Clinical trial NCT04322396
Conditions: Virus Diseases Infection Viral Corona Virus Infection
Sponsor: Chronic Obstructive Pulmonary Disease Trial Network, Denmark
Start date: 2020-04-06; Completion date: 2021-02-02
Enrollment: 117 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study explores whether patients acutely hospitalized may have shorter hospitalization and fewer admittances at Intensive Care Units by treatment with azithromycin and hydroxychloroquine.

Detailed description:
In the ongoing coronavirus pandemic, COVID-19, that arose in Wuhan China, there is still sparse data in the course, risk of various complications, and in particular how patients who are hospitalized are best treated to ensure high survival and short hospitalization. Despite the rapid spread of the disease globally, there is no solid data yet to recommend any specific treatments, which is why symptomatic, organ supportive therapy including respiratory therapy in acute pulmonary failure is recommended. There has been reported a high incidence of bacterial super-infections in patients with COVID-19. Patients with COVID-19 also have a higher risk of dying because of septic shock. Thus, there is an urgent need for treatment that can improve the patient's chance of the shortest hospitalization possible, and treatment that can lower the risk of secondary infection and death.

This is a randomized, placebo-controlled, double-blinded multi-center trial evaluating the effect of azithromycin and hydroxychloroquine treatment in patients with COVID-19 during hospitalization. The aim of the study is to investigate whether the treatment can shorten hospitalization, reduce the risk of non-invasive ventilation, admittance to Intensive Care Units and death.

Arms: arm 1: This arm will receive standard care and placebo in 15 days.

Azithromycin placebo:

Day 1-3: 500 mg x 1 Day 4-15: 250 mg x 1

Hydroxychloroquine placebo:

Day 1-15: 200 mg x 2 arm 2: This arm will receive standard care and azithromycin and hydroxychloroquine in 15 days.

Azithromycin:

Day 1-3: 500 mg x 1 Day 4-15: 250 mg x 1

Hydroxychloroquine:

Day 1-15: 200 mg x 2
Interventions: intervention 1: Azithromycin intervention 2: Hydroxychloroquine intervention 3: Placebo oral tablet intervention 4: Placebo oral tablet
Intervention descriptions: intervention 1: Azithromycin intervention 2: Hydroxychloroquine intervention 3: Placebo Azithromycin intervention 4: Placebo Hydroxychloroquine

Protocol documents:
Prot_000.pdf: 
Proactive Prophylaxis With Azithromycin and Chloroquine in Hospitalised Patients With COVID-19 
(ProPAC-COVID) 
1 
 
 
16APR2020   
 
 
 
 
                       V.1.8  
Study Protocol - Proactive Prophylaxis With Azithromycin and Chloroquine in 
Hospitalised Patients With COVID-19 (ProPAC-COVID) 
A Randomised, Good-Clinical-Practice-monitored, Placebo-controlled, double-blinded study to 
clarify whether hospital length and risk of intensive care stay may be reduced in hospitalized 
patients who have COVID-19 treated with azithromycin and hydroxychloroquine for 15 days 
after inclusion. 
Organisation: COP:TRIN – Chronic Obstructive Pulmonary Disease Trial Network: 
www.coptrin.dk  
Authors: 
Pradeesh Sivapalan1,2, Charlotte Suppli Ulrik3, Rasmus Dahlin Bojesen4, Therese Sophie Lapperre5, Josefin 
Viktoria Eklöf1, Kjell Erik Julius Håkansson3, Andrea Browatzki6, Casper Tidemandsen3, Jon Torgny Wilcke1, 
Julie Janner3, Vibeke Gottlieb1, Howraman Meteran1, Celeste Porsbjerg5, Birgitte Lindegård Madsen6, Mia 
Moberg3, Lars Pedersen5, Thomas Lars Benfield7, Jens Dilling Lundgren8, Filip Krag Knop9, Tor Biering-
Sørensen10, Muzhda Ghanizada5, Tine Peick Sonne1, Uffe Christian Steinholtz Bødtger2, 11, 12, Sidse Graff 
Jensen1, Daniel Bech Rasmussen11, Eva Brøndum3, Oliver Djurhuus Tupper3, Susanne Wiemann Sørensen3, 
Gitte Alstrup11, Christian Borbjerg Laursen13, Ulla Møller Weinreich14, Asger Sverrild5, Jens-Ulrik Stæhr 
Jensen1 (corresponding) 
1Section of Respiratory Medicine, Dep. of Medicine, Herlev and Gentofte Hospital University of 
Copenhagen, Hellerup, DK  
2Dep. of Internal Medicine, Zealand University Hospital, Roskilde, DK 
3Dep. of Respiratory Medicine, Amager and Hvidovre Hospital University of Copenhagen, Hvidovre, DK 
4Dep. of Surgery, Næstved-Slagelse-Ringsted Hospitals University of Southern Denmark, Slagelse, DK 
5Dep. of Respiratory Medicine, Bispebjerg and Frederiksberg Hospital University of Copenhagen, 
Copenhagen, DK 
6Dep. of Respiratory and Infectious Diseases, Nordsjællands Hospital University of Copenhagen, Hillerød, DK 
7Dep. of Infectious Diseases, Amager and Hvidovre Hospital University of Copenhagen, Hvidovre, DK 
8Dep. of Infectious Diseases, Rigshospitalet University of Copenhagen, Copenhagen, DK 
9Dep. of Clinical Metabolic Research, Herlev and Gentofte Hospital University of Copenhagen, Hellerup, DK 
10Dep. of Cardiology, Herlev and Gentofte Hospital University of Copenhagen, Hellerup, DK 
11Dep. of Respiratory Medicine, Næstved-Slagelse-Ringsted Hospitals University of Southern Denmark, 
Slagelse, DK 
12Institute for Regional Health Research University of Southern Denmark, Odense, DK 
13Dep. of Respiratory Medicine, Odense University Hospital University of Southern Denmark, Odense, DK 
14Dep. of Respiratory Medicine, Aalborg University Hospital University of Aalborg, Aalborg, DK 
This study is part of the Danish national non-commercial lung research network COP:TRIN 
(www.coptrin.dk) and is conducted as a randomised controlled trial. 
Supplemental Appendix 1


Proactive Prophylaxis With Azithromycin and Chloroquine in Hospitalised Patients With COVID-19 
(ProPAC-COVID) 
2 
 
Hypothesis: 
→ In patients with urgent hospital admission and a positive test SARS-CoV-2 treatment with 
hydroxychloroquine azithromycin leads to shorter hospitalisation and fewer admissions to the 
intensive care unit. 
EUdraCT-no.: 2020-001198-55 
ClinicalTrials.gov Identifier: NCT04322396 
The Danish Medicines Agency case no.: 2020033414  
The Danish National Committee on Health Research Ethics approval no.: H-20022574 
The Danish Data Protection Agency journal no.: P-2020-258  
 
Principal investigator / Study director and scientific sponsor: 
 
                           
Research Associate Professor, Research Manager, Jens-Ulrik Stæhr Jensen, MD, PhD.                   
Research Unit, Pulmonary Medicine Section, Gentofte Hospital, Kildegårdsvej 28, 2900 Hellerup, 
Tel: 38 67 30 57 + 28 93 81 68. Email: jens.ulrik.jensen@regionh.dk 
Research Centres: 
1. Pulmonary medicine section, Gentofte hospital, Kildegårdsvej 28, 2900 Hellerup 
Primary investigator: Jens-Ulrik Stæhr Jensen. 
Other investigators: Associate Professor, Senior Consultant Saher Shaker, Associate Professor, 
Senior Consultant Torgny Wilcke, Senior Consultant Karin Armbruster, Postdoc Pradeesh Sivapalan 
MD, PhD, PhD student Josefin Eklöf, MD, Howraman Meteran, MD, PhD, Chief physician Mette 
Vang Larsen, Chief physician Sidse Graff Jensen, PhD. 
2. Pulmonary Medicine Department, Hvidovre Hospital, Kettegaard alle 30, Hvidovre                    
Primary Investigator: Professor Charlotte Suppli Ulrik  
 
                                
Other investigators: Chief physician Julie Janner, Mia Moberg, MD, PhD,  PhD student Kjell 
Håkansson, MD. 
3. Pulmonary Medicine Section, Herlev Hospital, Herlev Ringvej, Herlev                                             
Primary Investigator: Professor Peter Lange 
 
 
                               
Other investigators:  Hans Henrik Lawaetz-Schultz, MD, PhD, Chief physician Vibeke Gottlieb, Chief 
physician, Christian Søborg, PhD, Chief Physician Pernille Ravn, PhD. 
4. Pulmonary and infectious medicine department, North Zealand Hospital, Dyrehavevej 29, 3400 
Hillerød 
 
 
 
 
 
                            
Primary Investigator: Chief physician Andrea Browatzki 
 
                        
Other investigators: Chief physician Birgitte Lindegaard Madsen, DMSc, Chief physician Zitta 
Barrella Harboe, PhD, Senior Consultant Thyge Lynghøj Nielsen, PhD. 


Proactive Prophylaxis With Azithromycin and Chloroquine in Hospitalised Patients With COVID-19 
(ProPAC-COVID) 
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5. Pulmonary Medicine Department, Aalborg Hospital, Hobrovej 18 -22, 9000 Aalborg                  
Primary investigator: Associate Professor, consultant, PhD, Ulla Møller Weinreich                                  
Other investigators: PhD student Peter Ascanius Jakobsen, PhD student Mia Solholt Godthaab 
Brath. 
6. Pulmonary Medicine Section, Medical Department, Roskilde Hospital, Roskilde                    
Primary investigator: Chief physician, PhD, Christian Niels Meyer    
                    
Coordinating Investigator: post doc, , Pradeesh Sivapalan 
7. Pulmonary Medicine Department, Bispebjerg Hospital, Bispebjerg Bakke 23, 2400 Copenhagen 
Primary investigator: Research Associate Professor, Chief Physician, PhD, Therese Lapperre 
8. Medical Department,Næstved-Slagelse-Ringsted Hospital  
 
 
                     
Primary investigator: Consultant in Pulmonology, PhD, associate research professor (University of 
Southern Denmark)Uffe Bødtger. 
9. Medical department, Odense University Hospital Primary investigator: Research Associate 
Professor, Chief Physician, PhD. Christian B. Laursen Investigator: Professor, Chief Physician, DMSc, 
Isik Somuncu Johansen 
Other participants (not experimental centres) 
1. Infectious Medicine Department, Rigshospitalet, Blegdamsvej, Copenhagen Ø.                   
Primary Investigator: Professor Jens D. Lundgren 
2. Intensive Treatment Section 41.31, Rigshospitalet, Blegdamsvej, Copenhagen Ø. Professor, Chief 
Physician, Anders Perner, DMSc 
3. Center for Rheumatology and Spine diseases, Rigshospitalet, Blegdamsvej, Copenhagen Ø. 
Professor, Chief Physician, Søren Jacobsen, DMSc 
4. Intensive care unit, Gentofte Hospital, Niels Andersen road 65, 2900 Hellerup.  
  
Head of Section, Thomas Mohr, Ph.D. 
5. Intensive therapy section, NOH, Hillerød, Helsevej 2, 3400 Hillerød Research Associate 
Professor, Morten Bestle, Ph.D. 
6. Cardiology department, Herlev-Gentofte Hospital, Niels Andersens Vej 65, 2900 Hellerup 
Associate Professor Tor Biering-Sørensen Ph.D. 
7. Clinical pharmacology department, Bispebjerg Hospital, Bispebjerg Bakke 23, 2400 Copenhagen 
Associate Professor, Doctor, Ph.D. Tonny Studsgaard Petersen 
8. Cardiac Catherization Laboratory 20.14, Heart Center, Rigshospitalet, Blegdamsvej, Copenhagen 
Ø Professor, Jens Kastrup, DMSc 
GCP monitoring: 


Proactive Prophylaxis With Azithromycin and Chloroquine in Hospitalised Patients With COVID-19 
(ProPAC-COVID) 
4 
 
The GCP units by GCP coordinator Kristina Devantier 
COP:TRIN, Steering Committee: Please see: http://coptrin.dk/steering-committee-members/  
 
Background information on the medication used in this trial: 
Azithromycin 
Categorized as an antibacterial agent. The drug is an approved, and marketed in Denmark, for 
treatment of upper and lower respiratory tract infection. Azithromycin is also, according to 
available evidence and current guidelines, used for treatment of asthma, COPD and bronchiectasis 
in order to improve disease control and reduce exacerbation rate. Please see enclosed product 
summaries for further information. 
Hydroxychloroquine: 
Categorized as an anti-inflammatory and anti-malaria agent.  
The drug is approved and marketed in Denmark for the prevention and treatment of malaria, for 
the treatment of rheumatoid arthritis, discoid and systemic lupus erythematosus and juvenile 
idiopathic arthritis. 
Manufacturing, packaging and labelling of IMP: 
The trial drugs (IMP) are manufactured by Glostrup pharmacy by pharmacist Kristian Østergaard 
Nielsen. Placebo capsules are thus made similar to the intervention medicine. The drug (and 
Placebo) are labelled, according to Appendix 13. Glostrup pharmacy has a key for blinding. 
Therefore, it will always be possible to unblind a patient if indicated. Investigator must notify 
sponsor on grounds if a patient is unblinded. 
Medical professionals dispense the IMP daily during hospitalization, except for patients preferring 
to handle their medication themselves. In the latter case, patient will fill in a medication diary 
(provided at randomisation). For all patients who are discharged during the intervention period, a 
medication diary will be provided. The medication diary is subsequently collected.  
Exactly the amount of medication or placebo that the patient is required to take during the study 
periode will be provided, but for patients who do not take all the medication (protocol deviation), 
the remaining medication will be collected by the study staff. The patient will receive a follow-up 
phone call to check whether they have adhered to the medication schedule according to the trial 
protocol. 
 
 


Proactive Prophylaxis With Azithromycin and Chloroquine in Hospitalised Patients With COVID-19 
(ProPAC-COVID) 
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1. Hypothesis and aims: 
1.1 Hypothesis: 
In patients with acute hospital admission, a positive test for 2019-nCoV and symptoms of COVID-
19 disease, treatment with virus-modifying agent hydroxychloroquine as well as virus-
immunomodulatory and antibacterial drug azithromycin can lead to shorter hospitalisation and 
fewer admissions to the intensive care unit. 
1.2 Aims: 
The aim of this randomised GCP-controlled trial is to clarify whether combination therapy with 
macrolide azithromycin and hydroxychloroquine via anti-inflammation/immune modulation, 
antiviral efficacy and pre-emptive treatment of supra-infections can shorten hospitalisation 
duration (measured as "days alive and out of hospital"as the primary outcome), reduce the risk of 
non-invasive ventilation, treatment in the intensive care unit and death. 
 
2. Background and scientific perspective: 
2.1 Background - rationale 
Coronavirus - COVID-19 
In the ongoing coronavirus pandemic, COVID-19, with its origin in Wuhan, China, there is still 
sparse data on the course, risk of various complications, and the best possible treatment of 
patients admitted to hospital to ensure best possible survival and reducing length of stay at 
hospital. The most frequent symptoms are fever (> 80%) and cough (70-80%), together with 
radiologically fingdings of "ground-glass infiltrates" or "patchy infiltrates" in the patients with the 
most severy ill patients (86%), compatible with severe viral pneumonitis (1, 2). The length of 
hospitalisation is observed to be relatively long, 10-15 days (3), which in itself is a problem as 
hospitals can quickly reach the maximum capacity for hospitalisation and the proportion of 
patients who become critically ill have, based on the observations reported so far, had a mortality 
rate of> 60% (4), and overall mortality for admitted patients in China with COVID-19 infection is 
apparently unusually high for viral respiratory tract infections with an estimate of 25% (2). 
COVID-19 and lung disease 
Only specific data on patients with Chronic Obstructive Pulmonary Disease (COPD) have been 
reported in a few studies, but the risk of in-hospital death appears to be very high (OR 5.4 [95% CI 
0.96-30.40]) (2). 
Lack of specific treatment 


Proactive Prophylaxis With Azithromycin and Chloroquine in Hospitalised Patients With COVID-19 
(ProPAC-COVID) 
6 
 
Despite the rapid spread of the disease globally, there is no solid data yet to recommend any 
specific treatments, and by that, symptomatic, organ supportive therapy is recommended, and in 
case of progression to severe acute respiratory failure mechanical ventilation (5). A high incidence 
of bacterial super-infections has been reported in patients with COVID-19 who died (50%) 
compared to survivors (1%) (p <0.0001), and likewise, an incidence of septic shock of 70% and 0%, 
respectively (2). Thus, there is an urgent need for treatments that can improve the course of the 
diseases in the individual patients, including positive impact on risk for hospital admission, 
duration of hospitalisation, risk of secondary infections and death. 
Macrolide azithromycin as a possible treatment for patients with COVID-19 
Azithromycin is a macrolide antibiotic that has shown convincing efficacy in several studies in 
recent years to reduce hospitalisation-related exacerbations in COPD (6, 7), and to reduce 
exacerbationrate in asthma (8) and non-cystic fibrosis bronchiectasis (9). At the same time, it has 
been shown that azithromycin has a distinct effect by down-regulating airway inflammation by 
reducing CXCL1, TNF-alpha, IL-13 and IL-12p40 (10). Furthermore, a strong association has also 
been reported between survival from Acute Respiratory Distress Syndrome (ARDS) and 
administration of azithromycin (HR for 90 days of death for all causes: 0.49 [95% CI 0.27 - 0.87] in a 
well-conducted study (11). 
Furthermore, it has been consistently observed in several recent publications that azithromycin 
itself appears to have an antiviral effect on a number of several viruses causing respiratory tract 
infections, such as Respiratory Syncytial Virus (RSV) (12), Rhinovirus (13) and Zika virus (14). 
Hydroxychloroquine as immunomodulatory and antiviral agent by COVID-19 
Hydroxychloroquine has been marketed since 1934, originally developed for prophylaxis and 
treatment of malaria, but has for years also been used an anti-inflammatory agent for rheumatic 
diseases. Large daily doses (up to 400 mg a day) of hydroxychloroquine are prescribed over many 
years to patients with arthritis such as systemic lupus erythematosus and rheumatoid arthritis for 
anti-inflammatory purposes, which is generally well-tolerated (16). but in addition to these effects, 
it is well described that the drug has an antiviral effect especially against flavivirus, retrovirus and 
coronavirus by inhibiting a number of low-pH-dependent steps in virus replication, as well as by 
inhibiting the pH-dependent endosomal mediated viral uptake in cells (15). The drug is well 
tolerated even with high dosage, for up to five years and there is no signal for birth defects with 
usage of the drug summarised by Savarino et al. (15).  
Cell studies with primate cells infected with the coronavirus that induced SARS-1 (formerly called 
SARS) have shown that chloroquine, in a dose-dependent manner, inhibits the ability of the 
corona virus to infect cells and to spread among cells (17). Thus, several researchers and health 
care professionals have, during the present SARS-CoV-2 pandemic, have proposed studies 
examining hydroxychloroquine/chloroquine as treatment for patients with COVID-19 disease (18, 
19). 


Proactive Prophylaxis With Azithromycin and Chloroquine in Hospitalised Patients With COVID-19 
(ProPAC-COVID) 
7 
 
2.2 Scientific perspective for this study 
The study will clarify whether treatment with azithromycin in combination with 
hydroxychloroquine for 15 days from the time of hospital admission with diagnosed COVID-19 
disease may reduce the length of hospitalisation, the risk of admission to the intensive care unit, 
treatment with non-invasive ventilation and death. The study will also clarify whether this 
treatment can reduce the need for oxygen supplementation (time for breathing on its own 
without oxygen supplementation) or for regular Long-Term Oxygen Therapy oxygen 
supplementation ("home oxygen"). 
If the treatment also improves the course of COVID-19 disease in patients with pre-existing lung 
disease, a very large number of patients could benefit from the treatment immediately. 
The study originates from the Danish national non-commercial lung research network COP:TRIN 
(Chronic Obstructive Pulmonary Disease: Trial Network). 
 
3. Method: 
3.1 Design: 
Randomised, Good-Clinical-Practice-monitored, placebo-controlled, double-blind study. 
3.2. Recruitment and inclusion: 
See point 12. 
3.3 Inclusion: 
Inclusion criteria: 
• Patient admitted to Danish emergency departments, respiratory medicine departments or 
internal medicine departments 
• Age≥ 18 years 
• Hospitalized ≤48 hours 
• Positive SARS-CoV-2 test / diagnosis during the hospitalization (confirmed). 
• Men or non-fertile women. Fertile women* must not be pregnant, i.e. negative pregnancy test 
must be available at inclusion 
• Informed consent signed 
*Defined as after menarche and until postmenopausal (no menstruation for 12 months) 
Exclusion criteria: 
• At the time of recruitment, the patient uses >5 LO2/min (equivalent to 40% FiO2 if measured) 
• Known intolerance/allergy to azithromycin or hydroxychloroquine or hypersensitivity to quinine 
or 4-aminoquinoline derivatives 


Proactive Prophylaxis With Azithromycin and Chloroquine in Hospitalised Patients With COVID-19 
(ProPAC-COVID) 
8 
 
• Neurogenic hearing loss 
• Psoriasis 
• Retinopathy 
• Maculopathy 
• Visual field changes 
• Breastfeeding 
• Severe liver diseases other than amoebiasis (spontaneous INR > 1.5) 
• Severe gastrointestinal, neurological and hematological disorders (investigator-assessed) 
• eGFR <45 ml/min/1.73 m2 
• Clinically significant cardiac conduction disorders/arrhythmias or prolonged QTc interval (QTc (f) 
of> 480/470 ms). 
• Myasthenia gravis 
• Treatment with digoxin* 
• Glucose-6-phosphate dehydrogenase deficiency 
• Porphyria 
• Hypoglycaemia (Blood glucose at any time since hospitalization of <3.0 mmol/L) 
• Severe mental illness which significantly impedes cooperation 
• Severe linguistic problems that significantly hinder cooperation 
• Treatment with ergot alkaloids 
*The patient must not be treated with digoxin for the duration of the intervention. For atrial 
fibrillation/flutter, select according to the Cardiovascular National Treatment Guide (NBV): 
Calcium antagonist, Beta blocker, direct current (DC) conversion or amiodarone. In case of urgent 
need for digoxin treatment (contraindication for the aforementioned equal alternatives), the test 
drug should be paused, and ECG should be recorded daily. 
 
Drug Interactions 
Interactions should be taken into account if the patient is taking other medications. For 
azithromycin, this includes antacids, ergotamine derivatives, colchicine and cyclosporine. For 
hydroxychloroquine, these include antidiabetic agents, tricyclic antidepressants, antipsychotics, 
halofantrine, cyclosporine, mefloquine, antiepileptic drugs, praziquantel and agalsidase. 
Standard Treatment 
As there is no specific treatment for COVID-19, standard assessment and treatment is based on 
organ supportive therapy such as oxygen therapy (central), fluid therapy, antibiotic therapy for 
secondary infections. If the disease progress to severe acute respiratory failure, the patients will 
often require referral to an intensive care unit for mechanical ventilation. 


Proactive Prophylaxis With Azithromycin and Chloroquine in Hospitalised Patients With COVID-19 
(ProPAC-COVID) 
9 
 
In addition, Danish national guidelines for handling of in-hospital Covid-19 patients can be 
obtained from  www.lungemedicin.dk or from the open access journal European Respiratory 
Clinical Journal (at present in press). 
3.3.2. Allocation: 
The sponsor generates a randomisation sequence. Randomisation will be in blocks of unknown 
size and the final allocation will be via an encrypted website (REDCap), where also inclusion and 
exclusion criteria are required to be filled in correctly in order to randomise a patient. 
Allocation will be stratified for age (>70 years vs. <=70 years), site of recruitment and whether the 
patient has any of the following chronic lung diseases: COPD, asthma, bronchiectasis, interstitial 
lung disease (Yes vs. No). 
3.3.3. Data collection, surveys and follow-up: 
The primary daily project management is carried out by the project manager. In addition, a project 
group (investigators), consisting of doctors from the departments involved, is trained to assist the 
project manager with the recruitment, sampling and follow-up of patients. All medical decisions 
regarding patients will be taken by a physician. Data is collected in Case Report Forms (CRF) for 
each individual patient. 
Prior to consent to participate in the trial, we will only assess the specific information needed to 
assess inclusion and exclusion criteria. No other information will be accessed. 
It is the attending physician who asks if patients are interested in hearing more about the trial. If 
yes, an investigator is contacted, who will inform the patient about the trial. 
As part of the study, all patients will be regularly monitored for oxygen saturation, heart rate, 
blood pressure, respiratory rate and temperature during hospitalisation. 
The following information will also be obtained: 
• Date of birth, age and gender 
• Height, weight and BMI 
• Use of medicine 
• For patients with chronic obstructive pulmonary disease (COPD) classification in GOLD 1-4 and 
GOLD A-D (symptoms assessed via MRC degree) 
• Systematic screening for co-morbidities 
• Smoking history with pack years, current smoking status and alcohol consumption 
• Information from the chest x-ray 
• Arterial-blood gas analysis (pH, pCO2, pO2, Base Excess, oxygen supplementation) 
• Hb, leucocytes + differential count, CRP, kidney function, liver parameters, electrolytes, LDH 
• ECG, vital status, and adverse events 
And from the patients’ medical journal: 


Proactive Prophylaxis With Azithromycin and Chloroquine in Hospitalised Patients With COVID-19 
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10 
 
• CT thorax 
• Home oxygen supplementation and dosage 
• Home NIV, acute NIV and respirator therapy 
• Re-admission 
• Prescribed medication 
All this information is passed on to the investigator. The information from the medical records is 
required to calculate demographic data, medication data and outcomes in the trial. No 
information that is not required according to the protocol will be obtained. Case Report Form is 
archived at the departments involved for 15 years. A separate database is created in REDCap 
(www.projectredcap.org) for data management. 
Table 1 (SPIRIT Figure): Overview of examinations that each participant will undergo: 
 
STUDY PERIOD 
 
Enrolment 
Allocation 
Post-allocation (days) 
Timepoint 
-24 hours 
1 
2-3 
  4 
5 to 
discharge 
15 
ENROLMENT: 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
Eligibility screening 
X 
 
 
 
 
 
Allocation 
 
X 
 
 
 
 
INTERVENTION: 
 
 
 
 
 
 
Group 0: Placebo treatment 
 
 
 
 
 
 
Group 1: Azithromycin 
/hydroxychloroquine 
treatment 
 
 
 
 
 
 
EXAMINATIONS: 
 
 
 
 
 
 
Blood sample* 
 
X 
X 
X 
X 
 
Pregnancy test (only fertile 
women) 
 
X 
 
 
 
 
Arterial blood gas 
 
X 
 
X 
 
 
ECG** 
 
X 
X*** 
X 
X 
 
MRC score + GOLD**** 
 
X 
 
 
 
 
Body mass index (BMI) 
 
X 
 
 
 
 
Oxygen supplementation 
(L/min) (open) 
 
X 
X 
X 
X 
 
FiO2 (%) (respirator) 
 
N/A 
X 
X 
X 
 
Chest x-ray 
 
During hospital admission 


Proactive Prophylaxis With Azithromycin and Chloroquine in Hospitalised Patients With COVID-19 
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*The blood samples include haemoglobin (Hb), leukocytes + differential count, thrombocytes, C-
reactive protein (CRP), Na+, K+, albumin, creatinine, urea, amylase, alkalic phosphatase, beta-2-
Microglubulin, fibrinogen, glucose, TSH, INR, billirubin, D-dimer, APTT, calcium, triglycerides, 
ferritin and lactate dehydrogenase (LDH). These blood tests will also be recommended daily for 
COVID patients outside studies in the recommendation of the Danish lung medicine association. 
**When screening for the study, any ECG from within the last 3 days can be used. ***A follow-up 
ECG can be recorded during any remaining days of the hospital admission. ****Only in patients 
with COPD. 
3.3.4 Intervention 
Neither patients nor study staff will know which group the patient is allocated to. The medicine 
will be marked neutral, e.g. "Azithromycin group A" and "Azithromycin group B" and the same for 
Hydroxychloroquine. 
NOTE: If the patient is receiving azithromycin prophylaxis, common practice is followed: the 
prophylaxis is paused and then restarted as usual. 
Control group: 
The control group will receive the standard treatment + placebo for both types of intervention 
IMP at all times. If part or all the intervention therapy being investigated becomes standard 
treatment during the study, this may also be offered to the control group. 
Intervention group: 
 
The patients in the intervention group will also receive standard care. Immediately after 
randomisation to the intervention group, the patient will begin treatment with : 
Azithromycin: 
Day 1-3: 500 mg x 1 
Day 4-15: 250 mg x 1 
If the patient is unable to take the medication orally by themselves, the medication will, if 
possible, be administered by either stomach-probe, or alternatively, temporary be changed to 
clarithromycin 500 mg x 2 (this only in agreement with either study coordinator Pradeesh 
Sivapalan or principal investigator Jens-Ulrik Stæhr Jensen). This will also be done in the control 
group if necessary. The patient will switch back to azithromycin when possible. 
Hydroxychloroquine: 
Furthermore, the patient will be treated with hydroxychloroquine as follows: 
Day 1-15: 200 mg x 2 


Proactive Prophylaxis With Azithromycin and Chloroquine in Hospitalised Patients With COVID-19 
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12 
 
Follow-up is done on days 14, 29, 90 and 365 days, by accessing the electronic medical record 
system. The specific information obtained, and its purpose can be found in section 3.3.3. 
 
Regarding dosage 
The Summary of Product Characteristics for Azithromycin suggests 500mg/day for three days or 
500mg/day for one day and then 250mg daily for four days. However, other clinical studies have 
found a positive effect of a daily dose of 250 mg for prolonged periods as prophylactic treatment. 
Mortality among hospitalised patients with COVID-19 is quite high and the median time for 
hospitalisation is 10-15 days, so it seems reasonable to give patients prophylactic dose for 12 days. 
The dosing of hydroxychloroquine follows the summary of product characteristics. 
Regarding other treatment with antibiotics: 
If antibiotic therapy is deemed indicated to the patient due to e.g. pneumonia or if it becomes 
standard therapy, piperacillin-tazobactam should be given as an empirical treatment at a dose 
adjusted to renal function. In case of penicillin allergy, cefuroxime is also given at a dose 
appropriate to renal function, weight and age. When positive microbiology is available, 
immediately switch to targeted treatment. 
If specific suspicion of atypical pneumonia is raised, ciprofloxacin is administered at a dose of 
corresponding to kidney function and concomitant examination for atypical pneumonia will be 
performed. If negative, ciprofloxacin is discontinued. If positive, ciprofloxacin treatment is 
continued for the duration of treatment corresponding to the microorganism detected. If there is 
a specific need for treatment with macrolide and where other options are not available (e.g. 
allergy to fluoroquinolones, or when there is an estimated need for combination treatment of e.g. 
legionella pneumonia), consult with an investigator, and in this case it may be decided to 
discontinue azithromycin (active) or azithromycin placebo. In this case, treatment stops without 
unblinding. 
Furthermore, ECG recordings during the treatment period will be analysed with focus on QTc. At 
QTc (F)> 480/470 ms for respectively women and men, IMP will be discontinued for safety reasons 
(but the patient remains in the study). 
3.3.5. Statistical analyses: 
Primary endpoint: 
• Number of days alive and discharged from hospital within 14 days (summarises both whether 
the patient is alive and discharged from hospital) ("Days alive and out of hospital") 
Secondary endpoints: 


Proactive Prophylaxis With Azithromycin and Chloroquine in Hospitalised Patients With COVID-19 
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Secondary endpoint no. 1: 
Ordinate outcome. The patient is categorized into one of the following 8 categories on day 15: 
1. Dead 
2. Hospitalised and mechanical ventilation or ExtraCorporalMembraneOxygenation (ECMO) 
3. Hospitalised and Non-invasive ventilation or high-flow oxygen device 
4. Hospitalised and given oxygen supplements that do not live up to oxygen supplements in 
(2) or (3) - e.g. oxygen on nasal catheter 
5. Hospitalised and do not receive oxygen supplementation but need treatment (COVID-19 
related or other) 
6. Hospitalised and do not receive oxygen supplements and do not need treatment (just 
observed) 
7. Discharged with restriction on activities, may be free of oxygen depletion or use LTOT 
("home oxygen") 
8. Discharged, no restrictions on activities 
Other secondary endpoints: 
• Admitted to the intensive care unit in the two groups (0 vs. 1) during the index admission 
o For patients admitted to intensive care unit: number of days on intensive care 
(Length of stay, ICU) 
• Have been on Non-Invasive Ventilation (NIV) (0 vs. 1) during index hospitalisation 
• Dead at day 30 
• Duration (days) of index hospital admission 
• Days alive and discharged from hospital within 30 days (summarises both whether the patient is 
alive and discharged from hospital) 
• Dead at day 90 (reported later) 
• Dead within 12 months (reported later) 
• Number of readmissions for all causes within 30 days 
• Number of days on NIV or mechanical ventilation during index admission 
• Delta PaO2 day 1 (baseline) to day 4 (72 hours). At the same time oxygen supplements and 
oxygen systems are registered 
• Delta PaCO2 day 1 (baseline) to day 4 (72 hours) 
• pH day 4 (72 hours) 


Proactive Prophylaxis With Azithromycin and Chloroquine in Hospitalised Patients With COVID-19 
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• Time to no oxygen supplement (or regular LTOT oxygen supplement) 
In addition, several explorative endpoints. 
Data is processed and analysed in SAS v.9.4 and graphs are generated in Microsoft Excel and 
SigmaPlot. 
3.3.6. Sample size: 
Randomised controlled study 
Prerequisite: Type 1 error rate = 5%. Power = 80%. Two-sided statistics. Group sequential design 
with one scheduled interim analysis after randomisation of 113 patients (50% recruitment). 
Analysis: T-test. 
Sample size is calculated based on the following estimates and indicative figures: 
Expected duration of hospitalisation with COVID-19: 10 days 
SD for "Days alive and discharged within 14 days" in patients with lung disease and COVID-19: 4 
days (up to 10 days hospitalization) 
Estimated time for improvement/deterioration: 1.5 days. 
This requires 226 patients randomised 1:1 with 113 in each group. This is a fixed sample size. It is 
assumed that most patients complete the intervention. 
However, for interim analysis, the Data and Safety Monitoring Board (DSMB) may recommend the 
steering committee to expand sample size. 
3.3.7 GCP Monitoring: 
Frequency and depth are determined by the GCP units. Initiation visits and the first monitoring 
visits to all centres will be conducted off-site, i.e. without a physical meeting, due to the SARS-CoV-
2 pandemic. Consent sheets will be scanned into an online system (REDCap or journal system) that 
can be accessed by GCP monitors. 
 
4. Interim Analysis and Data and Safety Monitoring Board 
After recruiting half the sample size (approximately 113 patients), an interim analysis will be 
performed focusing on safety. An external Data and Safety Monitoring Board is appointed. 
The interim analysis will be prepared and presented by physician Josefin Eklöf. The groups will be 
presented as "Group A" and "Group B" and DSMB will only be unblinded if they ask the steering 
committee for the study on this. 


Proactive Prophylaxis With Azithromycin and Chloroquine in Hospitalised Patients With COVID-19 
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5. Blood samples: 
As part of ususal care, blood samples are taken daily from the time of inclusion and as long as the 
patient is admitted. Blood samples include haemoglobin (Hb), leukocytes + differential count, 
thrombocytes, C-reactive protein (CRP), Na+, K+, albumin, creatinine, urea, amylase, alkalic 
phosphatase, beta-2-Microglobulin, fibrinogen, glucose, TSH, D-dimer, APTT, calcium, triglycerides, 
ferritin, bilirubin, ALAT, INR, and lactate dehydrogenase (LDH), see Table 1. These blood samples 
are analysed at the hospitals. 
In addition, supplemental blood tests and material obtained with nasal swaps will be performed 
according to the sub-study protocols. Material from this will be included in a research biobank for 
the trial, and after completion of the trial in another regional biobank. The trial is expected to end 
in February 2021, and the material will then be transferred to the regional biobank. 
For the present trial, the results of blood tests are collected from the patient record. 
 
6. Side effects, risks and disadvantages: 
The treating physician may at any time discontinue intervention with IMP if, in clinical and/or 
paraclinical assessment, it is deemed contraindicated. 
Blood tests: 
Serious side effects to regular blood sampling (venous puncture) are rare. Frequent (5-15%) can be 
seen transient discoloration of skin around the insertion site.  
X-ray: 
Chest X-rays correspond to a radiation dose of approx. 0.1 millisievert (mSv). This should be 
compared with the average background radiation in Denmark of approx. 3 mSv per year. There are 
no documented adverse effects of the radiation dose received by Chest X-rays in the literature. 
Therefore, we believe that the study is not associated with any risks or side effects. 
Side effects of the trial medicine: 
See www.medicin.dk 
Azithromycin: 
Very common (>10%) Abdominal pain, Diarrhoea, Flatulence, Nausea. 


Proactive Prophylaxis With Azithromycin and Chloroquine in Hospitalised Patients With COVID-19 
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Common (1-10%) Powerlessness, Decreased appetite. Vomiting, Taste Disorders. Decreased 
lymphocyte count. Decreased serum bicarbonate. Arthralgia. Headaches, Paraesthesia, Dizziness. 
Skin itching, rash. Visual disturbances. 
Uncommon (0.1-1%) Pain. Hepatitis, Oral candidiasis. Dyspnea, Pneumonia, Oedema. Eosinophilia, 
Leukopenia, Neutropenia. Elevated serum bicarbonate, Hyperchloremia, Hyperglycaemia, 
Hyperkalaemia, Hypernatremia, Hypokalaemia, Hyponatraemia. Arthritis, Back Pain. Nervousness, 
Somnolence. Facial oedema, Dermatitis, Photosensitivity. Candidiasis, Infections. Metrorrhagia, 
Kidney Pain, Testicular Disease, Vaginitis. Hearing loss, Tinnitus. 
Rare (0.01-0.1%) Cholestasis, Liver Impact. Agitation. Acute generalized exanthematous 
pustulosis*, Allergic reactions*, Angioedema*, Hypersensitivity. 
Not known  Fulminant hepatitis, Hepatotoxicity, Hepatic insufficiency, Pancreatitis, 
Pseudomembranous colitis. Arrhythmias, Extended QT interval, Hypotension, Torsades de pointes 
tachycardia. Haemolytic anaemia, Thrombocytopenia. Aggravated myasthenia gravis. 
Aggressiveness, Anxiety, Delirium, Hallucinations, Hyperactivity, Hypesthesia, Seizures, Syncope. 
DRESS - drug reaction with eosinophilia and systemic symptoms, Erythema multiforme, Stevens-
Johnson syndrome, Toxic epidermal necrolysis. Anaphylactic reaction. Acute renal failure, 
Interstitial nephritis. 
*In case of allergic reactions, including acute generalized exanthematous pustulosis and DRESS, 
azithromycin should be discontinued. 
Hydroxychloroquine: 
Very common (> 10%) Abdominal pain, Nausea. 
Common (1-10%) Eating refusals. Diarrhoea, Vomiting. Emotional lability, Headaches. Skin itching, 
rash. Accommodation difficulty. 
Uncommon (0.1-1%) Liver effect. Nervousness, Sensomotor disorders, Dizziness. Alopecia. Corneal 
oedema, Double vision, Retinopathy *, Tinnitus. 
Not known Fulminant liver failure. Bronchospasm, prolonged QT interval**, Cardiomyopathy. 
Aplastic Anaemia, Bone Marrow Depression, Influence of the Blood Image (agranulocytosis, 
anaemia, leukocytopenia, thrombocytopenia). Aggravation of Porphyria, Hypoglycaemia. 
Myopathy. Extrapyramidal genes, Cramps, Neuropathy, Palsy, Psychosis, Suicidal behaviour. Acute 
generalized exanthematous pustulosis***, Exfoliative dermatitis, Erythema multiforme, 
Photosensitivity, Stevens-Johnson syndrome, Toxic epidermal necrolysis. Allergic reactions 
(including DRESS syndrome), Angioedema. Hearing loss, Macular and retinal degeneration, 
Maculopathy. 
*Retinopathy: 


Proactive Prophylaxis With Azithromycin and Chloroquine in Hospitalised Patients With COVID-19 
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• With pigment change requires careful dosing and careful control. When using 
rheumatologic doses, eye examination by an ophthalmologist is recommended before 
starting treatment and with follow-up to check for any eye manifestations that may arise. 
Annual monitoring after 5 years of treatment is recommended, however in risk patients 
initially annual control, see also Chloroquine derivatives (inflammatory rheumatic 
diseases), side effects. 
• With cardiomyopathy can be fatal. 
• With macular degeneration is seen and may be irreversible. 
• With reversible corneal changes with oedema and blemishes can cause blurred vision or 
photophobia. 
• With blurred vision accommodation is dose-dependent and reversible. 
• In malaria treatment and prophylaxis, fewer and milder side effects occur. 
**Prolonged QT interval has been seen in patients with particular risk factors for it. 
***Acute generalized exanthematous pustulosis must be distinguished from psoriasis. Psoriasis 
exacerbation may occur. May be associated with fever and hyperleukocytosis. 
An adverse reaction (AR) is defined as any adverse and undesirable reaction to a trial drug 
regardless of dose. An adverse event (AE) is defined as any adverse event in a patient or subject in 
a clinical trial following treatment with a drug, without necessarily linking this treatment to the 
adverse event. 
Since the trial drugs are well known and have been used for many years, we will only record side 
effects not mentioned in the respective drug summary of the trial drug. 
A severe adverse reaction or event (SAR/SAE) is defined as an event or adverse event that, 
regardless of dose, results in death, is life-threatening, results in hospitalization or prolongs 
hospitalization, results in significant or persistent disability or incapacity, or leading to a congenital 
anomaly or malformation. 
Investigators must immediately (= within 24 hours) report serious incidents and serious adverse 
reactions (SAEs and SARs) to the sponsor regardless of whether they are described in the 
respective product summary. This allows the sponsor to assess the benefits and risks along the 
way in the study. 
Events and adverse events recorded during the period from the patient have received the first 
dose of trial medication up to and including day 15. 
Recording and reporting of all events and adverse events will end when the trial drug is stopped. 
A high degree of comorbidity and death is seen in this patient group and therefore it is also 
expected that prolonged admissions, re-admissions, NIV, Respirator treatment and death will 
occur in this patient group. Therefore, these parameters will not be considered as a SAE. 


Proactive Prophylaxis With Azithromycin and Chloroquine in Hospitalised Patients With COVID-19 
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All incidents and registered side effects are reported at the end of the trial in a final report to the 
Danish Medicines Agency. All serious suspected adverse reactions must be reported annually 
together with a report on the safety of the subjects and sent to the the Danish Medicines Agency 
(LMST) and the Danish National Committee on Health Research Ethics (VEK). 
The product summary of the trial drugs is used to assess whether a serious adverse event is 
unexpected and thus possibly a Suspected Unexpected Serious Adverse Reactions (SUSAR). 
In the event of a fatal or life-threatening SUSAR, this must be registered and reported to LMST and 
VEK within 7 days of the sponsor becoming aware of it. No later than 8 days after the report, the 
sponsor must provide LMST and VEK with all relevant information about the sponsors and 
investigators' follow-up on the event. All other SUSARs are reported to LMST and VEK within 15 
days of the sponsor becoming aware of them. 
The report must be followed up by a detailed written report, and in both the immediate report 
and the subsequent report, the investigator must identify the subjects with a personal code 
number. When reporting deaths, the investigator must provide any additional information that 
the sponsor may request. 
 
7. Economy: 
The research project is (investigator) initiated by COP:TRIN. Funding has been obtained from the 
Novo Nordisk Foundation of DKK 2.2 million for sponsor, remuneration of auxiliary personnel, 
payment of laboratory tests and equipment, as well as for manufaction of IMP treatment and 
placebo. The sponsors and investigators are not financially linked to private companies, 
foundations, etc. in this research project. 
Medical expenses are covered, if not obtained from other sources, by the section for respiratory 
medicine research, Gentofte Hospital. 
To the extent possible, the section for respiratory medicine research, Gentofte Hospital supports 
follow-up for endpoints and otherwise by appointment. 
 
8. Remuneration: 
Patients are not paid for participation in the trial. 
 
9. Availability of information and right to data: 
The consent gives the primary investigator, monitor and any control authority direct access to 
obtain information in the patient's medical record, etc., including electronic record, in order to see 


Proactive Prophylaxis With Azithromycin and Chloroquine in Hospitalised Patients With COVID-19 
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information about the subject's health conditions which are necessary as part of the 
implementation of the research project and for control purposes, including self-monitoring, 
quality-control etc. 
The project group that has designed and conducted this study has the right to data and the right 
(and duty) to publish based on data. Project management manages data and invites members of 
the study group to publications. All sites that recruit patients are entitled to at least one 
authorship on the primary publication, and for every 10 patients recruited, the site is entitled to 
an extra authorship. Sites that have not participated in the design of the study are entitled to a 
maximum of 3 authorships. It is the opinion of the steering committee that knowledge sharing 
creates more and better scientific results. Requests for knowledge sharing from other groups may 
be submitted to Project Management (Jens-Ulrik Jensen, Charlotte Ulrik, Pradeesh Sivapalan) who 
will evaluate primarily and who, if the project is found suitable, will discuss it with the COP:TRIN 
Steering Committee.  
Project Management has the first right to undertake sub-studies but may well assign projects to 
other contributors. In that case, the following considerations will be significant in the assessment: 
1) Participation in the design phase of this RCT and at what level, and 2) Number of patients 
recruited at a site. If the hypothesis to be investigated is not planned to be examined by our 
group, we will allow the use of our data if the Steering Committee finds the project scientifically 
sound and, if appropriate, a collaboration with members of the COP:TRIN Steering Committee will 
be proposed. However, it should be emphasized that data is used for a specific purpose, not for 
future purposes in general. This becomes conditional by the steering committee for data to be 
used in a sound way to test hypotheses with relevant scientific content. 
Information regarding subjects are processed and stored in accordance with the Data Protection 
Regulation (GDPR), the Data Protection Act and the Health Act and the project is properly notified 
in accordance with applicable rules and laws to the appropriate authorities. 
 
10. Publication of results: 
All project results will be sought published in scientific contexts, including international journals. 
This will happen regardless of whether the result is positive, negative or inconclusive. 
 
11. Scientific Ethics Statement: 
The study is conducted in accordance with the Declaration of Helsinki and is carried out in 
accordance with the rules of the Personal Data Act and the Health Act. The study has been 
registered at the Danish Data Protection Agency. 


Proactive Prophylaxis With Azithromycin and Chloroquine in Hospitalised Patients With COVID-19 
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Recruitment and inclusion will take place as previously described (section 3.3.1). Participation 
requires a signed statement of consent. Patients can withdraw their participation consent and 
withdraw from the research project at any time without this having any effect on their right to 
current or future treatment. Furthermore, the patient is entitled to bring a bystander to the 
information interview and is entitled to reflection time before any declaration of consent is signed. 
The important objective of the study is to investigate whether pro-active and pre-emptive 
treatment against COVID-19 can reduce the length of hospitalisation and the risk of intensive care 
and improve the survival of patients - an area that has so far been poorly researched and where 
the need for evidence-based guideline for handling and processing is large and very urgent. 
Potential disadvantages and side effects are described in the separate section 5. Among other 
things, it appears that the likelihood of serious adverse reactions to both treatment and 
examinations is rare. In addition, the treating physician can always discontinue treatment if it is 
considered contraindicated. 
Placebo is given patients allocated to the control group as no specific standard medical treatment 
is available. 
The experimental method and statistical analyses have been carefully considered in order to be 
able to disseminate and apply relevant and secure research results to clinical practice. 
Based on the above considerations, we believe that the experiment is sound ethically sound and 
can be conducted without exposing the test participant to unjustifiable risks. 
 
12. Recruitment of subjects and informed consent 
At each trial centre, screening of patients admitted with a positive SARS-CoV-2 test is performed. 
Patients are assessed against the inclusion and exclusion criteria of the attending physician who 
receives the patient's consent to contact the investigator. The Investigator then contacts the 
patient for recruitment to the study. Disclosure of information about the study and obtaining 
informed consent may also be undertaken by other healthcare professionals. This includes 
research assistants (medical students), clinical nursing specialists and project nurses (See below 
for specific requirements). These are all separately trained in the task and have the opportunity to 
call a physician should any medical issues arise. They can also contact the coordinating 
investigator as well as a hotline team for the trial should any questions arise about informed 
consent. This hotline is available 24 hours a day. All patients are offered a consultation with a 
physician if they ask for it. For project nurses, the following applies specifically: i) must have at 
least 5 years of seniority. These requirements are verified by primary investigator from each site 
that afterwards creates a document for these individuals from which the above specific 
requirements are verified. This document is dated and signed. 


Proactive Prophylaxis With Azithromycin and Chloroquine in Hospitalised Patients With COVID-19 
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21 
 
If a patient is considered suitable, the person will be invited to participate in the project. 
Participation in the trial is voluntary. Informed consent is obtained from the participants of the 
trial acc. to Executive Order No. 1149 of 30 September 2013 on information and consent for 
participation in health science research projects and on notification and supervision of health 
science research projects. The first contact with the the potential participant in the trial will be at 
admission to one of the participating departments. Participant information is provided both orally 
and in writing, and the patient is informed that they are entitled to 24 hours of reflection time 
before consent is given for participation in the trial. Participants who wish to do so themselves 
after the period of reflection time may give consent in connection with the information meeting.  
The right to a bystander is ensured by the patient being able to bring a bystander, however, 
subject to COVID isolation rules. If no bystanders come to the first call, they are ensured 
afterwards to a bystander, when the patient is out of isolation. It is ensured that the conversations 
are undisturbed by using the patient's isolation room. If the doctor carries a "pager" or telephone, 
these are handed in prior to the call. The trial participant will be provided with the document "The 
research subject's rights in a health science research project", which contains information about 
confidentiality, access to documents and access to complaints. The subjects are protected under 
the Personal Data Processing Act. The trial has been reported to the Regional Science Ethics 
Committee, the Danish Medicines Agency and the Danish Data Protection Agency. 
It must be ensured at all times that subjects have consented to participate in clinical trials. If an 
isolated subject with COVID-19 can sign consent declaration via electronic tool, this can be used 
instead of consent with signature. This can be, for example, a mobile phone, an iPad, a laptop with 
secure identification, for example by an easy ID (or other solution that meets the OCES standard). 
If the above described solution is not possible, the following solutions can be used as temporary 
documentation for the consent: 
• Copy of signed consent declaration – e.g. using camera: The subject can sign the consent form as 
usual. Since the signed form must not leave the isolation room, the signature can be documented 
in the form of a photograph of the signed form, for example through a window. 
• If the test subject cannot sign the consent declaration himself, e.g. due to problems with having 
electronic equipment in the room, or obtaining documentation for the consent out of the room, 
the witness can sign on behalf of the subject: If the subject verbally consents, a witness can on 
behalf of the subject sign the consent form. For both of the above solutions, documentation 
(photo and witness signature) will be filed in the investigator's section of the Trial Master File 
(TMF). Furthermore, it is ensured that the Data Protection Regulation and the Data Protection Act 
are complied with, although documentation of the consent is temporarily different than it usually 
is. If the situation is normalised, the correct signed consent form must be obtained from the 
subject as soon as possible. 
 


Proactive Prophylaxis With Azithromycin and Chloroquine in Hospitalised Patients With COVID-19 
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13. Exclusion and interruption of trials: 
Regular monitoring and quality control of the study will be carried out. If the physician responsible 
for the study deems it necessary, the physician may during treatment take the subject out of the 
study. The physician may also terminate the study at any time if there is a medical justification 
(such as the development of allergies to medicines), a safety risk or a requirement from the 
authorities. The test subject may also withdraw their informed consent and withdraw from the 
investigation at any time, as mentioned in the above paragraph. 
 
14. Information on compensation and compensation schemes: 
Patients who participate in these studies and who believe they have suffered injury can seek 
compensation through the patient compensation (http://patienterstatningen.dk/) cf. Danish law. 
 
15. References: 
1. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical Characteristics of Coronavirus 
Disease 2019 in China. N Engl J Med. 2020.  
2. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult 
inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020.  
3. Mo P, Xing Y, Xiao Y, Deng L, Zhao Q, Wang H, et al. Clinical characteristics of refractory COVID-
19 pneumonia in Wuhan, China. Clin Infect Dis. 2020.  
4. Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, et al. Clinical course and outcomes of critically ill patients 
with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational 
study. Lancet Respir Med. 2020.  
5. Murthy S, Gomersall CD, Fowler RA. Care for Critically Ill Patients With COVID-19. JAMA. 2020.  
6. Uzun S, Djamin RS, Kluytmans JA, Mulder PG, van't Veer NE, Ermens AA, et al. Azithromycin 
maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary 
disease (COLUMBUS): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 
2014;2(5):361-8.  
7. Albert RK, Connett J, Bailey WC, Casaburi R, Cooper JA, Jr., Criner GJ, et al. Azithromycin for 
prevention of exacerbations of COPD. N Engl J Med. 2011;365(8):689-98.  
8. Gibson PG, Yang IA, Upham JW, Reynolds PN, Hodge S, James AL, et al. Effect of azithromycin on 
asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): 
a randomised, double-blind, placebo-controlled trial. Lancet. 2017;390(10095):659-68.  


Proactive Prophylaxis With Azithromycin and Chloroquine in Hospitalised Patients With COVID-19 
(ProPAC-COVID) 
23 
 
9. Altenburg J, de Graaff CS, Stienstra Y, Sloos JH, van Haren EH, Koppers RJ, et al. Effect of 
azithromycin maintenance treatment on infectious exacerbations among patients with non-cystic 
fibrosis bronchiectasis: the BAT randomized controlled trial. JAMA. 2013;309(12):1251-9.  
10. Segal LN, Clemente JC, Wu BG, Wikoff WR, Gao Z, Li Y, et al. Randomised, double-blind, 
placebo-controlled trial with azithromycin selects for anti-inflammatory microbial metabolites in 
the emphysematous lung. Thorax. 2017;72(1):13-22.  
11. Kawamura K, Ichikado K, Takaki M, Eguchi Y, Anan K, Suga M. Adjunctive therapy with 
azithromycin for moderate and severe acute respiratory distress syndrome: a retrospective, 
propensity score-matching analysis of prospectively collected data at a single center. Int J 
Antimicrob Agents. 2018;51(6):918-24.  
12. Beigelman A, Mikols CL, Gunsten SP, Cannon CL, Brody SL, Walter MJ. Azithromycin attenuates 
airway inflammation in a mouse model of viral bronchiolitis. Respir Res. 2010;11:90.  
13. Gielen V, Johnston SL, Edwards MR. Azithromycin induces anti-viral responses in bronchial 
epithelial cells. Eur Respir J. 2010;36(3):646-54.  
14. Li C, Zu S, Deng YQ, Li D, Parvatiyar K, Quanquin N, et al. Azithromycin Protects against Zika 
virus Infection by Upregulating virus-induced Type I and III Interferon Responses. Antimicrob 
Agents Chemother. 2019.  
15. Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R. Effects of chloroquine on viral 
infections: an old drug against today's diseases? Lancet Infect Dis. 2003;3(11):722-7.  
16. Lee SJ, Silverman E, Bargman JM. The role of antimalarial agents in the treatment of SLE and 
lupus nephritis. Nat Rev Nephrol. 2011;7(12):718-29.  
17. Vincent MJ, Bergeron E, Benjannet S, Erickson BR, Rollin PE, Ksiazek TG, et al. Chloroquine is a 
potent inhibitor of SARS coronavirus infection and spread. Virol J. 2005;2:69.  
18. Colson P, Rolain JM, Raoult D. Chloroquine for the 2019 novel coronavirus SARS-CoV-2. Int J 
Antimicrob Agents. 2020;55(3):105923.  
19. Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in 
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SAP_001.pdf: 
 
1 
 
 Statistical Analysis Plan - Proactive Prophylaxis with Azithromycin 
and Chloroquine in Hospitalized Patients with COVID-19 (ProPAC-
COVID) 
 
19th May 2020 
A randomized, placebo-controlled, double-blinded multi-centre trial conducted in 
Departments of Internal Medicine, Emergency Medicine and Respiratory Medicine 
departments in Denmark 
Estimated Primary Completion Date: April 2021  
Estimated Study Completion Date: December 2021 
 
ClinicalTrials.org identifier: NCT04322396. Registered on 26th of March 2020. 
Authors: Pradeesh Sivapalan (PS) & Jens-Ulrik Stæhr Jensen (JUJ) 
 
 
Introduction 
In the ongoing coronavirus pandemic, COVID-19, that arose in Wuhan China, there is still sparse 
data in the course, risk of various complications, and how patients who are hospitalized are best 
treated to ensure high survival and short hospitalization. Despite the rapid spread of the disease 
globally, there is no robust data yet to recommend any specific treatments, which is why symptomatic, 
organ supportive therapy, including respiratory therapy in acute pulmonary failure, is recommended. 
There has been reported a high incidence of bacterial super-infections in patients with COVID-19. 
Patients with COVID-19 also have a higher risk of mortality because of septic shock. Thus, there is 
an urgent need for treatment that can improve the patient's chance of the shorter hospitalization and 
treatment that can lower the risk of secondary infection and death. 
This is a randomized, placebo-controlled, double-blinded multi-center trial evaluating the effect of 
azithromycin and hydroxychloroquine treatment in patients with COVID-19 during hospitalization. 
The aim of the study is to investigate whether the therapy can shorten hospitalization, reduce the risk 
of non-invasive ventilation, admittance to intensive care units and death 
 
 
 
Supplemental Appendix 2


 
2 
 
 
The patients are enrolled in the trial only after obtaining informed consent. The trial is conducted at 
eight centers in Denmark.  
 
1. Section of Respiratory Medicine, Herlev-Gentofte Hospital, Copenhagen, Denmark 
Principal investigator: Jens-Ulrik Jensen, Senior Consultant, Research Associate Professor, 
MD, PhD. Co-founder of COP:TRIN (www.coptrin.dk).  
 
2. Department of Respiratory Medicine, Hvidovre Hospital, and University of Copenhagen  
PI: Charlotte Suppli Ulrik Professor DMSc. Head of the Respiratory Research Unit and the 
Management of Asthma during Pregnancy (MAP) program at Hvidovre Hospital.  
 
3. University Hospital North Zealand Hospital, department of Pulmonary and Infectious 
diseases. PI: Andrea Browatzki Senior consultant, MD 
 
4. Respiratory Medicine at the Bispebjerg Hospital, Copenhagen, 
PI: Therese Lapperre, Senior Consultant, Research associate professor 
    
5. Respiratory medicine department, Zealand Hospital, Næstved and the University of 
Southern Denmark. PI: Uffe Bødtger, Research Associate Professor, Senior Consultant in 
Respiratory Medicine 
 
6. Respiratory medicine department, Odense University Hospital, Odense, Denmark. pi: 
Christian Laursen, Research Associate Professor, Senior Consultant in Respiratory Medicine 
 
7. Respiratory medicine department, Aarhus- and Aalborg University, PI: Ulla Weinreich, 
Research Associate Professor, Senior Consultant in Respiratory Medicine 
       
 
 


 
3 
 
Patients will be randomized to one of the two treatment arms: 
i) 
Intervention group: Azithromycin day 1-3: 500 mg x 1, day 4-15: 250 mg x 1 
Hydroxychloroquine: Day 1-15: 200 mg x 2 
 
ii) 
Control group: The control group will always receive the standard treatment and 
placebo for both types of intervention medication. If part or all the intervention therapy 
being investigated becomes standard treatment during the study, this may also be offered 
to the control group. 
 
The analyses described in this document will be performed by Pradeesh Sivapalan, MD, PhD 
coordinating investigator, in cooperation with the sponsor and principal investigator Jens Ulrik 
Jensen, research associate professor, Respiratory Medicine Section, University of Gentofte Hospital, 
once the data have been entered, cleaned and released for use. 
This document provides a detailed description of the statistical analyses that will be performed for 
the evaluation of the primary and secondary endpoints of protocolized for the ProPAC-COVID study.  
The analyses described in this document are compatible with the recommendations of the CONSORT 
2010 statement. 
The International Conference on Harmonisation (ICH) of Good Clinical Practice (GCP)(1) and 
leading experts recommend that randomized clinical trials should be analyzed according to predefined 
outcomes and a predefined detailed statistical analysis plan (2). To prevent selective reporting of 
outcomes and data-driven analysis results and increase transparency this paper will in detail describe 
the detailed statistical analysis plan for the ProPAC-COVID trial while enrolment of patients and 
collection of data is still on-going and before the database is accessed for trial results. 
Analysis population 
Data will be analyzed using intention-to-treat (ITT) principles and main analyses will also be subject 
to modified ITT analysis (started but not completed) and per protocol analysis (completed all 
intervention). When applying the ITT principle, all randomized patients will be analyzed in the groups 
to which they were originally allocated, regardless of whether they received the intended treatment 
or whether a protocol violation or protocol deviation occurred. 
Patients who withdrew consent for the use of their data will not be included in any analysis. Only the 
facts that they were enrolled into the trial and withdrew consent, and the original study group to which 
they were allocated, will be reported. 
A secondary analysis of the primary efficacy outcome will use a per protocol (PP) population.  
A Consort diagram of participants will be presented in the study. 


 
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For the secondary ordinary outcome, we will use a Wilcoxon rank sum test. The primary outcome 
uses an ordinal severity scale with 8 categories, analyzed using the proportional odds model. The key 
parameter of interest is the “common odds ratio,” which quantifies the shift in the severity distribution 
resulting from treatment. For an efficacious treatment, an odds ratio greater than 1 quantifies an 
improvement in disease severity; a value of 2 indicates a bigger improvement than a value of 1.25. 
 
Sample size  
The power to avoid type II error is 80% (1-β) at a two-sided 5% significance level, using a t-test for 
the primary outcome, and a group-sequential design allowing for one interim analysis at half target 
recruitment.  This provides a sample size of 226 subjects.  All confidence intervals reported will be 
95% confidence intervals. 
 
Analysis Software 
All analyses will be performed using SAS software version 9.4.   
 
DATA ANALYSIS 
Descriptive analyses – Baseline characteristics at study enrollment (defined as day 1).  
The following baseline characteristics of the study population will be summarized separately within 
each randomized group:  
• Age, median (IQR), y 
• Male sex, n (%) 
• Ethnicity (Caucasian, African (incl. Afro-American), Asian, Inuit, Unknown/other) 
• Body mass index (kg/m2, median, IQR) 
• Current smoker, n (%) 
• Ex-smoker, n (%) 
• Nonsmoker, n (%) 
• Pack-years history (median, IQR, y) 
• Use of oxygen therapy, n (%) 
• Use of CPAP, n (%) 
• Use of noninvasive mechanical ventilation, n (%) 
• Infiltrate on Chest X-ray, n (%) 
• Oxygen consumption: L/min (median, IQR) 
• Oxygen consumption: FiO2 (median, IQR) 
 
 


 
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Clinical findings 
• Systolic blood pressure (mm Hg) 
• Diastolic blood pressure (mm Hg) 
• Heart rate, beats/min 
• Oxygen saturation with nasal oxygen, median, IQR 
• Respiratory rate, breaths/min 
• Temperature (°C) 
 
Biochemistry findings (daily measurements) 
• Leukocyte count, x109 cells/L 
• Blood eosinophil count, x109 cells/L 
• CRP (mg/L) 
• Fibrin D-dimer 
• Ferritin 
• Lactate Dehydrogenase (U/L) 
 
Arterial Blood Gas (mean ± SD) day 1 and day 4 
• PCO2, mmHg 
• PO2, mmHg 
• HCo3 
• pH 
 
Other Lab findings 
 
• QTc (F) (via electronic measurement on ECG at baseline) 
 
Comorbid conditions, n (%)  
• Asthma 
• COPD 
• Bronchiectasis 
• Interstitial lung disease 
• Allergy 
• Diabetes mellitus 
• Previous myocardial infarction 
• Heart failure 
• Atrial fibrillation 
• Chronic renal insufficiency 
• Essential hypertension, 
• Osteoporosis 
• Peripheral vascular disease 


 
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• Cerebrovascular disease 
• Hematological diseases 
• Depression 
• Past or present lung cancer 
• Previous cancer (which is not lung cancer) 
• Former DVT or pulmonary embolism 
• Liver failure 
• Rheumatic diseases 
 
 
Follow-up data /missing data 
 
% followed for each outcome data parameter will be reported for all predefined outcomes (primary 
and all secondary). If exploratory outcome analyses will be planned by the study group on 
suggestion form the reviewers/editors, % followed /missing data will also be reported for these 
outcomes.  
 
Adherence data:  
 
N + % patients in both arms who: 
- 
Started azithromycin 
- 
Started hydroxychloroquine 
- 
Completed azithromycin (all days) 
- 
Completed hydroxychloroquine (all days) 
- 
Completed both drugs (all days)  
 
 
Medication during hospitalization 
• Type of antibiotics (non-study drugs) 
▪ Ciprofloxacin, Piperacillin/tazobactam, Ceftazidime, Meropenem, Colistin,  
▪ Gentamycin, Amoxicillin, Amoxicillin/Clavulanic, Surlid, Dicloxacillin, 
Penicillin, Azithromycin or other 
• Days with antibiotics - any (Median days on any type) 
• Days with corticosteroids (Median days) 
 
For continuous variables, means and standard deviations will be presented, when normally 
distributed, otherwise as medians and interquartile ranges (IQR). For categorical variables, the 
number and percentage of participants within each category will be presented. For each variable, the 
percent of missing values will be reported. For categorical values, chi-square, Fisher´s exact test. For 
time-to-event variables Cox regression and log-rank test will be used and for the latter, a 
corresponding Kaplan-Meier plot will be presented.  


 
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Primary objective and outcome 
The primary outcome is “days alive and out of hospital (DAOH) within 14 days after recruitment” 
defined as the time from hospital discharge and days without hospitalization up to 14 days from 
recruitment where the patient is alive. Data for the primary outcome analysis will be presented as 
mean [95%CI] and corresponding t-test and additionally for sensitivity analysis median [IQR] with 
corresponding non-parametric test, e.g. Mann-Whitney U-test 
The estimation from the study group is that DAOH14 will be a number above or equal to 4. If 
DAOH14 is < 4, DAOH at 21 days will be presented instead. In this case, SD is estimated to not 
exceed 3.8 days, and the sample size should thus not be adjusted.  
Apart from the main, unadjusted analysis, the primary outcome will be performed as an adjusted 
analysis using general linear models, while adjusting for the following variables: Age (per year 
increase), sex (M/F), COPD GOLD C/D (Yes vs. No), Heart failure NYHA III-IV (Yes vs. no), Active 
smoker (Yes vs. No). 
Secondary objective and outcomes 
1. Categorization of hospitalization status [ Time Frame: 14 days] 
The patient will be categorized into one of the following 8 categories depending on status of their 
hospitalization: 
a. Dead (yes/no) 
b. Hospitalized and receiving mechanical ventilation or Extra Corporal Membrane Oxygenation 
(ECMO) (yes/no) 
c. Hospitalized and receiving Non-invasive ventilation or "high-flow oxygen device" (yes/no) 
d. Hospitalized and given oxygen supplements different from (2) and (3) (yes/no) 
e. Hospitalized and without oxygen treatment, but receiving other treatment (both related to 
COVID-19 or other) (yes/no) 
f. Hospitalized for observation (yes/no) 
g. Discharged from hospital with restriction of activity level (yes/no) 
h. Discharged from hospital without any restrictions of activity level (yes/no) 
For this analysis, the patient will be assigned a number between 1 and 8. Frequencies for the 
categories will be presented. Furthermore, the location on the scale for each group will be 
presented by median (IQR). Significance for differences will be calculated by a Wilcoxon-Sign-
rank test (WSR).  
Only one category can be "yes". 


 
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2. Admitted to intensive care unit, if admitted to ICU then length of stay [ Time Frame: 14 days] 
Number of patients admitted to intensive care will be compared using chi-square test. Length of 
stay in ICU will be analyzed using a t-test. Days not alive within the time frame will be added to 
days at ICU. If days not alive are equal in the two treatment groups, we will further present days 
at ICU excluding days not alive. 
3. Have used Non-invasive ventilation (NIV) during hospitalization [ Time Frame: 14 days] 
Use of NIV will be compared by a chi-square test. 
4. Mortality [Time Frame: 30 days ] 
Differences in mortality will be displayed using the Kaplan-Meier plots method in 
combination with the log-rank test and as an adjusted analysis using Cox proportional hazards 
models, while adjusting for the following variables: Age (per year increase), sex (M/F), COPD 
GOLD C/D (Yes vs. No), Heart failure NYHA III-IV (Yes vs. no), Active smoker (Yes vs. 
No). 
5. Length of hospitalization [ Time Frame: 14 days] 
Length of hospitalization will be compared using t-test. 
6. Days alive and discharged from hospital [ Time Frame: 30 days] 
This is equal to the primary endpoint but with a longer time frame and will be analyzed like 
the that. 
7. Mortality [ Time Frame: 90 days] – reported in secondary publication. 
Differences in mortality will be displayed using the Kaplan-Meier plots method in 
combination with the log-rank test and as an adjusted analysis using Cox proportional hazards 
models, while adjusting for the following variables: Age (per year increase), sex (M/F), COPD 
GOLD C/D (Yes vs. No), Heart failure NYHA III-IV (Yes vs. no), Active smoker (Yes vs. 
No). 
8. Mortality [ Time Frame: 365 days] – reported in secondary publication. 
Differences in mortality will be displayed using the Kaplan-Meier plots method in 
combination with the log-rank test and as an adjusted analysis using Cox proportional hazards 
models, while adjusting for the following variables: Age (per year increase), sex (M/F), COPD 
GOLD C/D (Yes vs. No), Heart failure NYHA III-IV (Yes vs. no), Active smoker (Yes vs. 
No). 
9. Number of readmissions (all causes) [ Time Frame: 30 days] 
Number of readmission and compared using a Mann-Whitney test, treating death as a 
competing risk.  


 
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10. Number of days using non-invasive ventilation (NIV) [ Time Frame: 14 days] 
Number of days using non-invasive ventilation will be compared using t-test, treating death as a 
competing risk.  
11. Change in patient's oxygen partial pressure [ Time Frame: 4 days ] 
Delta PaO2 measured in arterial puncture 
Changes will be calculated by an ANCOVA method adjusting for baseline values. 
12. Change in patient's carbondioxid partial pressure [ Time Frame: 4 days ] 
Delta PaCO2 measured in arterial puncture 
Changes will be calculated by an ANCOVA method adjusting for baseline values. 
13. Level of pH in blood [ Time Frame: 4 days ] 
pH measured in arterial puncture 
Levels in pH will be compared using t-test 
14. Time to no oxygen supplement (or regular oxygen supplement "LTOT") [ Time Frame: 14 
days] 
Time to no oxygen supplement will be presented by the Kaplan-Meier method and differences 
calculated by log-rank test.   
 
For all analyses using parametric statistic (t-test, ANCOVA) the distribution will be inspected. 
Biochemical markers will be transformed if necessary whereas length of stays will not be 
transformed. If parametric statistics is considered inappropriate a non-parametric alternative will be 
used. For analyses with a dichotomous outcome Fisher’s exact test will be used if the chi-square test 
is not considered appropriate.    
Arrythmias:  
- 
ECG: Qtc: n (%) patients in both arms who at any time point after baseline had a QTc (F) 
>500 ms 
- 
N (%) ventricular arrythmias (apart from ventricular extrasystoles and non-sustained VT).  
 
Subgroup analyses (all according to baseline values) 
Scheduled to perform following stratified analyses for the primary outcome:  
- stratified analyzes in the presence of chronic lung disease or not 
- stratified analyzes for QTc across the median  
- stratified analyzes for < 2L nasal oxygen or ≥ 2L nasal oxygen 
-stratified analyzes CRP < 50 mg/L and CRP ≥ 50 mg/L 
- stratified analyzes D-dimer> 0.8 mg/L or D-dimer ≥ 0.8 mg/L 


 
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Figures and tables 
The first figure will be a Consolidated Standards of Reporting of Randomized Trials (CONSORT) 
flow chart. The second figure will be a Kaplan-Meier plot to describe the process of death by 
treatment arms.  The third figure will be a forest plot illustrating all the preplanned sub analyses.   
The first table will be the baseline characteristics of the ITT population. The second table will be of 
the primary and secondary outcomes according to the two groups and pair-wise comparisons.  
Blinding of the statistician 
The detailed analysis plan was written in strict concordance with the trial protocol approved by the 
regulatory authorities prior to recruitment initiation. The entire statistical analysis plan was published 
at www.coptrin.dk before the trial was finalized (while the database was closed).  All analyses will 
be done prior to breaking of the randomization code (analysis comparisons between “arm A” and 
“arm B” (random names). The coordinating investigator (PS) and the study sponsor and principal 
investigator (JUJ) will conjointly perform all the data analyses according to this plan, except the 
interim analyses which will be performed by Dr. Josefin Eklöf (who is not an investigator of this 
trial). An unblinding date will be chosen and published online at www.coptrin.dk and on this date, 
the allocation will be unblinded. After unblinding of the allocation, further analysis will not be done, 
except on reviewer/editor demand when submitted.  
Interim Analysis:  
The interim analysis will focus on reporting: selected baseline data (those readily available from the 
baseline data list above), primary outcome (in an O- Brien-Fleming Plot) and all-cause mortality at 
30 days (Chi-square or Fisher´s Exact test, whichever appropriate).  
Funding 
The trial was funding by Novo Nordisk Foundation with 2.2 million Dkr. No medical company is 
supporting this trial. The funding sources will have no influence on trial design, data collection, 
analysis, or reporting. 
Approved by: Ethics Committees of all participating sides (H-20022574) and the Danish 
Medicines Agency (EudraCT no: 2020-001198-55) and the Danish Data Protection Agency (2020-
256). 
Acknowledgements 
The Steering Committee of COP:TRIN for input and advice during the trial recruitment.  
 
 


 
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Contributor Information 
Pradeesh Sivapalan MD PhD Resp. trainee 
Department of Internal Medicine, Zealand University Hospital, Roskilde & 
Post Doc Respiratory Medicine Section, Herlev-Gentofte Hospital 
Pradeesh Sivapalan, Email: pradeesh.sivapalan.02@regionh.dk 
 
 
Jens-Ulrik Stæhr Jensen, PhD 
Research Associate Professor, University of Copenhagen &  
Research Leading senior consultant 
Respiratory Medicine Section Herlev-Gentofte Hospital 
Jens-Ulrik Jensen, Email: Jens.ulrik.jensen@regionh.dk 
 
Competing interests 
The authors declare that they have no competing interests. 
 
Abbreviations 
AECOPD 
Acute exacerbations of chronic obstructive pulmonary disease 
ANOVA 
Analysis of variance 
CAT 
COPD Assessment Test 
CONSORT Consolidated Standards of Reporting of Randomised Trials 
DAOH 
Days alive and out of hospital 
FEV1 
Forced expiratory volume in 1 second 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonisation 
ITT 
Intention-to-treat 
IQR 
Interquartile range 
 
 


 
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References 
1.  
ICH Harmonised Tripartite Guideline. Guideline for good clinical practice E6(R1). ICH 
Harmon Tripart Guidel. 1996;1996(4):i-53.  
2.  
Finfer S, Bellomo R. Why publish statistical analysis plans? Crit Care Resusc [Internet]. 
2009 Mar [cited 2018 Sep 20];11(1):5–6. Available from: 
http://www.ncbi.nlm.nih.gov/pubmed/19281437