Charlson Comorbidity Index (CCI) 
 
FEV1 % predicted (within 12 months) 
 
GOLD category 
 
 
Opioids 
 
Benzodiazepines  

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Known COPD is defined as the need for daily inhalation medication in the absence of 
asthma or COPD defined by an in-hospital diagnostic workup. 
Earlier AECOPD defined as COPD related admission within 12 months from event  
 
8.2.2 Pre-intervention characteristics 
 
Date and time for the enrolment  
 
EMT or Paramedic 
 
Initial contact to the EMS by general practitioner or an emergency call to the EMDC 
 
EMS response time 
 
SpO2 on ambulance arrival 
 
EtCO2 on ambulance arrival 
 
Respiratory rate on ambulance arrival 
 
Pulse rate on ambulance arrival 
 
Systolic blood pressure on ambulance arrival 
 
Diastolic blood pressure on ambulance arrival 
 
Patient-experienced dyspnoea 0-10 pre intervention (see section 8.3) 
 
GCS on ambulance arrival 
 
 
8.2.3 Post-intervention characteristics 
 
Study ID 
 
Enrollment time 
 
Acute oxygen before allocated treatment 
 
Salbutamol before allocated treatment 
 
SpO2 at hospital arrival 
 
EtCO2 at hospital arrival 
 
Respiratory rate at hospital arrival 
 
Pulse on hospital arrival 
 
Systolic blood pressure on hospital arrival 
 
Diastolic blood pressure on hospital arrival 
 
Temperature in degrees Celsius 
 
Transport time 
 
Patient-experienced dyspnoea 0-10 post intervention (see section 8.3)  
 
GCS on hospital arrival 
 
Prehospital Steroids  
 
Prehospital I.V./I.M./S.C. Beta-2-agonist 
 
Inhaled Beta-2-agonist  

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 
Inhaled anticholinergic 
 
Need for supplemental oxygen (besides flow for nebulizing) 
 
Prehospital Opioids 
 
Prehospital Benzodiazepines 
 
Hospital Opioids 
 
Hospital Benzodiazepines 
 
8.2.4 Outcomes 
 
Dead, 30-day 
 
Dead, 24-hour 
 
Dead, 7-day 
 
Acidosis on hospital arrival 
 
Size of acidosis (pH) 
 
Invasive ventilation in-hospital 
 
NIV, in-hospital 
 
ICU treatment 
 
Length of stay at ICU 
 
Hospital length of stay 
 
Hospital discharge diagnosis 
 
Readmission 
Patients experiencing readmission will be registered as "readmission" and only as dead if death 
occur within 30 days of first admission. 
 
8.2.5 Safety  
 
Untreated hypoxia 
 
SpO2 under 88% after allocation 
 
Prehospital termination of treatment 
 
 
8.2.6 ABG 
 
PaO2 on hospital ABG 
 
PaCO2 on hospital ABG 
 
pH on hospital ABG 
 
HCO3- on hospital ABG 
 
Lactate on hospital ABG 
 
Base excess on hospital ABG 

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8.3 Patient-experienced dyspnoea 
Patients will be asked to rate dyspnoea on a verbal numerical scale from 0 to 10. 0 being no 
dyspnoea and 10 being the worst imaginable dyspnoea. Patients will be asked to rate their 
dyspnoea two times. First time will be as soon as possible after first contact and before 
treatment is started. Second time will be at hospital arrival. In a recent study from the North 
Denmark Region, the dyspnoea score was useful for obtaining patient-reported outcomes of 
acute dyspnoea in the ambulance[38]. The dyspnoea scores were statistically associated with 
vital signs, but of limited clinical relevance. Therefore, the dyspnoea scoring in the STOP-COPD 
trial will be used to see whether the active treatment will change the patients experience of 
dyspnoea compared with standard treatment.  
 
8.4 Data quality and validity 
All clinically working personnel, EMTs and paramedics, involved in the treatment of enrolled 
patients will be trained to and informed about the importance of optimizing data quality and 
validity. This will further be optimized by having trained trial personnel entering all data from 
EPR and PPR to the eCRF according to the data dictionary. REDCap is designed such that data 
forms contain field-specific validation checks ensuring that mandatory fields are filled out and 
that continuous variables are within predefined ranges.  
Furthermore, REDCap allows for data quality rules warning of potential incorrect data (e.g., 
randomization before prehospital arrival). 
The eCRF will be validated thoroughly before enrolment of the first patient. 
Monitoring of data quality and validity will be performed by the Good Clinical Practice (GCP) 
unit according to the monitoring plan. received  
 
8.4.1 Protocol violations  
Tracing of SpO2 <88% in consecutive measurements over 5 min. without escalation of oxygen 
therapy in both groups. The violations will be registered in the eCRF. This data will be analysed 
by the DMC according to the charter, if they find systematic violations the study group will 
decide what measures need to be taken. 
Patients with SpO2 88-92% in the both groups will be recorded for protocol violation if SpO2 
>92% AND supplemental oxygen besides for nebulizing. 
 

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9 Safety 
 
Patients with AECOPD have a high in-hospital and 30-day mortality[5, 6, 8, 39, 40]. The aim of 
this study is to investigate the potential benefits of applying the in-hospital guidelines (national 
and international) to the prehospital setting regarding levels of SpO2 in patients with COPD[22, 
25]. Patients with a SpO2 of less than 88% is considered hypoxic and will be treated according 
to the protocol, no patient with hypoxia will be left untreated. 
Furthermore, AECOPD patients have a high prevalence of in-hospital need of/treatment with 
NIV[5, 6]. The current trial will assess how a titrated oxygen strategy potentially modifies 
these adverse effects. The overall benefit and potential harm will be captured in our primary 
and secondary outcomes. 
 
9.1 Standard treatment 
The standard treatment involves giving oxygen to patients with COPD, these patients may 
have respiratory hypercapnia either chronic or in addition to the AECOPD. Oxygen treatment to 
this group of patients may constitute a risk of worsening hypercapnia and acidosis. This risk is 
considered acceptable because of the current local treatment guidelines that include high flow 
oxygen in this patient population as part of standard treatment. 
 
9.2 Intervention treatment  
The intervention treatment involves giving compressed air plus oxygen, if needed. The 
compressed air constitutes no risk to the patient since this is composed of the same gases as 
the atmosphere and as shown in appendix 4 there are no known side effects to compressed 
air. Oxygen in this group is titrated to the national and international recommended SpO2 levels 
of 88-92%. This is expected to decrease the risk of hypercapnia and acidosis in AECOPD 
patients. Hypoxia therefore should not occur in this treatment group. The intervention 
treatment is therefore considered safe and benign to patients and expected to be beneficial as 
stated in section 3.  
 
9.3 Adverse events and reactions 
9.3.1 Definitions 
The following definitions will be used[41, 42]: 
 

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Adverse event (AE): Any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal relationship 
with this treatment 
 
Adverse reaction (AR): All untoward and unintended responses to an investigational 
medicinal product related to any dose administered. 
 
Serious adverse event (SAE): Any adverse event that results in death, is life-threatening, 
requires hospitalization or prolongation of existing hospitalization, results in persistent or 
significant disability or incapacity, or is a congenital anomaly or birth defect. 
 
Serious adverse reaction (SAR): Any adverse reaction that results in death, is life-
threatening, requires hospitalization or prolongation of existing hospitalization, results in 
persistent or significant disability or incapacity, or is a congenital anomaly or birth defect. The 
SARs are identified in the Danish Reference Safety Information (SmPC). 
 
Suspected unexpected adverse reaction (SUSAR): An adverse reaction, the nature or 
severity of which is not consistent with the applicable product information (e.g., investigator's 
brochure for an unauthorised investigational product or summary of product characteristics for 
an authorised product). 
 
9.3.2 Reporting 
AE/ARs: EMT's, paramedics or hospital physicians report AE/ARs to the study coordinator 
according to the SOP. The study coordinator registers the incidents and informs the sponsor-
investigator who shares the report with the sponsor. The AE/ARs are reported to the CTIS at 
the end of the trial by sponsor. This accounts for both investigational and auxiliary medicinal 
products. 
 
SAEs: EMT's, paramedics or hospital physicians report SAEs to the study coordinator according 
to the SOP as soon as possible and within 24 hours. The study coordinator registers the 
incidents and informs the Sponsor-investigator. Sponsor-investigator assess whether SAE is 
related to the intervention (SAR) or not. The SAEs are reported to the CTIS database at the 
end of the trial by sponsor. This accounts for both investigational and auxiliary medicinal 
products. 
 

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SARs: EMT's, paramedics or hospital physicians report SAEs to the study coordinator according 
to the SOP as soon as possible and within 24 hours. The study coordinator registers the 
incidents and informs the sponsor-investigator. Sponsor-investigator assess whether the SAE 
is related to the intervention (SAR) and whether the SAR are expected or not (SUSAR). The 
SARs are reported once a year to the CTIS database together with a patient safety report by 
sponsor. Investigational and auxiliary medicinal products will be reported in a single report. 
 
 
SUSARs: Sponsor-investigator decides whether a reported SAR is unexpected and thereby 
classified as a SUSAR. Sponsor-investigator reports SUSAR to the GCP unit of Aarhus University 
within 7 days in case of fatal reactions. The GCP unit handles the further reporting of SUSARs 
to the EudraVigiliance database. In case of non-fatal reactions, the SUSAR is reported within 
15 days.     
9.4 Specific adverse reactions  
 
The AR's and SAR's mentioned in section 9.4.1, 9.4.2 and 9.4.3 are anticipated and known 
reactions, furthermore they are all, except allergic reaction, symptoms on AECOPD. This 
correlation between adverse reactions and AECOPD symptoms makes it difficult to distinguish 
between the two. These reactions, will all be reported to the study coordinator and reported as 
mentioned in section 9.3.2 unless the treating clinician and sponsor-investigator are certain 
that the reaction are only related to the AECOPD. The DMC will follow the reporting of adverse 
reactions as stated in the charter. 
 
9.4.1 Medical Oxygen ”Air Liquide” 
According to the SmPC Oxygen (Medical Oxygen ”Air Liquide”) has the following relevant 
adverse reactions: Hypoventilation, atelectasis, pleuritis, bronchopulmonary dysplasia. 
 
9.4.2 Compressed Atmospheric Air ”Air Liquide” 
According to the SmPC compressed air (Atmospheric Air ”Air Liquide”) has no adverse 
reactions. 
 
9.4.3 Salbutamol 
According to SmPC for salbutamol the product has the following relevant adverse reactions: 
Tachycardia, palpitations, arrhythmias, headache, tremor, allergic reaction, cardiac ischemia, 
peripheral vasodilatation, paradox bronchospasm, agitation. 

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9.4.4 Berodual 
According to the SmPC for Berodual the product has the following relevant adverse reactions: 
Allergy and anaphylactic reactions, bronchospasm, vision disturbance, tachycardia, 
palpitations, arrhythmias, headache, tremor, nausea and vomiting, hypertension.  
 
 
 
9.5 Assessment of adverse events 
9.5.1 Timing 
In all participants, we will assess the occurrence of SARs until hospital admission using the PPR 
record. After hospital admission the patients will receive the usual in-hospital treatment on the 
full discretion of the treating physician. This in combination with the short half-life of the study 
drugs eliminates the need for further follow up on SARs. If the treating hospital physician 
suspects a SAR, it is reported to the study coordinator and sponsor-investigator according to 
the SOP. Patients experiencing AE, AR, SAE and SAR in the prehospital phase will have follow 
up 24 hours later by the study coordinator or sponsor-investigator.  
 
9.5.2 Classification of an event 
SAE/SARs will be reported to the sponsor-investigator who then classifies it as a SAE, SAR or 
SUSAR. 
Reporting will be according to those in section 9.3.2 mentioned possibilities. 
 
10 Sample size and statistical analysis plan 
 
10.1 Sample size calculation 
The RCT by Austin et al. [16] found an absolute risk reduction of 5% on mortality in the 
intention to treat analysis of suspected AECOPD. The trial used high flow oxygen in the 
standard treatment arm even if there was no need for inhaled bronchodilators, this will not be 
the case in the STOP-COPD trial. Furthermore, they used a cluster-randomized setup, making 
the risk of bias and confounding high. Thus, the suspected risk reduction is a conservatively 
estimated to 3%. To meet this uncertainty, a sample size re-estimation is planned, according 
to the DMC charter, once follow-up data have been collected for the initial 500 patients (see 
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To gain a power of 80% the minimum required total sample size is 1.888. The DMC can make 
recommendations on increasing the sample size according to the Charter for DMC. 
 
Study Parameters 
Standard treatment 
suspected mortality 
7% 
Study treatment 
suspected mortality 
4% 
Significance level 
0.05 
Power 
0.80 
Drop out (expected 
maximum) 
4% 
 
Sample Size 
Standard Treatment 
944 
Study treatment 
944 
Total 
1.888 
Total with a power of 0.85 
2.160 
Total with a power of 0.90 
2.526 
 
10.2 Feasibility  
Estimated enrolment rate per anno is 1.643 patients based on the following data: 
 
10.2.1 Patients 
Based on unpublished data from the PPR system on ambulance transports in the Central 
Denmark Region, prehospital inhalation treatment was given in 3.351 cases in 2019. Excluding 
patients under the age of 40 years, the number of patients was 3.135. The data do not specify 
the reason for inhalation treatment. Based on data from a Danish cohort study from 2019 our 
exclusion criteria, asthma and allergy (including angioedema) accounted for 6.12% and 6.93% 
respectively[43].  
 
 

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10.2.2 Clinician’s enrolment rate 
The EMT's and paramedics employed by the EMS in the CDR are familiar with prehospital trials. 
Based on other studies, the usual enrolment rates is around 60-70%[35]. 
 
Variable 
Percent 
Number 
Sum 
Raw data (all eligible patients) 
 
3.351
3.351
40 years or older  
 
3.135
3.135
Asthma 
-6.12%
-192
2.943
Allergy 
-6.93%
-204
2.739
Expected enrolment rate 
60%
-1.096
1.643
Patients suitable for enrolment yearly 
 
 
1.643
      
10.3 Stopping criteria 
The DMC will recommend immediate trial stop for reasons of futility or harm based on the 
following criteria: 
1) Patients have a statistically significantly higher risk of death in one treatment arm 
compared to the other (1% significance level) 
2) Patients have a significantly higher risk of safety issues (see 8.2.5) in one treatment 
arm compared to the other (significance level on discretion of the DMC) 
 
The DMC can also advocate for an early stop due to clear benefit or harm of a treatment, 
futility, slow recruitment or external evidence based on routine analyses. The sponsor-
investigator will make the final decision for early stopping of the trial. 
 
10.4 Statistical analysis plan 
 
Baseline characteristics will be presented as median with inter quartile range (IQR) or 
percentages and frequencies as applicable. 
 
10.4.1 Outcomes and statistics  
Differences in the primary outcome, 30-day mortality, are calculated both as risk difference 
(RD) and relative risk (RR) and is performed using mixed effects Linear and Poisson 
regression, respectively, with robust variance estimation and random intercept on the 
randomization blocks. For the primary analysis the estimation is an otherwise crude analysis. 
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intention-to-treat basis. This meaning all patients randomized will be analysed in the allocated 
groups. Primary and secondary binary outcome analysis will also be presented with number-
needed-to-treat or number-needed-to-harm depending on the results. 
 
All binary secondary outcomes will be analyzed as the primary outcome. The following effect 
measures will be used to assess the secondary outcomes: 
 
Mortality (binary, within 24 hours and 7-days yes/no): RD% and RR 
 
Length of hospital stay (time to event, days from inclusion to discharge): Aalen-
Johansen curves and Cox-regression presenting Hazard rate ratio (HR)  
 
Length of hospital stay (days from inclusion to discharge): mean differences using Tobit 
regression 
 
Admission at ICU (Binary, yes/no): RD% and RR 
 
Length of stay ICU (time to event, days from inclusion to discharge from ICU): Aalen-
Johansen curves and Cox-regression presenting Hazard rate ratio (HR)  
 
Length of stay ICU (total number of days from inclusion to discharge from ICU): mean 
differences using Tobit regression 
 
Ventilator treatment (NIV) – also performed at non-ICU (binary, within 24 hours, 7 
days and 30 days yes/no): RD% and RR 
 
Time to Ventilator treatment (NIV) (time to event, days from inclusion to initiation of 
NIV): Aalen-Johansen curves and Cox-regression presenting Hazard rate ratio (HR)  
 
Ventilator treatment (invasive) (binary, within 24 hours, 7 days and 30 days yes/no): 
RD% and RR 
 
Time to Ventilator treatment (invasive) (time to event, days from inclusion to initiation 
of NIV): Aalen-Johansen curves and Cox-regression presenting Hazard rate ratio (HR)  
 
Acidosis on hospital arrival (binary, acidosis yes/no): RD% and RR 
 
Degree of acidosis based on pH (continues): Mean/median difference 
 
Patient experienced dyspnea on verbal rating scale (Categorical: 0-10): Mean/median 
difference using linear mixed effects models 
 
Readmission rate from day 2 to day 30 after discharge (binary yes/no): RD% and RR 
 
Time to readmission from discharge up to day 30 (time to event, days from discharge 
to readmission, end at day 30): Aalen-Johansen curves and Cox-regression presenting 
Hazard rate ratio (HR) 
10.4.2 Subgroup analysis 
 
Primary and secondary outcome for groups defined by pulse oximetry measured blood 
saturation (<88%, 88-92% and >92%) determined prior to first administration of 
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 
Primary and secondary outcomes using prehospital transport time as a regression 
variable. 
 
Primary and secondary outcomes analysed on patient groups defined by a final 
diagnosis of AECOPD (yes/no). Analyzed as primary and secondary outcomes. 
 
Primary and secondary outcomes analysed on patient groups defined by NIV and 
invasive ventilation. Analyzed as primary and secondary outcomes. 
 
If statistical analysis and methods not described in the protocol are deemed useful and 
important, in the reporting of results, this will be clearly announced in the main article. 
 
10.5 Missing data 
Patients with missing data on the outcome will be excluded in the primary and secondary 
analysis. Sensitivity analysis will be made using multiple imputations chained equations with 
100 imputation sets and including relevant first and second order variables in the imputation 
model[44]. 
Possible differences in patient characteristics and exposure between complete cases and 
dropouts are addressed by sensitivity analysis adjusted by appropriate patient characteristics 
using inverse probability of treatment weights (IPTW). Balanced diagnostics are conducted 
using the threshold criteria given by Zhang et al.[45]. 
 
11 Data  
 
11.1 Storage  
Study data will be collected and managed using research electronic data capture (REDCap) 
tools hosted by Aarhus University[46, 47]. REDCap is a secure, web-based software platform 
designed to support data capture for research studies, providing 1) an intuitive interface for 
validated data capture; 2) audit trails for tracking data manipulation and export procedures; 3) 
automated export procedures for seamless data downloads to common statistical packages; 
and 4) procedures for data integration and interoperability with external sources. The REDCap 
data management system is secure and fully compliant with all regulatory guidelines and 
includes a complete audit-trail for data entry validation. Through these mechanisms, as well as 
relevant training for all involved parties, patient confidentiality will be safeguarded.  
The case report form and the consent form for each patient will be stored in REDCap during 
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electronic data base hosted by the CDR for 25 years according to EU regulations[29]. Data will 
be handled according to all relevant Danish and EU laws including the General Data Protection 
Regulation (GDPR)[48] and the Data Protection Act (“Databeskyttelsesloven”)[49]. The project 
will be registered with the CDR’s internal list of research projects.  
 
11.2 Data access 
Each patient will receive a unique trial identification number. During the trial, the sponsor-
investigator, employed study personnel and coordinator will have access to the entire database 
except randomization. The Good Clinical Practice (GDP) unit, regulatory agencies, and other 
relevant entities will have direct access to source data (PPR and EPR) and to all relevant trial 
data including the case report form as applicable. Upon trial completion the trial sponsor-
investigator, employed study personnel and coordinator will be granted access to the 
randomization key as well. 
 
11.3 Data sharing  
De-identified data will be made available for investigators whose proposed use of the data has 
been approved by local administration, 9 months after the publication and no longer accessible 
when data is no longer stored according to the current ICMJE recommendations and EU 
regulations[29, 50]. All trial-related documents will be publicly available at the trial-website 
www.STOP-COPD.com, patient related data will not be accessible on this website. 
 
12 Quality and monitoring 
12.1 Good Clinical Practice monitoring 
The investigation site PEMSCDR will be monitored by the GCP monitoring unit from Aarhus 
University and Central Denmark Region. No treatment or investigations related to the trial is 
performed at the hospitals. Hospitals are only locations for the collection of consent. Thus, 
hospitals are not defined as sites in relation to GCP monitoring. A detailed monitoring plan will 
be developed prior to trial commencement and patient enrolment. 
 
12.2 Data monitoring committee  
The DMC will be responsible for safeguarding the interests of trial participants, assessing the 
safety and efficacy of the interventions during the trial, and for monitoring the overall conduct 
of the clinical trial. The DMC will consist of three specialists with expertise in anaesthesiology, 
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recommended[51]. The DMC will review de-identified data for safety at five predetermined 
milestones (200, 500, 1000 and 1500 enrolled patients), but can, at any time, require extra 
reviews. Unless there are group differences necessitating unblinding (as determined by the 
DMC), the DMC will be blinded to treatment groups. The trial will continue while the DMC 
reviews data. After the reviews, the DMC will create a short report to the study group with 
recommendations for continuation, modifications, or termination of the trial. The formal stop 
criteria for the trial will be those mentioned in section 10.3. The final decision on potential 
modifications or termination will rest with the study group and the sponsor-investigator. A 
detailed charter for the DMC can be will be available on the trail web page after patient 
inclusion starts. The DMC will Undertake interim sample size re-estimation once follow-up data 
have been collected for the initial 500 patients, based on the risk difference between the 
intervention and the control group. The DMC will then make recommendations accordingly. 
When making recommendations the DMC must take into account clinical relevance and 
feasibility. 
13 Ethical Considerations 
 
13.1 Risk/benefit assessment  
13.1.1 Potential benefits 
One RCT found a significant reduction in mortality when using a titrated oxygen strategy for 
prehospital patients with suspected AECOPD [16]. Multiple observational studies have also 
shown positive effects when restricting or titrating oxygen to patients suspected of AECOPD[6, 
17, 18, 52]. The lack of more than one prehospital RCT’s have been confirmed by a Cochrane 
systematic review, and several manuscript authors. More RCTs could ensure good clinical 
impact and is essential to enable changes in guidelines for prehospital management of patients 
with suspected AECOPD. 
Details about the potential benefits of the interventions are provided in the background section 
(see section 1). In-hospital National and international guidelines and recommendations are 
also listed in section 1. 
 
13.1.2 Potential harms  
For now, high flow oxygen is standard treatment, with acceptance of the known or suspected 
harms following high flow oxygen to this patient population. We do not believe this trial to 
expose patients to more harm than usual care.  

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The only theoretical risk of harm is untreated or undetected hypoxia. As stated in section 7 
and 9 no patients are left hypoxic because the protocol includes different actions to avoid 
hypoxia to the extreme extend where a hypoxic patient would be treated with 100% oxygen 
also in the intervention arm of the study if needed. 
Known potential harms for oxygen and compressed air are listed in section 9 and in appendix 3 
and 4. Known potential severe adverse events that may be associated with administration of 
salbutamol are listed in section 9. 
Potential harms are monitored continuously through the trial by the data monitoring 
committee (see section 12) with pre-specified stopping criteria.   
 
13.1.3 Risk/benefit ratio  
As seen in section 1 and 9.1/9.2 the intervention in this trial constitutes little or no risk to the 
patient. In contrast, the standard treatment is considered potentially harmful according to the 
limited literature on prehospital treatment and the more extensive literature on in-hospital 
treatment. Therefore, the risk/benefit ratio is in favour of the study. 
 
13.2 Consent in emergency situations 
In the prehospital setting obtaining informed consent from the AECOPD patient is not possible. 
Patients with AECOPD are most often in severe dyspnoea, and therefore desperate and anxious 
with the need of prompt treatment. These patients are unable to receive and understand 
information about the trial. AECOPD patients presents with neurological impairment in at least 
11% [53]. All patients who are in need of inhalation therapy, and thereby eligibly in the study, 
are considered to meet these requirements and are considered incapacitated at the first 
contact. Despite these challenges, the need for more research is evident, as stated in section 
9, to improve outcomes for patients with AECOPD.  
All patients fulfilling the inclusion criteria in this study have impaired respiratory capacity with 
dyspnoea requiring acute treatment with inhaled bronchodilators. This means that all 
participants have moderate to severe pulmonary impairment precluding the possibility of an 
informed consent. Trying to obtain one could force the patient to consent just to receive 
treatment without further delay. 
 
Studies like RESIST (ClinicalTrials.gov identifier (NCT number): NCT03481777), TRIAGE 
(ClinicalTrials.gov identifier (NCT number): NCT03542188), REFACED (ClinicalTrials.gov 
identifier (NCT number): NCT05076435) and  "Prehospital Transfusion Strategy in Bleeding 
Patients" (ClinicalTrials.gov identifier (NCT number): NCT04879485) all have similar study 
setup as the STOP-COPD trial by including patients (not in cardiac arrest or with 

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unconsciousness), but who are in a stage of illness, that disallows an attempt to gain informed 
content. The above-mentioned trials are all approved as emergency trials by the Regional 
Ethical Committee, hence consent is gained after enrolment and intervention. 
 
The STOP-COPD trial will adhere to the Danish Medicinal Research Ethical Committee, the 
Danish Health Authority, the Danish Data Protection Agency, REGULATION (EU) No 536/2014, 
Declaration of Helsinki, GCP-ICH guidelines and Danish law[29, 37, 42, 48, 54-56].  
 
13.2.1 Regulations from the European Parliament 
Regulations from the European Parliament allows informed consent to be obtained after 
enrolment in emergency situations where the following criteria are met. The regulations are 
implemented in Danish law and regulations[29, 37]. Arguments for this trial are inserted under 
every criterion:  
 
a) "Due to the urgency of the situation, caused by a sudden life-threatening or other 
sudden serious medical condition, the subject is unable to provide prior informed 
consent and to receive prior information on the clinical trial." 
 
Patients with AECOPD with the need of inhalation treatment are most often in severe 
dyspnoea hence desperate to receive prompt treatment without the ability to receive 
and understand information about the trial. This can be due to one or more of the 
following: hypoxia, hypercapnia, exhaustion, infection all leading to altered cognitive 
abilities. Furthermore, the definition of AECOPD is an acute worsening of dyspnoea and 
thereby automatically contains a state of distress. 
 
b) "There are scientific grounds to expect that participation of the subject in the clinical 
trial will have the potential to produce a direct clinically relevant benefit for the subject 
resulting in a measurable health-related improvement alleviating the suffering and/or 
improving the health of the subject, or in the diagnosis of its condition." 
 
As stated in section 3, 7 and 9 the intervention is hypothesised to lower in-hospital 
mortality, need for in-hospital NIV, need for invasive ventilation and shorter hospital 
stay. All of which must be considered as a clinically relevant benefit for the patients. 
 
c) "It is not possible within the therapeutic window to supply all prior information to and 
obtain prior informed consent from his or her legally designated representative." 

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In the prehospital setting managing a desperate AECOPD patient with severe dyspnoea, 
it is not possible to supply the patient with information before enrolment. Because of 
the need for immediate treatment. 
 
d) "The investigator certifies that he or she is not aware of any objections to participate in 
the clinical trial previously expressed by the subject." 
 
All patients who decline to participate will be registered in the eCRF as not includible, if 
the patient later is sought included, the randomization site will automatically declare 
the patient not suitable for inclusion. The registration will be deleted as soon as the 
inclusion sample is met. 
 
e) "The clinical trial relates directly to the subject's medical condition because of which it is 
not possible within the therapeutic window to obtain prior informed consent from the 
subject or from his or her legally designated representative and to supply prior 
information, and the clinical trial is of such a nature that it may be conducted 
exclusively in emergency situations." 
 
The trial objectives are to investigate the effects of titrated oxygen on acute worsening 
of COPD (AECOPD) and thereby exclusively in the emergency situation. It is not 
possible to obtain consent prior to the worsened state of COPD (AECOPD) because the 
medical condition is the main reason for the EMS contact.    
 
f) "The clinical trial poses a minimal risk to, and imposes a minimal burden on, the subject 
in comparison with the standard treatment of the subject's condition." 
 
As stated in section 9.2 the potential harms for the intervention group are considered 
very small and the risk/benefit ratio is believed to favour the intervention. The 
intervention imposes no extra burden on the patient and requires minimal/no 
compliance. 
 
13.2.2 Obtaining informed consent 
Informed consent is obtained as soon as possible after hospitalization. Following scenarios, in 
order of priority, can occur: 
 

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1. The patient is stabilised when consent is sought:  
The patient is informed and accepts or declines to participate. 
 
2. The patient is not stabilised or is stabilised but comatose or invasive ventilated 
and a close relative is present: A close relative is sought to obtain consent as a 
surrogate together with a "legal guardian"  
 
3. The patient is not stabilised or is stabilised but comatose or invasive ventilated 
and a close relative is not present: Consent is obtained from a legal guardian. 
 
4. The patient dies before consent is obtained: A close relative is sought, within a 
reasonable extent, to obtain consent as a surrogate, together with a "legal 
guardian"[57]. If no close relative is found, consent is given only by the "legal 
guardian". 
 
  
Information regarding the trial will be written and verbal, and contain information about the 
background, in/exclusion criteria, risks and benefits and the trial design. Information about 
data sharing will also be given. The patient or surrogate will be informed that the intervention 
is prehospital and no other intervention regarding the trial will be performed and that a decline 
of consent will have no influence on any current or future treatment. The patient or surrogate 
then gains or declines to give consent. Consent forms will be electronic and placed in the 
REDCap database together with the eCRF. The conversation will be held in a calm and quiet 
environment. The patient will be informed about the right to have an independent assessor 
present during the conversation and the right to reflection time.  
 
In the case of a surrogate consent, the patient will be sought for informed consent as soon as 
possible after they regain the ability to provide consent.  
 
13.2.2.2 Gaining consent after discharge 
In the case a patient is discharged before consent is obtained, the patient is contacted by 
telephone and asked about the possibility to get information conversation done by video call. If 
the patient agrees to this, all the above-mentioned information will be given by video call, 
afterwards the written information will be send by e-mail or postal service. The video call will 
be held in a calm and quiet environment, this applies to both the patient and the person 
gaining consent, securing patient confidentiality. The platform used for video call is delivered 

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by the Central Denmark Region and is approved for patient consultation 
(https://bestilvideo.rm.dk/video/). The patient will be informed about the right to have an 
independent assessor present during the conversation and the right to reflection time. Correct 
patient identification will be secured by CRN. The process of video call will adhere to national 
guidelines[58].  
Signing of the consent form will be done by mailing an electronic eCRF link to the patient. This 
option is only chosen if the patient understands the procedure, or a relative can help and if the 
patient owns a tablet or smartphone.  
If the patient is unable to receive and understand the information over video call or is unable 
to use and understand the procedure about the eCRF link, the patient is sought out at home 
and informed as if still admitted to hospital. This applies only if the reason is due to lack of 
technical skills. If the reason is due to the patient being unable to provide consent, the rules 
for incapacitated participants apply.  
It is expected that the process of video call consent will be used in exceptional few cases. 
 
13.2.3 Responsibilities regarding consent 
The sponsor-investigator is responsible for collecting consent from patients and legal 
guardians. The sponsor-investigator can delegate the task of gaining consent to a qualified 
physician. The person who gains consent should have knowledge about the disease process of 
COPD, furthermore the person should know and be educated in the study protocol and legal 
aspects of consent. The person who gains consent will be educated in GCP-regulations using e-
learning from the GCP unit, certificates will be stored in the trial master file. 
 
A legal guardian, in context of the STOP-COPD trial, is a physician with speciality in intensive 
care medicine who are not involved in the STOP-COPD trial as an investigator or author and 
who are independent of the sponsor and investigators interests. This ensures that the legal 
guardian is a physician who treats AECOPD patients in their clinical routine work and has a 
professional insight in COPD. The legal guardian will be introduced to the study material and 
from here gain detailed insight to the study protocol including the in-/exclusion criteria and the 
responsibilities as legal guardian. The legal guardian acts according to the interest of the 
research participant. The legal guardian confirms these requirements when signing the consent 
form. 
 

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13.2.4 Decline of consent 
If a patient or surrogate decline to give consent/participate, collection of data stops at that 
point. Data collected up to that point is deleted and patient is registered as decline to 
participate in the eCRF and reported according to the consort flow diagram. 
A decline to participate will have no influence on the current or following treatment of the 
patient.   
Patient and/or relatives will be informed on mentioning a decline to participate in the trial if 
another EMS contact arises.  
 
 
13.3 Summary of ethical considerations 
AECOPD patients have a broad spectrum of severity. The group of patients with the most 
severe symptoms will obviously have a decreased level of consciousness based on a mix of 
hypoxia, hypercapnia and severe dyspnoea fulfilling the criteria listed in section 13.2.1. Even 
when patients suffer from less severe AECOPD, the nature of the condition with experienced 
dyspnoea make attempts to obtaining informed consent impossible and patients in this group 
thereby also fulfil the criteria listed in section 13.2.1. The intervention is, as stated in section 
9.2, without any known major risks, thus making it a safe trial for enrolled patients. The 
intervention in the trial is simple and easy to perform, with an expected high compliance from 
the EMT's and paramedics. We find that the conditions for an acute study are fully satisfied 
since the vast majority of AECOPD patients are unsuitable for informed consent to be acutely 
obtaining and because the treatment has to be initiated as soon as possible to correct the 
patients dyspnoea, hypoxia and hypercapnia and here through the patients outcome. 
Moreover, there are no reported serious risks from the intervention. 
Participating in the trial is voluntary and unpaid.  
 
13.4 Insurance 
The patients participating in the STOP-COPD trial are covered by the Danish patient 
insurance[59]. 
 
13.5 Approval from authorities 
The trial will be approved by the Danish Medicine Agency and the Medical Research Ethics 
Committees before initiation. 
14 Funding 
 

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 
“Den Landsdækkende Akutlægehelikopterordning” (title in Danish: The Nationwide 
Emergency Medical Helicopter Service) has supported the project with kr. 90.478 (euro 
12.000) to protocol development be providing 2 month salary to the study coordinator. 
 
"Simon Spies Fonden" has supported the project with kr. 15.000,- 
 
"Eva Merete Falck Crones Fond" has supported the project with kr. 50.000,- 
 
"Region Midtjyllands Strategiske Forskningsmidler" has supported the project with kr. 
1.175.000,- 
 
Further private and public organisations will be applied for funding. When additional funding is 
achieved, amendments will be submitted through the EU clinical trials system. 
 
All funding is handled by the financial department at PEMSCDR. Contributors have no influence 
on the trial e.g., the design, conduct, results or final manuscript.   

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15 Timeline 
Year
 
2022-2024 
2025 
2026 
2027 
2028 
Quarter 
20
21 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
Idea development
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol 
development
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ethical approval
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Danish medicine 
agency approval
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Creating data 
dictionary, SOPs and 
randomization site
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Creation of 
educational material
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Education of EMTs 
and paramedics
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GCP and DMC 
monitoring
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient enrolment
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Closing of database
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Closing trial 
prehospitally
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data analysis
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Main article writing
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Presentation of 
results
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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16 Publication 
The study will result in two articles. First a protocol article describing the trial and the analysis 
plan, the article will be published when the Danish authorities have approved the trial. The 
second article will be the main article, this article will be published regardless of the results, 
both negative, inconclusive or positive results  will be published following the CONSORT 
guidelines[60, 61]. The study coordinator will be the first and corresponding author and the 
sponsor-investigator the last author. Authorship will follow International Committee of Medical 
Journal Editors guidelines[50]. The article will be published as open access in an international 
peer-reviewed journal and as conference presentations.  
The trial results will be shared with the participating EMT's, paramedics, patients and other 
interested on the study website www.stop-copd.com 
Within one year from end of trial the results (according to CTR annex IV) will be uploaded to 
the CTIS database. 
 
17 Division of tasks 
Sponsor-Investigator: Protocol development, funding, budget, data dictionary development, 
Danish Medicine Agency approval, ethical approval, evaluation of SAE/SAR/SUSAR's, daily 
management in the absence of the coordinator, data analysis, presentation of results, trial 
registration, collection of consent. 
 
Coordinator: Protocol development, funding, budget, data dictionary development, Danish 
Medicine Agency approval, ethical approval, trial registration, daily management, contact to 
GCP unit, development of educational material, data analysis, presentation of results, article 
writing, assessing recruitment speed, completion of eCRF. 
 
Study group: Protocol development, data dictionary development, presentation of results. 
 
Student assistants: Completion of eCRF. 
 
Clinical staff: Enrolment, randomization and treatment of patients according to protocol. 
 
DMC: See section 12.2 
 
GCP: See section 12.1 

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18 References 
 
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2016. 21(1): p. 14-23. 
2. 
Lozano, R., et al., Global and regional mortality from 235 causes of death for 20 age 
groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 
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3. 
Moll, L., P. Lange, and B.H. Dahl. COPD – Disease, Treatment and Organization 
(translated from Danish). 2011: Munksgaard Denmark. 262. 
4. 
Jakobsen, M., et al., Study on drug costs associated with COPD prescription medicine in 
Denmark. The Clinical Respiratory Journal, 2013. 7(4): p. 328-337. 
5. 
Ringbaek, T.J., J. Terkelsen, and P. Lange, Outcomes of acute exacerbations in COPD in 
relation to pre-hospital oxygen therapy. Eur Clin Respir J, 2015. 2. 
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Bentsen, L.P., et al., A change from high-flow to titrated oxygen therapy in the 
prehospital setting is associated with lower mortality in COPD patients with acute 
exacerbations: an observational cohort study. Acute Med, 2020. 19(2): p. 76-82. 
7. 
Danish Register for Chronic Obstructive Pulmonary Disease, Danish Register for Chronic 
Obstructive Pulmonary Disease – Annual Report 2020. 2021. 
8. 
Donaldson, G.C. and J.A. Wedzicha, COPD exacerbations .1: Epidemiology. Thorax, 
2006. 61(2): p. 164-8. 
9. 
Neder, J.A., et al., Exertional ventilation/carbon dioxide output relationship in COPD: 
from physiological mechanisms to clinical applications. Eur Respir Rev, 2021. 30(161). 
10. 
Murphy, R., P. Driscoll, and R. O'Driscoll, Emergency oxygen therapy for the COPD 
patient. Emerg Med J, 2001. 18(5): p. 333-9. 
11. 
Aubier, M., et al., Effects of the administration of O2 on ventilation and blood gases in 
patients with chronic obstructive pulmonary disease during acute respiratory failure. Am 
Rev Respir Dis, 1980. 122(5): p. 747-54. 
12. 
Abdo, W.F. and L.M. Heunks, Oxygen-induced hypercapnia in COPD: myths and facts. 
Crit Care, 2012. 16(5): p. 323. 
13. 
Hanson, C.W., 3rd, et al., Causes of hypercarbia with oxygen therapy in patients with 
chronic obstructive pulmonary disease. Crit Care Med, 1996. 24(1): p. 23-8. 
14. 
Savi, A., et al., Influence of FIO2 on PaCO2 during noninvasive ventilation in patients 
with COPD. Respir Care, 2014. 59(3): p. 383-7. 
15. 
Kopsaftis, Z., et al., Oxygen therapy in the pre-hospital setting for acute exacerbations 
of chronic obstructive pulmonary disease. Cochrane Database Syst Rev, 2020. 1: p. 
CD005534. 
16. 
Austin, M.A., et al., Effect of high flow oxygen on mortality in chronic obstructive 
pulmonary disease patients in prehospital setting: randomised controlled trial. Bmj, 
2010. 341: p. c5462. 
17. 
Cameron, L., et al., The risk of serious adverse outcomes associated with hypoxaemia 
and hyperoxaemia in acute exacerbations of COPD. Postgrad Med J, 2012. 88(1046): p. 
684-9. 
18. 
Wijesinghe, M., et al., Pre-hospital oxygen therapy in acute exacerbations of chronic 
obstructive pulmonary disease. Intern Med J, 2011. 41(8): p. 618-22. 
19. 
Bardsley, G., et al., Oxygen versus air-driven nebulisers for exacerbations of chronic 
obstructive pulmonary disease: a randomised controlled trial. BMC pulmonary medicine, 
2018. 18(1): p. 157-157. 
20. 
Edwards, L., et al., Randomised controlled crossover trial of the effect on 
PtCO2 of oxygen-driven versus air-driven nebulisers in 
severe chronic obstructive pulmonary disease. Emergency Medicine Journal, 2012. 29(11): p. 
894. 

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21. 
Gunawardena, K.A., et al., Oxygen as a driving gas for nebulisers: safe or dangerous? 
Br Med J (Clin Res Ed), 1984. 288(6413): p. 272-4. 
22. 
O'Driscoll, B.R., et al., BTS guideline for oxygen use in adults in healthcare and 
emergency settings. Thorax, 2017. 72(Suppl 1): p. ii1-ii90. 
23. 
NICE, chronic obstructive pulmonary disease in over 16s diagnosis and management. 
24. 
Beasley, R., et al., Thoracic Society of Australia and New Zealand oxygen guidelines for 
acute oxygen use in adults: 'Swimming between the flags'. Respirology (Carlton, Vic.), 
2015. 20(8): p. 1182-1191. 
25. 
Danish Health Authority, National Clinical Guideline on Oxygen Therapy for the Acutely 
Ill Adult Patient (translated from Danish). 2019. 
26. 
Hansen, E.F., et al. Chronic Obstructive Pulmonary Disease (COPD) in Exacerbation and 
Non-Invasive Ventilation (NIV) (translated from Danish). The Danish Society for 
Respiratory Medicine. 2020. 
27. 
Susanto, C. and P.S. Thomas, Assessing the use of initial oxygen therapy in chronic 
obstructive pulmonary disease patients: a retrospective audit of pre-hospital and 
hospital emergency management. Internal Medicine Journal, 2015. 45(5): p. 510-516. 
28. 
Taylor, M.J., Systematic review of the application of the plan-do-study-act method to 
improve quality in healthcare. BMJ quality & safety, 2014. 23(4): p. 290-298. 
29. 
REGULATION (EU) No 536/2014 OF THE EUROPEAN PARLIAMENT AND OF THE 
COUNCIL. 2014. 
30. 
Directive 2001/83/EC of the European Parliament and of the Council of 6 November 
2001 on the Community code relating to medicinal products for human use (OJ L 311, 
28.11.2001, p. 67). 2001 
31. 
Johannesdottir, S.A., et al., Hospitalization with acute exacerbation of chronic 
obstructive pulmonary disease and associated health resource utilization: A population-
based Danish cohort study. Journal of Medical Economics, 2013. 16(7): p. 897-906. 
32. 
Littner, M.R., In the clinic. Chronic obstructive pulmonary disease. Ann Intern Med, 
2011. 154(7): p. ITC4-1-ITC4-15; quiz ITC4-16. 
33. 
Patil, S.P., et al., In-Hospital Mortality Following Acute Exacerbations of Chronic 
Obstructive Pulmonary Disease. Archives of Internal Medicine, 2003. 163(10): p. 1180-
1186. 
34. 
Acute Coronary Syndrome and Use of Tele-ECG, Prehospital Emergency Medical 
Services, Editor (translated from Danish). 2022. 
35. 
Vallentin, M.F., et al., Effect of Intravenous or Intraosseous Calcium vs Saline on Return 
of Spontaneous Circulation in Adults With Out-of-Hospital Cardiac Arrest: A Randomized 
Clinical Trial. JAMA, 2021. 
36. 
Behrndtz, A., et al., TRIAGE-STROKE: Treatment strategy In Acute larGE vessel 
occlusion: Prioritize IV or endovascular treatment-A randomized trial. Int J Stroke, 
2020. 15(1): p. 103-108. 
37. 
Act no. 620 of 08/06/2016 on Clinical Trials of Medicinal Products (translated from 
Danish). 2016. 
38. 
Lindskou, T.A., et al., Patient experience of severe acute dyspnoea and relief during 
treatment in ambulances: a prospective observational study. Scand J Trauma Resusc 
Emerg Med, 2020. 28(1): p. 24. 
39. 
Echevarria, C., et al., Oxygen therapy and inpatient mortality in COPD exacerbation. 
Emerg Med J, 2021. 38(3): p. 170-177. 
40. 
Lindskou, T.A., Prehospital dyspnoea measurements. Aalborg Universitet. Det 
Sundhedsvidenskabelige Fakultet. Ph.D.-Serien. 2019: Aalborg Universitetsforlag. 
41. 
European Parlement, Directive 2001/20/EC of the European Parliament and of the 
Council of 4 April 2001 on the approximation of the laws, regulations and administrative 
provisions of the Member States relating to the implementation of good clinical practice 
in the conduct of clinical trials on medicinal products for human use. 2001. 
42. 
European Medicines Agency, Guideline for good clinical practice E6(R2). 2015. 

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43. 
Lindskou, T.A., et al., Symptom, diagnosis and mortality among respiratory emergency 
medical service patients. PloS one, 2019. 14(2): p. e0213145-e0213145. 
44. 
White, I.R., P. Royston, and A.M. Wood, Multiple imputation using chained equations: 
Issues and guidance for practice. Stat Med, 2011. 30(4): p. 377-99. 
45. 
Zhang, Z., et al., Balance diagnostics after propensity score matching. Ann Transl Med, 
2019. 7(1): p. 16. 
46. 
Harris, P.A., et al., The REDCap consortium: Building an international community of 
software platform partners. Journal of Biomedical Informatics, 2019. 95: p. 103208. 
47. 
Harris, P.A., et al., Research electronic data capture (REDCap)--a metadata-driven 
methodology and workflow process for providing translational research informatics 
support. Journal of biomedical informatics, 2009. 42(2): p. 377-381. 
48. 
EuropeanCommission, REGULATION (EU) 2016/679 OF THE EUROPEAN PARLIAMENT 
AND OF THE COUNCIL of 27 April 2016 on the protection of natural persons with regard 
to the processing of personal data and on the free movement of such data, and 
repealing Directive 95/46/EC (General Data Protection Regulation). 2016. 
49. 
The Danish Parliament, Act on Supplementary Provisions to the Regulation on the 
Protection of Natural Persons with Regard to the Processing of Personal Data and on the 
Free Movement of Such Data (the Data Protection Act)) 2018 (translated from Danish). 
50. 
International Committee of Medical Journal Editors, Recommendations for the Conduct, 
Reporting, Editing, and Publication of Scholarly Work in Medical Journals. 2019. 
51. 
Tyson, J., et al., Stopping guidelines for an effectiveness trial: What should the protocol 
specify? Trials, 2016. 17. 
52. 
Durrington, H.J., et al., Initial oxygen management in patients with an exacerbation of 
chronic obstructive pulmonary disease. Qjm, 2005. 98(7): p. 499-504. 
53. 
Roche, N., et al., Predictors of outcomes in COPD exacerbation cases presenting to the 
emergency department. European Respiratory Journal, 2008. 32(4): p. 953. 
54. 
World Medical Association Declaration of Helsinki: ethical principles for medical research 
involving human subjects. Jama, 2013. 310(20): p. 2191-4. 
55. 
Executive Order BEK no. 1464 of 02/12/2016 on Information and Consent for 
Participation in Health Science Research Projects, and on Notification and Supervision of 
Such Projects. 2016 (translated from Danish). 
56. 
Consolidated Act LBK no. 903 of 26/08/2019 on the Health Act. 2019 (translated from 
Danish). 
57. 
Act amending the Act on Clinical Trials of Medicinal Products, the Act on Ethical Review 
of Health Science Research Projects and Health Data Science Research Projects, and the 
Health Act, Ministry of Health, Editor. 2022 (translated from Danish). 
58. 
Ethics, D.N.C.f., Guidance on decentralised clinical trials. 
59. 
Consolidated Act no. 1113 of 07/11/2011 on Complaints and Compensation Access 
within the Healthcare System. 2011 (translated from Danish). 
60. 
Moher, D., et al., CONSORT 2010 Explanation and Elaboration: updated guidelines for 
reporting parallel group randomised trials. BMJ, 2010. 340: p. c869. 
61. 
Schulz, K.F., D.G. Altman, and D. Moher, CONSORT 2010 Statement: updated 
guidelines for reporting parallel group randomised trials. BMJ, 2010. 340: p. c332. 
 
 
 
 
 
 

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Appendices 
Appendix 1 CONSORT flow diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Suspected AECOPD patients 
assessed for eligibility (n=) 
Excluded (n=) 
 
Not meeting inclusion criteria 
(n=) 
 
Meeting one or more 
exclusion criteria (n=)  
 
Declined to participate (n=) 
 
Other reasons (n=) 
Analysed  (n=) 
 Excluded from analysis (give reasons) (n=) 
Lost to follow-up (give reasons) (n=) 
Discontinued intervention (give reasons) (n=) 
Allocated to titrated oxygen (n=) 
 Received allocated intervention (n=) 
 Did not receive allocated intervention (give 
reasons) (n=) 
Lost to follow-up (give reasons) (n=) 
Discontinued intervention (give reasons) (n=) 
Allocated to standard treatment (n=) 
 Received allocated intervention (n=) 
 Did not receive allocated intervention (give 
reasons) (n=) 
Analysed  (n=) 
 Excluded from analysis (give reasons) (n=) 
Allocation
Analysis
Follow-Up
Randomized (n=) 
Enrollment

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Appendix 2: [Removed from the ClinicalTrials.gov submission version] 
This appendix contained an SOP in Danish and was removed to comply with ClinicalTrials.gov 
language requirements. 
 
Appendix 3: [Removed from the ClinicalTrials.gov submission version] 
This appendix contained a Summary of Product Characteristics (SmPC) for Medical Oxygen in 
Danish and was removed to comply with ClinicalTrials.gov language requirements. 
 
Appendix 4: [Removed from the ClinicalTrials.gov submission version] 
This appendix contained a Summary of Product Characteristics (SmPC) for Compressed 
Atmospheric Air in Danish and was removed to comply with ClinicalTrials.gov language 
requirements. 
 
Appendix 5: [Removed from the ClinicalTrials.gov submission version] 
This appendix contained photos of the ambulance outlet labels (oxygen and atmospheric air). 
The labels were in Danish and have been removed to comply with ClinicalTrials.gov language 
requirements. 
 
Appendix 6: [Removed from the ClinicalTrials.gov submission version] 
This appendix contained a photo of the Medical Oxygen (Air Liquide) cylinder label used in 
ambulances. The label was in Danish and has been removed to comply with ClinicalTrials.gov 
language requirements. 
 
Appendix 7: [Removed from the ClinicalTrials.gov submission version] 
This appendix contained a photo of the Compressed Atmospheric Air (Air Liquide) cylinder label 
used in ambulances. The label was in Danish and has been removed to comply with 
ClinicalTrials.gov language requirements.