Antibiotic Therapy in Viral Airway Infections: An Open Labeled Randomized Controlled Pragmatic Trial to Evaluate the Efficacy and Safety of Discontinuing Antibiotic Therapy in Adult Patients With Respiratory Viruses
Phase: PHASE4
Conditions: Infectious Disease, Influenza, Respiratory Syncytial Virus (RSV), Respiratory Tract Infections
Sponsor: University Hospital, Akershus

 
 
 
ANTIBIOTIC THERAPY IN VIRAL AIRWAY INFECTIONS (ATHENIAN):  
AN OPEN LABELED RANDOMIZED CONTROLLED PRAGMATIC TRIAL TO 
EVALUATE THE EFFICACY AND SAFETY OF DISCONTINUING ANTIBIOTIC 
THERAPY IN ADULT PATIENTS INFECTED WITH RESPIRATORY VIRUSES 
 
 
Protocol Identification Number: Ahus-ATHENIAN 
 
EudraCT Number: 2021-004248-11 
EU CT number: 2023-509286-20-00 
ClinicalTrials.gov Identifier: NCT05045612 
 
 
SPONSOR: 
Akershus University Hospital 
Head of Department / Associate Professor Jan Erik Berdal 
Department of Infectious Diseases 
Akershus University Hospital 
Sykehusveien 25 
1478 Lørenskog, Norway 
Tel: +47 48 20 58 17 
E-mail: jan.erik.berdal@medisin.uio.no 
 
 
 
 
PROTOCOL VERSION NO. 1.13 – 13.12.24 

 
Protocol ATHENIAN Version no. 1.13 – 13.12.2024 
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CONTACT DETAILS  
Sponsor: 
Head of Department / Associate Professor Jan Erik Berdal, MD PhD 
Department of Infectious Diseases, Division of Medicine 
Akershus University Hospital 
Sykehusveien 25 
1478 Lørenskog, Norway 
Tel: +47 48 20 58 17 
E-mail: jan.erik.berdal@medisin.uio.no  
 
Principal Investigator: 
Associate Professor Magnus Lyngbakken, MD PhD 
Department of Infectious Diseases, Division of Medicine 
Akershus University Hospital 
Sykehusveien 25 
1478 Lørenskog, Norway 
Tel: +47 93 40 88 37 
E-mail: magnus.lyngbakken@medisin.uio.no  
 
Investigator: 
Professor Olav Dalgard, MD PhD 
Department of Infectious Diseases, Division of Medicine 
Akershus University Hospital 
Sykehusveien 25 
1478 Lørenskog, Norway 
Tel: +47 92 61 68 00 
E-mail: odalgard@uio.no  
 
Investigator: 
PhD fellow Magrit Jarlsdatter Hovind, MD 
Department of Infectious Diseases, Division of Medicine 
Akershus University Hospital 
Sykehusveien 25 
1478 Lørenskog, Norway 
Tel: +47 97 54 06 81 
E-mail: m.j.hovind@medisin.uio.no  
 
Investigator: 
Associate Professor Truls Leegaard, MD PhD 
Department of Microbiology and Infection Control 
Akershus University Hospital 
Sykehusveien 25 
1478 Lørenskog, Norway 
Tel: +47 90 64 62 65 
E-mail: Truls.Michael.Leegaard@ahus.no   
 
Investigator: 
Associate Professor Jørgen Vildershøj Bjørnholt, MD PhD 
Department of Microbiology 
University of Oslo, OUS HF Rikshospitalet 
Postboks 4950 Nydalen  
0424 Oslo 
Tel: +47 90 21 39 59 
E-mail: j.v.bjornholt@medisin.uio.no  
 

 
Protocol ATHENIAN Version no. 1.13 – 13.12.2024 
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Investigator: 
Professor Jan Kristian Damås, MD PhD 
Department of Infectious Diseases 
St. Olavs hospital 
Postboks 3250 Torgarden 
7006 Trondheim  
Tel: +47 91 11 20 46 
E-mail: jan.k.damas@ntnu.no 
 
Investigator: 
Associate Professor Vegard Skogen, MD PhD 
Department of Infectious Diseases 
University Hospital of North Norway 
Postboks 100 
9038 Tromsø 
Tel: +47 91 36 45 41 
E-mail: vegard.skogen@unn.no 
 
Investigator 
PhD fellow Dagfinn Lunde Markussen, MD 
Emergency Care Clinic 
Haukeland University Hospital 
Postboks 1400 
5021 Bergen 
Tel: +47 99 27 00 71 
E-mail: dagfinn.lunde.markussen@helse-bergen.no 
 
Investigator 
Researcher Karl Erik Müller, MD PhD 
Department of Internal Medicine 
Drammen Hospital, Vestre Viken Hospital Trust 
Postboks 800 
3004 Drammen 
Tel: +47 97 50 14 75 
E-mail: kamull@vestreviken.no  
 
Investigator 
Associate Professor Kristian Tonby, MD PhD 
Department of Infectious Diseases 
Oslo University Hospital  
Postboks 4956 Nydalen  
N-0424 Oslo  
Tel: +47 41 55 05 65 
E-mail: kritonby@ous-hf.no 
 
Investigator 
Researcher Åse Garløv Riis 
Department of Infectious Diseases  
Stavanger University Hospital  
Postboks 8100  
4068 Stavanger  
Tel: +47 45 21 71 23  
E-mail: ase.garlov.riis@sus.no 
 

 
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Investigator 
Researcher Asgeir Johannessen, MD PhD 
Department of Infectious Diseases  
Vestfold Hospital Trust  
Postboks 2168 
3103 Tønsberg 
Tel: +47 97 98 32 64 
E-mail: asgeir.johannessen@siv.no 
 
Investigator 
Researcher Sara Foss Debes, MD PhD 
Center for Laboratory Medicine  
Østfold Hospital Trust Kalnes  
1714 Grålum, Norway 
Tel: +47 95 86 86 06 
E-mail: sara.foss.debes@so-hf.no 
 
Investigator 
Researcher Hans Kristian Fløystad, MD  
Department of Internal Medicine  
Sørlandet sykehus Kristiansand  
Sørlandet sykehus HF 
Postboks 416 Lundsiden 
4604 Kristiansand 
Tel: +47 97 64 85 26 
E-mail: hans.kristian.floystad@sshf.no 
 
Investigator  
Researcher Marjut Anneli Sarjomaa, MD 
Infection Control  
Telemark Hospital Trust  
Postboks 2900 Kjørbekk 
3710 Skien  
Tel: +47 46 66 09 06 
E-mail: SARM@sthf.no   
 
 
Data Monitoring Committee: 
Postdoctoral Fellow Aleksander Rygh Holten, MD PhD 
Department of Infectious Diseases 
University of Oslo, OUS HF Ullevål 
Postboks 4956 Nydalen 
0424 Oslo 
Tel: +47 99 27 57 84 
E-mail: a.r.holten@medisin.uio.no  
 
Associate Professor Dag Henrik Reikvam, MD PhD 
Department of Infectious Diseases 
University of Oslo, OUS HF Ullevål 
Postboks 4956 Nydalen 
0424 Oslo 
Tel: +47 94 85 89 39 
E-mail: d.h.reikvam@medisin.uio.no  
 

 
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Monitor: 
Mari Wildhagen 
Clinical Trials Unit (CTU) 
Oslo University Hospital  
Postboks 4950 Nydalen 
0424 Oslo, Norway 
Tel: + 47 48 25 34 62 
E-mail: mawild@ous-hf.no 
 
Mariann Glenna Davidsen 
Division of Research and Innovation 
Akershus University Hospital 
Sykehusveien 25 
1478 Lørenskog, Norway 
Tel: +47 67 96 87 04 
E-mail: Mariann.Glenna.Davidsen@ahus.no  
 
Stine Lien Pedersen 
Division of Research and Innovation 
Akershus University Hospital 
Sykehusveien 25 
1478 Lørenskog, Norway 
Tel: +47 90 75 30 52 
E-mail: Stine.Lien.Pedersen@ahus.no  
 
Shalina Alom  
Department of Research and Development 
Haukeland University Hospital 
Postboks 1400 
5021 Bergen, Norway 
Tel: +47 93633272 
E-mail: shalina.alom@helse-bergen.no 
 
Mari Johannessen Walquist  
Department of Clinical Research   
University Hospital of North Norway 
Postboks 100 
9038 Tromsø 
Tel: +47 76 17 63 88 
E-mail: mari.walquist@unn.no 
 
Statistician: 
Jurate Saltyte Benth, PhD 
Health Services Research Unit 
Akershus University Hospital 
Sykehusveien 25 
1478 Lørenskog, Norway 
Tel: +47 48 22 44 31 
E-mail: j.s.benth@medisin.uio.no  
 

 
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SIGNATURE PAGE 
 
Title 
Antibiotic THErapy iN vIral Airway iNfections (ATHENIAN): An open labelled randomized controlled 
pragmatic trial to evaluate the efficacy and safety of discontinuing antibiotic therapy in adult patients 
infected with respiratory viruses 
Protocol ID: 
ATHENIAN 
EudraCT no: 
2021-004248-11 
 
 
I hereby declare that I will conduct the study in compliance with the Protocol, ICH GCP and the applicable 
regulatory requirements: 
 
Name 
Title 
Role 
Signature 
Date 
Jan Erik Berdal 
Head of Department/ 
Associate Professor 
Sponsor’s representative 
 
 
Magnus Nakrem 
Lyngbakken 
Associate Professor 
Principal investigator 
 
 
 
 

 
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SIGNATURE PAGE SITE INVESTIGATORS 
 
Title 
Antibiotic THErapy iN vIral Airway iNfections (ATHENIAN): An open labelled randomized controlled 
pragmatic trial to evaluate the efficacy and safety of discontinuing antibiotic therapy in adult patients 
infected with respiratory viruses 
Protocol ID: 
ATHENIAN 
EudraCT no: 
2021-004248-11 
 
 
I hereby declare that I will conduct the study in compliance with the Protocol, ICH GCP and the applicable regulatory 
requirements: 
 
 
 
 
Name 
Title 
Signature 
Date 
 
PROTOCOL SYNOPSIS 
 
Antibiotic THErapy iN vIral Airway iNfections (ATHENIAN): An open labelled randomized controlled pragmatic trial to 
evaluate the efficacy and safety of discontinuing antibiotic therapy in adult patients infected with respiratory viruses 
 
Sponsor 
Akershus University Hospital HF 
Phase and study type 
Phase 4, non-inferiority treatment trial 
Investigational Medical Product 
(IMP) (including active 
comparator and placebo) :        
Antibiotic therapy 
No active or placebo control 
Centers: 
Akershus University Hospital HF  
St. Olavs hospital 
University Hospital of North Norway 
Haukeland University Hospital  
Drammen Hospital, Vestre Viken Hospital Trust 
Oslo University Hospital  
Stavanger University Hospital  
Vestfold Hospital Trust  
Østfold Hospital Trust 
Sørlandet hospital Kristiansand 
Telemark Hospital Trust 

 
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Study Period: 
 
Estimated date of first patient enrolled: 01.12.21 
Anticipated recruitment period: 54 months 
End of study (last patient’s last visit): 01.05.2026 
Estimated study termination: 30.11.29 
Time-frame of study data retention: 30.11.44 
 
Treatment Duration: 
At the discretion of the treating physician in the control arm of the study 
Follow-up: 
At five and 30 days 
Objectives  
Overall objective:  
In patients with positive airway sample for respiratory viruses, assess whether 
discontinuation of antibiotic therapy is safe and non-inferior to continuation of 
antibiotic therapy 
 
Specific objectives: 
In patients with positive airway sample for respiratory viruses, assess whether 
discontinuation of antibiotic therapy is non-inferior to continuation of antibiotic therapy 
with regard to 
 
1. Early clinical response 
2. In-hospital mortality and mortality after 30 days 
3. Duration of hospital admission 
4. Days of therapy with antibiotics 
5. Rescue antibiotic therapy during hospital admission 
6. New antibiotic therapy up to 30 days after discharge 
7. Hospital readmission up to 30 days after discharge 
Endpoints: 
Primary endpoint: 
• 
Early clinical response assessed at 120 hours after randomization, defined as 
survival with symptom improvement without receipt of rescue antibacterial 
therapy 
Secondary endpoints: 
• 
In-hospital mortality 
• 
Mortality at 30 days 
• 
Duration of hospital admission 
• 
Days of therapy with antibiotics 
• 
Rescue antibiotic therapy during hospital admission 
• 
New antibiotic therapy for presumed airway infection up to 30 days after 
discharge 
• 
Hospital readmissions up to 30 days after discharge 
Study Design: 
Two-arm, open label, multicenter, pragmatic study 
Main Inclusion Criteria:    
1. Hospitalized 
2. Adults 18 year or older 
3. Moderately severe disease (CRB65 ≤ 2 at time of inclusion) 
4. Nasopharyngeal swab positive for influenza virus,  parainfluenza virus, respiratory 
syncytial virus (RSV) or human metapneumovirus (hMPV) 
5. On antibiotic therapy as instituted by the receiving physician from the emergency 
department 

 
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6. Signed informed consent must be obtained and documented according to ICH 
GCP, and national/local regulations. 
Main Exclusion Criteria 
1. Requiring ICU admission at screening 
2. Requiring high-flow oxygen therapy or non-invasive ventilation at screening 
3. Signs of severe pneumonia (abscesses, massive pleural effusion, a well-defined 
lobar infiltrate on chest X-ray strongly suggestive of bacterial etiology) 
4. Not immunocompetent (i.e. on active chemotherapy, corticosteroid therapy 
equaling ≥ 20 mg prednisolone daily for ≥ 4 weeks, chronic immunosuppression 
due to solid organ transplant) 
5. SARS-CoV-2 positive 
6. Bacteremia 
7. Urine antigen test positive for legionella 
8. Any other infection necessitating antibiotic treatment 
9. Antibiotic use for assumed airway infection within the last 24 hours before 
admission to hospital 
10. Time from initiation of antibiotic therapy to screening >48 hours  
Sample Size: 
380 patients (1:1 randomized to intervention and control), considering screening 
failure and loss to follow-up, we will aim to include at least 400 patients 
Efficacy Assessments: 
Early clinical response assessed at 120 hours after randomization, defined as 
survival with symptom improvement without receipt of rescue antibacterial therapy 
Safety Assessments: 
Serious Adverse Events (SAE) and Suspected Unexpected Serious Adverse 
Reactions (SUSAR). 

 
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TABLE OF CONTENTS 
 
CONTACT DETAILS .......................................................................................................................................................... 2 
SIGNATURE PAGE ............................................................................................................................................................ 6 
SIGNATURE PAGE SITE INVESTIGATORS ..................................................................................................................... 7 
PROTOCOL SYNOPSIS .................................................................................................................................................... 7 
TABLE OF CONTENTS ................................................................................................................................................... 10 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .......................................................................................... 13 
1 
INTRODUCTION ...................................................................................................................................................... 13 
1.1 
Background – Disease ....................................................................................................................................... 13 
1.2 
Background - Therapeutic Information ............................................................................................................... 14 
1.3 
Rationale for the Study and Purpose .................................................................................................................. 14 
2 
STUDY OBJECTIVES AND RELATED ENDPOINTS ............................................................................................. 14 
2.1 
Primary Endpoint ................................................................................................................................................ 15 
2.2 
Secondary Endpoints ......................................................................................................................................... 15 
3 
OVERALL STUDY DESIGN ..................................................................................................................................... 16 
4 
STUDY POPULATION ............................................................................................................................................. 17 
4.1 
Selection of Study Population ............................................................................................................................. 17 
4.2 
Number of Patients ............................................................................................................................................. 17 
4.3 
Inclusion Criteria ................................................................................................................................................. 17 
4.4 
Exclusion Criteria ................................................................................................................................................ 18 
5 
TREATMENT............................................................................................................................................................ 18 
5.1 
Drug Identity, Dosage and Administration .......................................................................................................... 18 
5.2 
Duration of Therapy ............................................................................................................................................ 18 
5.3 
Concomitant Medication ..................................................................................................................................... 18 
5.4 
Subject Compliance ............................................................................................................................................ 18 
5.5 
Drug Accountability ............................................................................................................................................. 19 
5.6 
Subject Numbering ............................................................................................................................................. 19 
6 
RISKS AND BENEFITS ........................................................................................................................................... 19 
7 
STUDY PROCEDURES ........................................................................................................................................... 19 
7.1 
Criteria for Patient Discontinuation ..................................................................................................................... 20 
7.2 
Procedures for Discontinuation .......................................................................................................................... 20 
7.2.1 
Patient Discontinuation ................................................................................................................................. 20 
7.2.2 
Trial Discontinuation ..................................................................................................................................... 20 
7.3 
Laboratory Tests ................................................................................................................................................. 21 
7.4 
Clinical variables ................................................................................................................................................. 21 
8 
ASSESSMENTS....................................................................................................................................................... 22 

 
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8.1 
Assessment of Efficacy / Response ................................................................................................................... 22 
8.2 
Safety and Tolerability Assessments .................................................................................................................. 22 
9 
SAFETY MONITORING AND REPORTING ............................................................................................................ 23 
9.1 
Adverse Events .................................................................................................................................................. 23 
9.2 
Serious Adverse Event (SAE) ............................................................................................................................ 23 
9.3 
Suspected Unexpected Serious Adverse Reactions (SUSAR)........................................................................... 23 
9.4 
Safety and reporting ........................................................................................................................................... 23 
9.5 
Data Monitoring Committee (DMC) .................................................................................................................... 24 
10 DATA MANAGEMENT AND MONITORING ............................................................................................................ 24 
10.1 Electronic Case Report Forms (eCRF) ............................................................................................................... 24 
10.2 Source Data........................................................................................................................................................ 24 
10.3 Study Monitoring ................................................................................................................................................. 24 
10.4 Confidentiality ..................................................................................................................................................... 25 
10.5 Database management ...................................................................................................................................... 25 
11 STATISTICAL METHODS ....................................................................................................................................... 25 
11.1 Determination of Sample Size ............................................................................................................................ 25 
11.2 Randomization .................................................................................................................................................... 26 
11.2.1 Allocation - sequence generation ................................................................................................................. 26 
11.2.2 Allocation - procedure to randomize a patient .............................................................................................. 26 
11.2.3 Blinding and emergency unblinding.............................................................................................................. 26 
11.3 Population for Analysis ....................................................................................................................................... 26 
11.4 Planned analyses ............................................................................................................................................... 27 
11.5 Statistical Analysis .............................................................................................................................................. 27 
11.5.1 Primary analysis ........................................................................................................................................... 27 
11.5.2 Secondary analyses ..................................................................................................................................... 27 
11.5.3 Safety analyses ............................................................................................................................................ 28 
11.5.4 Descriptive statistics ..................................................................................................................................... 28 
11.5.5 Missing data ................................................................................................................................................. 28 
11.5.6 Subgroup analyses ....................................................................................................................................... 28 
12 STUDY MANAGEMENT .......................................................................................................................................... 28 
12.1 Investigator Delegation Procedure ..................................................................................................................... 28 
12.2 Protocol Adherence ............................................................................................................................................ 28 
12.3 Study Amendments ............................................................................................................................................ 29 
12.4 Audit and Inspections ......................................................................................................................................... 29 
13 ETHICAL AND REGULATORY REQUIREMENTS ................................................................................................. 29 
13.1 Ethics Committee Approval ................................................................................................................................ 29 
13.2 Other Regulatory Approvals ............................................................................................................................... 29 
13.3 Informed Consent Procedure ............................................................................................................................. 29 

 
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13.4 Subject Identification .......................................................................................................................................... 29 
14 TRIAL SPONSORSHIP AND FINANCING .............................................................................................................. 30 
15 TRIAL INSURANCE ................................................................................................................................................. 30 
16 PUBLICATION POLICY ........................................................................................................................................... 30 
17 LIST OF APPENDICES ............................................................................................................................................ 30 
18 REFERENCES ......................................................................................................................................................... 30 
 
 

 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation or special term 
Explanation 
AE 
Adverse Event  
CRF 
Case Report Form (electronic/paper) 
CSA 
Clinical Study Agreement 
DAE 
Discontinuation due to Adverse Event 
EC 
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC) 
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization 
IMP 
Investigational Medicinal Product (includes active comparator and placebo) 
ITT 
Intention to treat 
PP 
Per-protocol 
SAE 
Serious Adverse Event   
SAP 
Statistical Analysis Plan 
SOP 
Standard Operating Procedure 
 
1 
INTRODUCTION 
1.1 
Background – Disease  
Patients with lower respiratory tract infections constitute a heterogeneous group of patients with substantial short- and 
long-term mortality, and community acquired pneumonia (CAP) is a leading cause of morbidity and mortality worldwide. 
The etiology of CAP is often not possible to determine even in stringent scientific studies. The most commonly identified 
agents are typical bacteria (e.g. S. pneumoniae and H influenzae), atypical bacteria (e.g. Legionella species and 
Mycoplasma pneumoniae), or respiratory viruses (e.g. influenza viruses and respiratory syncytial virus) (1). In a large 
epidemiological study conducted by the Centers for Disease Control and Prevention, despite the extensive diagnostic 
workup performed, no pathogen was detected in 62 per cent of the cases. A viral pathogen was detected as single 
pathogen in 22 per cent, whereas solely bacterial pathogens were detected in 11 per cent and coinfection virus-bacteria 
were detected in 3 per cent of the cases (2). Among the viral pathogens detected, human rhinovirus was the most 
commonly detected followed by influenza virus. Common symptoms of CAP include fever, cough, dyspnea, and pleuritic 
chest pain, but clinical signs do not accurately reflect the underlying microbiological pathology. In the case of convincing 
signs and symptoms of CAP, antibiotic therapy is generally started immediately after admission, as delays in appropriate 
antibiotic treatment that exceed four hours have been associated with increased mortality (3). Considering the vastly 
diverse microbiological etiologies of CAP, frequently including a principal viral cause, antibacterial treatment is often 
futile and will only contribute to progressive antimicrobial resistance. 
 
Overuse of antibiotics is a main driver of antibiotic resistance. Misuse of antibiotics is particularly common in respiratory 
tract infections, where a large proportion is caused by respiratory viruses (2). In the hospital setting, widespread 
availability of nucleic acid amplification tests (NAAT) for respiratory tract specimens allows rapid viral detection, offering 
the possibility of withholding or stopping antibiotic therapy when respiratory viruses are believed to be causative agents. 
In the 2012 to 2013 winter season, the majority of patients admitted to Akershus University Hospital with RSV (82.7% 
n=133), H3N2 (73.3% n=176) and H1N1 (68.2% n=132) flu virus were treated with antibiotics. Data on the proportion of 
these patients who continued antibiotics after hospital discharge is unknown, but the prescription pattern likely 
represents antibiotic overtreatment. 
 

 
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In an acutely ill patient with CAP, detection of respiratory viruses may represent infection involving the lower respiratory 
tract, but could also be colonization, persistent shedding after a prior infection or infection restricted to the upper 
respiratory tract (4). No clear consensus has been reached about whether patients with CAP and respiratory viruses 
detected in the respiratory tract need to be treated with antibiotics, but antibiotic treatment for all hospitalized patients 
with CAP is commonly recommended due to the near impossibility of excluding bacterial co-infection. However, a 
general recommendation to treat all hospitalized CAP patients with antibiotics likely leads to significant antibiotic 
overtreatment (5). The wide availability of NAAT enables us to define individuals with CAP who can be managed without 
antibiotics.  
1.2 
Background - Therapeutic Information 
Antibiotic therapy has revolutionized modern medicine and made treatment of potentially life-threatening bacterial 
infections possible. However, antibacterial therapeutics have no effect on viruses, and merely subject the patient to side 
effects besides contributing to increasing antimicrobial resistance. Specific antiviral therapy is limited, especially for 
respiratory viruses, and supportive care is usually the treatment of choice in established viral respiratory infections. 
1.3 
Rationale for the Study and Purpose 
In patients with positive airway sample for respiratory viruses, we hypothesize that discontinuation of antibiotic therapy is 
safe and non-inferior to continuation of antibiotic therapy. More specifically, we hypothesize that the early clinical response 
assessed at 120 hours after randomization, defined as survival with symptom improvement without receipt of rescue 
antibacterial therapy, will be similar between patients who discontinue and continue antibiotic therapy. Furthermore, we 
hypothesize that discontinuation of antibiotic therapy is associated with similar mortality rates, duration of hospital 
admission, readmission rates and reduced number of days of therapy with antibiotics. Antimicrobial resistance is one of 
the most urgent health threats of our time, and Norwegian hospitals were required but failed to reduce the use of broad-
spectrum antibiotics with 30% by the end of 2020. In this context, novel initiatives aiming at reducing use of antibiotics are 
direly needed. 
2 
STUDY OBJECTIVES AND RELATED ENDPOINTS 
The primary aim is to assess whether discontinuation of antibiotic therapy in patients with positive airway sample for 
respiratory viruses is safe and associated with early clinical response assessed at 120 hours after randomization that is 
comparable to patients who continue antibiotic therapy. 
The secondary aims are to assess whether discontinuation of antibiotic therapy in patients with positive airway sample 
for respiratory viruses is associated comparable (1) mortality rates, (2) duration of hospital admission, (3) days of therapy 
with antibiotics, (4) rate of rescue antibiotic therapy during hospital admission, (5) frequency of new antibiotic therapy 
after discharge, and (6) hospital readmissions.  
 
Specific objectives 
• 
In patients with positive airway sample for respiratory viruses, assess the impact of discontinuing antibiotic therapy 
on early clinical response quantified as survival with symptom improvement without receipt of rescue antibacterial 
therapy. Early clinical response is defined as improvement of one or more levels relative to baseline in two or more 
symptoms of the investigator’s assessment of symptoms of community-acquired bacterial pneumonia and no 
worsening of one or more levels in other symptoms (Table 1). 
• 
In patients with positive airway sample for respiratory viruses, assess the impact of discontinuing antibiotic therapy 
on in-hospital mortality 
• 
In patients with positive airway sample for respiratory viruses, assess the impact of discontinuing antibiotic therapy 
on 30-day mortality 
• 
In patients with positive airway sample for respiratory viruses, assess the impact of discontinuing antibiotic therapy 
on duration of hospital admission 

 
Protocol ATHENIAN Version no. 1.13 – 13.12.2024 
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• 
In patients with positive airway sample for respiratory viruses, assess the impact of discontinuing antibiotic therapy 
on days of therapy with antibiotics 
• 
In patients with positive airway sample for respiratory viruses, assess the impact of discontinuing antibiotic therapy 
on rescue antibiotic therapy 
• 
In patients with positive airway sample for respiratory viruses, assess the impact of discontinuing antibiotic therapy 
on new prescriptions of antibiotics for airway infections up to 30 days after hospital discharge 
• 
In patients with positive airway sample for respiratory viruses, assess the impact of discontinuing antibiotic therapy 
on hospital readmissions up to 30 days after hospital discharge 
 
2.1 
Primary Endpoint  
• 
Early clinical response at 120 hours after randomization, quantified as survival with symptom improvement without 
receipt of rescue antibacterial therapy. 
2.2 
Secondary Endpoints 
• Duration of hospital admission 
• In-hospital mortality 
• 30-day mortality 
• Days of therapy with antibiotics 
• In-hospital rescue antibiotic therapy 
Table 1. Symptom severity assessment  
Absent  
Mild  
Moderate  
Severe 
COUGH? 
No cough or resolution of 
cough to pre-CAP baseline 
Cough present but it does not 
interfere with subject’s usual 
daily activities 
Cough present, frequent and 
it does interfere with some of 
the subject’s usual daily 
activities 
Cough is present throughout 
the day and night; it limits 
most of the subjects’ usual 
daily activities and sleep 
patterns 
PLEURITIC CHEST PAIN? 
No chest pain or resolution of 
chest pain to pre-CAP 
baseline 
Chest pain present 
occasionally with deep 
breathing but it does not 
interfere with subject’s usual 
daily activities 
Chest pain is present with 
normal breaths and it does 
interfere with the subject’s 
usual daily activities 
Chest pain is present at rest 
and/or with shallow breathing; 
it limits most of the subject’s 
usual daily activities 
SHORTNESS OF BREATH? 
No shortness of breath or 
resolution of shortness of 
breath to pre-CAP baseline 
Shortness of breath with 
strenuous activities only but it 
does not interfere with 
subject’s usual daily activities 
Shortness of breath with 
usual activities and it does 
interfere with the subject’s 
usual daily activities 
Shortness of breath with 
minimal exertion or at rest; it 
limits most of the subject’s 
usual daily activities 
PHLEGM/SPUTUM PRODUCTION? 
No coughing up of 
phlegm/sputum or resolution 
of coughing up 
phlegm/sputum to pre-CAP 
baseline 
Subject coughs up a small 
amount of phlegm/sputum 
Subject coughs up a 
moderate amount of 
phlegm/sputum 
Subject coughs up a large 
amount of phlegm/sputum 
From Stets et al. N Engl J Med. 2019;380:517-527. (6) 

 
Protocol ATHENIAN Version no. 1.13 – 13.12.2024 
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• New antibiotic therapy for assumed airway infection within 30 days after discharge 
• Hospital readmissions up to 30 days after discharge  
 
3 
OVERALL STUDY DESIGN 
The study is a two-arm, open label, pragmatic randomized controlled non-inferiority stop trial designed to assess the safety 
and efficacy of discontinuing antibiotic therapy in patients with positive airway sample for respiratory viruses. Pragmatic 
clinical trials (PCT) are characterized by 3 attributes: (1) focus on informing decision-makers (e.g. patients, politicians, 
administrators) on optimal clinical medicine practice, as opposed to elucidating a biological or social process; (2) intent to 
enroll a population representative to the decision in practice and for whom the decision is relevant; and (3) either an intent 
to streamline procedures and data collection in the trial or to measure a broad range of outcomes. By utilizing resources 
already paid for by the hospitals (physicians and nurses in daily clinical practice), pragmatic clinical trials can include a 
larger number of patients at a short time duration and at a lower cost than studies utilizing traditional randomized controlled 
trial (RCT) designs with an external study organization (e.g. study nurses, study physicians). A pragmatic approach will 
enable swift initiation of randomization and treatment. We will especially use data from the data warehouse for eligible 
patient identification (i.e. electronic surveillance) and for automatic data extraction to the study specific database. The 
study will examine the effects of discontinuing treatment and the study will accordingly not be placebo-controlled. 
 
In the initial phase of the study, patients will be included from a single center (Akershus University Hospital). With the 
extension to a multicenter study from winter 2023/2024, patients will be included from ten additional study sites (St. Olavs 
hospital, University Hospital of North Norway, Haukeland University Hospital, Drammen Hospital, Vestre Viken Hospital 
Trust, Oslo University Hospital, Stavanger University Hospital, Vestfold Hospital Trust, Østfold Hospital Trust, Sørlandet 
hospital Kristiansand and Telemark Hospital Trust). The study will have interim efficacy and safety analyses after the 
inclusion of 40 patients or after the first winter season (March 2022), whichever comes first. Subsequent interim analyses 
will be performed after 100 and 200 completed patients. Extraordinary interim meeting will also be conducted if deemed 
necessary by the Sponsor. This approach will enable frequent assessment of the primary outcome measure and safety 
measures. See Section 10 Statistical methods and data analysis for further details. 
 
All patients admitted to one of the eleven study sites with suspicion of acute respiratory tract infections are examined with 
a nasopharyngeal swab, with subsequent microbiological examination, including specific polymerase chain reaction (PCR) 
for respiratory viruses. Laboratory reports from the Department of Microbiology are surveilled real-time for positive samples 
in the local data warehouse, which will allow for immediate screening and randomization in all eligible subjects. Figure 1 
gives a schematic overview of the study. 
 
 
 
Figure 1. Trial design 
 
Study Period of initial 
study phase:  
 
Estimated date of first patient enrolled: 01.12.21 
Anticipated recruitment period: 54 months 
Estimated date of last patient completed: 01.05.2026 

 
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Estimated study termination: 30.11.29 
Treatment Duration: 
Patients randomized to continuation of antibiotic therapy will be treated according to the 
discretion of the treating physician, commonly five days of antibiotic therapy if suspicion of 
pneumonia 
Follow-up: 
Symptom severity assessment at 120 hours after randomization 
Mortality assessment during admission and after 30 days 
4 
STUDY POPULATION 
4.1 
Selection of Study Population 
Participants will be recruited from the entirety of the inpatients at the participating hospitals. Electronic real-time 
surveillance of laboratory reports from the Department of Microbiology will be examined regularly, with maximum interval 
24 hours, for patients positive for respiratory viruses. 
4.2 
Number of Patients 
We aim to include a total of 380 patients randomized in a 1:1 fashion to intervention (stop antibiotic therapy) or control 
(continue antibiotic therapy at the discretion of the treating physician). Interim analyses are planned after 40, 100, and 200 
included patients. See Section 10 Statistical methods and data analysis for further details on the analysis populations. 
4.3 
Inclusion Criteria 
All of the following conditions must apply to the prospective patient at screening prior to inclusion: 
1. 
Hospitalized 
2. 
Adults 18 year or older 
3. 
Moderately severe disease (CRB65 ≤ 2 at time of inclusion; Figure 2) 
4. 
Nasopharyngeal swab positive for influenza virus, parainfluenza virus, respiratory syncytial virus (RSV) or human 
metapneumovirus (hMPV) 
5. 
On antibiotic therapy as instituted by the receiving physician from the emergency department 
6. 
Signed informed consent must be obtained and documented according to ICH GCP, and national/local regulations.  
 
 
Figure 2. CRB65 severity score. From Lim et al. Thorax. 2009 Oct;64 Suppl 3:iii1-55. (7) 
 

 
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4.4 
Exclusion Criteria 
Patients will be excluded from participation in the study if they meet any of the following criteria: 
1. 
Requiring ICU admission at screening 
2. 
Requiring high-flow oxygen therapy or non-invasive ventilation at screening 
3. 
Signs of severe pneumonia (abscesses, massive pleural effusion, a well-defined lobar infiltrate on chest X-ray 
strongly suggestive of bacterial etiology) 
4. 
Not immunocompetent (i.e. on active chemotherapy, corticosteroid therapy equaling ≥ 20 mg prednisolone daily for 
≥ 4 weeks, chronic immunosuppression due to solid organ transplant) 
5. 
SARS-CoV-2 positive 
6. 
Bacteremia 
7. 
Urine antigen test positive for legionella 
8. 
Any other infection necessitating antibiotic treatment 
9. 
Antibiotic use for assumed airway infection within the last 24 hours before admission to hospital 
10. Time from initiation of antibiotic therapy to screening >48 hours 
5 
TREATMENT 
Antibiotic therapy has limited effect in infection due to respiratory viruses. Early in the ongoing SARS-CoV-2 pandemic, 
antibiotic therapy was frequently prescribed to patients admitted with covid-19 due to fear to bacterial coinfections. 
Coinfection are however infrequent in patients hospitalized with covid-19, and current guidelines do not recommend 
empiric antibiotic therapy in patients with moderate disease not in need of ICU admission (8). The wide availability of NAAT 
for rapid viral detection together with radiographic CAP has the potential to define patients who can be managed without 
antibiotics.  
 
The active intervention in this study is to stop antibiotic therapy in patients with positive airway sample for respiratory 
viruses. Patients randomized to the control group will continue antibiotic therapy at the discretion of the treating physician. 
Apart from this, local standard-of-care will apply to all study patients. 
5.1 
Drug Identity, Dosage and Administration 
At enrollment, all patients will be under antibiotic treatment as initiated by the receiving physician in the emergency 
department. All included patients randomized to intervention will discontinue antibiotic therapy, and all patients randomized 
to the control group will continue antibiotic therapy at the discretion of the treating physician.  
 
All drug treatment will be provided by the participating hospitals as part of clinical routine. 
5.2 
Duration of Therapy 
Duration of therapy for study patients randomized to the control group is at the discretion of the treating physician, study 
participants randomized to the intervention group will discontinue antibiotic therapy at randomization. 
5.3 
Concomitant Medication 
Data on prescription of antimicrobial therapy and oseltamivir during hospital admission will be retrieved from the hospital 
electronic prescribing system. 
5.4 
Subject Compliance 
All study medication will be administered by health care personnel during hospital admission. Study patients discharged 
with per oral antibiotic therapy will not be followed up with regard to compliance. 

 
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5.5 
Drug Accountability 
Not applicable.  
5.6 
Subject Numbering 
Each subject is identified in the study by a unique subject number that is assigned when subject signs the Informed 
Consent Form. Once assigned the subject number cannot be reused for any other subject.  
 
6 
RISKS AND BENEFITS 
As described previously, antimicrobial resistance is one of the most urgent health threats of our time and overuse of 
antibiotics is a main driver of antibiotic resistance. In this context, novel initiatives aiming at reducing use of antibiotics 
are direly needed. This study holds strong potential to influence established clinical practice and contribute to novel 
approaches in the management of lower airway infections.  
A personal benefit for the participant is a closer follow-up than the clinical routine with the assessment 120 hours after 
randomization. The participants may also find the opportunity to contribute to research meaningful. A reduction in 
antibiotic-resistant microbes will benefit the future patients and the participant themselves when they need antibiotics for 
an infection caused by a bacteria. Participants in the intervention group will have reduced risk of antibiotic-related side 
effects, such as infection caused by C. difficile.   
In all antibiotic stewardship programs, antibiotic de-escalation and discontinuation inevitably carry a risk to the individual 
for the benefit of the community at large, as the non-existence of a condition (bacterial infection) cannot be proven. For 
the participant there is a potential risk of undertreatment of a bacterial co-infection despite the detection of respiratory 
virus.  The risk will be minimized by including only low-to-moderate risk patients, offering close monitoring and deferring 
discontinuation decisions to after a short observation period where one to three doses of antibiotics are given pending 
results of NAAT for viruses. A pragmatic study design allows rescue antibiotic therapy at the discretion of the treating 
physician and participants will be encouraged to seek health care in case of deterioration after discharge. The possible 
benefits on individual, national and international scale greatly outweighs individual risk. 
 
7 
STUDY PROCEDURES 
As described in Section 3, the current study will utilize a pragmatic approach. In this regard, we will utilize resources 
already paid for by the hospitals, and all study procedures will be performed at the discretion of the treating physician, 
including laboratory testing, medical imaging and other procedures deemed clinically necessary (Table 2). 
 
 

 
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Table 2. Study flow chart 
 
Time after randomization 
 
Admission 
Randomization 
24 h 
48 h 
72 h 
96 h 
120h 
30 d 
Nasopharyngeal test 
X 
 
 
 
 
 
 
 
Inclusion/exclusion evaluation 
 
X 
 
 
 
 
 
 
Informed consent 
 
X 
 
 
 
 
 
 
Physical examination 
1X 
 
2X 
2X 
2X 
2X 
2X 
 
Blood samples 
2X 
 
2X 
2X 
2X 
2X 
2X 
 
SAE and SUSAR3 
 
 
X 
X 
X 
X 
X 
 
Record of concurrent medication4 
 
X 
 
 
 
 
 
 
Mortality 
 
 
X 
X 
X 
X 
X 
X 
Symptom severity assessment 
 
X 
 
 
 
 
5X 
 
1Clinical examination at the discretion of the admitting physician (full clinical examination including heart, lungs, abdomen, 
extremities), as well as medical history, substance use, allergies, current medication, etc. 
2At the discretion of the treating physician 
3If discharged before end of treatment, assessment of SAE will be performed by phone directly to the patient at 120 hours 
4Current medication at admission and antimicrobial therapy initiated at admission 
5By phone if discharged 
 
7.1 
Criteria for Patient Discontinuation  
Patients may be discontinued from the study any time. Specific reasons for discontinuing a patient for this study are: 
 
• 
Voluntary discontinuation by the patient who is at any time free to discontinue his/her participation in the study, 
without prejudice to further treatment. 
• 
Incorrect enrolment i.e. the patient does not meet the required inclusion/exclusion criteria for the study 
7.2 
Procedures for Discontinuation 
7.2.1 
Patient Discontinuation 
The reason for discontinuation will be recorded, if the patient chooses to disclose it. Management of patients who 
withdraw or are withdrawn from the study will have to be individualized and will be discussed with the Local project 
manager at each study site and the Principal Investigator. All patients randomized will be included in the study 
population. 
7.2.2 
Trial Discontinuation 
The whole trial may be discontinued at the discretion of the sponsor in the event of any of the following: 
1. Occurrence of SAEs unknown to date in respect of their nature, severity and duration that may negatively affect 
the benefit/risk of the trial. 
2. Medical or ethical reasons affecting the continued performance of the trial 
3. Difficulties in the recruitment of patients 
4. The sponsor and principal investigator(s) will inform all investigators, the relevant Competent Authorities and 
Ethics Committees of the termination of the trial along with the reasons for such action. If the study is terminated 
early on grounds of safety, the Competent Authorities and Ethics Committees will be informed within 15 days. 

 
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7.3 
Laboratory Tests 
On admission, a standard panel of laboratory test will be performed on all patients (covering hematology, electrolytes, 
liver- and renal function, standard serology, inflammatory markers), and these will be performed locally in accordance with 
hospital/laboratory standard procedures. Nasopharyngeal sampling, blood cultures and urine antigen tests will be 
performed at the discretion of the receiving physician in the emergency department. 
7.4 
Clinical variables 
Collection of clinical variables will start at admission and for the entirety of the hospital stay. Data will be collected from the 
hospital electronic record system, including electronic patient records, laboratory and medical imaging systems, and 
prescribing systems. The data warehouse at each study site will be utilized for automatic data extraction to the study 
specific database if possible. All clinical variables will be registered in the study eCRF system, including clinical endpoints. 
 
Data retrieved from hospital electronic record system 
Date of birth 
 
Sex 
 
Dependency level 
 
Admission date 
 
Discharge date 
 
Date of symptom onset 
 
Admission signs and symptoms 
Chills 
Sore throat 
Myalgia 
Cough 
Sputum production 
Chest pain 
Shortness of breath 
Headache 
Gastrointestinal symptoms 
Confusion  
Acute functional decline  
Imaging on admission (chest X-ray, CT, etc)  
Infiltrates 
Pleural effusion 
Ground glass opacities 
Co-morbidities 
Hypertension 
Cardiovascular disease 
Chronic obstructive pulmonary disease 
Chronic kidney disease 
Diabetes mellitus 
Cognitive impairment/dementia 
Cancer 
Neurological disease  
Substance use 
Tobacco consumption 
Clinical biochemistry on admission 
At the discretion of the treating physician  
Results from microbiology 
Nasopharyngeal specimen 
Blood culture results 
Legionella urine antigen tests  
Anthropometrics  
Height (cm) 

 
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Weight (kg) 
Vital signs at inclusion 
Respiratory rate 
Oxygen saturation 
Supplemental oxygen 
Temperature 
Blood pressure 
Heart rate 
Level of consciousness (alert, verbal, pain, unresponsive) 
NEWS2 score 
Medical therapy/medication 
Antimicrobial therapy initiated at admission 
Antimicrobial therapy during admission 
Oseltamivir during admission  
Clinical outcomes 
Early clinical response (combination of all of the following) 
• 
Survival 
• 
Improvement of one or more levels relative to baseline in 
two or more symptoms of the investigator’s assessment of 
symptoms of community-acquired bacterial pneumonia and 
no worsening of one or more levels in other symptoms 
• 
No rescue antibiotic therapy 
 
Mortality (in-hospital and after 30 days) 
 
Duration of hospital admission 
 
Days of therapy with antibiotics, including antibiotic therapy during 
admission and per oral antibiotics after discharge 
 
Rescue antibiotic therapy during admission 
 
New antibiotic therapy prescribed for presumed airway infection 
within 30 days after discharge 
 
Hospital readmissions up to 30 days after discharge 
Safety monitoring and reporting 
Serious adverse events 
Suspected unexpected serious adverse reactions 
 
8 
ASSESSMENTS 
8.1 
Assessment of Efficacy / Response 
Early clinical response at 120 hours after randomization is the primary efficacy measure. 
8.2 
Safety and Tolerability Assessments  
Safety will be monitored by the assessments described below.  

 
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9 
SAFETY MONITORING AND REPORTING 
9.1 
Adverse Events 
An AE is any untoward medical occurrence in a patient in relation to administration of a pharmaceutical product and which 
does not necessarily have a causal relationship with this treatment. An adverse event (AE) can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.  
The term AE is used to include both serious and non-serious AEs. 
 
In the current study, the control group will continue antibiotic therapy as prescribed by the treating physician (i.e. “standard 
of care”). Common side effects of antibiotic therapy including nausea, vomiting, diarrhea, various skin rashes and other 
common side effects reported in the SPC (section «Bivirkninger») of the IMPs are considered expected effects in the 
control group and will not be recorded as AE. 
 
Traditional Adverse Event reporting, i.e. reporting side effects to the sponsor is not within the scope of this study for several 
reasons. The study is a stop trial investigating the safety and efficacy of discontinuing possibly futile treatment (antibiotic 
therapy for viral infection). Complications caused by the lack treatment does not constitute Adverse Event in this regard. 
Further, antibiotic therapy currently used at all study sites is approved by the Norwegian Medical Agency, and have 
established side effect profiles.  
9.2 
Serious Adverse Event (SAE) 
Any untoward medical occurrence that at any dose:  
• 
Results in death 
• 
Is immediately life-threatening 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization  
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital abnormality or birth defect 
• 
Is an important medical event that may jeopardize the subject or may require medical intervention to prevent one 
of the outcomes listed above, 
 
Medical and scientific judgment is to be exercised in deciding on the seriousness of a case. Important medical events may 
not be immediately life threatening or result in death or hospitalization, but may jeopardize the subject or may require 
intervention to prevent one of the listed outcomes in the definitions above. In such situations, or in doubtful cases, the case 
should be considered as serious. 
9.3 
Suspected Unexpected Serious Adverse Reactions (SUSAR) 
The Sponsor’s Medical Officer will review all SAEs reported as related to the trial drug and evaluate whether the event is 
expected according to the Reference Safety Information (RSI). The SPC of the current drug is used as Reference Safety 
Information in this trial. SUSARs will be reported to the Competent Authority according to national regulation. SUSARs will 
be reported to the Norwegian Medicines Agency and REK Sør-Øst according to national regulation. The sponsor will 
ensure that all relevant information about SUSARs that are fatal or life-threatening is recorded and reported as soon as 
possible and in no case later than seven days after knowledge by the sponsor of such a case, and that relevant follow-up 
information is subsequently communicated within an additional eight days. 
9.4 
Safety and reporting 
The Data Monitoring Committee (DMC) will overview the outcomes throughout the study. SAE and SUSAR will be surveyed 
and reported as described above. 

 
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9.5 
Data Monitoring Committee (DMC) 
A data monitoring committee (DMC) will be established to monitor the safety and efficacy of the study treatment and will 
consist of one statistician and two physicians with experience from virology/infectious disease and clinical studies. All 
members will be independent from the sponsor and will not be investigators or collaborators in the current study. The DMC 
will review all SAEs. The study investigators may call on the DMC to review specific SAEs. The DMC will conduct its tasks 
according to the EMA guideline (9). A DMC charter based on the NORCRIN template (10) will be signed and included in 
the Trial Master File. 
10 
DATA MANAGEMENT AND MONITORING   
10.1 
Electronic Case Report Forms (eCRF) 
The Clinical Data Management System (CDMS) used for the electronic case report form (eCRF) in this study was initially 
REDCap. After extension to multicenter study Viedoc is used as CDMS. The Investigators at each site will enter all data 
required by the protocol into the eCRF. The Investigators are responsible for assuring that data entered into the eCRF is 
complete, accurate, and that entry is performed in a timely manner. The signature of the investigators will attest the 
accuracy of the data on each eCRF. If any assessments are omitted, the reason for such omissions will be noted on the 
eCRFs. Corrections, with the reason for the corrections will also be recorded. After database lock, the investigator will 
receive a digital copy of the subject data for archiving at the investigational site. 
10.2 
Source Data  
Source data are all information in original records and certified copies of original records of clinical findings, observations, 
or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained 
in source documents (original records or certified copies). 
 
The medical records for each patient should contain information that is important for the patient’s safety and continued 
care, and to fulfil the requirement that critical study data should be verifiable. To achieve this, the medical records of each 
patient should clearly describe at least: 
 
• 
That the patient is participating in the study, e.g. by including the enrolment number and the study code or other 
study identification; 
• 
Date when Informed Consent was obtained from the patient and statement that patient received a copy of the 
signed and dated Informed Consent; 
• 
Results of all assessments confirming a patient’s eligibility for the study; 
• 
Diseases (past and current; both the disease studied and others, as relevant); 
• 
Results of assessments performed during the study; 
• 
Serious Adverse Events (if any) including causality assessments;  
• 
Date of, and reason for, withdrawal from study; 
10.3 
Study Monitoring  
The investigator will be visited on a regular basis by the Clinical Study Monitor, who will check the following: 
• 
Informed consent process 
• 
Reporting of adverse events and all other safety data 
• 
Adherence to protocol 
• 
Maintenance of required regulatory documents 
• 
Facilities and equipment if applicable 
• 
Data completion on the CRFs including source data verification 
 

 
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The monitor will review the relevant CRFs for accuracy and completeness and will ask the site staff to adjust any 
discrepancies as required.  
 
Sponsor’s representatives (e.g. monitors, auditors) and/or competent authorities will be allowed access to source data for 
source data verification in which case a review of those parts of the hospital records relevant to the study will be required.  
10.4 
Confidentiality 
The investigator shall arrange for the secure retention of the patient identification and the code list. Patient files shall be 
kept for the maximum period permitted by each hospital. The study documentation (CRFs, Site File etc) shall be retained 
and stored during the study and for 25 years after study closure. All information concerning the study will be stored in a 
safe place inaccessible to unauthorized personnel. 
10.5 
Database management 
Data management will be performed by the data management unit at the Clinical Trials Unit, Oslo University Hospital. The 
Data management procedures will be performed in accordance with the department’s SOPs and ICH guidelines. The data 
management process will be described in the study specific Data Handling Plan and the study specific Data Handling 
Report after database closure. 
Data entered into the eCRF will be validated as defined in the Data Validation Plan. Validation includes, but is not limited 
to, validity checks (e.g. range checks), consistency checks and customized checks (logical checks between variables to 
ensure that study data are accurately reported) for eCRF data and external data (e.g. laboratory data). A majority of edit 
checks will be triggered during data entry and will therefore facilitate efficient ‘point of entry’ data cleaning. 
 
Data management personnel will perform both manual eCRF review and review of additional electronic edit checks to 
ensure that the data are complete, consistent and reasonable. The electronic edit checks will run continually throughout 
the course of the study and the issues will be reviewed manually online to determine what action needs to be taken. 
Manual queries may be added to the system by clinical data management or study monitor. Clinical data managers and 
study monitors are able to remotely and proactively monitor the patient eCRFs to improve data quality. 
 
All updates to queried data will be made by authorized study center personnel only and all modifications to the database 
will be recorded in an audit trail. Once the queries have been resolved, eCRFs will be signed by electronic signature. Any 
changes to signed eCRFs will be approved and resigned by the Investigator. 
Medical history will be coded from the verbatim description (Investigator term) using the Medical Dictionary for Regulatory 
Activities (MedDRA).Once the full set of eCRFs have been completed and locked, the Sponsor will authorize database 
lock and all electronic data will be sent to the designated statistician for analysis. Subsequent changes to the database 
will then be made only by written agreement. 
 
The data will be stored in dedicated and secured areas at all study sites. Akershus University Hospital will additionally 
store copies of all data from all study sites, including signed consent forms. Data will be stored in a de-identified manner, 
where each study participant is recognizable by his/her unique trial subject number. The data will be stored until 25 years 
following the last patient’s final study visit. 
11 
STATISTICAL METHODS 
11.1 
Determination of Sample Size 
The clinical course of viral airway infections is heterogeneous and depend on patient demographics and comorbidities, as 
well as causative viral agent. In patients with influenza, clinical improvement is expected at around day 3 to 7 (11, 12). The 
proportion of study patients with early clinical improvement from randomization to 120 hours will be used as the basis for 
determination of sample size. Early clinical improvement does not equate to complete resolution of symptoms, and the in-
hospital mortality rate of moderately ill patients admitted with viral airway infections is very low. Accordingly, we assume 

 
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an early clinical improvement of 90% in both treatment groups, with a non-inferiority margin of 10%. Under these 
assumptions using a 2.5% one-sided significance level and 90% power, we would need to include a total of 380 patients 
(190 randomized to the intervention group and 190 randomized to the control group). To account for screening failures 
and loss to follow-up, we aim to include up to 400 patients in the current study. The first interim analysis will be at 40 
included patients, and subsequent interim analyses will be performed after 100 and 200 completed patients. Extraordinary 
interim meeting will also be conducted if deemed necessary by the Sponsor.  
 
The study will be conducted at multiple sites in Norway and a possible clustering effect on site level might be present. 
However, Norway has a universal health care system with equal access for all citizens and patient treatment algorithms 
for hospital admitted patients are homogenous throughout the country. There is therefore little reason to believe that 
treatment and short-term outcomes for respiratory tract infections are vastly different in Norwegian hospitals, and the study 
intervention is expected to have similar effect across including sites, which are predominantly University hospitals and 
large regional hospitals. Due to a negligible risk of cluster effect, there was no adjustment implemented in the power 
calculations. 
 
11.2 
Randomization 
11.2.1 
Allocation - sequence generation 
Eligible patients will be allocated in a 1:1 ratio, using a computer-generated block-randomization procedure. The allocation 
sequence will be prepared by an independent statistician. The randomization sequence will use block randomization with 
randomized block sizes (2, 4, 6 and 8), and a separate randomization sequence will be prepared for each study site. At 
every newly included site, the stratified randomization will be performed to assure balanced arms within the site. No such 
stratification is performed in Akershus University Hospital. 
11.2.2 
Allocation - procedure to randomize a patient 
The computer-generated randomized allocation sequence will be imported into the eCRF system and made available to 
site personnel responsible for the participant enrolment. Randomization allocation will automatically be visible when 
enrolling a new eligible patient. This is an open-label study and no steps to conceal allocation are necessary.  
The study statistician will be blinded to the randomization allocation for the writing of the statistical analysis plan (SAP). 
The authorizations bound to role of the study statistician in the eCRF when reading or downloading data will ensure that 
the statistician will not see the treatment allocation until database lock.  
11.2.3 
Blinding and emergency unblinding 
This is an open-label study. However, the statistician responsible for analysis of the data will be blinded to the treatment 
allocation for the writing of the SAP. 
11.3 
Population for Analysis 
The following populations will be considered for the analyses:  
- 
Intention to treat (ITT) population: All randomized participants will be included in the main ITT analyses, 
regardless of protocol adherence.   
- 
Per-protocol population (PP): Includes all patients in the ITT population having completed the study treatment 
without major protocol violations. Criteria for inclusion in the PP population will be specified in the SAP and the 
final criteria will be defined prior to database lock 
- 
Safety population: Includes all subjects with any safety information after baseline. 
- 
Total population: All enrolled participants independent of study arm will be used for additional analyses in the 
total population.  
The primary population is the ITT population.   

 
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11.4 
Planned analyses 
Interim analyses are planned after 40, 100, and 200 completed patients.  
Each statistical analysis is planned when  
• 
The planned number of patients have been included  
• 
All included patients have either finalized their last assessment discharge or has/is withdrawn/lost to follow-up 
according to protocol procedures 
• 
All data have been entered, verified and validated according to the data management plan 
Prior to each statistical analysis, the data in the database will be exported and the exported data will be locked for further 
altering of data. A SAP will provide details on the planned statistical analyses. The SAP will be finalized, signed and dated 
prior to first interim analysis. The statistical interim analysis will be performed by an unblinded Data Monitoring Committee 
(DMC) statistician based on program code from the trial statistician. The trial statistician will remain blinded to treatment 
when finalizing the SAP prior to first interim analysis and throughout the trial until final database lock. The unblinded 
statistician performing the analysis will only provide the study group with information on whether the trial should be stopped 
or continued. Details of the DMC and their procedures will be given in a separate DMC charter.  
11.5 
Statistical Analysis 
11.5.1 
Primary analysis 
The primary outcome is early clinical response defined as a combination of all of the following:  
1. Survival 
2. Improvement of one or more levels relative to baseline in two or more symptoms of the investigator’s assessment 
of symptoms of community-acquired bacterial pneumonia and no worsening of one or more levels in other 
symptoms 
3. No rescue antibiotic therapy 
 
The primary outcome will be analyzed on the ITT population using a logistic regression model and direct comparison of 
proportions. 
11.5.2 
Secondary analyses 
1. Mortality (in-hospital and after 30 days) 
2. Duration of hospital admission 
3. Antibiotic therapy prescribed after discharge 
4. Days of therapy with antibiotics, including antibiotic therapy during admission and per oral antibiotics after 
discharge 
5. Rescue antibiotic therapy during admission 
6. New antibiotic prescription for presumed airway infection within 30 days after discharge 
7. Hospital readmissions up to 30 days after discharge 
 
Between group comparisons will be performed for the primary variable on the per-protocol population in addition to 
secondary efficacy endpoints on both efficacy populations (ITT and PP populations). 
 
The between-group comparisons for secondary variables will be tested as for the primary variable where applicable and 
additional analyses will be performed based on the following methods (but not limited to): 
- 
Continuous variables will be subject to linear regression models or appropriate non-parametric alternatives.  
- 
Time-to-event endpoints and durations will be analyzed using the Kaplan-Meier method and comparisons 
between the two groups will be performed using the log rank test or Cox regression analyses. 
- 
Binary response variables will be analyzed using logistic regression 
 

 
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Unless otherwise specified, all statistical hypotheses will be tested as the primary variable, i.e. with an assessment of 
non-inferiority of the estimated difference between the groups. All efficacy analyses will be presented with the results 
from the hypothesis testing (by p-value) in addition to estimates and 95% confidence limits of the treatment effect. 
 
In case of inconsistency between the SAP and the statistical chapter of the study protocol (Chapter 11), the SAP will 
have precedence. 
11.5.3 
Centre effect 
The centre effect is expected to be negligible. Thus, no adjustment in the power calculations and planned statistical 
analyses will be made. 
11.5.4 
Safety analyses 
The safety analyses population will include all patients. Safety analyses will be descriptive and presented as summary 
tables by treatment group.  
11.5.5 
Descriptive statistics 
Descriptive statistics will be presented with number and percentages for categorical variables, and means, standard 
deviation, and range for continuous variables. In case of clearly skewed continuous variables, they will be presented with 
median, interquartile range (25th and 75th percentiles) and range. Demographics and baseline characteristics will be 
presented with descriptive statistics without any hypothesis testing.  
11.5.6 
Missing data 
If missing data is regarded as having a significant effect on the conclusions of the trial, sensitivity analyses with different 
methods for handling missing data will be included. Such methods may include complete case analyses, last observation 
carried forward, worst case/best case imputation and multiple imputation techniques. 
11.5.7 
Subgroup analyses 
The primary analysis results will be assessed separately according to the following subgroups: 
• 
Sex 
• 
Age above/below 65 years 
• 
Admission C-reactive protein above/below 100 mg/L 
• 
Patients with/without history of diabetes mellitus 
• 
Patients with/without history of obstructive pulmonary disease (COPD or asthma) 
• 
Patients with/without history of cardiovascular disease 
• 
Type of respiratory virus detected (influenza, parainfluenza virus, RSV, or hMPV) 
• 
Patients with and without radiographic evidence of pneumonia (lobar infiltrates, bronchopneumonia, etc) 
12 
STUDY MANAGEMENT 
12.1 
Investigator Delegation Procedure 
The principal investigator is responsible for making and updating a “delegation of tasks” document listing all the involved 
co-workers and their role in the project. He will ensure that appropriate training relevant to the study is given to all of these 
staff, and that any new information of relevance to the performance of this study is forwarded to the staff involved. 
12.2 
Protocol Adherence 
Investigators ascertain that they will apply due diligence to avoid protocol deviations. All significant protocol deviations will 
be recorded and reported in the Clinical Study Report (CSR). Criteria of protocol adherence will be defined in the SAP 
prior to database lock.  

 
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12.3 
Study Amendments 
If it is necessary for the study protocol to be amended, the amendment and/or a new version of the study protocol 
(Amended Protocol) must be notified to and approved by the Competent Authority and the Ethics Committee according to 
EU and national regulations. 
12.4 
Audit and Inspections 
Authorized representatives of a Competent Authority and Ethics Committee will visit the center to perform inspections, 
including source data verification. Likewise, the representatives from sponsor may visit the center to perform an audit. The 
purpose of an audit or inspection is to systematically and independently examine all study-related activities and documents 
to determine whether these activities were conducted, and data were recorded, analyzed, and accurately reported 
according to the protocol, Good Clinical Practice (ICH GCP), and any applicable regulatory requirements. The principal 
investigator will ensure that the inspectors and auditors will be provided with access to source data/documents. 
13 
ETHICAL AND REGULATORY REQUIREMENTS 
The study will be conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and 
are consistent with ICH/Good Clinical Practice and applicable regulatory requirements. Registration of patient data will be 
carried out in accordance with national personal data laws. 
13.1 
Ethics Committee Approval 
The study protocol, including the patient information and informed consent form to be used, must be approved by the 
regional ethics committee before enrolment of any patients into the study. 
13.2 
Other Regulatory Approvals 
The protocol will be submitted and approved by the applicable competent authorities before commencement of the study. 
Amendments to the protocol will be submitted to the competent authorities according to local regulations. 
The protocol will be registered in www.clinicaltrials.gov before inclusion of the first patient. 
Application to the Norwegian Medicines Agency will be approved before inclusion of the first patient. 
Collection, storage and analyses of all data and sensitive information will be conducted according to current General Data 
Protection Regulation (GDPR) and in accordance with approval from the local Data Protection Official. 
13.3 
Informed Consent Procedure 
The investigator is responsible for giving the patients full and adequate verbal and written information about the nature, 
purpose, possible risk and benefit of the study. They will be informed as to the strict confidentiality of their patient data, but 
that their medical records may be reviewed for trial purposes by authorized individuals other than their treating physician.  
It will be emphasized that the participation is voluntary and that the patient is allowed to refuse further participation in the 
protocol whenever she/he wants. This will not prejudice the patient’s subsequent care. Documented informed consent 
must be obtained for all patients included in the study before they are registered in the study. This will be done in 
accordance with the national and local regulatory requirements. The investigator is responsible for obtaining signed 
informed consent. 
 
A copy of the patient information and consent will be given to the patients. The signed and dated patient consent forms 
will be filed in the Investigator Site File binder. In cases where the patient does not speak Norwegian or English, a 
professional translator will be used. 
13.4 
Subject Identification 
The investigator is responsible for keeping a list of all included patients including patient’s date of birth and personal 
number, full names and last known addresses. The patients will be identified in the CRFs by patient number. 

 
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14 
TRIAL SPONSORSHIP AND FINANCING 
The study is sponsored by Akershus University Hospital. 
15 
TRIAL INSURANCE 
The Principal Investigator has insurance coverage for this study through membership of the Drug Liability Association (see 
http://www.laf.no for more details).  
16 
PUBLICATION POLICY 
Upon study completion and finalization of the study report, the results of this study will either be submitted for publication 
and/or posted in a publicly assessable database of clinical study results. All personnel who have contributed significantly 
with the planning and performance of the study (Vancouver convention 1988) may be included in the list of authors. 
17 
LIST OF APPENDICES 
18 
REFERENCES 
1. Holter JC, et al. BMC Infect Dis 2015;15:64. 
2. Jain S, et al. N Engl J Med 2015;373:415-27. 
3. Seymour CW, et al. N Engl J Med 2017;376:2235-44. 
4. Ruuskanen O, et al. Lancet 2011;377:1264-75. 
5. Niederman MS. CHEST 2010;138:767-9. 
6. Stets R, et al. N Engl J Med 2019;380:517-27. 
7. Lim WS, et al. Thorax 2009;64 Suppl 3:iii1-55. 
8. Centers for Disease Control and Prevention. Co-infection and antimicrobial stewardship. 
https://www.idsociety.org/covid-19-real-time-learning-network/disease-manifestations--complications/co-infection-and-
Antimicrobial-Stewardship/ 
9. European Medicines Agency. Guideline on data monitoring committees. 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003635.pdf 
10. NorCRIN. Klinisk utprøving av legemidler. https://www.norcrin.no/prosedyrer-kliniske-studier/klinisk-utproving-av-
legemidler/ 
11. Centers for Disease Control and Prevention. Clinical signs and symptoms of influenza. 
https://www.cdc.gov/flu/professionals/acip/clinical.htm 
12. Jefferson T, et al. Cochrane Database Syst Rev 2014:CD008965.