Low-dose CT Compared to Lung Ultrasonography vs Standard of Care for the Diagnosis of Pneumonia in the Elderly: a Multicentre Randomized Controlled Study
Phase: NA
Conditions: Pneumonia, Elderly Infection
Sponsor: University Hospital, Geneva

 
 
OCTOPLUS: lOw-dose CT cOmPared to Lung UltraSonography vs 
standard care for the diagnosis of pneumonia in the elderly: a 
multicentre randomized controlled study 
 
Study Type: 
Randomized Clinical trial 
Study Categorisation: 
Risk category according to HRA: A 
Study Registration: 
Intended registry: Clinicaltrials.gov, SNCTP 
 
Study Identifier: 
OCTOPLUS 
Principal Investigator: 
Dr Virginie Prendki, Division of Internal Medicine of the 
Aged, Department of Rehabilitation and Geriatrics, Geneva 
University Hospitals and University of Geneva 
Hôpital des Trois-Chêne, Chemin du Pont-Bochet 3, 1226 
Thônex-Genève 
Switzerland 
Tel: +41795538308 
Fax: +41223056115 
Email: virginie.prendki@hcuge.ch 
 
Sponsor 
 University Hospitals of Geneva 
Rue Gabrielle-Perret-Gentil 4 
Geneva, Switzerland 1205 
Represented by the Principal Investigator 
 
Trial sites & investigators 
Dr Virginie Prendki, Geneva Trois-Chêne 
Dr Jérôme Stirnemann, Geneva Cluse-Roseraie 
Pr Wolf Hautz, Bern 
Pr Enos Bernasconi , Lugano 
Pr Nicolas Garin, Rennaz 
 
Methodological advisors 
Dr Christophe Combescure 
External monitor 
 Clinical Trials Unit, HUG 
Investigational Product: 
 Diagnosis methods: CXR, LDCT and LUS in pneumonia 
Protocol Version and Date: 
V5.2 (05/10/2023) 
 
CONFIDENTIAL 
e.g. “The information contained in this document is confidential and the property of the Geneva University Hospitals. The information 
may not - in full or in part - be transmitted, reproduced, published, or disclosed to others than the applicable Competent Ethics 
Committee(s) and Regulatory Authority(ies) without prior written authorisation from the sponsor except to the extent necessary to 
obtain informed consent from those who will participate in the study. 
 
Version 
Nr 
Version date 
Description, comments 
1 
03.07.2019 
Initial version 
2 
20.11.2019 
Corrected version after 1st review 
3 
25.01.2020 
Corrected version after 2nd review 
4 
03.01.2021 
Changes after SNF review and after SARS-CoV-2 pandemic 
5 
03.05.2021 
Corrected version before launch of the study (safety, flow-chart, …) 
5.1 
31.05.2021 
Correction in the inclusion criteria 
5.2 
05.10.2023 
Change of monitoring plan for the Berne site 
 
 
 
 
Study 2019-01288 - Protocol “Octoplus” V5.2, 05/10/2023 

Study 2019-01288 - Protocol “Octoplus” V5.2, 05/10/2023 
1 
 
Signature Page(s) 
 
Study number 
The study will be registered on ClinicalTrials.gov 
Study Title 
OCTOPLUS: 
lOw-dose 
CT 
cOmPared 
to 
Lung 
UltraSonography vs standard care for the diagnosis of 
pneumonia in the elderly: a multicentre randomized clinical 
study 
 
The Sponsor-Investigator and trial statistician have approved the protocol version V5.2 
(05/10/2023) and confirm hereby to conduct the study according to the protocol, current version 
of the World Medical Association Declaration of Helsinki, ICH-GCP guidelines and the local legally 
applicable requirements. 
 
Sponsor-Investigator: 
Dr Virginie Prendki 
Geneva/Thonex, 
05 October 2023 
 
Place/Date 
Signature 
Local site investigators 
 
I have read and understood this trial protocol and agree to conduct the trial as set out in this study 
protocol, the current version of the World Medical Association Declaration of Helsinki, ICH-GCP 
guidelines and the local legally applicable requirements. 
 
 
Dr Jérôme Stirnemann 
05 October 2023 
Local investigator, Geneva Cluse-Roseraie 
Date 
Signature 
 
 
Pr Wolf Hautz 
05 October 2023 
Local investigator, Bern 
Date 
Signature 
 
 
Pr Enos Bernasconi 
05 October 2023 
Local investigator, Lugano 
Date 
Signature 
 
 
 
Pr Nicolas Garin 
05 October 2023 
Local investigator, Rennaz 
Date 
Signature 

Study 2019-01288 - Protocol “Octoplus” V5.2, 05/10/2023 
2 
 
TABLE OF CONTENTS 
GLOSSARY OF ABBREVIATIONS 
3 
1 
STUDY SYNOPSIS 4 
2 
BACKGROUND AND RATIONALE 
15 
3. STUDY OBJECTIVES AND DESIGN 17 
3.1 HYPOTHESIS AND PRIMARY OBJECTIVE 
17 
3.2 PRIMARY AND SECONDARY ENDPOINTS 
18 
3.3 STUDY DESIGN 
19 
4. STUDY POPULATION AND STUDY PROCEDURES 
21 
4.1 INCLUSION 
AND EXCLUSION 
CRITERIA, 
JUSTIFICATION 
OF STUDY 
POPULATION 
 21 
4.2 RECRUITMENT, SCREENING AND INFORMED CONSENT PROCEDURE 22 
4.3 STUDY PROCEDURES 
23 
4.4 WITHDRAWAL AND DISCONTINUATION 26 
5. STATISTICS AND METHODOLOGY 27 
5.1. STATISTICAL ANALYSIS PLAN AND SAMPLE SIZE CALCULATION 
27 
5.2. HANDLING OF MISSING DATA AND DROP-OUTS 
29 
6. REGULATORY ASPECTS AND SAFETY 
29 
6.1 LOCAL REGULATIONS / DECLARATION OF HELSINKI 
29 
6.2 (SERIOUS) ADVERSE EVENTS 
29 
6.3 (PERIODIC) SAFETY REPORTING 30 
6.4 RADIATION 
30 
6.5 PREGNANCY 30 
NA 
30 
6.6 AMENDMENTS30 
6.7 (PREMATURE) TERMINATION OF STUDY 
30 
6.8 INSURANCE 
31 
7. 
FURTHER ASPECTS 
31 
7.1 OVERALL ETHICAL CONSIDERATIONS 31 
7.2 RISK-BENEFIT ASSESSMENT 
31 
8. 
QUALITY CONTROL AND DATA PROTECTION 
32 
8.1 QUALITY MEASURES 
32 
8.2 DATA RECORDING AND SOURCE DATA32 
8.3 CONFIDENTIALITY AND CODING 33 
8.4 RETENTION AND DESTRUCTION OF STUDY DATA AND BIOLOGICAL 
MATERIAL 33 
9. 
MONITORING AND REGISTRATION 
34 
10. 
FUNDING / PUBLICATION / DECLARATION OF INTEREST 
35 
11. 
REFERENCES 
35 

Study 2019-01288 - Protocol “Octoplus” V5.2, 05/10/2023 
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GLOSSARY OF ABBREVIATIONS 
AE 
Adverse Event 
ASR/DSUR 
Annual Safety Repot / Development Safety Report 
BASEC 
 Business Administration System for Ethical Committees 
ClinO 
 Ordinance on Clinical Trials in Human Research (in German: KlinV, in French: 
OClin, in Italian: OSRUm) 
CAP 
Community-Acquired Pneumonia 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CXR 
 Chest x ray 
ED 
Emergency Department 
FADP 
Federal Act on Data Protection (in German: DSG, in French: LPD, in Italian: LPD) 
eCRF 
electronic Case Report Form 
FOPH 
Federal Office of Public Health 
GCP 
Good Clinical Practice 
GRL 
Genomic Research Laboratory 
HRA 
Human Research Act (in German: HFG, in French: LRH, in Italian: LRUm) 
HUG 
Geneva University Hospitals 
ICH 
International Conference on Harmonisation 
ICU 
Intensive Care Unit 
LDCT 
Low dose CT scan 
LTCF 
Long-term care facility 
LUS 
Lung Ultrasound 
PACS 
Research picture archiving and communication system 
PI 
 Principal Investigator 
QOL 
Quality of Life 
RCT 
Randomized-controlled trial 
SAE 
Serious Adverse Event 
SNF 
Swiss National Funding 

1 
STUDY SYNOPSIS 
 
Sponsor / Sponsor-
Investigator 
Dr Virginie Prendki, Division of Internal Medicine of the Aged, 
Department of Rehabilitation and Geriatrics, Geneva University 
Hospitals and University of Geneva 
Hôpital des Trois-Chêne, Chemin du Pont-Bochet 3, 1226 
Thônex-Genève 
Switzerland 
Tel: +41795538308 
Fax: +41223056115 
Email: virginie.prendki@hcuge.ch 
Study Title 
lOw-dose CT cOmPared to Lung UltraSonography vs standard 
care for the diagnosis of pneumonia in the elderly: a multicentre 
randomized clinical study 
Short Title / Study ID 
OCTOPLUS 
Protocol Version and 
Date 
V5.2 (05/10/2023) 
Study Registration 
Clinicaltrials.gov; Swiss National Clinical Trial Portal 
Study Category and 
Rationale 
Risk category according to HRA: A 
Background and 
Rationale 
Principal study: OCTOPLUS 
Pneumonia is one of the leading causes of morbidity and mortality 
from infection in elderly patients, and is one of the first causes of 
antimicrobial therapy prescription. 
Its diagnosis is challenging, particularly in elderly patients, 
because of the lack of sensitivity and specificity of clinical signs 
and symptoms and because of the high incidence of differential 
diagnoses. Limitation of chest X-Ray (CXR) for this diagnosis 
have been abundantly documented. Hence, clinical studies are 
needed to improve diagnosis of pneumonia, leading to better 
management of the patients and more appropriate antimicrobial 
therapy prescription. 
We showed in a previous study that low-dose CT scan (LDCT) 
changed the probability of pneumonia in 45% of elderly patients 
(>65 years, median age 84 years) suspected of pneumonia 
according to clinical presentation and CXR (Prendki, Eur Resp J 
2018). LDCT mostly helped the clinician to exclude a diagnosis 
of pneumonia. Another study showed a similar impact of CT in 
adult patients (>18 years, median age 65 years) consulting in the 
emergency department (ED) for a suspicion of pneumonia 
(Claessens, Am J Respir Crit Care Med 2015). Hence, CT-scan 
could contribute to a more accurate diagnosis of pneumonia in 
the emergency department setting. However, availability, costs, 
and associated irradiation are significant issues. 
Lung ultrasonography (LUS) is a promising diagnostic tool for the 
detection of pulmonary infiltrates, with a reported accuracy 
outperforming CXR (Nazerian, Am J Emerg Med 2015). As it is 
readily available at the bedside, use of ultrasonography by non-
specialists in the emergency room has significantly increased. 
However, published studies have mainly been conducted by team 
experts in LUS, and generalizability of their results to less 
specialized settings is unwarranted. 
Finally, only a randomized-controlled trial (RCT) may establish if 
one diagnostic strategy leads to better or equivalent clinical 
 
 
Study 2019-01288 - Protocol “Octoplus” V5.2, 05/10/2023 

Study 2019-01288 - Protocol “Octoplus” V5.2, 05/10/2023 
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outcomes while allowing a more judicious AT prescription. Such 
RCT has yet not been reported. 
In 2020, Coronavirus disease (COVID-19) has caused a 
pandemic threatening millions of people worldwide. Patients with 
SARS CoV-2 infection will be excluded from the trial if COVID 
diagnosis has been done by PCR or antigenic test within the past 
3 weeks and before the arrival to the ED. 
Ancillary 
study: 
GEROBIOTA 
(GERiatric, 
Oral 
health 
assessment and oral microBIOTA): 
The burden of pneumonia in elderly and comorbid patients will 
increase in the coming years. Functional, cognitive impairments 
and malnutrition are frequently associated with pneumonia and 
its mortality in the elderly. 
Despite evidence of a link between oral health and the risk of 
pneumonia, the oral status is not yet routinely screened in elderly 
patients hospitalized for pneumonia. In the same line, aspiration, 
mostly due to oropharyngeal dysphagia is a frequent mechanism 
of pneumonia and is not routinely screened any either. Links have 
been highlighted between oral care and mortality from pneumonia 
(low level of evidence). Like in other organ systems, microbiota 
may have a major role in maintaining health in the airways and 
lungs, being involved in immunity and homeostasis, and 
preventing colonization by respiratory pathogens. Moreover 
inflammation, vaccinal response and genetic markers are other 
factors  involved  in  the  occurrence  and  the  outcome  of 
pneumonia. 
Long-term 
mortality 
and 
readmission 
were 
associated with persistent inflammation in patients hospitalized 
with sepsis. 
This study is carried out in an emergency situation and the 
expected results can only be achieved in an emergency situation. 
Indeed pneumonia is a major cause of morbidity and mortality 
and the patient’s prognosis is engaged. Diagnosing and the 
decision of treating the patient consulting the ED must be 
performed within  first hours (the international guidelines 
Risk / Benefit 
recommend treating the patient while he/she is still in the ED for 
a suspicion of pneumonia). 
-Risk of the CT: LDCT is well-tolerated and its mean radiation 
exposure is much lower than a full-dose CT scan (about 1mSv). 
-Risk of LUS: there will be many clinicians performing LUS at 
each site. LUS is known to have a fast-learning curve. To 
minimize heterogeneity between the clinicians and centres, 
Assessment 
standardization of LUS practice will be performed in all centres 
before the beginning of the study. 
-Risk of the blinding: blinding is one of the major challenges of the 
trial. It will be performed in each site using a research PACS 
thanks to radiologist engineering. To allow for compliance and 
smooth running of the study, all ED and radiology staff will be 
regularly informed regarding methods and stakes. As soon as the 
patient is included, the research staff will anticipate and inform the 
radiology staff who will take care of the patient, and the clinician 
to perform LUS about the necessity of blinding and the CRF to fill 
in. The research staff will be the only one able to provide the 
attending clinician with the result of the allocated imaging 
modality, and ensure that it is accessible in the patient’s 

Study 2019-01288 - Protocol “Octoplus” V5.2, 05/10/2023 
6 
 
 
medical record. The two other imaging modalities will be 
concealed until day 5, and will only be accessible on the PACS. 
According to a predefined list of emergency findings, the 
radiologist interpreting CXR or LDCT or the clinician performing 
LUS will be able to immediately ask the investigator for 
unblinding. 
At day 5, the research staff will ensure that the two blinded 
imaging modalities are made accessible again to the treating 
clinician. 
The risk of a false negative (meaning a missed diagnosis of 
pneumonia) will be counterbalanced by the fact that the clinician 
will be allowed to prescribe antimicrobial therapy for another 
diagnosis than pneumonia. As patients with severe pneumonia 
will not be included, a delay of a few hours in the diagnosis of 
pneumonia is unlikely to lead to an unfavourable outcome. 
Indeed, a longer time to antibiotic administration was not 
associated with an unfavourable outcome in moderately severe 
Community-Acquired Pneumonia (CAP) in the literature (Garin 
et al). 
Finally, we estimated that risks inherent to the trial are minimal 
and inferior to the benefices of the study which could deliver key 
results which would provide long-term benefit to all patients with 
pneumonia. 
Objective(s) 
Primary objective: 
To assess the difference in diagnostic accuracy for patients with 
suspected pneumonia using LDCT compared to CXR. We 
hypothesize that it will be higher in LDCT than in CXR arm. 
Main secondary objectives: 
To evaluate whether a diagnostic strategy using LUS compared 
with CXR, and using LUS compared with LDCT leads to better 
diagnostic, therapeutic (antibiotic consumption at day 30), and 
clinical outcomes (time to clinical stability, length of hospital stay, 
admission to the intensive care unit, 1-month and 3-month 
mortality and readmission, and quality of life); cost outcomes; 
concordance between physicians at the ED and experts and the 
association of biomarkers and the presence of an infiltrate. 
GEROBIOTA 
To identify factors associated with the probability of pneumonia, 
the probability of aspiration pneumonia, 1 month and 1 year 
mortality, 1 year readmission and to create a biobank allowing the 
assessment of inflammation, immune status and genetic markers. 
Endpoint(s) 
Primary outcome measure: 
The primary outcome will be the difference in accuracy between 
LDCT and CXR, assessed at the end of the ED evaluation, using 
the expert panel as the reference standard, accuracy being 
computed as (true positive + true negative cases) / (true positive 
+ true negative + false positive + false negative cases). 
Main secondary outcome measures: 
Diagnostic outcomes: 
• 
Proportion of patients with an adequate diagnosis using 
LUS compared to CXR 
• 
Proportion of patients with an adequate diagnosis using 
LUS compared to LDCT 

Study 2019-01288 - Protocol “Octoplus” V5.2, 05/10/2023 
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• 
Proportion of patients with an alternative diagnosis 
• 
Number of additional imaging studies and invasive 
procedures prescribed during the acute setting 
• 
Prevalence of unmasked imaging results (for an 
emergency finding) 
• 
Prevalence of incidentalomes 
Treatment outcomes: 
• 
Number of antibiotic free days at day 30 
Clinical outcomes: 
• 
Time to clinical stability during the first 2 weeks 
• 
Length of hospital stay 
• 
Proportion of patients with an unplanned transfer to the 
ICU or operating room 
• 
Proportion of patients admitted to rehabilitation or long- 
term care facility (LTCF) days through 3 months 
• 
All-cause mortality through 1 month and 3 months 
• 
All-cause readmission to the acute care setting through 1 
month and 3 months 
• 
Quality of life at admission, discharge and 3 months 
Agreement for the diagnosis of pneumonia between clinicians 
and a panel of experts 
Association between biological markers (C-reactive protein and 
procalcitonin) and the presence of an infiltrate 
Cost outcomes: 
Costs of care, physician, imaging, laboratory, treatment 
(including antibiotic therapy) and others per patient, health 
related quality of life until 3 months; unit of work consumption per 
hospital (number of minutes of care, physician, laboratory and 
imaging points) 
Safety outcomes: unplanned transfer to the ICU after initial 
admission; 1-month mortality. 
GEROBIOTA 
The probability of pneumonia/aspiration pneumonia according to 
the panel of experts; 
Proportion of patients admitted to 
rehabilitation or LTCF days through 3 months; all-cause mortality 
through one-year; all-cause readmission to hospital or LTCF 
through one-year. 
Definitions 
-Reference diagnosis: it will be done a posteriori by a panel of 
experts, including one radiologist, who will have access to all 
imaging studies (CXR, LUS, and LDCT), along with all clinical and 
biological data, including follow-up data up to one month after 
admission. They will give their probability of pneumonia, 
aspiration pneumonia, bacterial vs viral pneumonia or alternative 
diagnosis. 
-Time to clinical stability: number of days from admission to the 
first time all of the following parameters are above/under the 
threshold value and maintained for a minimum of 24 hours: heart 
rate <100 beats/min, systolic blood pressure >90 mmHg, 
temperature <37.8°C (axillary or tympanic), respiratory rate <24 
breath/min, oxygen saturation >90% while breathing room air, or 
need for more than 28% fraction of inspired oxygen to maintain 
adequate oxygen saturation, resolution of delirium if present at 
admission) 

Study 2019-01288 - Protocol “Octoplus” V5.2, 05/10/2023 
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-Viral pneumonia: presence of an infiltrate on CT scan and a PCR 
positive for a virus 
-Aspiration 
pneumonia: 
compatible 
radiological 
findings 
witnessed aspiration or risk factors for aspiration 
Study Design 
OCTOPLUS is a Swiss multicentre superiority randomized 
clinical study with 3 parallel arms. Randomization will be 1:1:1 
using randomly permutated block sizes and be stratified by 
centre. Patients will be either randomized into the CXR, the LDCT 
or the LUS arm. The 3 imaging modalities will be performed in the 
ED (and before the patient is discharged) 
for all included patients but only one will be available to the 
clinician according to the allocation arm. 
The concealed results of the imaging procedures will be 
unblinded at day 5. 
The duration of follow-up will be 3 months for OCTOPLUS. The 
panel of experts will provide their diagnosis a posteriori. An 
intermediate safety analysis will be performed after 200 patients 
have completed the 1-month follow-up. 
CIRCUS 
(Calibration 
of 
reasoning confidence in 
uncertain situations) is a substudy from OCTOPLUS which 
aims to understand which factors (of the physician such as 
experience or gender, of the patient such as urgency or 
presenting complaint and of the context such as daytime) 
affect physician confidence in their diagnosis (see appendix 
at the end of the protocol). 
GEROBIOTA is an observational substudy to OCTOPLUS. It will 
be performed in two academic hospitals and the duration will be 
one year. Comprehensive assessment of functional, cognitive, 
nutritional, oral health status and oral/respiratory microbiota will 
be done in order to identify factors associated with the diagnosis 
of pneumonia and its outcome. The creation of a biobank will 
allow the assessment of inflammation, vaccinal status and 
genetic markers. Identification of risk factors will pave the way for 
interventional studies aimed at reducing the onset and the 
recurrence of pneumonia. The reference diagnosis will be 
provided by the panel of experts: in addition to the probability of 
pneumonia, the experts will be asked to rate the probability of 
aspiration pneumonia. 
NB: only CXR will be billed to the participant, as this is the actual 
standard of care imaging 
Methodology 
Statistical 
Dr Christophe Combescure; Methodological support Unit, 
Clinical research center, Geneva University Hospitals, Rue 
Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland, Email: 
christophe.combescure@hcuge.ch, Tel: +41 22 37 29 136 
Considerations 
diagnosis of pneumonia (proportion of true positive plus true 
negative) will be higher in LDCT arm than in CXR arm. The null 
hypothesis that will be tested in the primary analysis is the 
equality of proportion of correctly classified patients in LDCT and 
CXR arm. 

Study 2019-01288 - Protocol “Octoplus” V5.2, 05/10/2023 
9 
 
The analysis will follow the intention to treat principle. A sensitivity 
analysis will be conducted on the per protocol population (i.e. 
excluding patients who have not received the allocated 
intervention, and patients who crossed over). Another sensitivity 
analysis will be conducted excluding patients who will have had 
CXR before LDCT and LUS. 
Subgroup analysis will be performed in patients aged over 80 
years (versus less than 80 years) and in patients with positive 
PCR (i.e. virus detected, including SARS-CoV-2) at the 
beginning of the study (versus with a negative PCR). 
The diagnosis made by the panel of experts will be the reference 
diagnosis for calculation of the primary outcome in each arm, and 
to determine diagnostic accuracy expressed as sensitivity, 
specificity, predictive values and likelihood ratios. The primary 
outcome in each arm will be compared to the two other ones. 
Inclusion- / Exclusion 
Criteria 
Study population: patients >65y with suspected CAP or 
nursing-home acquired (NHAP) pneumonia consulting to the ED. 
Key inclusion criteria: 
-presence of at least one respiratory symptom (new or increasing 
cough, purulent sputum, pleuritic chest pain, new or increasing 
dyspnea, respiratory rate >20/min, focal auscultatory findings or 
oxygen saturation <90% on room air). 
-AND at least one symptom or laboratory finding compatible with 
an infection (temperature >37.8°C or <36.0°C, C reactive protein 
(CRP) >10 mg/L, PCT >0.25µg/L, leukocyte count >10 G/L with 
>85% neutrophils or band forms) 
The presence of acute delirium or unexplained acute fall can 
substitute for the presence of either the respiratory or the 
infectious symptom in the oldest old group (patients ≥80y). 
Key exclusion criteria: 
patients for whom an immediate admission to the intensive care 
unit (ICU) is required; patients who were diagnosed with 
pneumonia in the past 3 months; patients who had positive PCR 
for SARS-CoV-2 and antigenic test within 3 past weeks; who were 
transferred from another hospital with a diagnosis of pneumonia; 
who already a thoracic imaging (CXR, CT scan or LUS) during 
the present episode; and who require an immediate contrast-
enhanced CT; furthermore, patients with advanced care planning 
limiting therapy to comfort care only; prisoners; patients with 
known uncontrolled psychiatric disorders; and patients who were 
previously enrolled into the current study. 
Number of Participants 
with Rationale 
The number of patients has been computed based on the number 
of diagnoses of pneumonia correctly classified according to the 
panel of experts who had access to the results of LDCT in the 
PneumOldCT study (Prendki, Eur Resp J 2018 and unpublished 
data). 
Power calculation has not been performed for the LUS arm as 
there is too few data in the literature comparing directly LUS and 
LDCT. 
With an expected improvement of the diagnosis with LDCT in 
16% of the patients, we calculated that 150 patients will be 
required in each arm to prove the superiority of LDCT over CRX 
with an alpha error =0.05 and a power of 0.9. Allowing for a 10% 
dropout after randomization, the plan is to enrol 165 in each arm, 
for a total of 495 patients. 

Study 2019-01288 - Protocol “Octoplus” V5.2, 05/10/2023 
10 
 
 
500 patients will be recruited for the study. 
For GEROBIOTA, sample size is based on the power calculation 
of the principal study. 
Study Intervention 
OCTOPLUS 
Performance of CXR, LDCT and LUS, in all patients during their 
time in the ED. 
CXR will be interpreted in real-time by the resident radiologist. 
LDCT (with no injection) will be interpreted in real-time by a 
senior radiologist 
LUS will be performed by another clinician than the one in charge 
of the patient; LUS practice of the former will be standardized 
before the launching of the study. 
GEROBIOTA 
At admission: 
-Microbiota samples (saliva and respiratory samples) before 
antibiotic administration at the ED if possible. 
They will be stored at -80. 
NB: respiratory samples will be those taken for routine methods 
including sputum, induced sputum, tracheal aspirate or broncho-
alveolar lavage if done and still available 
- Biobank stored at -80 one saliva sample, serum (2 tubes), 
plasma EDTA (2 tubes), plasma citrate (2 tubes), PAX gene DNA 
(1 tube), PAX gene RNA (1 tube). 
During hospitalization: 
-Oral health examination by a medical dentist as soon as the 
patient is stabilized (≈30 min) 
-Geriatric assessment by the research staff during the first week 
of hospitalization (≈45min) 
At discharge: 2 tubes of serum, 2 tubes of plasma 
Pneumoscope 
Patients will also be proposed to participate to the Pneumoscope 
study. Registration of pulmonary sounds will be done with an 
intelligent stethoscope. 
Control Intervention 
LDCT (and LUS) will be compared to CXR, preferably with the 
patient standing and with two incidences, as recommended by 
international guidelines for the diagnosis of pneumonia. 
Study procedures 
OCTOPLUS 
The inclusions will be done on working days and hours. 
Performance of CXR, LDCT and LUS, in all patients during their 
time in the ED. 
CXR will be interpreted in real-time by the resident radiologist. 
LDCT will be interpreted in real-time by another radiologist. 
LUS will be performed by another clinician than the clinician in 
charge, and LUS practice of the former will be standardized 
before the launching of the study. 
After identification in the emergency department, included 
patients will be randomized 1:1:1 to one of the following three 
arms (stratified by participating center): 
-Only CXR (image and standardized report)) will be available to 
the clinician (control arm). LDCT and LUS will be performed but 
not available (clinician will be blinded to LDCT and LUS) 

Study 2019-01288 - Protocol “Octoplus” V5.2, 05/10/2023 
11 
 
-Only LDCT (image and standardized report) will be available to 
the clinician (first intervention arm). CXR and LUS will be 
performed but not available (clinician will be blinded to CXR and 
LUS) 
-Only LUS (image and standardized report) will be available to 
the clinician (second intervention arm). CXR and LDCT will be 
performed but not available (clinician will be blinded to CXR and 
LDCT) 
The blinding will be maintained during the first 5 days, and hence 
will not influence the diagnosis and the treatment of the patient. 
Before discharge of the ED, the clinician in charge will be asked 
to assess on a 3-level Likert scale the probability of pneumonia 
(high, intermediate, low level) while considering all available 
clinical and biological data, plus the imaging modality according 
to the randomization arm. 
He will document the intended treatment strategy (antibiotic 
prescription or not, which molecule, for which indication if not for 
pneumonia, intended duration). 
He will be allowed to prescribe antibiotic for another indication 
than pneumonia by documenting a principal alternative diagnosis 
(e.g. urinary tract infection, acute exacerbation of a chronic 
obstructive pulmonary disease, cardiac failure...) and strongly 
encouraged not to prescribe antibiotic for pneumonia if he rated 
a low probability of the disease. 
Patients will be followed-up daily during the hospitalization by 
research staff and by phone up to 3 months to assess 
readmission as well as mortality. 
A previously trained panel of experts will adjudicate the final 
diagnosis in all patients, having access to all data (clinical, CXR, 
LDCT and LUS and outcome data at day 28), while blinded to the 
allocation arm. Their diagnosis will be considered as the 
reference diagnosis. 
Safety 
Number of death and admissions to the ICU in each arm will be 
communicated to a dedicated data safety monitoring board after 
200 inclusions for a safety interim analysis. 
Blinding of the imaging modalities: For each patient, the two 
blinded imaging modalities will be registered on a secured 
research picture archiving and communication system (PACS). 
The CRFs filled for these imaging modalities will be kept 
unavailable during the time of the blinding. 
Unblinding: The research staff will ensure that unblinding (of 
imaging and CRF) is done at day 5 and that all results are 
available in the electronic health record. 
Unblinding will be performed at the ED if the radiologist/clinician 
performing LUS diagnoses immediately life-threatening findings: 
pneumothorax, pleural effusion in large quantities (white lung) 
with mediastinal shift, complete atelectasis of one lung, indirect 
sign of aneurysmal rupture (haemomediastinum), massive 
pericardial effusion, tracheal foreign body, pneumoperitoneum, 
haemothorax, 
pneumomediastinum, 
suspicion 
of 
acute 
tuberculosis. 
Pulmonary embolism won’t be excluded as LDCT will be 
performed without intravenous contrast. 

Study 2019-01288 - Protocol “Octoplus” V5.2, 05/10/2023 
12 
 
 
In case of such finding, the radiologist interpreting CXR or LDCT 
and clinician performing LUS will call in emergency the 
investigator to be allowed to communicate the results to the 
clinician. 
In case of subsequent clinical deterioration, the clinician in charge 
of the patient may prescribe any new imaging deemed necessary: 
a new CXR for the diagnosis of heart failure; injected full-dose 
chest CT scan to eliminate a pulmonary embolism or to a 
suppurative complication. Nevertheless, the local investigator will 
be able to proceed to a deblinding in justified cases. 
Study Duration and 
Schedule 
3 years (2 years of recruitment plus 3 months of follow-up for 
OCTOPLUS and one year for GEROBIOTA) 
Planned 06/2021 of First-Participant-In 
Planned 12/2023 of Last-Participant-Out for OCTOPLUS 
Planned 09/2024 of Last-Participant-Out for GEROBIOTA 
Investigator(s) 
OCTOPLUS 
Principal investigator 
Dr Virginie Prendki; Division of Internal Medicine of the Aged, 
Department of Rehabilitation and Geriatrics, Geneva University 
Hospitals and University of Geneva (HUG), Hôpital des Trois-
Chêne, Chemin du Pont-Bochet 3, 1226 Thônex-Geneva, 
Switzerland,   Email:   virginie.prendki@hcuge.ch,   Tel: 
+41795538308 
Name(s) of all head investigator(s) of each site 
- Geneva Trois-Chêne (HUG); Dr Virginie Prendki (see above) 
- Geneva Cluse-Roseraie (HUG): Dr Jérôme Stirnemann, 
Department of Internal Medicine, Geneva University Hospitals, 
Rue  Gabrielle-Perret-Gentil  4,  1205  Geneva,  Email: 
jerome.stirnemann@hcuge.ch, Tel: +41 22 372 9101 
- Bern: Pr Wolf Hautz MME, Department of Emergency Medicine, 
Inselspital University Hospital Bern, Freiburgstrasse, 3010 Bern, 
Email: wolf.hautz@insel.ch, Tel: +41 31 632 4587 
- Lugano: Pr Enos Bernasconi, Department of Infectious 
Diseases, Ospedale Regionale Civico, Via Tesserete 46, 6903 
Lugano, Email: enos.bernasconi@eoc.ch, Tel: +41 91 811 60 22 
- Rennaz: Pr Nicolas Garin, Department of Internal Medicine, 
Riviera-Chablais Hospitals, Route de Morgins, 1870 Monthey, 
Email: nicolas.garin@hopitalrivierachablais.ch, Tel: +41 24 468 
8075 
CIRCUS 
PI CIRCUS: Prof. Dr. Wolf Hautz, University of Bern 
Co-Investigators CIRCUS: Prof. Stefan Schauber, University of 
Oslo, Dr. Juliane Kämmer, Max Planck Institute for Human 
Development Berlin, Dr. Stefanie Hautz and Dr. Thomas Sauter, 
University of Bern 
GEROBIOTA 
Principal investigator: Dr Virginie Prendki 
Including centers: Geneva and Bern 
Pneumoscope 
Principal investigator: Pr Alain Gervaix 
Including center: Geneva. 
Study Center(s) 
Swiss multicenter study, total of 5 centers: Geneva Trois-Chêne, 
Geneva Cluse-Roseraie, Bern, Lugano, Rennaz (Hôpital Riviera 
Chablais). 

Study 2019-01288 - Protocol “Octoplus” V5.2, 05/10/2023 
13 
 
 
Data privacy 
Privacy and confidentiality of the patient's medical data will be 
maintained through the study. 
eCRFs and all other documents sent to the sponsor will be de-
identified and carry only the numeric patient's identifier code. The 
study site will maintain the link between the patients’ identifier 
code and their name. 
All electronic data will be password protected, and any paper 
documents will be stored in a locked cabinet. For monitoring, 
audits, and regulatory inspections, source data and documents 
will be made available, per routine protocols. 
Direct access to source documents will be permitted for purposes 
of monitoring, audits and inspections and should declare who will 
have access to protocol, dataset, statistical code, etc. during and 
after the study (publication, dissemination). 
The investigating team will provide direct access to all trial-
related source data, documents and reports for the purpose of 
monitoring and auditing by the sponsor and inspection by local 
and regulatory authorities. 
The investigators will comply with the rules enacted by the Swiss 
Academy of Medical Sciences for biobanks, particularly 
concerning quality standards, data protection, transfer of samples 
and data. They will comply with the Swiss Human Research 
Act (HRA). 
Samples will be de-identified as soon as possible, but at the latest 
upon arrival of the sample in the biobank. Each sample will be 
coded, and access to personal data will be impossible without the 
code, which will be conserved separately. The code file will be 
kept by a designated member of the research staff, who will not 
be directly involved in research and analysis on the biobank 
samples. 
A specific consent form will be signed by the patient, allowing 
storage and re-use of his/her biological samples for research 
aims, 
including 
research 
on 
biomarkers 
and 
genetic 
polymorphisms associated with respiratory infection. The patient 
will be free to be included in the main cohort study, in both 
OCTOPLUS and GEROBIOTA or in none of them. He will be 
allowed to withdraw from participation at any moment. 
Ethical consideration 
Reasons for inclusion of vulnerable participants: elderly 
patients will be included. Although pneumonia is amongst the first 
causes of morbi-mortality and antibiotic prescription in elderly 
patients, clinical studies in this population are scarce, in part 
because informed consent is difficult to obtain due to acute 
confusion or permanent cognitive impairment. Diagnostic criteria 
need to be revised in this vulnerable population in order to 
improve antibiotic prescription and patient management. 
Consent: 
- 
The patient has his ability to consent in the emergency 
room: he signs the standard consent for participant. 
- 
The patient has not his ability to consent in the emergency 
room 
o he does not express either orally or by any 
particular behaviour his/her refusal of being part 
of the research project. 

Study 2019-01288 - Protocol “Octoplus” V5.2, 05/10/2023 
14 
 
 
o a physician independent of the study will be 
sought to defend the interest of the patient (HRA 
30-31) and sign the dedicated written confirmation 
Everything will be done to establish the will of the patient as soon 
as possible 
o the 
patient 
recovers 
his 
capacity 
during 
hospitalization : he signs the standard consent for 
participant. 
o the patient is known to no longer have the ability 
to consent or does not recover his ability to discern 
during 
hospitalization: 
the 
relative/legal 
representative sign the dedicated consent. 
GCP Statement 
This study will be conducted in compliance with the protocol, the 
current version of the Declaration of Helsinki, the ICH-GCP, the 
HRA as well as other locally relevant legal and regulatory 
requirements. 

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Study 2019-01288 - Protocol “Octoplus” V5.2, 05.10.2023 
 
2 
BACKGROUND AND RATIONALE 
 
By 2050 one in four persons in Europe and Northern America will be aged 65 years or over 
according to demographic projections (1). Pneumonia principally affects older people, with two 
thirds of patients hospitalized for pneumonia were more than 70 years old in a nation-wide German 
study (2). Accordingly, the burden of pneumonia on health and economic outcomes is expected 
to increase. Pneumonia is also the most frequent cause of antimicrobial therapy prescription in 
this population (3) (4). However, studies specifically investigating the elderly are scarce. 
 
According to international guidelines, the diagnosis of pneumonia is based on clinical signs and 
symptoms and the presence of a new infiltrate on chest x-ray (CXR) (5) (6).The challenge in 
diagnosing pneumonia is to distinguish it from milder forms of respiratory infections, which do not 
require antibiotic treatment, and from other medical conditions. In fact, the clinical presentation of 
other common conditions in the elderly like acute heart failure, chronic obstructive pulmonary 
disease exacerbation, pulmonary embolism, lung cancer, non-infectious pneumonitis and non-
respiratory sepsis overlaps with pneumonia. Signs and symptoms of pneumonia have poorer 
sensitivity and specificity in older patients, who also have a higher prevalence of abnormalities on 
CXR due to concomitant conditions, further compounding the diagnostic issues (7) (8) (9) (10) 
(11) (12).Indeed, more than one disease can simultaneously affect the same individual, with 
frequent comorbidities like heart failure exacerbating by infection (13) (14). Accordingly, it is not 
surprising that the specificity of an initial diagnosis of community-acquired pneumonia in 
hospitalized patients is low compared with the final diagnosis, with a positive predictive value of 
only 60% to 75% (15) (16). Misdiagnosis of pneumonia may translate into inappropriate antibiotic 
prescription, but also in harmful delays in the correct management of the real cause of patients’ 
symptoms, an understudied issue. Finally, CXR also lacks sensitivity to detect pneumonia, which 
exposes patients to the risk of late initiation of appropriate antibiotic treatment (17). 
Alternative imaging strategies have been proposed to surpass the acknowledged drawbacks of 
the current diagnostic work-up of pneumonia. The use of computed tomography (CT) scan is 
recommended by some authors if standard imaging is inconclusive (17) (18). In a cohort of 319 
adult patients with suspected pneumonia at the emergency department (ED), Claessens et al 
reported that early CT scan changed the diagnostic classification of pneumonia in 59% of them 
with an increased probability of pneumonia in 19% (19). For 80% of the patients (i.e. 25% of the 
total population), modification of pneumonia probability was concordant with the final classification 
of an adjudication committee that used all available information, including follow-up data. The 
absolute Net Reclassification Improvement, which calculates the absolute number of patients 
correctly reclassified, was 60/319 (18%). Most appropriate modifications of pneumonia probability 
according to the reference diagnosis consisted in downgrading of the probability. The authors also 
demonstrated the feasibility of rapidly performing a CT scan in the emergency department settings 
for patients suspected of pneumonia. We obtained similar results with elderly patients in the 
PneumO-LD-CT cohort (20).The advantages of CT scan could be greater in elderly patients as it 
can be challenging to obtain good quality CXR and, as mentioned above, pneumonia can be 
difficult to distinguish from other frequent conditions. Native low-dose CT scan (LDCT) is 
appropriate to study the lung fields, is free of risks associated with contrast medium injection, and 
the irradiation burden is low. In the Netherlands, a cluster-randomized clinical trial is underway to 
determine the added value of LDCT in the diagnostic work-up of pneumonia to minimize selective 
antibiotic pressure while maintaining patient safety (ClinicalTrials.gov Identifier: NCT03360851). 
Nevertheless, neither CT scan nor LDCT have been directly compared to CXR in a randomized 
trial. 
 
Lung ultrasonography (LUS) is another imaging modality under investigation for the diagnosis of 
pneumonia. LUS is increasingly available as a point-of-care, non-irradiating tool, often being 
performed directly at the bedside by trained emergency physicians. Diagnostic studies evaluating 

16 
Study 2019-01288 - Protocol “Octoplus” V5.2, 05.10.2023 
 
LUS have reported a sensitivity of 80% to 90% and a specificity of 70% to 90% in diagnosing 
pneumonia, using various reference standards (diagnosis of pneumonia at discharge, or 
occasionally CT scan) (21) (22) (23) (24). In studies using CT scan as the reference standard, 
LUS showed a higher sensitivity than CXR, with similar specificity (24) (25). LUS was never 
compared with CXR or LDCT for the diagnosis of pneumonia in a randomized controlled study. 
Literature on its performance in elderly patients is scarce (26) (27). 
Based on these premises, an LDCT or LUS-based work-up of suspected pneumonia may have 
significant advantages over standard CXR. Superior diagnostic accuracy of either modality can 
lead to better outcomes for patients through early appropriate management of the actual 
symptom-causing disease, but also to a more appropriate antibiotics use, a key issue in an era 
of growing bacterial resistance. 
However, only a randomized trial comparing each diagnostic strategy head to head will allow for 
an unbiased assessment of each strategy’s performance on a range of diagnostic, therapeutic 
and clinical outcomes. 
 
Personal work 
We assessed the impact of LDCT on the diagnosis of pneumonia in elderly patients in a 
prospective observational study, conducted at Geneva University Hospitals (20). We included 
200 consecutive hospitalized patients, with a median age of 84 years and with suspicion of 
pneumonia. We showed that LDCT changed the presumptive diagnosis in a high proportion of 
patients (45%), with an upgrade in 15% of patients and a downgrade in 30% of patients. LDCT 
changed the probability of disease in more than 80% of the patients who had an intermediate 
probability of pneumonia after a standard work-up including CXR. After the use of an adjudication 
committee blinded to the results of LDCT as the reference diagnosis, the changes in clinician’s 
probability matched the reference diagnoses in 68% of modifications (61/90) and in 31% of all 
patients (61/200). The absolute Net Reclassification Improvement was 16/200 patients (8%) (20). 
Correct reclassification was mainly observed in patients not having pneumonia according to the 
reference diagnosis, suggesting that LDCT will mainly reduce the overdiagnosis of pneumonia 
(28). 
We explored strategies to guide LDCT indication in patients suspected of pneumonia, aiming to 
perform LDCT preferentially in patients with intermediate risk of pneumonia after standard work-
up. We derived a simple prediction score to guide performance of LDCT in elderly patients with a 
suspicion of pneumonia in our cohort, and validated it in an independent cohort (29). This score, 
based on four readily available variables, would theoretically allow withholding LDCT in 46% of 
the patients, with moderate accuracy. In a similar approach, we validated a more complex 
algorithm in our cohort based on six variables, including the results of viral polymerase chain 
reaction of nasopharyngeal swabs derived from data obtained in a French cohort (30). 
GEROBIOTA 
Comorbidities, functional and cognitive impairments and malnutrition are frequently associated 
with pneumonia of the elderly and its mortality (31) (32) (33). Despite evidence of a link between 
oral health and the risk of pneumonia, the oral status is not yet routinely screened in elderly 
patients hospitalized for pneumonia (34) (35). In the same line, aspiration, mostly due to 
oropharyngeal dysphagia, is a frequent mechanism of pneumonia and is not routinely screened 
any either (33) (36). Links have been highlighted between oral care and mortality from pneumonia 
(low level of evidence) (34). A new tool allows to describe the oral function of the elderly, 
classifying the patient into four different stages: healthy state, oral frailty, oral hypofunction and 
oral dysfunction (37). Like in other organ systems, microbiota may have a major role in maintaining 
health in the airways and lungs, being involved in immunity and physiologic homeostasis, and 
preventing colonization by respiratory pathogens (38) (39). An imbalanced oropharyngeal and 
respiratory microbiota is known to raise the susceptibility to pneumonia (40). Moreover, 
inflammation, vaccinal response, and genetic markers are other factors involved in the occurrence 
and the outcome of pneumonia. Long-term mortality and readmission are associated with 
persistent inflammation in patients hospitalized with sepsis (41). The links between inflammation, 
poor response to vaccination and microbiota need to be further investigated (42) 

17 
Study 2019-01288 - Protocol “Octoplus” V5.2, 05.10.2023 
 
(43). At last, genetic variants of the FER gene (encoding protein-tyrosine kinases) and interferon 
regulatory factor 5 are associated with susceptibility to and severity of pneumonia (44) (45). 
In GEROBIOTA, we aim to identify factors associated with the diagnosis of pneumonia in the 
elderly and its recurrence, the most important being oral hypofunction and the presence of 
particular oral/respiratory microbiota. A biobank (including serum, plasma and saliva) at 
admission and discharge will allow the assessment of inflammation, immune, and genetic 
markers. 
 
We described the risk factors for pneumonia in the elderly patients in two narrative reviews (one 
being under review), highlighting the relevance of oral health and microbiota (46) (47).The Division 
of Gerodontology is currently undertaking a pilot study to validate the oral hypofunction tool (37). 
The Genomic Research Laboratory, which has expertise in the application of metataxonomic and 
metagenomic tools from sample preparation to data analysis, showed that oropharyngeal and 
tracheal microbiota cluster close to salivary and throat microbiota (48) (49) (50). In a recent work, 
metataxonomic data from oropharyngeal secretions and endotracheal aspirate samples obtained 
from intubated patients showed that bacterial diversity, and intra and inter-individual similarity 
decreased over time, while the abundance of several taxa changed significantly. Overall 
microbiota profiles of oropharyngeal secretions, and the abundance of certain bacterial taxa in 
oropharyngeal and tracheal secretions at baseline correlated with the later development of 
ventilator-associated pneumonia during intubation (51). 
 
Risk category 
The risk category of the study according to ClinO, Art. 61 is classified A, because CXR, LDCT 
and LUS are prescribed everyday in clinical practice and very often at the ED. The irradiation 
induced by a low-dose CT scan is low, about 1 mSv and under the Swiss annual irradiation) and 
there is no intravenous injection. 
3. STUDY OBJECTIVES AND DESIGN 
 
3.1 Hypothesis and primary objective 
 
Overall aim: To compare the diagnostic, therapeutic and clinical outcomes of three diagnostic 
strategies based on CXR (standard care), low-dose CT scan (LDCT) or lung ultrasonography 
(LUS) in elderly patients with suspected community or nursing-home acquired pneumonia in the 
ED. 
 
Primary objective: To evaluate whether a diagnostic strategy using LDCT compared with CXR 
leads to a more accurate diagnosis in suspected pneumonia. 
Secondary objectives: 
Diagnostic objectives: 
• 
To assess the difference in diagnostic accuracy for patients with suspected pneumonia 
using LUS compared to CXR, and using LUS compared to LDCT 
• 
To assess sensitivity and specificity of CXR, LDCT and LUS; the number of additional 
imaging studies and invasive procedures prescribed during the acute setting; the imaging studies 
needing unmasking in emergency; the incidentalomes. 
 
Treatment objectives: to assess whether there is a difference between the diagnostic strategies 
in: 
• 
Antibiotic consumption up to one month 
 
Clinical objectives: to assess whether there is a difference between the diagnostic strategies in: 
• 
Time to clinical stability 
• 
Length of hospital stay 

18 
Study 2019-01288 - Protocol “Octoplus” V5.2, 05.10.2023 
 
• 
Unplanned transfer to the intensive care unit or operating room 
• 
Admission to rehabilitation/long-term care facility (LTCF) up to 3 months 
• 
All-cause mortality up to 3 months 
• 
All-cause readmission up to 3 months 
• 
Quality of life at admission, discharge and 3 months 
 
Cost outcomes 
Diagnosis concordance between physicians at the ER and experts 
The association of biomarkers and the presence of an infiltrate. 
 
GEROBIOTA objectives 
To identify factors associated with the probability of pneumonia, and aspiration pneumonia, 1 
month and 1 year mortality, 1 year readmission and to create a biobank allowing the assessment 
of inflammation, immune status and genetic markers. 
 
3.2 Primary and secondary endpoints 
 
Primary outcome measure: 
The primary outcome will be the difference in accuracy between LDCT and CXR, assessed at the 
end of the ED evaluation, using the expert panel as the reference standard, accuracy being 
computed as (true positive + true negative cases) / (true positive + true negative + false positive 
+ false negative cases). 
Main secondary outcome measures: 
Diagnostic outcomes: 
• 
Difference in accuracy between LUS and CXR, assessed at the end of the ED evaluation, 
using the expert panel as the reference standard 
• 
Sensitivity, specificity of CXR, LDCT and LUS 
 Number of additional imaging studies and invasive procedures prescribed during the acute 
setting 
• 
Prevalence of viral pneumonia 
• 
Prevalence of unmasked imaging results (for an emergency finding) 
• 
Prevalence of incidentalomes 
 
Treatment outcomes: 
• 
Number of antibiotic free days at day 30 
 
Clinical outcomes: 
 Time to clinical stability during the first 2 weeks (number of days from admission to the 
first time all of the following parameters are above/under the threshold value and 
maintained for a minimum of 24 hours: heart rate <100 beats/min, systolic blood pressure 
>90 mmHg, temperature <37.8°C (axillary or tympanic), respiratory rate <24 breath/min, 
oxygen saturation >90% while breathing room air, or need for more than 28% fraction of 
inspired oxygen to maintain adequate oxygen saturation, resolution of delirium if present 
at admission) 
Length of hospital stay (in the ED and in the acute setting) 
Proportion of patients with an unplanned transfer to the ICU 
Proportion of patients admitted to rehabilitation or LTCF days through 3 months 
All-cause mortality through 1 month and 3 months 
All-cause readmission to the acute care setting through 1 month and 3 months 
• 
Quality of life at admission, discharge and 3 months (measured by EQ-5D-3L and a CAP 
score questionnaire) 
 Interagreement rate for the probability of pneumonia between physicians participating to 
the trial and a consensus of experts in chest imaging, for each method 

19 
Study 2019-01288 - Protocol “Octoplus” V5.2, 05.10.2023 
 
 Association between biological markers (CRP and PCT) and the presence of an infiltrate 
Cost outcomes: 
Costs of care, physician, imaging, laboratory, treatment (including antibiotic therapy) and others 
per patient, health related quality of life until 3 months; unit of work consumption per hospital 
(number of minutes of care, physician, laboratory and imaging points) 
Safety outcomes: unplanned transfer to the ICU; 1-month mortality. 
GEROBIOTA: 
The probability of pneumonia/aspiration pneumonia according to the panel of experts, all cause 
1 month and 1 year mortality, 1 year readmission for pneumonia. 
 
3.3 Study design 
 
This is a Swiss multicentre superiority randomized clinical study with 3 parallel arms. 
Randomization will be 1:1:1 using randomly permutated block sizes and be stratified by centre. 
Patients will be either randomized into the CXR, the LDCT or the LUS arm. The 3 imaging 
modalities will be performed in all included patients but only one will be available to the clinician 
according to the allocation arm. The concealed results of the imaging procedures will be 
unblinded at day 5. The duration of follow-up will be 3 months for OCTOPLUS. The panel of 
experts will provide their diagnosis a posteriori. An intermediate safety analysis will be performed 
after 200 patients have completed the 1-month follow-up. 
 
 
Figure 1: Study design 
 
 
Known or potential problems associated with the trial design: 
-Insufficient recruitment: given the case load of the participating centres and the required sample 
size, this scenario is unlikely. 
-Risk of the CT: LDCT is well-tolerated and its mean radiation exposure is much lower than a 
full-dose CT scan (about 1mSv) (52). In a previous study, a mean (sd) radiation exposure of 1.5 
(0.47) mSv was measured, which can be compared to the mean (sd) exposure of conventional 
CXR of 0.05 (0.03) mSv (20). 

20 
Study 2019-01288 - Protocol “Octoplus” V5.2, 05.10.2023 
 
-Risk of LUS: there will be many clinicians performing LUS at each site. LUS is known to have a 
fast-learning curve. To minimize heterogeneity between the clinicians and centres, standardization 
of LUS practice will be performed in all participating centres before the beginning of the study. 
-Risk of the blinding: blinding is one of the major challenges of the trial. It will be performed in 
each site using a secured research picture archiving and communication system (PACS) thanks 
to radiologist engineering. To allow for compliance and smooth running of the study, all ED and 
radiology staff will be regularly informed regarding methods and stakes. As soon as the patient is 
included, the research staff will anticipate and inform the radiology staff who will take care of the 
patient, and the clinician to perform LUS about the necessity of blinding and the CRF to fill in. The 
research staff will be the only one able to provide the attending clinician with the result of the 
allocated imaging modality, and ensure that it is accessible in the patient’s medical record. The 
two other imaging modalities will be concealed until day 5, and will only be accessible on the 
PACS. 
According to a predefined list of emergency findings, the radiologist interpreting CXR or LDCT or 
the clinician performing LUS will be able to immediately ask the investigator for unblinding. 
At day 5, the research staff will ensure that the two blinded imaging modalities are made 
accessible again to the treating clinician. 
-The risk of a false negative (meaning a missed diagnosis of pneumonia) will be 
counterbalanced by the fact that the clinician will be allowed to prescribe antimicrobial therapy for 
another diagnosis than pneumonia. As patients with severe pneumonia will not be included, a 
delay of a few hours in the diagnosis of pneumonia is unlikely to lead to an unfavourable outcome. 
Indeed, a longer time to antibiotic administration was not associated with an unfavourable 
outcome in moderately severe CAP (53). 
-The panel of experts: we already used the Delphi method with a panel of experts for the 
reference diagnostic in our previous study. The panel of experts will be composed by board-
certified specialists in infectious diseases, respiratory diseases, internal medicine and radiology. 
All will be senior attending physicians with expertise in caring for patients with pneumonia. They 
will be previously trained for the diagnosis of pneumonia using international and Swiss guidelines. 
They will have access to all imaging studies, to avoid any potential incorporation bias. 
-Coordination: as this is a multicentre and multidisciplinary trial, particular emphasis will be put 
on coordination. 
Finally, we estimated that risks inherent to the trial are minimal and inferior to the benefices of the 
study which could deliver key results which would provide long-term benefit to all patients with 
pneumonia. 
 
Sequential realization of the 3 imaging modalities may delay the final working diagnosis of the 
physician in charge. However, this delay will be minimized by the research staff, who will make 
any effort to guarantee quick delivery of all diagnostic procedures. As severe pneumonia will not 
be included, a delay of at most a few hours before adequate treatment is not expected to have a 
negative impact on patients’ evolution (54). All imaging must be done before leaving the ED. A 
transfer from one ED to another is not considered as an exit from the ED (e.g. a transfer of the 3-
Chêne to Cluse-Roseraie for Geneva) 
Methods of minimising bias: 
-Stratified randomization will be used in this study. 
-Allocation sequence 
Participants will be randomized 1:1:1 to either the CXR, the LDCT, or the LUS arm as per a 
computer-generated randomization schedule stratified by study centre using investigator blinded 
randomly permuted blocks of varying size. 
-Concealment mechanism 
Patients will be randomized via eCRF directly. 
-Implementation 

21 
Study 2019-01288 - Protocol “Octoplus” V5.2, 05.10.2023 
 
An independent statistician will create confidential randomization lists for each site. The lists will 
be given to the data-manager to implement the randomization list in the eCRF. Each site will have 
a dedicated research staff responsible for approaching patients attending the ED regarding 
inclusion in the study. The triage nurses and the physician working at the ED will also be asked 
to help the study team by alerting the research staff to the presence of any potential participant. 
The site’s coinvestigator(s) will also be on hand to answer any additional questions the patient 
might have. If the patient agrees to participate in the study, the patient’s written informed consent 
will be obtained and the study coordinator randomized the patient directly through the eCRF. The 
research staff will keep the “crosswalk”, a table linking the participant’s randomization number with 
his/her identifying data, in a locked document. 
3.4. Study intervention 
 
CXR, LDCT and LUS are prescribed at ED for the diagnosis of pneumonia, but have never been 
compared to each other in a randomized trial. 
NB: only the first imagery made accessible to the participant will be billed 
Experimental interventions 
LDCT will be performed at the radiology unit of the ED. There will be no administration of 
intravenous contrast. Interpretation will be done in real-time by a radiologist who will record his 
probability of pneumonia on a specific CRF. 
LUS will be performed at bedside in the ED by a physician trained in point-of-care LUS for 
pneumonia, and different from the treating clinician. He/she will also record his probability of 
pneumonia. 
As with all ultrasound examinations, it will be important to standardize the examination procedure 
for LUS to minimize the influence of setting and examiner. Standardization will be performed 
among centres, before the beginning of the study. The ultrasound and educational experts, 
experienced as directors of Point-of-Care Ultrasound Certification (POCUS) courses and 
approved instructors of thoracic ultrasound, will supervise this standardisation procedure. 
Control intervention 
The control diagnostic procedure will be CXR, preferentially standing, and with 2 incidences, 
which is the recommended and most commonly used diagnostic imaging technique for pneumonia 
in guidelines (5) (6) (55). A radiologist other than the one who interpreted LDCT will evaluate the 
CXR and rate his/her probability of pneumonia and fill in a specific CRF. 
 
Patients who already had CXR, LDCT and LUS prior to randomization will be excluded. 
Registration of pulmonary sounds will be done in a securized Cloud with an intelligent stethoscope 
in the Pneumoscope study (protocol in appendix). 
4. STUDY POPULATION AND STUDY PROCEDURES 
4.1 Inclusion and exclusion criteria, justification of study population 
Patient eligibility criteria 
To be eligible for study participation, all patients will be required to meet the following inclusion 
criteria, and none of the exclusion criteria: 
 
Inclusion criteria 
1. Suspicion of community acquired pneumonia (CAP) or nursing-home acquired pneumonia 
consulting to the ED 
2. Age>65 years 
3. Signed informed consent 
4. Presence of at least one respiratory symptom (new or increasing cough or dyspnoea, 
purulent sputum, pleuritic chest pain, respiratory rate >20/min, focal auscultatory findings 

22 
Study 2019-01288 - Protocol “Octoplus” V5.2, 05.10.2023 
 
or oxygen saturation <90% on room air) 
5. and at least one sign or laboratory finding compatible with an infection (temperature 
>37.8°C or <36.0°C, CRP >10 mg/L, PCT >0.25µg/L, leukocyte count >10G/L with 
>85% neutrophils or band forms) will be required 
presence of acute delirium or unexplained acute fall can substitute for the presence of 
either the respiratory or the infectious symptom in patients older than 80 years 
 
Exclusion criteria: 
1. Need for an immediate admission to the intensive care unit (ICU) 
2. Diagnosis of pneumonia in the past 3 months 
3. SARS CoV-2 infection diagnosed by PCR or antigenic test within the past 3 weeks and 
before the arrival to the ED 
4. Transfer from another hospital with a diagnosis of pneumonia 
5. Thoracic CXR or CT scan or US already performed during the present episode 
6. Need for an immediate contrast-enhanced CT 
7. Advanced care planning limiting therapy to comfort care only 
8. Prisoners 
9. Known uncontrolled psychiatric disorders 
10. Previous enrollment into the current study 
 
Reasons for inclusion of vulnerable participants: 
Patients over 65 years of age presenting to the ED with a suspicion of pneumonia will be included, 
even if the potential benefit is not restricted to elderly patients. As pneumonia is a common 
pathology in elderly patients, our study will frequently include vulnerable participants, e.g. 
participants incapable of judgment or participants under tutelage (of note, one third of the patients 
of the PneumO-LD-CT cohort had dementia or delirium and consent was obtained from next of 
kin). We think it is meaningful to study this population because overdiagnosis of pneumonia and 
over-prescription of antibiotics in the elderly is likely. Moreover, although being more affected by 
the disease, elderly patients are often excluded from clinical trials in part because informed 
consent is difficult to obtain due to delirium or permanent cognitive impairment. This results in 
guidelines and recommendations being developed on a younger and healthier population, 
although they are mainly used for elderly patients. Diagnostic criteria need to be revised in this 
vulnerable population in order to improve antibiotic prescription and patient management. 
4.2 Recruitment, screening and informed consent procedure 
 
Recruitment: 
Patients will be recruited at their admission to the ED during the triage process. Inclusions will be 
done on working days and hours. 
The participating sites will identify all eligible patients. The investigator and the research staff will 
approach each potential patient and inquire about their interest and eligibility in participating in this 
study. This inquiry will include screening questions to confirm eligibility as well as a description of 
the study and responsibilities for participating. All enrolled patients should be followed up within the 
study, except if their participation is prematurely terminated. 
The recruitment period will be up to 2 years, during which 500 patients are planned to be enrolled, 
which means between 1 to 2 patients per site and per week. If the enrolment goals are not met, 
the study will be extended until achievement. The recruitment is competitive between the sites. 
Emergency situation (HRA, Art. 30-31 and OClin Art. 15) 
This study is carried out in an emergency situation and the expected results can only be achieved 
in an emergency situation. Indeed pneumonia is a major cause of morbidity and mortality and of 
antibiotic prescription in hospitalized patients whom prognosis is engaged. Making the diagnosis 
and the decision of treating the patient consulting the ED must be performed within first hours (the 
international guidelines recommend treating the patient while he/she is still in the ED for a 
suspicion of pneumonia). 

23 
Study 2019-01288 - Protocol “Octoplus” V5.2, 05.10.2023 
 
Description of the informed consent process (HRA, Art. 7, 16, and 18, 42; ClinO, Art. 7 - 9) 
including time for consideration given to the participants: 
The investigators will explain to each participant/or their representative the nature of the study, 
its purpose, the procedures involved, the expected duration, the potential risks and benefits and 
any discomfort it may entail. Each participant or their representative will be informed that the 
participation in the study is voluntary and that he or she may withdraw from the study at any time 
and that withdrawal of consent will not affect his or her subsequent medical assistance and 
treatment. The participant or his/her representative will be informed that the medical records may 
be examined by authorised individuals other than their treating physician. 
Consent: 
- 
The patient has his ability to consent in the emergency room: he signs the standard 
consent for participant. 
- 
The patient has not his ability to consent in the emergency room 
o he does not express either orally or by any particular behaviour his/her refusal of 
being part of the research project. 
o a physician independent of the study will be sought to defend the interest of the 
patient (HRA 30-31) and sign the dedicated written confirmation 
Everything will be done to establish the will of the patient as soon as possible 
o the patient recovers his capacity during hospitalization : he signs the standard 
consent for participant. 
o the patient is known to no longer have the ability to consent or does not recover 
his ability to discern during hospitalization: the relative/legal representative sign the 
dedicated consent. 
 
CIRCUS: an information letter will be given to the clinican in charge of the patient at the ED 
(appendix). 
GEROBIOTA 
The patient will be able to participate to GEROBIOTA in Geneva and Bern. He will also be asked 
to give his consent to participate to the biobank. 
 
Pneumoscope 
The patient will be able to participate to this ancillary study when included in Geneva. 
 
4.3 Study procedures 
 
3 years (2 years of recruitment plus 3 months of follow-up for OCTOPLUS and one year for 
GEROBIOTA), inclusions on working days and hours (see Figure 1) 
CXR will be interpreted in real-time by a first radiologist and a CRF will be filled in, including the 
probability of pneumonia. 
LDCT will be interpreted in real-time by another radiologist and a CRF will be filled in, including 
the probability of pneumonia. Both will be blinded to the other’s interpretation. 
LUS will be performed by another clinician than the one in charge of the patient, and his practice 
of LUS will be standardized before the launching of the study. 
After identification in the ED, included patients will be randomized 1:1:1 to one of the following 
three arms (stratified by participating center): 
-Only CXR (image and CRF) will be available to the clinician (control arm). LDCT and LUS will be 
performed but not available (clinician will be blinded to LDCT and LUS) 
-Only LDCT (image and CRF) will be available to the clinician (first intervention arm). CXR and 

24 
Study 2019-01288 - Protocol “Octoplus” V5.2, 05.10.2023 
 
LUS will be performed but not available (clinician will be blinded to CXR and LUS) 
-Only LUS (image and CRF) will be available to the clinician (second intervention arm). CXR and 
LDCT will be performed but not available (clinician will be blinded to CXR and LDCT) 
The blinding will be maintained during the first 5 days, and hence will not influence the diagnosis 
and the treatment of the patient. 
Before discharge of the ED, the clinician in charge will be asked to assess on a 3-level Likert 
scale the probability of pneumonia (high, intermediate, low level) while considering all available 
clinical and biological data, plus the imaging modality according to the randomization arm. 
He will document the intended treatment strategy (antibiotic prescription or not, which molecule, 
for which indication if not for pneumonia, intended duration). 
He will be allowed to prescribe antibiotic for another indication than pneumonia by documenting 
a principal alternative diagnosis (e.g. urinary tract infection, acute exacerbation of a chronic 
obstructive pulmonary disease, cardiac failure...) and strongly encouraged not to prescribe 
antibiotic for pneumonia if he rated a low probability of the disease. 
Patients will be followed-up daily during the hospitalization by research staff and by phone up to 
3 months to assess readmission as well as mortality. 
A panel of experts will adjudicate the final diagnosis in all patients, having access to all data 
(clinical, CXR, LDCT and LUS and outcome data at day 28), while blinded to the allocation arm. 
Their diagnosis will be considered as the reference diagnosis. 
Safety: Number of death and admissions to the ICU in each arm will be communicated to a 
dedicated data safety monitoring board after 200 inclusions for a safety interim analysis. 
Blinding of the imaging modalities: For each patient, the two blinded imaging modalities will 
be registered on a secured PACS. The CRFs filled for these imaging modalities will be kept 
unavailable as well as images until day 5. 
 
Unblinding: The research staff will ensure that unblinding of imaging and CRFs is done at day 5 
and that all results are available in the electronic health record. 
 
Unblinding will be performed in emergency at the ED if the radiologist/clinician performing LUS 
diagnoses immediately life-threatening findings: pneumothorax, pleural effusion in large quantities 
(white lung) with mediastinal shift, complete atelectasis of one lung, indirect sign of aneurysmal 
rupture 
(haemomediastinum), 
massive 
pericardial 
effusion, 
tracheal 
foreign 
body, 
pneumoperitoneum, haemothorax, pneumomediastinum, suspicion of acute tuberculosis (NB: 
pulmonary embolism won’t be excluded as LDCT will be performed without intravenous contrast). 
 
In case of such finding, the radiologist interpreting CXR or LDCT and the clinician performing LUS 
will call in emergency the investigator to be allowed to communicate the results to the clinician. 
In case of subsequent clinical deterioration, the clinician in charge of the patient may prescribe 
any new imaging deemed necessary: a new CXR for the diagnosis of heart failure; injected chest 
CT scan to eliminate a pulmonary embolism or a suppurative complication. 
Nevertheless, the local investigator will be accessible and able to proceed to a deblinding in 
justified cases. 
GEROBIOTA 
At admission: 
-Microbiota samples (saliva and respiratory samples) before antibiotic administration at the ED if 
possible. They will be stored at -80. 
NB: respiratory samples will be those taken for routine methods including sputum, induced 
sputum, tracheal aspirate or broncho-alveolar lavage if done and still available 
 
-Blood: Serum (2 tubes), plasma EDTA (2 tubes), plasma citrate (2 tubes), PAX gene DNA (1 
tube), PAX gene RNA (1 tube). 

25 
Study 2019-01288 - Protocol “Octoplus” V5.2, 05.10.2023 
 
During hospitalization: 
-Oral health examination by a medical dentist as soon as the patient is stabilized (≈30 min) 
-Geriatric assessment by the research staff during the first week of hospitalization (≈45min) 
At discharge: 2 tubes of serum, 4 tubes of plasma 
 
 
 
Table 1: Timeline of patient enrolment/allocation, interventions, and assessments 
Study periods 
Screening 
Inclusion 
Discharge from 
the ED 
Discharge from 
the acute setting 
1 month 
3 months 
Reference 
diagnosis 
Visit 
1 
2 
3 
5 
6 
7 
8 
Time (day) 
From the ED 
admission until the 
ED discharge (D0). 
d15 
d30 
d90 
Windows (days) 
NA 
NA 
NA 
-2/+5 
-2/+10 -2/+15 NA 
Patient/representative IC or 
independent physician 
x 
In-/exclusion criteria 
x 
Randomization 
x 
Demographics 
x 
Medical history 
x 
Physical examination 
x 
Vital signs 
Time to clinical stability 
x 
x 
x 
x 
Laboratory tests 
x 
CXR, LDCT, LUS 
x 
Main diagnosis, other 
diagnosis, and therapeutic 
outcomes before ED 
discharge 
x 
No. of days of AT 
prescription 
Other diagnosis outcomes 
x 
Clinical outcomes (safety 
outcomes) 
x 
x 
x 
QoL questionnaire 
x 
x 
x 
Panel of experts 
x 
AT = antimicrobial therapy, CXR = chest x-ray, ED = emergency department, IC = informed 
consent, LDCT = low-dose computed tomography, LUS = lung ultrasonography, QoL = quality of 
life 
Table 1 bis: GEROBIOTA 
 
Study period 
Inclusion Hospitalization 
Discharge 1-year 
Biobank 
x 
x 

26 
Study 2019-01288 - Protocol “Octoplus” V5.2, 05.10.2023 
 
Geriatric and oral health assessment 
x (once) 
Phone call 
x 
 
Table 2 : Interventions in both studies 
 
OCTOPLUS 
GEROBIOTA 
CXR, LDCT and LUS 
Blood 
(30 
ml), 
saliva, 
respiratory 
samples 
(biobank) at admission 
Follow-up 
during 
the Oral health assessment and 
Geriatric assessment during 
hospitalization 
hospitalization 
by 
the 
research staff 
Phone call at 1 and 3 months 
Saliva and blood (6 tubes) 
(biobank) before discharge 
Phone call at 1 year 
Measures taken to reduce biases: 
-Blinding of patients, attending physicians, investigators: 
-the clinician in charge will know the allocation arm but will be blinded to the results of the 
two other exams 
-the radiologist interpreting LDCT will not have access to CXR and LUS 
-the clinician performing LUS will have access to the electronic file (including clinical data) 
but not to CXR and LDCT 
-the participants will be blinded, meaning they will know their diagnosis but not the 
allocation arm 
-the panel of experts will be blinded to the arm of allocation and to the probability of 
pneumonia according to the clinician to perform the final review 
-the investigators will be blinded to the allocation arm 
-Blinding of outcomes assessment and data analysis: 
Clinical data on all included patients will be collected by the study personnel and recorded in the 
CRF and database. HUG data managers experienced in generating blinded reports will then 
provide data exports to a blinding outcomes accessor and a blinded data analyst. These exports 
will contain recoded study identification numbers and no information on diagnostic assignments 
allowing for both fully blinded outcomes assessment and data analysis. For analyses, data 
management will be asked to export data with only coded treatment group labelling. 
-Blinding of the imaging results: 
As explained above, these blinded results will be available on a research PACS until day 5, when 
the research staff will proceed to unblinding. 
4.4 Withdrawal and discontinuation 
Withdrawal: 
If a patient wishes to withdraw consent, the investigator will be informed, and the patient will be 
excluded from the study without any consequence on his care. 
As the validity of the clinical trial or its results could be distorted in essential points by the 
destruction of biological material and personal health-related data, their use in the clinical trial will 
allowed despite the refusal of the patient. Since pneumonia is very frequent in elderly patients 
and since this population is very rarely included in clinical trials, we think it is very important to 
carry out this trial and not to destroy data which would be valuable for further elderly patients 
having pneumonia. 

27 
Study 2019-01288 - Protocol “Octoplus” V5.2, 05.10.2023 
 
In case of protocol violation, the patient will stay in the randomized arm for the intention to treat 
analysis and will be excluded from the arm for the per protocol analysis. If the patient gets lost to 
follow-up, the data will be censored after the last visit. In case of death, the civil registry will be 
consulted regarding the information on mortality. 
Death of the patient: 
 
In case of death before obtaining provisional consent, there will be no inclusion. 
In case of death of the person after provisional consent, it will be verified whether the patient has 
issued Advance Directives authorizing the use of data or biological materials for research 
purposes. If this is not the case, the consent of the representative will be necessary. 
 
5. STATISTICS AND METHODOLOGY 
5.1. Statistical analysis plan and sample size calculation 
Methodology 
Dr Christophe Combescure; Investigation Unit, Geneva University Hospitals, Rue Gabrielle-
Perret-Gentil 4, 1205 Geneva, Switzerland, Email: christophe.combescure@hcuge.ch, Tel: +41 
22 37 29 136 
 
We hypothesize that the proportion of patients with a correct diagnosis of pneumonia (proportion 
of true positive plus true negative) will be higher in LDCT arm than in CXR arm. The null hypothesis 
that will be tested in the primary analysis is the equality of proportion of correctly classified patients 
in LDCT and CXR arm. 
The analysis will follow the intention to treat principle. A sensitivity analysis will be conducted on 
the per protocol population (i.e. excluding patients who have not received the allocated 
intervention, and patients who crossed over). Another sensitivity analysis will be conducted 
excluding patients who will have had CXR before LDCT and LUS. 
The diagnosis made by the panel of experts will be the reference diagnosis for calculation of the 
primary outcome in each arm, and to determine diagnostic accuracy expressed as sensitivity, 
specificity, predictive values and likelihood ratios. The primary outcome in each arm will be 
compared to the two other ones. 
Primary analysis 
The reference diagnosis will be positive (respectively “negative”) if the panel of experts rates the 
probability of pneumonia diagnosis “intermediate” or “high” (respectively “low”) on the Likert scale. 
The clinician’s diagnosis will be positive (respectively “negative”) if the clinician rates the 
probability of pneumonia diagnosis “intermediate” or “high” (respectively “low”) on the Likert scale. 
We will assume an adequate diagnosis classification, if the clinician’s diagnosis and the reference 
diagnosis (panel of experts) agree (true positive and true negative diagnoses). The proportions 
of correctly classified patients in the LDCT and CXR arms will be calculated with 95% Clopper-
Pearson confidence intervals (CIs), and will be compared with a logistic regression model 
adjusted for sites to account for the stratified randomization. The statistical test will be two-sided 
and the significance threshold will be 0.05. 
Secondary analyses 
1) The proportion of adequate diagnoses in the LUS arm will be also calculated with the 95% 
Clopper-Pearson CI, and will be compared with the CXR arm using a logistic regression model 
adjusted for sites. 
2) 
Similarly, the proportion of adequate diagnoses in the LUS arm will be compared with the 
LDCT arm. 
3) 
The sensitivity (proportion of positive diagnoses among patients with a positive reference 
diagnosis) and specificity (proportion of negative diagnoses among patients with a negative 
reference diagnosis) will be also calculated with 95% Clopper-Pearson CIs in each arm. The 

28 
Study 2019-01288 - Protocol “Octoplus” V5.2, 05.10.2023 
 
sensitivity between the LUS and CXR arms and between the LUS and LDCT arms will be 
compared using a logistic regression model adjusted for sites. 
4) 
Positive and negative predictive values, and likelihood ratios will be calculated with 95% 
Clopper-Pearson CIs in each arm. 
5) 
As a sensitivity analysis, the primary and secondary analyses 1) to 4) will be repeated, 
whereby only the level “high” on the Likert scale is regarded as positive diagnosis (clinician’s 
diagnoses and reference diagnoses). 
6) 
Treatment outcomes: The cumulative incidence of antibiotic free patients will be 
investigated over 30 days by using a non-parametric competing risk model with death before 
antibiotic intake as a competing event and will be compared between arms. Comparisons will be 
stratified on sites. 
As a sensitivity analysis, this analysis will be repeated excluding exacerbation of COPD, where 
the need for antibiotic therapy is still debated. 
7) 
Diagnosis outcomes: We will describe each of the alternative diagnoses by frequencies in 
each arm, and the percentage of patients with an alternative diagnosis consistent between 
radiologists and experts will be evaluated. 95% Clopper-Person CIs will be reported. The 
proportions of imaging results needing unmasking and of additional radiological studies (and 
invasive procedures) during the 2 first weeks will be also reported with their 95% Clopper-Pearson 
CIs. A post-hoc procedure will be applied for pairwise comparisons. 
8) 
Clinical outcomes: We will use Kaplan Meier’s estimates to evaluate the time to clinical 
stability over 15 days in each arm, and a log-rank to compare them. Patients who die in the first 
2 weeks will be censored at day 15 (i.e. considered has never reaching clinical stability). The 
Mann-Whitney test will be used to compare the length of hospital stay between the groups. The 
proportion of patients with an unplanned transfer to the ICU or operating room will be reported by 
arm and compared between the arms using a logistic regression model adjusted for sites. All-
cause mortality during the 3-month follow-up will be investigated with Kaplan Meier’s survival 
curves, and compared between the arms using a log-rank test stratified on sites. Readmissions 
during the 3-month follow-up will be investigated using survival models with competing risk. Death 
before readmission will be the competing event. 
9) Cost outcomes: Mean cost per patient will be assessed and compared between arms using 
multiple linear regression models adjusted for sites. Reweighted estimators will be used to 
account for censoring. 
10) Interagreement rate for the probability of pneumonia rated on a 3-level Likert scale: the 
agreement between raters participating to the trial and a consensus of two experts will be 
investigated by using kappa statistics. 
11) The association between biological markers (CRP and PCT) and infiltrates will be assessed 
by differences in the mean levels of markers between patients with and without infiltrates and 
tested by using t test. Transformations on markers will be applied if needed. Multiple linear 
regression models will be used for adjustment. Similar methods will be used to investigate the 
association between markers and the probability of pneumonia rated on the 3-level scale. The 
analyses will be conducted for each arm. 
Interim and safety analyses 
There will be no comparative analysis for efficacy or futility. An initial safety analysis will be 
performed after 200 patients have reached the 1-month follow-up. The study’s data manager will 
ensure that the data will be exported with “scrambled” allocation labels and that study investigators 
do not have access to the data. The results will be transmitted to the principal investigators and 
the safety monitoring board. The latter will be free to lift the blind if deemed necessary, and will 
be asked to make the final decision on the continuation of the study without modification, or 
terminating the study. 
Sub-group analyses 
The primary analysis and the secondary analyses related to the assessment of diagnostic 
performances (secondary analyses 1) to 4)) will be conducted in sub-groups of patients: 1) 

29 
Study 2019-01288 - Protocol “Octoplus” V5.2, 05.10.2023 
 
patients aged less than 80 years versus patients aged over 80 years, 2) patients with a positive 
PCR (i.e. detection of a virus) at the beginning of the study versus patients with a negative PCR. 
 
5.2. Handling of missing data and drop-outs 
Some patients will be discharged from the ED, but they won’t be considered as dropout patients 
as the diagnosis of pneumonia will be made before the discharge, and follow-up will be done by 
phone. Missing data that cannot be avoided will be excluded from the primary analysis (complete 
case analysis) and signalled as such. In addition, multiple imputation will be performed if more 
than 10% of data of the outcome are missing. 
 
6. REGULATORY ASPECTS AND SAFETY 
 
6.1 Local regulations / Declaration of Helsinki 
 
This study is conducted in compliance with the protocol, the current version of the Declaration of 
Helsinki, the ICH-GCP. 
 
6.2 (Serious) Adverse Events 
 
An Adverse Event (AE) is any untoward medical occurrence in a patient or a clinical investigation 
subject which does not necessarily have a causal relationship with the trial procedure. An AE can 
therefore be any unfavourable or unintended finding, symptom, or disease temporally associated 
with a trial procedure, whether or not related to it. According to the local regulation (Clin O Art.39), 
no documentation of the AE is planned in this study. 
A Serious Adverse Event (SAE) (ClinO, Art. 63) is any untoward medical occurrence that 
- 
Results in death or is life-threatening, 
- 
Requires in-patient hospitalisation or prolongation of existing hospitalisation, 
- 
Results in persistent or significant disability or incapacity, or 
- 
Causes a congenital anomaly or birth defect 
Both Investigator and Sponsor-Investigator make a causality assessment of the event to the trial 
intervention, (see table below based on the terms given in ICH E2A guidelines). Any event 
assessed as possibly, probably or definitely related is classified as related to the trial intervention. 
 
Relationship 
Description 
Definitely 
Temporal relationship 
Improvement after dechallenge* 
Recurrence after rechallenge 
(or other proof of drug cause) 
Probably 
Temporal relationship 
Improvement after dechallenge 
No other cause evident 
Possibly 
Temporal relationship 
Other cause possible 
Unlikely 
Any assessable reaction that does not fulfil the above 
conditions 
Not related 
Causal relationship can be ruled out 
*Improvement after dechallenge only taken into consideration, if applicable to reaction 

30 
Study 2019-01288 - Protocol “Octoplus” V5.2, 05.10.2023 
 
Both Investigator and Sponsor-Investigator make a severity assessment of the event as mild, 
moderate or severe. Mild means the complication is tolerable, moderate means it interferes with 
daily activities and severe means it renders daily activities impossible. 
Reporting of SAEs (see ClinO, Art. 63) 
All SAEs are documented and reported immediately (within a maximum of 24 hours) to the 
Sponsor-Investigator of the study. If it cannot be excluded that the SAE occurring in Switzerland 
is attributable to the intervention under investigation, the Investigator reports it to the Ethics 
Committee via BASEC within 15 days (only 7 days for a death). If the SAE potentially attributable 
to the intervention occurs at one of the study sites, the coordinating Investigator reports the events 
to the Ethics Committee concerned, within 15 days (only 7 days for a death). 
Reporting of death, no attributable to the intervention (see ClinO Art.40) 
Only death attributable to the intervention will report to the Ethics Committee via BASEC within 7 
days. All deaths due to another cause will be reported in the annual report. 
6.3 (Periodic) safety reporting 
 
An annual safety report (ASR/DSUR) is submitted once a year to the local Ethics Committee by 
the Investigator (ClinO, Art. 43 Abs). 
In international multicentric studies the ASR/DSUR contains information from all sites including 
information from sites outside of Switzerland. The Sponsor-Investigator distributes the 
ASR/DSUR to all the participating Investigators. 
 
6.4 Radiation 
 
If the permitted dose guidance value (5 mSv per year if no direct benefit is expected for the 
participants) is exceeded at any time, the local Investigator notifies the Ethics Committee via 
BASEC within 7 working days of it becoming known (see ClinO, Art. 44). 
The dose expected for LDCT is 1 to 1.5 mSV (see paragraph 3.3 with references on risk of CR, 
page 17). 
6.5 Pregnancy 
 
NA 
 
6.6 Amendments 
 
Substantial changes to the study setup and study organization, the protocol and relevant study 
documents are submitted to the Ethics Committee for approval before implementation. Under 
emergency circumstances, deviations from the protocol to protect the rights, safety and well-being 
of human subjects may proceed without prior approval of the Ethics Committee. Such deviations 
shall be documented and reported to the Ethics Committee as soon as possible. 
Substantial amendments are changes that affect the safety, health, rights and obligations of 
participants, changes in the protocol that affect study objective(s) or central research topic, 
changes of study site(s) or of study leader and sponsor (ClinO, Art. 29). 
A list of all non-substantial amendements will be submitted once a year to the competent EC 
together with the ASR. 
 
6.7 (Premature) termination of study 
 
The Sponsor-Investigator may terminate the study prematurely according to certain 
circumstances, e.g. 
- 
Ethical concerns, 
- 
Insufficient participant recruitment, 

31 
Study 2019-01288 - Protocol “Octoplus” V5.2, 05.10.2023 
 
- 
When the safety of the participants is doubtful or at risk (e.g. when the benefit-risk 
assessment is no longer positive), 
- 
Alterations in accepted clinical practice that make the continuation of the study unwise, or 
- 
Early evidence of harm or benefit of the experimental intervention 
Upon regular study termination, the Ethics Committee is notified via BASEC within 90 days (ClinO, 
Art. 38). 
Upon premature study termination or study interruption, the Ethics Committee is notified via 
BASEC within 15 days (ClinO, Art. 38). 
6.8 Insurance 
 
In the event of study-related damage or injuries, the liability of the institution HUG provides 
compensation, except for claims that arise from misconduct or gross negligence. 
7. 
FURTHER ASPECTS 
7.1 Overall ethical considerations 
Ethical conduct of the study 
The study will be carried out in accordance to the protocol and with principles enunciated in the 
current version of the Declaration of Helsinki, the guidelines of Good Clinical Practice (GCP) 
issued by ICH and the Swiss Law and Swiss regulatory authority’s requirements. The Competent 
Ethics Committee will receive annual safety and interim reports and be informed about study 
stop/end in agreement with local requirements. 
Participant privacy and confidentiality 
The investigator affirms and upholds the principle of the participant's right to privacy and that they 
shall comply with applicable privacy laws. Especially, anonymity of the participants shall be 
guaranteed when presenting the data at scientific meetings or publishing them in scientific 
journals. 
Individual subject medical information obtained as a result of this study is considered confidential 
and disclosure to third parties is prohibited. Subject confidentiality will be further ensured by 
utilising subject identification code numbers to correspond to treatment data in the computer files. 
For data verification purposes, authorized representatives of the Sponsor (-Investigator), an ethics 
committee may require direct access to parts of the medical records relevant to the study, including 
participants’ medical history. 
Early termination of the study 
An initial safety “checkpoint” analysis will be performed after 200 patients have reached the 30-
day follow-up. 
The Sponsor-Investigator may terminate the study prematurely if there is evidence of benefit or 
harm of the experimental intervention according to the advice of Safety Monitoring Board. 
The safety outcomes in each arm will be transmitted to the Safety Monitoring Board who will 
decide if the study has to be stopped prematurely in case of higher risk of transfer to intensive 
care unit (ICU) or mortality in a study arm compared with the two other arms (members of the 
Safety Monitoring Board will be blinded to the allocation arm). 
About vulnerability of the population, please see paragraph 4.1 
7.2 Risk-benefit assessment 
 
This study will not have an immediate benefit to the study participant, but its results should benefit 
future patients. 
Pneumonia is the leading cause of morbidity and mortality from infection in elderly patients, and 
one of the main causes of antibiotic prescription. Its diagnosis is, however, particularly challenging 
in elderly patients, because of the lack of sensitivity and specificity of clinical signs, symptoms 
and CXR findings, and because of the high incidence of alternative diagnoses. Hence, new 

32 
Study 2019-01288 - Protocol “Octoplus” V5.2, 05.10.2023 
 
strategies are needed to improve the diagnosis of pneumonia, leading to patient management 
and more appropriate use of antibiotics in an era of increasing antibiotic resistance. 
An LDCT or LUS-based work-up of suspected pneumonia may have significant advantages over 
standard CXR. Superior diagnostic accuracy of either modality can lead to better outcomes for 
patients through early appropriate management of the actual symptom-causing disease, but also 
to a more appropriate antibiotics use, a key issue in an era of growing bacterial resistance. 
8. 
QUALITY CONTROL AND DATA PROTECTION 
 
8.1 Quality measures 
 
The quality of the clinical investigation is derived from the quality of the investigation planning and 
reliability of the results. Sponsor's quality assurance policies and guidelines apply to the planning, 
selection of investigators and participating clinics, contracts, monitoring, recording of data and its 
analysis, documentation and archiving, evaluations, and reporting of the entire clinical study. This 
clinical study is conducted in accordance to the ICH-GCP guidelines. 
Prior to recruiting the first patient, the study site PI, Subinvestigators, and Study Coordinator(s) 
will undergo a defined training program. This will occur during an investigator meeting prior to 
recruitment start. The training includes explanations of the procedures, inclusion and exclusion 
criteria, the CRFs, and general aspects of GCP. The training will be performed by the principal 
investigators. A training record is maintained for all study site personnel involved in study-specific 
activities. In the case of a change in the study site personnel, the new staff will be retrained. 
All research team members will have current GCP or equivalent training/certification. 
The Study Coordinator with primary responsibility for managing the study at each study site will 
be provided with comprehensive training on the study procedures, duties and responsibilities of 
the Study Coordinator. 
 
The PI at each study site will be responsible for the supervision of the study and will provide 
direction and training to all other research personnel, as necessary. 
A double data entry will be performed. 
 
Independent data review will be done through an independent Safety Monitoring Board and a trial 
monitoring. 
 
For quality assurance the sponsor, the Ethics Committee or an independent trial monitor may visit 
the research sites. Direct access to the source data and all study related files will be done on 
such occasions. All involved parties will keep the participant data strictly confidential. 
8.2 Data recording and source data 
 
For each participant a CRF will be maintained. It will not identify participants by their name or birth 
date, but will provide appropriate coded identification. 
This study will use REDCAP®, an encrypted, web-based platform for clinical trials used widely in 
Switzerland and abroad. Data from source documents will be entered directly into the CRF with 
restricted access to research associates and other members of the research staff, as 
prospectively determined by principal investigators in coordination with data management. 
REDCAP has built-in safeguards with pre-defined ranges and other rules for all data values; the 
CRF will be constructed with these rules well before study launch to allow for careful validation 
(repeated testing with mock participants) by members of the central and peripheral study sites. 
Source data (demographic data, visit dates, participation in study and Informed Consent Forms, 
randomization number, all the outcomes, results of relevant examinations, see CRF in appendix) 
will be available at the site to document the existence of the study participants. They will include 
the original documents relating to the study, as well as the medical treatment and medical history 
of the participant. 

33 
Study 2019-01288 - Protocol “Octoplus” V5.2, 05.10.2023 
 
Only routinely collected data is part of participant file but it may be transferred to the participant’s 
CRF under the condition that, in this case, the CRF will no longer be considered as source data. 
After database lock, data will be fully anonymized and registered in a FAIR-compliant repository 
(see data management plan). 
8.3 Confidentiality and coding 
 
Trial and participant data will be handled with uttermost discretion and is only accessible to 
authorised personnel who require the data to fulfil their duties within the scope of the study. On 
the CRFs and other study specific documents, participants are only identified by a unique 
participant number. 
 
Privacy and confidentiality of the patient's medical data will be maintained through the study. 
CRFs and all other documents sent to the sponsor will be de-identified and carry only the numeric 
patient's identifier code. The study site will maintain the link between the patient identifier code 
and the patient's names. 
 
All electronic data will be password protected, and any paper documents will be stored in a locked 
cabinet. For monitoring, audits, and regulatory inspections, source data and documents will be 
made available, per routine protocols. 
Direct access to source documents will be permitted for purposes of monitoring, audits and 
inspections and should declare who will have access to protocol, dataset, statistical code, etc. 
during and after the study (publication, dissemination). 
 
The investigating team will provide direct access to all trial-related source data, documents and 
reports for the purpose of monitoring and auditing by the sponsor and inspection by local and 
regulatory authorities. 
Biobank 
 
PAX gene RNA and DNA will be taken for the biobank performed at inclusion and coded genetic 
data will be used when the material will be used at the end of the study. 
Biological material in this study will be not identified by participant name but by a unique 
participant number. Biological material will be appropriately stored in a restricted area only 
accessible to the authorized personnel. 
If biological material or data collected during the study are to be shipped outside the study site, 
include the receiver address, the responsible person to whom the materials or data are sent, the 
purpose of shipment, if applicable, temperature control and how participant confidentiality is 
guaranteed. Biological material or genetic data can only be sent abroad in the scope of the 
research study, if the participant involved has given his or her consent to do so upon having been 
sufficiently informed. Non-genetic health-related personal data can be sent abroad for research if 
the requirements of Swiss data protection law are met (FADP, Art. 6). 
8.4 Retention and destruction of study data and biological material 
 
All study data will be conserved for 10 years after study termination or premature termination of 
the clinical trial. They will be stored in a locked storage cabinet in the principal investigator’s office. 
They will be destroyed afterwards and this will be documented 
 
The investigators will comply with the rules enacted by the Swiss Academy of Medical Sciences 
for biobanks, particularly concerning quality standards, data protection, transfer of samples and 
data. They will comply with the Swiss Human Research Act. 

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Study 2019-01288 - Protocol “Octoplus” V5.2, 05.10.2023 
 
Samples will be reversibly de-identified as soon as possible, but at the latest upon arrival of the 
sample in the biobank. Each sample will be coded, and access to personal data will be impossible 
without the code, which will be conserved separately. The code file will be kept by a designated 
member of the research staff, who will not be directly involved in research and analysis on the 
biobank samples. 
A specific consent form will be signed by the patient, allowing storage of his/her biological samples 
for research aims, including research on biomarkers and genetic polymorphisms associated with 
respiratory infection. The patient will be free to be included in the main cohort study, in 
GEROBIOTA and the biobank. He will be allowed to withdraw from participation at any moment. 
If a person included in a clinical trial in an emergency situation dies without consent or refusal in 
accordance with Article 15, the biological materials and personal health data collected may only 
be used if that person has consented to the use of his or her biological materials and personal 
health data for research purposes in an advance directive or otherwise. If there is no expression 
of will, the use of biological materials and personal health data is only permitted with the consent 
of relatives or a trustworthy person designated by the data subject. 
Data handling for the GEROBIOTA nested study 
 
Included case patients will continue to be identified by their OCTOPLUS study randomization 
number. This code will be used to label the samples that will be transferred to the Genomic 
Research Laboratory (GRL), where DNA extraction and metagenomic analysis will be performed. 
Saliva and respiratory samples will be stored at GRL at -80°C in the secured (locked) deep-
freezers (24/7 monitoring system) in HUG to maintain pre-set temperatures and respond quickly 
to emergencies such as temperature out of range. Biological materials will be destroyed 10 years 
after termination of metagenomic analysis following HUG’s routine destruction procedure for 
biological samples. 
 
Coded raw metagenomic data and result files (obtained by data analysis) will be kept for at least 
10 years on a Genomic Research Laboratory server (separate from the RedCAP database) with 
an appropriate system for backup generation. If a central (HUG) data storage system (appropriate 
for metagenomic data) becomes available, the raw data will also be directly submitted to this 
facility. Access to metagenomic data on these servers will be restricted by entering a user name 
and password of GRL investigators. GRL investigators involved in the project will not have any 
access to the electronic patient’s files on the HUG intranet - they will not be able to associate 
metagenomics data with patient’s identity. 
 
In line with SNSF policies and general principles of fair data sharing, publication of metagenomics 
results will require depositing the raw sequence data into a public sequence database. Before 
deposition to a database, any sequence read matching the human genomic sequence will be 
removed. Sequence file names and metadata that will be deposited will not contain any direct 
identifier or strong indirect identifier (e.g., name, initials, address, e-mail, phone number) and will 
contain only a minimum of indirect identifiers (sex, age [years], diagnosis, symptoms, treatment 
details). 
9. 
MONITORING AND REGISTRATION 
 
External monitoring will be performed according to the ICH Good Clinical Practice (GCP) by local 
CTU for Geneva and Lugano sites. Following a Monitoring Plan and written SOPs, the monitors 
will verify that the clinical trial is conducted and data are generated, documented and reported in 
compliance with the protocol, GCP and the applicable regulatory requirements. For the Bern site, 
internal monitoring will be carried out according to the same monitoring plan 
The investigating team will provide direct access to all trial-related source data, documents and 
reports for the purpose of monitoring and auditing by the sponsor and inspection by local and 
regulatory authorities. 

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Study 2019-01288 - Protocol “Octoplus” V5.2, 05.10.2023 
 
According to international guidelines, the risk of monitoring is considered to be low. 
The source data/documents will be accessible to monitors and questions will be answered during 
monitoring. 
Registration will be done in the Swiss National Clinical trial Portal (SNCTP via BASEC). In 
addition, the study will be registered in Clinical Trial Gov. 
10. FUNDING / PUBLICATION / DECLARATION OF INTEREST 
 
A funding has been obtained from the Swiss National Science Foundation, la Ligue Pulmonaire 
Genevoise and the Nakao foundation. 
 
Blinded scanners and ultrasounds performed at the ED will be paid by the funding of the study in 
order to avoid costs for health insurance and insurance companies. 
 
An agreement will be done between HUG and external sites (Bern, Lugano and Rennaz). 
 
Trial results will be disseminated on several levels. Healthcare professionals, hospital 
administrators and policymakers will be alerted to the trial’s findings by means of publication in a 
peer-reviewed, high-impact journal with an international readership and presentation of data at 
international conferences. Trial findings will be integrated into national and international 
guidelines. As described in the data management plan, data will be shared according to FAIR data 
principles and thus in a FAIR-compliant data repository. The study protocol will be provided as 
part of the online supplement to the main publication reporting the trial’s results. As described 
above and in the data management plan, data will be stored in a FAIR-compliant data repository. 
Statistical code for the study’s analyses will be kept in code logs and do files and can also be 
shared upon request. 
 
The investigators declare no conflict of interest (independence, intellectual, financial, proprietary 
etc.). 
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