Primary Outcomes

Description: Viral clearance on Day 5 (human influenza) on a throat swab, assessed by RT PCR. Viral clearance on Day 10 (avian influenza) on a throat swab, assessed by RT PCR.

Measure: Viral clearance

Time: 5-10 days

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Description: • Cmax, Tmax, AUC, apparent volume of distribution, clearance, terminal elimination half-life

Measure: Pharmacokinetics of Oseltamivir

Time: Day 0 and Day 9

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Secondary Outcomes

Description: Time to viral clearance on a throat swab, assessed by RT PCR. The time to no detectable influenza virus by culture for the throat swab. Change in viral load (log10 copies/mL) over time for all virological samples (lower limit of detection: 1000 copies/mL) Viral susceptibility of cultured influenza virus to antiviral drugs at baseline and post treatment, assessed by genotypical and phenotypical analyses

Measure: Viral end points

Time: 5-10 days

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Description: Time to fever clearance In hospital mortality and mortality by follow up Time to death Time to trans cutaneous O2 saturation of ≥ 95% on room air Clinical course: pneumothorax, encephalitis/encephalopathy Number of days in hospital Number of days ventilated

Measure: Clinical Efficacy Endpoints

Time: 5-10 days

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Description: Documented serious adverse events (SAEs) and relationships to oseltamivir AEs leading to drug withdrawal Grade 3 & 4 clinical and laboratory AEs that are probably or definitely related to oseltamivir Skin rashes of any grade Changes in haematological and biochemical parameters over time

Measure: Safety Endpoints

Time: 5-10 days

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Primary Outcomes

Description: The Wisconsin Upper Respiratory Symptom Survey (WURSS-24) will be used to assess common cold illness severity and symptoms (see attached questionnaire). Subjects will fill in the one-page WURSS-24 at the end of each day during the 12-week monitoring period. This 12-week period will cover the winter and early spring period of 2014. From the responses recorded during the 84-day study, an ARI severity score will be calculated by summing the daily ARI global severity score (0=not sick, 1=very mild ARI to 7=severe). The ARI symptom score for the 84-day period will be calculated by summing all 10 symptom scores for each day's entry (0=do not have this symptom, 1=very mild to 7=severe). In similar fashion, the ARI function ability score for the 84-day period will be calculated by summing all 9 function scores for each day's entry (0=do not have this symptom, 1=very mild to 7=severe). Separate scores will be calculated comparing groups for each illness episode recorded by the subjects.

Measure: Common cold symptoms

Time: 12-weeks

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Primary Outcomes

Measure: The number of new viruses and/or bacteria identified and characterized by respiratory and pharyngeal carriage among pilgrims between the departure and the return of Hajj

Time: up to 3 years

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Primary Outcomes

Description: Clinically relevant difference in MxA-levels between cases with viral and bacterial clinical CAP

Measure: MxA - cases with viral and bacterial clinical CAP

Time: 2021

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Description: Clinically relevant difference in MxA-levels between cases with viral clinical CAP and controls

Measure: Mxa viral clinical CAP and controls

Time: 2021

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Description: Proportion of respiratory pathogens in cases and controls, using real time PCR

Measure: PCR - respiratory pathogens in cases and controls

Time: 2020

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Description: Sensitivity and specificity for different respiratory viruses with MariPOC® Respi as compared to real-time PCR

Measure: Sensitivity and specificity - MariPOC

Time: 2021

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Description: Sensitivity and specificity for different respiratory viruses with a novel PCR-based point-of-care test as compared to PCR

Measure: Sensitivity and specificity a novel PCR-based point-of-care test

Time: 2021

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Description: Difference in asthma prevalence between cases and controls and difference in number of hospital-requiring respiratory infections between cases and controls after 3, 7 and 10 years

Measure: Difference asthma prevalence and number of hospital-requiring respiratory infections - cases and controls,

Time: 2027

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Secondary Outcomes

Description: Clinically relevant difference in MxA-levels comparing cases with viral clinical CAP with cases with atypical and mixed viral-bacterial clinical CAP as well as with controls with and without presence of respiratory viruses by PCR

Measure: Specific assessment of MxA as a clinical biomarker

Time: 2021

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Description: Clinically relevant differences in MxA-levels in cases with regard to specific respiratory agents

Measure: Specific assessment of MxA as a clinical biomarker

Time: 2021

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Description: Sensitivity and specificity for MxA in identifying viral clinical CAP

Measure: Specific assessment of MxA as a clinical biomarker

Time: 2021

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Description: Sensitivity and specificity for identifying viral and bacterial infection respectively for CRP, PCT and combination test of CRP, PCT and MxA

Measure: Specific assessment of MxA as a clinical biomarker

Time: 2021

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Description: Difference in CRP and PCT between children with viral, bacterial, atypical bacterial and mixed viral-bacterial infection

Measure: Assessment of PCT and CRP as clinical biomarkers

Time: 2021

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Description: Differences in symptom, antibiotic treatment, acute complications, radiologic exams admission rate and length of stay between cases with viral, bacterial, atypical bacterial and mixed viral-bacterial infection

Measure: Descriptive statistics of study cohort with regard to etiologic agent

Time: 2020

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Description: Differences in symptom, antibiotic treatment, acute complications, radiologic exams admission rate and length of stay between cases who tested positive for respiratory virus by MariPOC® Respi as compared to those with a negative test

Measure: Evaluation of MariPOC® Respi in a clinical setting

Time: 2022

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Description: Number of hospital-requiring respiratory infections in cases and controls

Measure: Assessment of long-term outcomes of children with CAP

Time: 2027

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Description: Difference in asthma prevalence between cases with viral and bacterial clinical CAP as compared to an estimate of the prevalence in the general population

Measure: Assessment of long-term outcomes of children with CAP

Time: 2027

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Description: Difference in proportion of hospital-requiring respiratory infections between cases with viral, bacterial, atypical and mixed viral-bacterial infection

Measure: Assessment of long-term outcomes of children with CAP

Time: 2027

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Description: Difference in MxA-levels between PCR+/MariPOC® Respi+ and PCR+/MariPOC® Respi- study subjects.

Measure: Evaluation of MariPOC® Respi

Time: 2022

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Description: Estimation of etiology of cases using two levels of certainty (definitive as well as probable definition).

Measure: Etiology of cases in TREND study

Time: 2020

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Primary Outcomes

Description: Measure the number of unanticipated adverse events over the duration of the study protocol

Measure: Measure the safety of 160ppm inhaled nitric oxide delivery in NTM subjects

Time: 26 Days

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Secondary Outcomes

Description: Measure the change in absolute FEV1.0 change from baseline during 160 ppm inhalation therapy

Measure: Measure the effect of 160ppm inhaled nitric oxide delivery on lung spirometry in NTM subjects

Time: Day 5,12,19 and 26

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Description: Measure the difference from baseline NTM species bacterial load (0 to +4) in sputum during 160ppm nitric oxide inhalation therapy

Measure: Measure the antimicrobial effect of 160ppm inhaled nitric oxide on lung NTM bacterial load in the sputum

Time: Day 19 and 26

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Description: Measure the difference from baseline CRISS (0-100) during 160ppm nitric oxide inhalation therapy (lower score represents higher quality of life)

Measure: Measure the effect of 160ppm inhaled nitric oxide on Quality of Life (CRISS) Score

Time: Day 19 and 26

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Other Outcomes

Description: Measuring reduction in the incidence of mechanical assistance including oxygen therapy, BIPAP, CPAP, intubation and mechanical ventilation during the study period.

Measure: Sub-Study Primary Endpoint(s): Efficacy to reduce respiratory interventions

Time: Day 26

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Description: Measured by death from all causes

Measure: Efficacy in reduction of mortality

Time: Day 26

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Description: Assessed by time to negative conversion of COVID-19 RT-PCR from upper respiratory tract

Measure: Antiviral effect

Time: Day 26

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Description: Time to clinical recovery as measured by resolution of clinical signs

Measure: Efficacy on clinical improvement

Time: Day 26

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Description: Measured by change in the Modified Jackson Cold Score

Measure: Efficacy on the respiratory symptoms

Time: Day 26

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Primary Outcomes

Description: Removal of all oxygen support (with stable SpO2)

Measure: Percent of subjects who Return to Room Air (RTRA) (main study)

Time: by Day 28

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Measure: Percent of subjects with improved COVID-19 Clinical Status Scale (sub-study)

Time: Day 14

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Secondary Outcomes

Measure: All-cause mortality rate (main study)

Time: at Day 28

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Measure: Percent of subjects who Return to Room Air (RTRA) (main study)

Time: by Day 21

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Measure: Time (in days) to RTRA (main study)

Time: Days 10, 14, 21, 28

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Measure: Percent of subjects who achieve clinical stability (main study)

Time: by Day 28

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Measure: Percent of subjects discharged (without mortality and hospice) (main study)

Time: by Days 14, 21, 28 and 35

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Measure: Time (in days) to first hospital discharge (without hospice) (main study)

Time: through Day 35

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Measure: Total number of inpatient days (main study)

Time: up to Day 35

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Measure: Baseline SAD-RV infection-related mortality rate (main study)

Time: at Day 28

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Measure: Baseline SAD-RV infection-related mortality rate (main study)

Time: at Day 35

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Measure: All-cause mortality rate (main study)

Time: at Day 35

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Measure: Change in pulmonary function (FEV1% predicted) (main study)

Time: Day 1, Day 7, Day 14, Day 28

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Measure: Time to improved COVID19 clinical status (Sub-study)

Time: Day 5, Day 10, Day 21, Day 28

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Measure: Time to RTRA

Time: Day 10, Day 14, Day 21, Day 28

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Measure: Time to Clinical stability

Time: Day 14, Day 21, Day 28

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Measure: Time to SARS-CoV-2 RNA in the respiratory specimens being undetectable

Time: Day 5, Day 10, Day 14, Day 21, Day 28

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Measure: Time to Clinical deterioration

Time: Day 5, Day 10, Day 14, Day 21, Day 28

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Measure: Time to Discharge from hospital (without readmission before Day 28).

Time: Day 14, Day 21, Day 28

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Measure: Time to Death (all causes)

Time: Day 14, Day 21, Day 28

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Primary Outcomes

Description: The number of pregnant women who have awareness about the disease

Measure: The number of pregnant women who know the exact symptoms of the disease

Time: Within one month

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Primary Outcomes

Description: compare clinician collected nasopharyngeal (NP) samples to patient-obtained tongue, nasal and mid-turbinate (MT) samples in the detection of SARS-CoV-2 in an outpatient clinic setting

Measure: Accuracy of patient administered tests

Time: 2 weeks

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Primary Outcomes

Measure: Incidence of influenza

Time: Jan 1st 1998 - May 31st 2016

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Primary Outcomes

Description: Size of collected audio dataset measured as number of collected cough sounds, targeting ≥10,000 identified coughs.

Measure: Dataset size

Time: 14 days

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Secondary Outcomes

Description: Identification of cough sounds by the existing mathematical model with ≥ 99% specificity and ≥ 60% sensitivity

Measure: Cough sound identification

Time: 14 days

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Description: Increase in the sensitivity of the mathematical model to cough sounds to ≥ 70% while retaining the specificity of ≥ 99%

Measure: Improvement of the existing model

Time: 14 days

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Description: Determination of the level of acceptance and satisfaction of the solution by patients by means of a Standard Usability Questionnaire to provide feedback. The score ranges from 10 to 50, higher score indicating a better usability.

Measure: Evaluate the usability of the application

Time: 14 days

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Primary Outcomes

Description: We will determine the COVID Ordinal Scale for all patients on study day 15 COVID Ordinal Scale defined as: Death Hospitalized on invasive mechanical ventilation or ECMO ( extracorporeal membrane oxygenation) Hospitalized on non-invasive ventilation or high flow nasal cannula Hospitalized on supplemental oxygen Hospitalized not on supplemental oxygen Not hospitalized with limitation in activity (continued symptoms) Not hospitalized without limitation in activity (no symptoms)

Measure: COVID Ordinal Outcomes Scale on Day 15

Time: assessed on study day 15

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Secondary Outcomes

Description: Vital status of the patient on day 15 will be determined using any of the following methods: medical record review, phone calls to patient or proxy

Measure: all-location, all-cause mortality assessed on day 15

Time: assessed on study day 15

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Description: Vital status of the patient at day 28 will be determined using any of the following methods: medical record review, phone calls to patient or proxy

Measure: all-location, all-cause mortality assessed on day 29

Time: assessed on study day 29

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Description: We will determine the COVID Ordinal Scale for all patients on study day 3

Measure: COVID Ordinal Outcomes Scale on Study Day 3

Time: assessed on study day 3

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Description: We will determine the COVID Ordinal Scale on study day 8

Measure: COVID Ordinal Outcomes Scale on Study Day 8

Time: assessed on study day 8

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Description: We will determine the COVID Ordinal Scale on study day 29

Measure: COVID Ordinal Outcomes Scale on Study Day 29

Time: assessed on study day 29

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Description: We will determine the number of patients who are either dead or on ECMO ( extracorporeal membrane oxygenation) between enrollment and day 28

Measure: Number of patients dead or with receipt of ECMO between enrollment and Day 28

Time: Enrollment to Day 28

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Description: The number of calendar days between randomization and 28 days later that the patient is alive and without the use of oxygen therapy. Patients who die prior to day 28 are assigned zero oxygen free days.

Measure: Oxygen-free days through Day 28

Time: 28 days after randomization

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Description: Ventilator-free days is defined to be 28 days minus the duration of mechanical ventilation through day 28. Participants who do not survive to day 28 are assigned zero ventilator-free days.

Measure: Ventilator-free days through Day 28

Time: 28 days after randomization

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Description: The number of calendar days between randomization and 28 days later that the patient is alive and without the use of vasopressor therapy. Patients who die prior to day 28 are assigned zero vasopressor free days.

Measure: Vasopressor-free days through Day 28

Time: 28 days after randomization

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Description: The number of days spent out of the ICU to day 28.

Measure: ICU-free days to Day 28

Time: 28 days after randomization

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Description: Defined as 28 days minus the number of days from randomization to discharge home.If a patient has not been discharged home prior to day 28 or dies prior to day 28, hospital free days will be zero.

Measure: Hospital-free days to Day 28

Time: 28 days after randomization

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Other Outcomes

Description: We will determine the number of patients that experience seizure between randomization and day 28

Measure: Number of patients with seizures to day 28

Time: 28 days after randomization

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Description: We will determine the number of patients that experience ventricular arrhythmia between randomization and day 28

Measure: Number of patients with atrial or ventricular arrhythmia to day 28

Time: 28 days after randomization

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Description: We will determine the number of patients that experience cardiac arrest between randomization and day 28

Measure: Number of patients with cardiac arrest to day 28

Time: 28 days after randomization

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Description: We will determine the number of patients that experience elevation in aspartate aminotransferase or alanine aminotransferase to twice the local upper limit of normal between randomization and day 28

Measure: Number of patients with elevation in aspartate aminotransferase or alanine aminotransferase to twice the local upper limit of normal to day 28

Time: 28 days after randomization

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Description: We will determine the number of patients that experience acute pancreatitis between randomization and day 28

Measure: Number of patients with acute pancreatitis arrest to day 28

Time: 28 days after randomization

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Description: We will determine the number of patients that experience acute kidney injury between randomization and day 28

Measure: Number of patients with acute kidney injury to day28

Time: 28 days after randomization

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Description: We will determine the number of patients that experience renal replacement therapy between randomization and day 28

Measure: Number of patients with receipt of renal replacement therapy to day 28

Time: 28 days after randomization

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Description: We will determine the number of patients that experience symptomatic hypoglycemia between randomization and day 28

Measure: Number of patients with symptomatic hypoglycemia to day 28

Time: 28 days after randomization

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Description: We will determine the number of patients that experience neutropenia, lymphopenia, anemia, or thrombocytopenia between randomization and day 28

Measure: Number of patients with neutropenia, lymphopenia, anemia, or thrombocytopenia to day 28

Time: 28 days after randomization

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Description: We will determine the number of patients that experience severe dermatologic reaction between randomization and day 28

Measure: Number of patients with severe dermatologic reaction to day 28

Time: 28 days after randomization

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Description: Time to recovery, defined as time to reaching level 5, 6, or 7 on the COVID Outcomes Scale, which is the time to the earlier of final liberation from supplemental oxygen or hospital discharge

Measure: Time to recovery, defined as time to reaching level 5, 6, or 7 on the COVID Outcomes Scale, which is the time to the earlier of final liberation from supplemental oxygen or hospital discharge

Time: 28 days after randomization

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Primary Outcomes

Description: Estimated by Polymerase chain reaction (PCR)

Measure: The change of viral load in patients with SARS-COVID-19.

Time: Upon patient inclusion in the study, after 96 hours and on the 10day;

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Description: Assessed through the entire patient participation in the study

Measure: The frequency of development of Acute Respiratory Distress Syndrome (ADRS)

Time: up to 10 days

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Description: The number of days a patient is hospitalized

Measure: Duration of hospitalization

Time: up to 10 days

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Description: Early mortality from all causes will be estimated

Measure: The frequency of early mortality

Time: up to 30 days

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Description: Late mortality from all causes will be estimated

Measure: The frequency of late mortality

Time: up to 90 days

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Description: Clinical status at the time of completion of participation in the study will be estimated based upon the following criteria: Death; Hospitalization is extended, on invasive mechanical ventilation of the lungs with extracorporeal membrane oxygenation; Hospitalization extended, on non-invasive ventilation; Hospitalization is extended, needs additional oxygen; Hospitalization is extended, additional oxygen is not required; Discharged.

Measure: Clinical status at the time of completion of participation in the study

Time: an average of 10 days

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Primary Outcomes

Description: The primary study endpoint is the ratio of patients who will develop serious respiratory failure SRF until day 14. Patients dying before study visit of day 14 are considered achieving the primary endpoint.

Measure: The ratio of patients who will develop serious respiratory failure (SRF)

Time: Visit study day 14

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Secondary Outcomes

Description: Evaluation of clinical data (pO2/FiO2 and need of mechanical ventilation) between baseline and study visit day 14 will be compared with comparators from Hellenic Sepsis Study Group Database

Measure: Comparison of the rate of patients who will develop serious respiratory failure (SRF) until day 14 with comparators from Hellenic Sepsis Study Group Database receiving standard-of-care treatment

Time: Visit study day 14

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Description: Change of scoring for respiratory symptoms (evaluation of cough, chest pain, shortness of breath and sputum) in enrolled subjects between days 1 and 7

Measure: Change of scoring for respiratory symptoms in enrolled subjects between days 1 and 7

Time: Visit study day 1, visit study day 7

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Description: Change of scoring for respiratory symptoms (evaluation of cough, chest pain, shortness of breath and sputum) in enrolled subjects between days 1 and 14

Measure: Change of scoring for respiratory symptoms in enrolled subjects between days 1 and 14

Time: Visit study day 1, visit study day 14

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Description: Change of Sequential organ failure assessment (SOFA) score of enrolled subjects between days 1 and 7 (Sequential organ failure assessment range 0-24, high score associated with worst outcome)

Measure: Change of SOFA score in enrolled subjects between days 1 and 7

Time: Visit study day 1, visit study day 7

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Description: Change of Sequential organ failure assessment (SOFA) score of enrolled subjects between days 1 and 14 (Sequential organ failure assessment range 0-24, high score associated with worst outcome)

Measure: Change of Sequential organ failure assessment (SOFA) score in enrolled subjects between days 1 and 14

Time: Visit study day 1, visit study day 14

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Description: Change of peripheral mononuclear blood cells' (PBMCs) functionality of enrolled subjects will be compared between days 1 and 7

Measure: Change of peripheral mononuclear blood cells' (PBMCs) functionality between days 1 and 7

Time: Visit study day 1, visit study day 7

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Description: Change of plasma inflammatory mediators measured levels will be compared between days 1 and 7

Measure: Change of plasma inflammatory mediators levels between days 1 and 7

Time: Visit study day 1, visit study day 7

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Description: Mortality on day 30

Measure: Rate of Mortality

Time: Visit study day 30

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Description: Mortality on day 90

Measure: Rate of Mortality

Time: Visit study day 90

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Description: Transcriptional, proteomic and metabolomic change will be compared between days 1 and 7

Measure: Change of gene expression between days 1 nad 7

Time: days 1 and 7

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Primary Outcomes

Description: To assess the improvement in oxygenation as determined by the PaO2/FiO2 ratio after treatment with study treatment

Measure: Oxygenation Improvement

Time: 3 months

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Description: To assess the improvement in pulmonary ventilation as determined by the Ventilation Index (VI), where VI = [RR x (PIP - PEEP) × PaCO2]/1000 after study treatment.

Measure: Pulmonary ventilation Improvement

Time: 3 months

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Secondary Outcomes

Description: To assess safety as judged by the frequency and severity of adverse events and severe adverse events (SAEs).

Measure: Safety Assessment of Frequency and Severity of Adverse Events

Time: 3 months

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Primary Outcomes

Description: Number and severity of adverse events

Measure: Phase 1: Frequency and Severity of Adverse Events (AE)

Time: Up to 6 months

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Description: Proportion of subjects with "negative" measurement of COVID-19 by rRT-PCR

Measure: Phase 1: Rate of clearance of SARS-CoV-2

Time: Up to 6 months

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Description: Proportion of subjects who improved clinical symptoms related to lower respiratory tract infection, as measured by National Early Warning Score 2 (NEWS2) score.

Measure: Phase 1: Rate of clinical improvement

Time: Up to 6 months

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Description: Time from the date of randomization to the clearance of SARS-CoV-2 by rRT-PCR. Negative results will need to be confirmed by a second negative result in the same sample type at least 24 hours after the first negative result.

Measure: Phase 2: Time to Clearance of SARS-CoV-2

Time: Up to 28 days

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Description: Time from the date of randomization to the first date of improved clinical symptoms related to lower respiratory tract infection. Improvement as measured by National Early Warning Score 2 (NEWS2) Score.

Measure: Phase 2: Time to Clinical Improvement by NEWS2 Score

Time: Up to 28 days

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Secondary Outcomes

Description: Proportion of subjects with "negative" measurement of COVID-19 by rRT-PCR

Measure: Rate of Clearance of SARS-CoV-2

Time: Up to 6 months

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Description: Number and severity of adverse events

Measure: Phase 2: Frequency and Severity of Adverse Events (AE)

Time: up to 6 months

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Description: Time to medical discharge as an assessment of overall clinical benefit

Measure: Overall Clinical Benefit by time to medical discharge

Time: up to 6 months

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Description: Hospital utilization will be measured as an assessment of overall clinical benefit

Measure: Overall Clinical Benefit by hospital utilization

Time: up to 6 months

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Description: Mortality rate will be measured as an assessment of overall clinical benefit

Measure: Overall Clinical Benefit by measuring mortality rate

Time: up to 6 months

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Description: Assess the impact of CYNK-001 on changes in sequential organ failure assessment (SOFA) score.

Measure: Impact of CYNK-001 on sequential organ failure assessment (SOFA) score

Time: Up to 28 days

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Description: Time from randomization to the date of disappearance of virus from lower respiratory tract infection (LRTI) specimen where it has previously been found (induced sputum, endotracheal aspirate).

Measure: Time to Pulmonary Clearance

Time: Up to 28 days

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Description: For ventilatory support subjects, the days with supplemental oxygen-free.

Measure: Supplemental oxygen-free days

Time: Up to 28 days

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Description: Proportion of subjects who need invasive or non-invasive ventilation

Measure: Proportion of subjects requiring ventilation

Time: Up to 28 days

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Primary Outcomes

Description: Mortality

Measure: Mortality

Time: 90 days following the enrollment

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Description: Th1/Th2/Th17/Treg balance, Type I Interferons and inflammation

Measure: Immune response - Plasma cytokine profile

Time: Through study completion (90 days following the enrollment)

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Description: T cells (CD3, CD4, CD8, PD1, FAS, CD45RO, CTLA4+, CXCR5, CXCR3, CCR6, CD69, CD95, HLA-DR) and B cells (CD3, CD19, CD27, IgD, CD69) with cell subtypes and memory/naive compartments (CD27, CD38, IgD, IgG1, IgG2, IgG3, CD20, CD24), NK cells (CD14, CD16, CD56, HLA-DR), monocytes (CD14, CD45, HLA-DR, PDL-1)

Measure: Immune response - Phenotype of circulating cells

Time: Through study completion (90 days following the enrollment)

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Secondary Outcomes

Description: Number of days in intensive care unit

Measure: Severity criteria - Duration of stay in intensive care unit

Time: 90 days following the enrollment

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Description: Number of days of hospitalization

Measure: Severity criteria - Duration of hospitalization stay

Time: 90 days following the enrollment

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Description: Number of days out of hospital

Measure: Severity criteria - Duration of period out of hospital

Time: 90 days following the enrollment

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Description: Number of days without mechanical ventilation (invasive/non-invasive)

Measure: Severity criteria - Duration without mechanical ventilation

Time: 90 days following the enrollment

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Description: Number of days not being ventilated

Measure: Severity criteria - Duration without ventilation

Time: 90 days following the enrollment

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Description: Number of days not being intubated

Measure: Severity criteria - Duration without intubation

Time: 90 days following the enrollment

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Description: Number of transfusions

Measure: Severity criteria - Number of transfusions

Time: 90 days following the enrollment

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Description: Number of days without cathecholamines

Measure: Severity criteria - Duration of the period without cathecholamines

Time: 90 days following the enrollment

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Description: Number of days without dialysis

Measure: Severity criteria - Duration of the period without dialysis

Time: 90 days following the enrollment

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Description: Sepsis-related Organ Failure Assessment (SOFA) Score

Measure: Severity criteria - SOFA

Time: Through study completion (90 days following the enrollment)

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Description: Lung Injury Score (LIS)

Measure: Severity criteria - LIS

Time: Through study completion (90 days following the enrollment)

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Description: SARS-Cov2 viral load will be measured in blood and in broncho-tracheal secretions

Measure: SARS-Cov2 viral load

Time: Through study completion (90 days following the enrollment)

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Description: Co-infections and acquired infections (bacterial or fungal) in intensive care unit, in particular based on an all-site positive PCR for EBV and/or CMV and/or HSV

Measure: Emergence of concomitant infections

Time: 90 days following the enrollment

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Description: T cells (CD3, CD4, CD8, PD1, FAS, CD45RO, CTLA4+, CXCR5, CXCR3, CCR6, CD69, CD95, HLA-DR) and B cells (CD3, CD19, CD27, IgD, CD69) with cell subtypes and memory/naive compartments (CD27, CD38, IgD, IgG1, IgG2, IgG3, CD20, CD24), NK cells (CD14, CD16, CD56, HLA-DR), monocytes (CD14, CD45, HLA-DR, PDL-1)

Measure: Emergence of concomitant infections - Phenotype of circulating cells

Time: Through study completion (90 days following the enrollment)

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Description: Heart rate variability

Measure: Stress physiological profile - Sympathetic tone

Time: Through study completion (90 days following the enrollment)

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Description: Core temperature

Measure: Stress physiological profile - Temperature

Time: Through study completion (90 days following the enrollment)

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Description: Quantity of glucocorticoids in the urine during 24 hours and at night

Measure: Stress physiological profile - Glucocorticoids

Time: Through study completion (90 days following the enrollment)

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Description: ACE Polymorphism

Measure: Angiotensin converting enzyme type II (ACE2) polymorphism - ACE

Time: At enrollment

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Description: Protein expression of ACE2 vs. ACE1 and angiotensin II chain proteins

Measure: Angiotensin converting enzyme type II (ACE2) polymorphism - ACE2/ACE1

Time: At enrollment

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Description: Diabete diagnosis

Measure: Comorbidities - diabetes

Time: At enrollment

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Description: Heart disease diagnosis

Measure: Comorbidities - Heart disease

Time: At enrollment

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Description: Organ failure diagnosis

Measure: Comorbidities - organ failure

Time: At enrollment

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Description: GABA level in blood and urine

Measure: Plasma concentrations of several metabolic pathways - GABA

Time: Through study completion (90 days following the enrollment)

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Description: Glucocorticoid level in blood and urine

Measure: Plasma concentrations of several metabolic pathways - Glucocorticoid

Time: Through study completion (90 days following the enrollment)

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Description: Tryptophan in blood and urine

Measure: Plasma concentrations of several metabolic pathways - Tryptophan

Time: Through study completion (90 days following the enrollment)

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Description: Serotonin level in blood and urine

Measure: Plasma concentrations of several metabolic pathways - Serotonin

Time: Through study completion (90 days following the enrollment)

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Description: Dopamin level in blood and urine

Measure: Plasma concentrations of several metabolic pathways - Dopamin

Time: Through study completion (90 days following the enrollment)

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Description: Catecholamines level in blood and urine

Measure: Plasma concentrations of several metabolic pathways - Cathecholamines

Time: Through study completion (90 days following the enrollment)

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Description: Arachidonic acid derivatives level in blood and urine

Measure: Plasma concentrations of several metabolic pathways - Arachidonic acid derivatives

Time: Through study completion (90 days following the enrollment)

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Description: Endocannabinoids level in blood and urine

Measure: Plasma concentrations of several metabolic pathways - Endocannabinoids

Time: Through study completion (90 days following the enrollment)

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Primary Outcomes

Measure: Solicited local reactions at the injection site (pain, tenderness, erythema/redness, induration/swelling) recorded up to 7±1 days after each immunization.

Time: up to 7 days following each dose administration

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Measure: Solicited systemic reactions (nausea, vomiting, diarrhea, headache, fatigue, myalgia, arthralgia, chills, loss of appetite, malaise, and fever) recorded up to 7±1 days after each immunization.

Time: up to 7 days following each dose administration

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Description: For BNT162a1, BNT162b1, BNT162b2, and BNT162c2 (P/B): occurring up to 21±2 days after the prime immunization.

Measure: The proportion of subjects with at least 1 unsolicited treatment emergent adverse event (TEAE):

Time: 21 days following dose administration

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Description: For BNT162a1, BNT162b1, BNT162b2, and BNT162c2 (P/B): occurring up to 28±4 days after the boost immunization. For BNT162c2 (SD): The proportion of subjects with at least 1 unsolicited TEAE occurring up to 28±4 days after the immunization.

Measure: The proportion of subjects with at least 1 unsolicited treatment emergent adverse event (TEAE):

Time: 28 days following dose administration

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Secondary Outcomes

Description: Functional antibody responses at 7±1 days and 21±2 days after primary immunization and at 21±2 days, 28±4 days, 63±5 days, and 162±7 days after the boost immunization.

Measure: For BNT162a1, BNT162b1, BNT162b2, and BNT162c2 (P/B):

Time: up to 162 days following dose administration

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Description: Fold increase in functional antibody titers 7±1 days and 21±2 days after primary immunization and at 21±2 days, 28±4 days, 63±5 days, and 162±7 days after the boost immunization.

Measure: For BNT162a1, BNT162b1, BNT162b2, and BNT162c2 (P/B):

Time: up to 162 days following dose administration

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Description: Number of subjects with seroconversion defined as a minimum of 4-fold increase of functional antibody titers as compared to baseline at 7±1 days and 21±2 days after primary immunization and at 21±2 days, 28±4 days, 63±5 days, and 162±7 days after the boost immunization.

Measure: For BNT162a1, BNT162b1, BNT162b2, and BNT162c2 (P/B):

Time: up to 162 days following dose administration

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Description: Functional antibody responses at 7±1 days, 21±2 days, 29±3 days, 42±3 days, 84±5 days, and 183±7 days after the primary immunization.

Measure: For BNT162c2 (SD):

Time: up to 183 days following dose administration

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Description: Fold increase in functional antibody titers at 7±1 days, 21±2 days, 29±3 days, 42±3 days, 84±5 days, and 183±7 days after the primary immunization.

Measure: For BNT162c2 (SD):

Time: up to 183 days following dose administration

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Description: Number of subjects with seroconversion defined as a minimum of 4-fold increase of functional antibody titers as compared to baseline at 7±1 days, 21±2 days, 29±3 days, 42±3 days, 84±5 days, and 183±7 days after the primary immunization.

Measure: For BNT162c2 (SD):

Time: up to 183 days following dose administration

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Primary Outcomes

Description: Time until participant reports well

Measure: Time to resolution of symptoms as defined by the single question 'how unwell do you feel today'.

Time: Maximum of 14 days

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Secondary Outcomes

Description: Recorded using validated Wisconsin Upper Respiratory Symptom Survey-24 (WURSS-24) questionnaire and daily diaries. The WURSS-24 questionnaire assesses the interference on daily life and severity of symptoms on a scale of 1 (not at all) to 7 (severe)

Measure: Severity of all symptoms

Time: 1-14 days or until the participant reports that they are well

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Description: Recorded using validated Wisconsin Upper Respiratory Symptom Survey-24 (WURSS-24) questionnaire and daily diaries. The WURSS-24 questionnaire assesses the interference on daily life and severity of symptoms on a scale of 1 (not at all) to 7 (severe)

Measure: The length of time for individual symptoms to resolve

Time: 1-14 days or until the participant reports that they are well

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Description: Recorded using validated Wisconsin Upper Respiratory Symptom Survey-24 (WURSS-24) questionnaire and daily diaries. The WURSS-24 questionnaire assesses the interference on daily life and severity of symptoms on a scale of 1 (not at all) to 7 (severe)

Measure: Severity of individual symptoms

Time: 1-14 days or until the participant reports that they are well

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Description: Number of participants and frequency of contacts

Measure: Contacting healthcare (NHS 24, OOH, GP)

Time: 1-14 days or until the participant reports that they are well

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Description: Number of participants and frequency of contacts

Measure: Participants needing GP appointments

Time: 1-14 days or until the participant reports that they are well

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Description: Number of participants

Measure: Participants attending hospital

Time: 1-14 days or until the participant reports that they are well

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Description: Number of days

Measure: Length of stay in hospital if admitted

Time: 1-14 days or until the participant reports that they are well

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Description: Number of participants

Measure: Number of participants reporting over the counter medication use

Time: 1-14 days or until the participant reports that they are well

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Description: Number of people within participant's household who develop symptoms

Measure: Reduction in transmission to household contacts

Time: 1-14 days or until the participant reports that they are well

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Description: Number of participants in intervention arm reporting side effects

Measure: Number of participants reporting side effects of nasal irrigation

Time: 1-14 days or until the participant reports that they are well

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Description: Participants asked if they have experienced common side effects or other and to rate the severity on a 7 point scale of 'Did not have this side effect' to 'severe'

Measure: Types and severity of side effects reported

Time: 1-14 days or until the participant reports that they are well

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Description: Estimated cost requested when participant states over the counter medication used

Measure: Cost of over the counter medication used

Time: 1-14 days or until the participant reports that they are well

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Primary Outcomes

Description: Improvement of fever in degrees celsius

Measure: COVID 19 induced fever in both groups

Time: 4 weeks

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Description: improvement of dyspnea by normalization of respiratory rate

Measure: COVID 19 induced dyspnea in both groups

Time: 4 weeks

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Description: PCR of COVID 19 changes from positive to negative

Measure: COVID 19 viral load in both groups

Time: 4 weeks

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Secondary Outcomes

Description: CRP in mg/dL

Measure: laboratory clearance in both groups: CRP in mg/dL

Time: 4 weeks

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Primary Outcomes

Measure: Number of days absent from work due to respiratory disease (with or without documented SARS-CoV-2 infection)

Time: From day 0 to day 240

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Secondary Outcomes

Measure: Cumulative incidence of documented SARS-CoV-2 infection

Time: From day 0 to day 240

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Measure: Number of days absent from work due to documented SARS-CoV-2 infection

Time: From day 0 to day 240

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Measure: Number of days absent from work due to exposure to person with documented SARS-CoV-2 infection

Time: From day 0 to day 240

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Measure: Number of days absent from work due to symptoms of respiratory disease, documented SARS-CoV-2 infection, or fever (≥ 38 °C)

Time: From day 0 to day 240

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Measure: Number of days of self-reported fever (≥ 38 °C)

Time: From day 0 to day 240

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Measure: Number of days of self-reported acute respiratory symptoms

Time: From day 0 to day 240

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Measure: Cumulative incidence of self-reported acute respiratory symptoms

Time: From day 0 to day 240

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Measure: Cumulative incidence of death for any reason

Time: From day 0 to day 240

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Measure: Cumulative incidence of death due to documented SARS-CoV-2 infection

Time: From day 0 to day 240

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Measure: Cumulative incidence of ICU admission for any reason

Time: From day 0 to day 240

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Measure: Cumulative incidence of ICU admission due to documented SARS-CoV-2 infection

Time: From day 0 to day 240

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Measure: Cumulative incidence of hospital admission for any reason

Time: From day 0 to day 240

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Measure: Cumulative incidence of hospital admission due to documented SARS-CoV-2 infection

Time: From day 0 to day 240

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Primary Outcomes

Description: Hospitalization is defined as at least 24 hours of acute care in a hospital or similar acute care facility (emergency settings, temporary emergency facilities created for acute care of COVID-19 pandemic)

Measure: Proportion of participants who were hospitalized for progression of COVID-19 disease

Time: Measuring during 28-day period since randomization (Intention to treat analysis)

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Measure: Proportion of participants who died due to COVID-19 progression and/ or complications

Time: Measuring during 28-day period since randomization (Intention to treat analysis)

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Secondary Outcomes

Description: Viral load change on 03, 07, 10 and 14 after randomization (200 patients per arm)

Measure: Proportion of participants with viral load change on 03, 07, 10 and 14 after randomization

Time: Measuring during 14-day period since randomization

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Description: Proportion of participants with clinical improvement, defined as normalization of temperature, Respiratory rate, SaO2, and cough relief (> 50% compared to baseline measured on a visual analog scale) in the last 72 hours.

Measure: Time to clinical improvement

Time: Measuring during 28-day period since randomization

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Description: Proportion of participants with clinical improvement, defined as as time to need for hospitalization due to dyspnea, death, need for mechanical ventilation, shock and need for vasoactive amines;

Measure: Time to clinical failure

Time: Measuring during 28-day period since randomization

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Description: Proportion of participants with hospitalization for any cause

Measure: Hospitalization for any cause

Time: Measuring during 28-day period since randomization

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Measure: Proportion of participants who died due to pulmonary complications

Time: Measuring during 28-day period since randomization

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Measure: Proportion of participants who died due to cardiovascular complications

Time: Measuring during 28-day period since randomization

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Description: Evaluation of adverse events evaluated as associated to any of study arms

Measure: Proportion of participants who presented with adverse events

Time: Measuring during 28-day period since randomization

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Description: Proportion of participants who presented sustained improvement on respiratory scale defined as at least 48 hours of improvement.

Measure: Time to improvement on respiratory scale symptoms

Time: Measuring during 28-day period since randomization

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Measure: proportion of non-adherent participants to any of study drugs

Time: Measuring during 10-day period since randomization

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Primary Outcomes

Measure: Number of days with severe respiratory disease at hospital and/or at home

Time: From day 0 to day 240

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Secondary Outcomes

Measure: Cumulative incidence of hospital admissions

Time: From day 0 to day 240

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Measure: Cumulative incidence of documented SARS-CoV-2 infection

Time: From day 0 to day 240

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Measure: Number of days with self-reported fever (≥ 38 ºC)

Time: From day 0 to day 240

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Measure: Number of days with self-reported acute respiratory symptoms

Time: From day 0 to day 240

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Measure: Cumulative incidence of self-reported acute respiratory symptoms

Time: From day 0 to day 240

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Measure: Cumulative incidence of death for any reason

Time: From day 0 to day 240

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Measure: Cumulative incidence of death due to documented SARS-CoV-2 infection

Time: From day 0 to day 240

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Measure: Cumulative incidence of ICU admission for any reason

Time: From day 0 to day 240

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Measure: Cumulative incidence of ICU admission due to documented SARS-CoV-2 infection

Time: From day 0 to day 240

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Measure: Cumulative incidence of hospital admission due to documented SARSCoV- 2 infection

Time: From day 0 to day 240

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Primary Outcomes

Description: Time (hours) from randomization to recovery defined as 1) absence of fever, as defined as at least 48 hours since last temperature ≥ 38.0°C without the use of fever-reducing medications AND 2) absence of symptoms of greater than mild severity for 24 hours AND 3) not requiring supplemental oxygen beyond pre-COVID baseline AND 4) freedom from mechanical ventilation or death

Measure: 1. Time (Hours) to recovery

Time: [ Time Frame: 36 days ]

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Secondary Outcomes

Description: Time to resolution of fever defined as at least 48 hours since last temperature ≥ 38.0°C without the use of fever-reducing medications

Measure: Time fever resolution

Time: [ Time Frame: 36 days ]

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Primary Outcomes

Description: asymptomatic seroconversion for SARS-CoV-2

Measure: Seroconversion

Time: 24 weeks

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Description: asymptomatic seroconversion for SARS-CoV-2

Measure: Interim analysis - seropositivity at 12 weeks

Time: 12 weeks

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Secondary Outcomes

Description: Sensitivity and specificity of dried blood spot assay compared with venous blood serology

Measure: Dried Blood Spot performance

Time: 24 weeks

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Description: Sensitivity and specificity of salivary IgA compared with venous blood serology

Measure: Salivary IgA performance

Time: 24 weeks

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Description: The background 'point' prevalence and subsequent rate of increase in seropositivity for SARS-CoV-2 in healthy young adults.

Measure: Prevalence of SARS-CoV-2

Time: 24 weeks

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Description: The individual reductions in seropositivity to SARS-CoV-2 over time, and changes in seropositivity in a defined young adult population over time

Measure: Change in seropositivity

Time: 24 weeks

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Description: The effect of vitamin D supplementation on seroconversion rates stratified by: i) level of baseline vitamin D 'deficiency/ insufficiency/ sufficiency' status; ii) extent of BMI-defined normal/overweight/obesity cut-offs, iii) gender iv) ethnicity

Measure: Change in seroconversion rate

Time: 24 weeks

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Primary Outcomes

Description: Survival without needs of ventilator utilization (including non invasive ventilation and high flow) at day 14. Thus, events considered are needing ventilator utilization (including Non Invasive Ventilation, NIV or high flow), or death.

Measure: Survival without needs of ventilator utilization at day 14

Time: day 14

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Secondary Outcomes

Description: WHO progression scale: Uninfected; non viral RNA detected: 0 Asymptomatic; viral RNA detected: 1 Symptomatic; Independent: 2 Symptomatic; Assistance needed: 3 Hospitalized; No oxygen therapy: 4 Hospitalized; oxygen by mask or nasal prongs: 5 Hospitalized; oxygen by NIV or High flow: 6 Intubation and Mechanical ventilation, pO2/FIO2>=150 OR SpO2/FIO2>=200: 7 Mechanical ventilation, (pO2/FIO2<150 OR SpO2/FIO2<200) OR vasopressors (norepinephrine >0.3 microg/kg/min): 8 Mechanical ventilation, pO2/FIO2<150 AND vasopressors (norepinephrine >0.3 microg/kg/min), OR Dialysis OR ECMO: 9 Dead: 10

Measure: WHO progression scale at day 7 and 14

Time: day 7 and day 14

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Description: Overall survival

Measure: Overall survival at 14, 28, 60 and 90 days

Time: 14, 28, 60 and 90 days

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Description: Cumulative incidence of discharge alive

Measure: Cumulative incidence of discharge alive at 14 and 28 days

Time: 14 and 28 days

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Description: Survival without needs of mechanical ventilation at day 1. New DNR order (if given after the inclusion of the patient) will be considered as an event at the date of the DNR.

Measure: Survival without needs of mechanical ventilation at day 1

Time: day 1

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Description: Cumulative incidence of oxygen supply independency

Measure: Cumulative incidence of oxygen supply independency at 14 and 28 days

Time: 14 and 28 days

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Primary Outcomes

Description: AEs will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) V5.0

Measure: Proportion of Participants Experiencing any Treatment-Emergent Adverse Events

Time: First dose date up to Day 30 Follow-up Assessment

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Description: This will be assessed at various time points by clinical laboratory tests and vital signs.

Measure: Proportion of Participants Experiencing any Treatment-Emergent Graded Laboratory Abnormalities

Time: First dose date up to Day 30 Follow-up Assessment

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Secondary Outcomes

Description: Monitoring of the levels of drugs in subject sera at various time points to elucidate the maximum concentration (Cmax) of NA-831 and GS-5734 in human serum.

Measure: Maximum Concentration (Cmax) - Pharmacokinetic Assessment

Time: 7 days

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Description: Monitoring of the levels of drugs in subject sera at various time points to elucidate the time to maximum concentration (Tmax) of NA-831 and GS-5734 in human serum

Measure: Time to Maximum Concentration (Tmax) - Pharmacokinetic Assessment

Time: 7 days

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Description: Monitoring of the levels of drugs in subject sera at various time points to elucidate the area under the curve from time of administration to the last measurable of NA-831 and GS-5734

Measure: AUC calculated from time of administration to the last measurable concentration (AUC0-last) - Pharmacokinetic Assessment

Time: 7 days

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Description: Monitoring of the levels of drugs in subject sera at various time points to elucidate the area under the curve extrapolated to infinity (AUC0-∞) of NA-831 and GS-5734

Measure: Area Under the Curve Extrapolated to Infinity (AUC0-∞)

Time: 7 days

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Description: Monitoring of the levels of drugs in subject sera at various time points to elucidate the half-life (t1/2) of NA-831 and GS-5734 in human serum.

Measure: Half-Life (t1/2) - Pharmacokinetic Assessment

Time: 7 days

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Description: Monitoring of the levels of drugs in subject sera through various time points to elucidate the volume of distribution (Vd) of NA-831 and GS-5734 in human serum.

Measure: Volume of Distribution (Vd) - Pharmacokinetic Assessment

Time: 7 days

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Description: Monitoring of the levels of drugs in subject sera through at various time points to elucidate clearance [CL] of NA-831 and GS-5734 in human serum.

Measure: Clearance [CL] - Pharmacokinetic Assessment

Time: 7 days

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Primary Outcomes

Description: Confirmed viral URIs (i.e., including recurrent events) (i.e., COVID-19, influenza, and other known viral respiratory pathogens) based on laboratory testing (i.e., FDA or locally-approved testing modalities) with an oxygen saturation <94% on room air and/or requiring any form of supplemental oxygen.

Measure: Percentage of patients with moderate or severe confirmed viral URIs

Time: 0-12 months

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Description: At any point in time based on a 7-point ordinal scale (i.e., 1 = death, 2 = mechanically ventilated/extracorporeal membrane oxygenation, 3 = high flow supplemental oxygen, 4 = low flow supplemental oxygen, 5 = hospitalized with no supplemental oxygen requirements, 6 = urgent care or emergency department visit not leading to hospitalization, and 7 = no relevant clinical encounters)

Measure: Worst clinical status due to a confirmed viral URI

Time: 0-12 months

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Other Outcomes

Measure: Percentage of participants who die due to any cause

Time: 0-12 months

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Description: Death due to any cause, hospitalization for myocardial infarction, or hospitalization for ischemic stroke

Measure: Percentage of participants experiencing a major adverse cardiovascular event

Time: 0-12 months

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Description: Major adverse cardiovascular events, hospitalization for acute coronary syndrome, and coronary revascularization (i.e., percutaneous coronary intervention and/or coronary artery bypass graft)

Measure: Percentage of participants experiencing an expanded major adverse cardiovascular event

Time: 0-12 months

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Measure: Percentage of participants who are hospitalized for heart failure

Time: 0-12 months

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Measure: Percentage of participants who are hospitalized for any reason

Time: 0-12 months

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Measure: Percentage of participants who have an emergency department visit for any reason

Time: 0-12 months

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Primary Outcomes

Description: This study will assess the time to the occurrence of influenza-like illness (ILI) or acute respiratory infection (ARI) in subjects previously COVID+ compared to subjects known as COVID- (controls), more specifically subjects will belong to two subgroups: nursing home residents (65+) and nursing home staff (18-65y). COVID+ is defined as a past SARS-CoV-2 infection.

Measure: Time to occurrence of ILI and ARI both in participants previously exposed to SARS-COV-2 and controls

Time: up to 8 months

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Secondary Outcomes

Measure: Number of patients with ILI or ARI, diagnosed with COVID-19, influenza, RSV

Time: up to 8 months

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Measure: Validation of (SimplySpiro) to replace nasopharyngeal swabs

Time: up to 8 months

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Measure: Identify the antibody characteristics in participants with reinfection with SARS-CoV-2

Time: up to 8 months

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Description: Disease severity will be measured by hospitalization and mortality

Measure: Correlation of the pre-existing antibody characteristics for COVID-19 with disease severity.

Time: up to 8 months

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Measure: Correlation of the level of neutralization antibodies against influenza subtypes with protection against influenza reinfection

Time: up to 8 months

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Primary Outcomes

Description: Clinically relevant relevant respiratory tract infection is composed of clinical symptoms in combination with the need for medical intervention. Exact criteria for clinically relevant respiratory tract infection and COVID-19 are described in the protocol. A blinded adjudication committee will determine the status of the primary endpoints of all participants with a potential primary endpoint, based on information provided in a standardized narrative using data reported by the participant and from GP and hospital medical records when relevant. For detection of ARI, symptoms are checked on a weekly (from week 1-4) or bi-weekly basis (from week 4 onward).

Measure: The trial has an adaptive primary endpoint. Based on predefined objective and quantitative criteria the primary endpoint will be either a clinically relevant respiratory tract infection, or COVID-19.

Time: 180 days

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Secondary Outcomes

Description: Cumulative incidence of SARS-CoV-2 infection regardless of symptomatology defined as having had COVID-19 as described under primary endpoints above and/or SARS-CoV-2 positive test in real time as part of the test-and-trace program of the Dutch government and/of documented SARS-CoV-2 seroconversion at 6 months. Seroconversion will be defined as antibody-positive at 6 months but negative at baseline.

Measure: Cumulative incidence of SARS-CoV-2 infection (irrespective the presence of symptoms)

Time: 180 days

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Measure: Cumulative incidence of asymptomatic, mild/moderate, and severe (requiring hospitalization) SARS-CoV-2 infection.

Time: 180 days

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Description: Defined as either of 1) ARI + microbiological evidence of influenza infection, 2) seroconversion of influenza between enrolment and month 6.

Measure: Influenza infection

Time: 180 days

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Description: Meeting the definition stated in the primary outcome. Irrespective of requiring an intervention.

Measure: An acute respiratory tract infection

Time: 180 days

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Description: Meeting the definition stated in the primary outcome including the requirement of an intervention.

Measure: Medically attended acute respiratory tract infection

Time: 180 days

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Description: Meeting the definition stated in the primary outcome including the need of hospitalization.

Measure: Acute respiratory tract infection related hospital admission

Time: 180 days

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Measure: Pneumonia diagnosed by a GP or medical specialist

Time: 180 days

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Description: Using the Katz Activities of Daily Living (ADL) scale, from A (fully independent) to G (dependent in feeding, continence, transferring, going to toilet, dressing, and bathing)

Measure: Functioning in daily activities

Time: 180 days

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Measure: Serious adverse events and adverse events.

Time: 180 days

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Measure: Major cardiovascular events

Time: 180 days

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Measure: All cause 6-month mortality

Time: 180 days

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Measure: History of falls

Time: 180 days

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Description: Using the EQ5D quality of life instrument, with questions on 4 domains (mobility, self-care, usual activities, pain discomfort) and the percepted health of the participant with 100 meaning the best health you can imagine, and 0 meaning the worst health you can imagine

Measure: Quality of life using the EQ5D quality of life instrument

Time: 180 days

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Description: Using the 6-item Lawton Activities of Daily Living questionnaire, with scores ranging from 0 (low function, dependent) to 8 (high function, independent) for women (0 through 5 for men)

Measure: Activities in daily living

Time: 180 days

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Primary Outcomes

Description: The total antibiotic use, expressed as Daily Defined Doses (DDD) of antibiotics in grams. This will be aggregated with the amount of hospitalizations to arrive at one reported value: DDD/hospitalization (expressed as grams/hospitalization), for every antibiotic and antibiotic formulation (IV or PO) separately but also for all prescribed antibiotics in general.

Measure: Total antimicrobial consumption for suspicion of secondary bacterial respiratory infections in hospitalized patients in COVID wards with a clinical or PCR-based COVID diagnosis, expressed as 'Daily defined doses/hospitalization'.

Time: 7 months

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Description: The total antibiotic use, expressed as Daily Defined Doses (DDD) in grams. This will be aggregated with the total amount of hospitalized patient days to arrive at one reported value: DDD/1000 hospitalization patient days (expressed as grams/1000 hospitalization days), for every antibiotic and antibiotic formulation (IV or PO) separately but also for all prescribed antibiotics in general. 1000 hospitalised patient days for every antibiotic and antibiotic formulation (IV or PO) separately but also for all prescribed antibiotics in general.

Measure: Total antimicrobial consumption for suspicion of secondary bacterial respiratory infections in hospitalized patients in COVID wards with a clinical or PCR-based COVID diagnosis, expressed as 'Daily defined doses/1000 hospitalized patient days'.

Time: 7 months

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Description: The total antibiotic use, expressed as Daily Doses of Administration (DDA) of antibiotics in grams. This will be aggregated with the amount of hospitalizations to arrive at one reported value: DDA/hospitalization (expressed as grams/hospitalization), for every antibiotic and antibiotic formulation (IV or PO) separately but also for all prescribed antibiotics in general.

Measure: Total antimicrobial consumption for suspicion of secondary bacterial respiratory infections in hospitalized patients in COVID wards with a clinical or PCR-based COVID diagnosis, expressed as 'Daily doses of administration/hospitalization'.

Time: 7 months

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Description: The total antibiotic use, expressed as Daily Doses of Administration (DDA) in grams. This will be aggregated with the total amount of hospitalized patient days to arrive at one reported value: DDA/1000 hospitalization patient days (expressed as grams/1000 hospitalization days), for every antibiotic and antibiotic formulation (IV or PO) separately but also for all prescribed antibiotics in general.

Measure: Total antimicrobial consumption for suspicion of secondary bacterial respiratory infections in hospitalized patients in COVID wards, expressed as 'Daily doses of administration (DDA)/1000 hospitalized patient days'.

Time: 7 months

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Secondary Outcomes

Description: The degree of appropriateness for each antibiotic (AB) formulation separately but also for all prescribed antibiotics in general, with distinction between 'Appropriate', 'Unnecessary', 'inappropriate' and 'suboptimal' AB choice. Results will be expressed as DDD or DDA of appropriate AB/1000 patient days, DDD or DDA of unnecessary AB/1000 patient days, DDD or DDA of inappropriate AB/1000 patient days and DDD or DDA of suboptimal AB/1000 patient days. Used units: g/1000 hospitalized patients days

Measure: The degree of appropriateness of antimicrobial prescriptions for presumed respiratory tract (super)infection

Time: 7 months

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Description: The degree of appropriateness for each antibiotic (AB) formulation separately but also for all prescribed antibiotics in general, with distinction between 'Appropriate', 'Unnecessary', 'inappropriate' and 'suboptimal' AB choice. Results will be expressed as DDD or DDA of appropriate AB/hospitalization, DDD or DDA of unnecessary AB/hospitalization, DDD or DDA of inappropriate AB/hospitalization and DDD or DDA of suboptimal AB/hospitalization. Used units: g/hospitalization

Measure: The degree of appropriateness of antimicrobial prescriptions for presumed respiratory tract (super)infection, denominator 2

Time: 7 months

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Description: The number of C. Difficile infections in the inpatient setting

Measure: Rate of Clostridioides Difficile infections

Time: 7 months

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Description: median or mean age (number) , comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics?

Measure: Is there a significant difference in age comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics?

Time: 7 months

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Description: median or mean weight (kg), comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics?

Measure: Is there a significant difference in weight comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics?

Time: 7 months

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Description: rate of comorbidities expressed as mean Charlson Comorbidity Index score, comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics

Measure: significant difference in amount of comorbidities comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics?

Time: 7 months

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Description: rate of chronical pulmonary disease, comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics

Measure: significant difference in rate of chronical pulmonary disease as a comorbidity, comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics?

Time: 7 months

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Description: rate of haematological or solid neoplasia, comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics

Measure: significant difference in rate of haematological or solid neoplasia as a comorbidity, comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics?

Time: 7 months

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Description: rate of diabetes mellitus, comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics

Measure: significant difference in rate of diabetes mellitus as a comorbidity, comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics?

Time: 7 months

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Description: rate of patients with fever (t°>38°c), dyspnea, cough, runny nose, throat pain, thoracic pain, myalgia, fatigue, anosmia, confusion at admission, comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics?

Measure: significant difference in rate of patients with presence or not of at least one suggestive symptom of COVID-19 symptomatology, comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics?

Time: 7 months

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Description: rate of patients rate of patients having received an antibiotic prescription for a suspicion of respiratory tract infection during the 3 weeks before hospitalization, comparing the group receiving antibiotics for a suspicion of COVID-19 surinfection and the group without antibiotics?

Measure: significant difference in rate of patients with recent AB prescription, comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics?

Time: 7 months

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Description: rate of patients with significant positive respiratory cultures, comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics?

Measure: Is there a significant difference in the rate of patients having had at least one positive significant respiratory germ culture, comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics?

Time: 7 months

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Description: rate of patients with oxygen suppletion need, comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics?

Measure: Is there a significant difference in the rate of patients needing oxygen supletion at day 1 of hospitalization, comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics?

Time: 7 months

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Description: mean duration of hospitalization on a COVID-ward, comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics?

Measure: significant difference in the mean duration of hospitalization, comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics?

Time: 7 months

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Description: rate of ICU admission, comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics?

Measure: significant difference in the rate of ICU admission, comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics?

Time: 7 months

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Description: mean SatO2/FiO2 ratio (number ranging from 50-500), comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics?

Measure: Is there a significant difference in the mean value of oxygen saturation percentage over fractional oxygen percentage, comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics?

Time: 7 months

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Description: mean/median qSOFA score at admission, comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics?

Measure: Is there a significant difference in qSOFA score level at admission, comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics?

Time: 7 months

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Description: Rate of lymphopenia (<1250/mcl), comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics?

Measure: Is there a significant difference in the rate of lymphopenia, comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics?

Time: 7 months

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Description: mean CRP values (mg/dl) at day 1 of hospitalization, comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics

Measure: significant difference in the mean value of C-reactive protein measured at day 1 of hospitalization on a COVID-ward ,comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics?

Time: 7 months

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Description: mean WBC count (/mcl) values at day 1 of hospitalization, comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics

Measure: significant difference in the mean value of white blood cell count measured at day 1 of hospitalization on a COVID-ward ,comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics?

Time: 7 months

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Description: mean neutrophil count (/mcl) values at day 1 of hospitalization, comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics

Measure: significant difference in the mean value of neutrophil count measured at day 1 of hospitalization on a COVID-ward ,comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics?

Time: 7 months

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Description: mean lymphocyte count (/mcl) values at day 1 of hospitalization, comparing the group receiving antibiotics for a suspicion of COVID-19 surinfection and the group without antibiotics

Measure: significant difference in the mean value of lymphocyte count measured at day 1 of hospitalization on a COVID-ward ,comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics?

Time: 7 months

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Description: mean creatinine (mg/dl) values at day 1 of hospitalization, comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics

Measure: significant difference in the mean value of creatinine measured at day 1 of hospitalization on a COVID-ward ,comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics?

Time: 7 months

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Description: mean LDH (U/L) values at day 1 of hospitalization, comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics

Measure: significant difference in the mean value of LDH measured at day 1 of hospitalization on a COVID-ward ,comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics?

Time: 7 months

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Description: mean bilirubin (mg/dl) values at day 1 of hospitalization, comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics

Measure: significant difference in the mean value of bilirubin measured at day 1 of hospitalization on a COVID-ward ,comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics?

Time: 7 months

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Description: mean ferritin (mcg/l) values, comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics

Measure: significant difference in the mean value of ferritin (first value during hospitalization),comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics?

Time: 7 months

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Description: mean troponin (mcg/l) values, comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics

Measure: significant difference in the mean value of troponins (first value during hospitalization),comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics?

Time: 7 months

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Description: mean D-dimer (ng/ml) values, comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics

Measure: significant difference in the mean value of D-dimers (first value during hospitalization),comparing the group receiving antibiotics for a suspicion of COVID-19 superinfection and the group without antibiotics?

Time: 7 months

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Primary Outcomes

Description: Feasibility assessment

Measure: Proportion of quality signals obtained out of all monitoring time for each device

Time: 8 weeks from first enrollment

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Description: Algorithm development, sensitivity, specificity, positive and negative predictive value at different lead times ahead of symptom onset

Measure: Predictive characteristics of the algorithm for respiratory tract infection

Time: 2 months

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Primary Outcomes

Measure: Proportion of participants experiencing at least one doctor-diagnosed or laboratory-confirmed acute respiratory infection of any cause.

Time: Over 6 months

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Secondary Outcomes

Description: Secondary efficacy outcome

Measure: Proportion of participants seroconverting to SARS-CoV-2 (i.e. with test results for antibodies to SARS-CoV-2 transitioning from negative at baseline to positive at follow-up)

Time: Over 6 months

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Description: Secondary efficacy outcome

Measure: Proportion of participants developing antigen test-positive COVID-19

Time: Over 6 months

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Description: Secondary efficacy outcome

Measure: Proportion of participants developing 'probable COVID-19', as adjudged using a validated symptom score

Time: Over 6 months

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Description: Secondary efficacy outcome

Measure: Proportion of participants developing antigen test-positive influenza

Time: Over 6 months

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Description: Secondary efficacy outcome

Measure: Proportion of participants reporting symptoms of acute respiratory infection

Time: Over 6 months

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Description: Secondary efficacy outcome

Measure: Proportion of participants who are prescribed one or more courses of antibiotic treatment for acute respiratory infection

Time: Over 6 months

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Description: Secondary efficacy outcome

Measure: Proportion of participants with asthma who experience one or more exacerbations of asthma requiring treatment with oral corticosteroids and/or requiring hospital treatment

Time: Over 6 months

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Description: Secondary efficacy outcome

Measure: Proportion of participants with COPD who experience one or more exacerbations of COPD requiring treatment with oral corticosteroids and/or antibiotics, and/or requiring hospital treatment

Time: Over 6 months

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Description: Secondary efficacy outcome

Measure: Proportion of participants who have had antigen test- or antibody test-confirmed SARS-CoV-2 infection who report symptoms of COVID-19 lasting more than 4 weeks after onset

Time: Over 6 months

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Description: Secondary efficacy outcome

Measure: Mean MRC dyspnoea score at the end of the study in people who have had antigen test- or antibody test-confirmed SARS-CoV-2 infection

Time: 6 months

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Description: Secondary efficacy outcome

Measure: Mean FACIT Fatigue Scale score at the end of the study in people who have had antigen test- or antibody test-confirmed SARS-CoV-2 infection

Time: 6 months

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Description: Secondary efficacy outcome

Measure: Mean COVID-19 Recovery Questionnaire score at the end of the study in people who have had antigen test- or antibody test-confirmed SARS-CoV-2 infection

Time: 6 months

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Description: Secondary efficacy outcome

Measure: Proportion of participants who experience one or more acute respiratory infections requiring hospitalisation

Time: Over 6 months

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Description: Secondary efficacy outcome

Measure: Proportion of participants who experience COVID-19 requiring hospitalisation

Time: Over 6 months

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Description: Secondary efficacy outcome

Measure: Proportion of participants hospitalised for COVID-19 requiring ventilatory support

Time: Over 6 months

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Description: Secondary efficacy outcome

Measure: Proportion of participants who experience influenza requiring hospitalisation

Time: Over 6 months

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Description: Secondary efficacy outcome

Measure: Proportion of participants dying of any cause during participation in the trial

Time: Over 6 months

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Description: Secondary efficacy outcome

Measure: Proportion of participants dying of acute respiratory infection during participation in the trial

Time: Over 6 months

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Description: Secondary efficacy outcome

Measure: Proportion of participants dying of COVID-19 during participation in the trial

Time: Over 6 months

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Description: Secondary efficacy outcome

Measure: Proportion of participants dying of influenza during participation in the trial • mean end-study 25(OH)D concentrations (sub-set of participants having end-study tests of vitamin D status)

Time: Over 6 months

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Description: Secondary efficacy outcome

Measure: mean end-study 25(OH)D concentration (sub-set of participants having end-study tests of vitamin D status) Mean end-study 25(OH)D concentration (sub-set of participants having end-study tests of vitamin D status)

Time: 6 months

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Description: Secondary safety outcome

Measure: Proportion of participants experiencing known hypercalcaemia

Time: Over 6 months

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Description: Secondary safety outcome

Measure: Proportion of participants experiencing a probable or definite adverse reaction to vitamin D supplementation

Time: Over 6 months

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Description: Secondary safety outcome

Measure: Proportion of participants experiencing a serious adverse event of any cause

Time: Over 6 months

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Primary Outcomes

Description: Respiratory infections incidence (includes LRTI, pneumonia and exacerbations of COPD): all new episodes of respiratory infections recorded in the clinical history or in the reports presented by the patient will be recorded. LRTI: presence of at least 2 of the following symptoms without other cause to explain them: fever, cough, purulent expectoration, rhonchi or wheezing. Pneumonia: performing 1 or more radiographic tests with new condensation, fever or leukopenia or leukocytosis and at least: cough, purulent expectoration, dyspnea, tachypnea, suggestive auscultation or worsening of gas exchange. COPD exacerbation: acute exacerbation of COPD is a sudden worsening of COPD symptoms (shortness of breath, quantity and color of phlegm) that typically lasts for several days. It may be triggered by an infection with bacteria or viruses or by environmental pollutants.

Measure: Respiratory infections incidence.

Time: From discharge to 6 months follow-up

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Secondary Outcomes

Description: Mortality: the date and reason for death will be recorded (hospitalization, 1, 3 and 6 months).

Measure: Mortality

Time: Through study completion, during hospitalization, and at 1, 3 and 6 months from disharge.

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Description: General readmissions and readmissions for respiratory infections (1, 3 and 6 months): LRTI, pneumonia and exacerbations of COPD: the reason for admission will be that stated in the hospital database (CMBDAH) according to CIM-10. The information source of the readmissions will be the registration of hospital discharges that is integrated into the hospital information system and that includes the CIM-10 codes of the main and secondary diagnoses of the episode that caused the admission, the date of admission and discharge and the days of hospitalization. Readmissions from pneumonia (codes CIM-10): J13, J18.1, J15.1, J14, J15.4, J15.211, J15.5, A48.1, J15.8, J18.0, J18.8, J69.0; readmissions for LRTI (no pneumonic): J20.0 - J20.9, J10.1, J11.1, J41.8, J44.1 and J44.0. Readmissions from exacerbation of COPD: J441.

Measure: General readmissions and readmissions for respiratory infections

Time: Through study completion, at 1, 3 and 6 months from disharge.

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Description: Mini-nutritional assessment form (MNA) (hospitalization, 1, 3 and 6 months).

Measure: Nutritional status (MNA)

Time: Through study completion, during hospitalization, and at 1, 3 and 6 months from disharge.

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Description: Heigh in cm (hospitalization, 1, 3 and 6 months).

Measure: Nutritional status (Anthropometric measures)

Time: Through study completion, during hospitalization, and at 1, 3 and 6 months from disharge.

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Description: Weight in kg (hospitalization, 1, 3 and 6 months).

Measure: Nutritional status (Anthropometric measures2)

Time: Through study completion, during hospitalization, and at 1, 3 and 6 months from disharge.

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Description: Biochemical parameters from blood analysis (hospitalization, 3 and 6 months).

Measure: Nutritional status (Biochemical parameters)

Time: Through study completion, during hospitalization, and at 1, 3 and 6 months from disharge.

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Description: Hydration status: we will register total body water and intracellular water with bioimpedance (hospitalization, 1, 3 and 6 months).

Measure: Hydration status (bioimpedance)

Time: Through study completion, during hospitalization, and at 1, 3 and 6 months from disharge.

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Description: Quality of life: EQ-5D questionnaire will be used (hospitalization, 1, 3 and 6 months).

Measure: Quality of life of patients during the study period

Time: Through study completion, during hospitalization, and at 1, 3 and 6 months from disharge.

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Description: Functional status: we will use the Barthel Index (hospitalization, 1, 3 and 6 months).

Measure: Functional status

Time: Through study completion, during hospitalization, and at 1, 3 and 6 months from disharge.

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Description: Oral Hygiene: the OHI-S (simplified oroal hygiene index) will be collected (hospitalization, 1, 3 and 6 months).

Measure: Oral Hygiene

Time: Through study completion, during hospitalization, and at 1, 3 and 6 months from disharge.

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Description: Severity of dysphagia: according to the different viscosities that patients will be able to swallow and with the Functional Oral Intake Scale (V-VST/FOIS) (hospitalization, 1, 3 and 6 months).

Measure: Dysphagia severity

Time: Through study completion, during hospitalization, and at 1, 3 and 6 months from disharge.

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Other Outcomes

Description: Sociodemographic characteristics of the study population.

Measure: Sociodemographics

Time: Baseline

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Description: Swallowing function (V-VST) (hospitalization, 1, 3 and 6 months).

Measure: Swallowing function (V-VST)

Time: Through study completion, during hospitalization, and at 1, 3 and 6 months from disharge.

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Description: Rate of institutionalization (1, 3 and 6 months).

Measure: Institutionalization

Time: Through study completion, at 1, 3 and 6 months from disharge.

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Description: Drugs taken by the patient.

Measure: Pharmacological treatment

Time: Baseline

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Description: Geriatric syndromes

Measure: Geriatric syndromes

Time: Baseline

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Description: Fried criteria (hospitalization, 1, 3 and 6 months).

Measure: Frailty 1

Time: Through study completion, during hospitalization, and at 1, 3 and 6 months from disharge.

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Description: Edmonton frail scale (hospitalization, 1, 3 and 6 months).

Measure: Frailty 2

Time: Through study completion, during hospitalization, and at 1, 3 and 6 months from disharge.

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Description: Smoking and alcohol consumption

Measure: Toxic habits

Time: Baseline

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Description: Compliance with the recommendations of the study intervention (adaptations of fluid, prescribed diets and oral hygiene) (hospitalization, 1, 3 and 6 months).

Measure: Compliance

Time: Through study completion, during hospitalization, and at 1, 3 and 6 months from disharge.

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Description: Palatability of the intervention products will be measured with the 5-point facial hedonic scale (hospitalization, 1, 3 and 6 months).

Measure: Palatability

Time: Through study completion, during hospitalization, and at 1, 3 and 6 months from disharge.

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Description: Acceptability of the dietes will be measured with the Food Action Rating Scale (hospitalization, 1, 3 and 6 months)

Measure: Acceptability

Time: Through study completion, during hospitalization, and at 1, 3 and 6 months from disharge.

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Primary Outcomes

Description: The RRS is an ordinal scale assessing a participant's clinical status.

Measure: Respiratory Syncytial Virus (RSV) Recovery Scale (RRS)

Time: Up to Day 8

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Secondary Outcomes

Description: Clinical resolution is defined by free of oxygen supplementation, and free of supplemental feeding, and no medical need for intensive care unit (ICU), and key RSV Signs/Symptoms resolved to absent or mild as per the Pediatric RSV Electronic Severity and Outcome Rating Scale (PRESORS) Clinician Rated Outcome (ClinRO) Signs/Symptoms questionnaire.

Measure: Percentage of Participants with Clinically Resolved RSV Disease as Assessed by ClinRO Sign/Symptoms Questionnaire

Time: Up to Day 8

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Description: Time from first study dose to resolution of key RSV Signs/symptoms (absent or mild) will be assessed based on parent's/caregiver's PRESORS Observer Rated Outcome (ObsRO) signs/symptoms and supplementation free (oxygen and feeding/hydration).

Measure: Time From First Study Dose to Resolution of key RSV Signs/Symptoms Based on ObsRO

Time: Up to Day 21

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Description: Time from discharge to resolution of key RSV Signs/symptoms will be assessed based on PRESORS ObsRO Sign/Symptoms (only including participants who did not reach resolution before first discharge).

Measure: Time From Discharge to Resolution of key RSV Signs/Symptoms based on ObsRO Sign/Symptoms Questionnaire

Time: Up to Day 21

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Description: Time from first dosing to end of oxygen supplementation will be assessed (only including participants who were receiving oxygen supplementation at the time of first dosing).

Measure: Time From First Dosing to end of Oxygen Supplementation

Time: Up to Day 35

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Description: Number of participants with post-baseline RSV-related complications will be assessed.

Measure: Number of Participants with Post-baseline RSV-Related Complications

Time: Up to Day 35

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Description: An AE is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non investigational) product. An AE does not necessarily have a causal relationship with the intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal finding), symptom, or disease temporally associated with the use of a medicinal (investigational or non investigational) product, whether or not related to that medicinal (investigational or non investigational) product.

Measure: Number of Participants with Adverse Events

Time: Up to Day 35

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Description: Number of participants with abnormalities in Clinical laboratory values (Hematology, Clinical chemistry, and routine urinalysis) will be assessed.

Measure: Number of Participants with Abnormalities in Clinical Laboratory Values

Time: Up to Day 35

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Description: Number of participants with ECG abnormalities will be assessed.

Measure: Number of Participants with Abnormalities in Electrocardiograms (ECG)

Time: Up to Day 35

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Description: Number of participants with vital signs (Temperature, pulse/heart rate, and peripheral capillary oxygen saturation [SpO2]) abnormalities will be assessed.

Measure: Number of Participants with Abnormalities in Vital Signs

Time: Up to Day 35

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Description: Time to resolution of signs/symptoms (absent or mild) of RSV disease as assessed by PRESORS ObsRO signs/symptoms questionnaire.

Measure: Time to Resolution of Signs/symptoms of RSV Disease as Assessed by ObsRO Signs/Symptoms Questionnaire

Time: Up to Day 21

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Description: PRESORS ObsRO Signs/Symptoms Questionnaire Scores will be assessed. PRESORS is a questionnaire recording presence and severity of signs and symptoms of RSV disease.

Measure: PRESORS ObsRO Signs/Symptoms Questionnaire Scores

Time: Up to Day 21

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Description: Change from baseline in PRESORS ObsRO Signs/Symptoms questionnaire scores over time will be assessed. PRESORS is a questionnaire recording presence and severity of signs and symptoms of RSV disease.

Measure: Change From Baseline in PRESORS ObsRO Signs/Symptoms Questionnaire Scores Over Time

Time: Baseline up to Day 21

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Description: Time to improvement on PRESORS ObsRO GHQ will be assessed. ObsRO GHQ contains questions which are used to record the caregiver's general impression of the child's RSV disease severity, change in RSV disease severity, and overall health status.

Measure: Time to Improvement in ObsRO General Health Questions (GHQ)

Time: Up to Day 21

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Description: Time to resolution of signs/symptoms of RSV disease as assessed by ClinRO signs/symptoms questionnaire will be reported.

Measure: Time to resolution of Signs/Symptoms of RSV Disease as Assessed by ClinRO Signs/Symptoms Questionnaire

Time: Up to Day 21

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Description: PRESORS ClinRO signs/symptoms questionnaire score will be reported. PRESORS is a questionnaire recording presence and severity of signs and symptoms of RSV disease.

Measure: PRESORS ClinRO Signs/Symptoms Questionnaire Scores

Time: Up to Day 21

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Description: Change from baseline in PRESORS ClinRO signs/symptoms questionnaire scores over time will be assessed.

Measure: Change From Baseline in ClinRO Signs/Symptoms Questionnaire Scores

Time: Baseline up to Day 21

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Description: Percentage of participants with clinically resolved RSV disease based on PRESORS ClinRO signs/symptoms will be assessed.

Measure: Percentage of Participants with Clinically Resolved RSV Disease Based on ClinRO Signs/symptoms

Time: Day 2 to 8

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Description: Change from baseline in ClinRO GHQ score over time will be assessed. ClinRO GHQ contains questions which are used to record the caregiver's general impression of the child's RSV disease severity, change in RSV disease severity, and overall health status.

Measure: Change from Baseline in ClinRO GHQ Score Over Time

Time: Baseline up to Day 21

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Description: Time to hospital discharge from start of dosing will be assessed.

Measure: Time to Hospital Discharge From Start of Dosing

Time: Up to Day 35

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Description: Time to readiness of participants for hospital discharge (as evaluated by the investigator) will be assessed.

Measure: Time to Readiness for Hospital Discharge

Time: Up to Day 35

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Description: Percentage of participants requiring ICU stay will be assessed.

Measure: Percentage of Participants Requiring Intensive Care Unit (ICU) Stay

Time: Up to Day 35

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Description: Duration of requiring ICU stay will be assessed.

Measure: Duration of Requiring ICU Stay

Time: Up to Day 35

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Description: Percentage of participants requiring re-hospitalization for respiratory/other reasons will be assessed.

Measure: Percentage of Participants Requiring Re-hospitalization for Respiratory/other Reasons

Time: Up to Day 35

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Description: Time to end of oxygen supplementation will be assessed.

Measure: Time to end of Oxygen Supplementation

Time: Up to Day 35

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Description: Percentage of participants requiring oxygen supplementation will be assessed.

Measure: Percentage of Participants Requiring Oxygen Supplementation

Time: Up to Day 35

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Description: Duration of oxygen supplementation will be assessed.

Measure: Duration of Oxygen Supplementation

Time: Up to Day 35

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Description: Time to end of supplemental feeding/hydration will be assessed.

Measure: Time to end of Supplemental Feeding/hydration

Time: Up to Day 35

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Description: Percentage of participants requiring hydration and/or feeding by IV administration or nasogastric tube will be assessed.

Measure: Percentage of Participants Requiring Hydration and/or Feeding by Intravenous (IV) Administration or Nasogastric Tube

Time: Up to Day 35

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Description: Duration of supplemental feeding/hydration will be assessed.

Measure: Duration of Supplemental Feeding/hydration

Time: Up to Day 35

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Description: Time to end of supplemental oxygen and/or feeding/hydration will be assessed.

Measure: Time to end of Supplemental Oxygen and/or Feeding/hydration

Time: Up to Day 35

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Description: Number of participants with medical care encounters and treatments (including physician or emergency room visits, tests and procedures, and medications, surgeries and other procedures) will be reported.

Measure: Number of Participants with Medical Encounters and Treatments

Time: Up to Day 35

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Description: Number of participants with antibiotic treatment episodes will be assessed.

Measure: Number of Participants with Antibiotic Treatment Episodes

Time: Up to Day 35

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Description: Number of participants with systemic or inhaled corticosteroids and bronchodilators use will be assessed.

Measure: Number of Participants with Systemic or Inhaled Corticosteroids and Bronchodilators use

Time: Up to Day 35

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Description: RSV viral load area under the RSV viral load-time curve [AUC] will be assessed by quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) assay of nasal swabs.

Measure: RSV Viral Load Area Under the RSV Viral Load-time Curve [AUC]) From Immediately Prior to First Dose of Study Intervention (Baseline) Through Day 3, Day 5, and Day 8

Time: Baseline, Day 3, 5 and Day 8

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Description: RSV viral load over time will be assessed by qRT-PCR assay in the mid-turbinate nasal swab specimens.

Measure: RSV Viral Load Over Time

Time: From Baseline to Day 21

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Description: Change From baseline in RSV viral load over time will be assessed by qRT-PCR assay in the mid-turbinate nasal swabs specimens.

Measure: Change From Baseline in RSV Viral Load Over Time

Time: Baseline to Day 21

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Description: Percentage of participants with undetectable RSV viral load will be assessed.

Measure: Percentage of Participants with Undetectable RSV Viral Load

Time: Up to Day 21

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Description: Number of participants with post-baseline changes in the RSV F-gene compared with baseline sequences will be assessed.

Measure: Number of Participants with Post-baseline Changes in the RSV F-gene Compared with Baseline Sequences

Time: Up to Day 21

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Description: Plasma concentration of rilematovir will be assessed.

Measure: Plasma Concentration of Rilematovir

Time: Post-dose (Day 1) and pre-dose (Day 2)

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Description: Acceptability and palatability of the rilematovir formulation will be assessed through a questionnaire completed by parent(s)/caregiver(s).

Measure: Acceptability and Palatability of the Rilematovir Formulation as Assessed by Parent(s)/Caregiver(s)

Time: Day 8

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Primary Outcomes

Measure: time to complete intubation

Time: immediately after intervention

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Secondary Outcomes

Description: Team Emergency Assessment Measure, minimal score is 0 and the maximal score is 4. Higher score means a better outcome.

Measure: teamwork score

Time: immediately after intervention

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Measure: exposure time in isolation rooms

Time: immediately after intervention

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Primary Outcomes

Description: Unsuitable (bad quality) measured by microscopy - ≥ 10 squamous epithelial cells and < than 25 polymorphonuclear leucocytes per low power field of view (x10) Suitable (good quality) measured by microscopy - Samples with ≤ 10 squamous epithelial cells and > than 25 polymorphonuclear leucocytes per low power field of view

Measure: Quality of specimen from the lower respiratory tract

Time: From collection to culture results - up to 5 days

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Secondary Outcomes

Description: Assessed as number of colony forming units per millilitre with a cut off of 10^5 assessed semi-quantitatively as either numerous, some, or few or none.

Measure: Density of microorganisms

Time: From collection to culture results - up to 5 days

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Description: The patients are asked about 4 specific symptoms (Cough, Expectoration, Chest pain and Dyspnea). The clinical symptoms are measured as following: yes/no/yes worse than usual. Ten minutes after the intervention they will be asked the same questions with yes/no/worse than before the intervention.

Measure: Patient clinical symptoms

Time: Patients are followed before intervention and 10 minutes after intervention

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Description: This will be counted by the health professional attending the patient and is the number of breaths per minute in rest. It is assessed by counting the number of times the patients chest rises in a half minute multiplied by 2.

Measure: Respiratory rate

Time: Measured twice: Baseline ( at admission) and follow up (10 minutes after intervention)

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Description: This is measured using a pulse oximetry device - a non-invasive method to measure artieral oxygen saturation level in percentages

Measure: Oxygen saturation

Time: Measured twice: Baseline ( at admission) and follow up (10 minutes after intervention)

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Description: Measured using the Borg Categorical rate 10 scale and a single likert-scale question - 'How does the patient experience the procedure' (only measured after the intervention).

Measure: Patient well-being and experience of procedure

Time: Measured twice: Baseline ( at admission) and follow up (10 minutes after intervention)

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Primary Outcomes

Description: The number of participants with first time SARS-CoV-2 positive nasopharyngeal and or pharyngeal swabs (or any other sample used for detection of current disease) analyzed by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) nucleic acid amplification test or antigen tests used by accredited Norwegian microbiology laboratories in the period from one week after the start of cod liver oil/placebo taking to the end of this period together with any of the following: A) Self-reported dyspnea and fever concurrent (within four weeks) with the positive test OR B) hospitalization caused by Covid-19 concurrent (within four weeks) with the positive test OR C) death where the Covid-19 infection was wholly or partly responsible as judged by the death certificate (see endpoint in the protocol)

Measure: Number of participants diagnosed with serious Covid-19

Time: 6 months

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Description: The number of participants diagnosed with first time SARS-CoV-2 positive nasopharyngeal and or pharyngeal swabs (or any other sample used for detection of current disease) analyzed by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) nucleic acid amplification test or antigen tests used by accredited Norwegian microbiology laboratories from one week after the start of cod liver oil/placebo taking.

Measure: Number of participants diagnosed with New Covid-19

Time: 6 months

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Description: Number of participants with an airway sample positive for a respiratory pathogen* (either PCR or culture). *Influenza virus (A and B), parainfluenzavirus (1,2,3), metapneumovirus, rhinovirus, coronavirus (non-SARS), Respiratory Syncytial virus, Haemophilus Influenzae, Moraxella Catharralis, Streptococcus Pneumonia, Beta-hemolytic streptococci, Mycoplasma pneumonia, Chlamydophila pneumonia, Enterovirus, Bordetella pertussis. The list can be expanded based on the analyses performed in Norwegian Microbiology laboratories.

Measure: Number of participants with laboratory confirmed respiratory tract infection

Time: 6 months

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Description: The number of episodes with any two of the following symptoms: fever, cough, nasal congestion or sore throat

Measure: Number of participants with self-reported airway infection

Time: 6 months

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Secondary Outcomes

Description: Number of participants hospitalized wholly or partly caused by Covid-19.

Measure: Number of participants hospitalized due to Covid-19

Time: 6 months

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Description: Number of participants with ICU care wholly or partly caused by Covid-19.

Measure: Number of participants in Intensiv Care Unit (ICU) caused by Covid-19

Time: 6 months

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Description: Number of participants with any admissions to hospital based on the Norwegian Patient Registry data.

Measure: Number of participants with any admissions to hospital

Time: 6 months

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Description: An airway sample positive for a respiratory pathogen* (either PCR or culture) in the period from one week after the start of cod liver oil/placebo taking to the end of this period. *Influenza virus (A and B), parainfluenzavirus (1,2,3), metapneumovirus, rhinovirus, coronavirus (non-SARS), Respiratory Syncytial virus, Haemophilus Influenzae, Moraxella Catharralis, Streptococcus Pneumonia, Beta-hemolytic streptococci, Mycoplasma pneumonia, Chlamydophila pneumonia, Enterovirus, Bordetella pertussis. The list can be expanded based on the analyses performed in Norwegian Microbiology laboratories.

Measure: Infection with each of the mentioned pathogens

Time: 6 months

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Description: Based on The Norwegian Reimbursement Database

Measure: Number of visits at GP for infections

Time: 6 months

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Description: Based on The Norwegian Reimbursement Database

Measure: Number of visits at GP

Time: 6 months

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Other Outcomes

Description: Based on self-reporting and Norwegian Registries

Measure: Incidence of Cardiovascular disease

Time: 6 months

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Description: Based on self-reporting and Norwegian Registries

Measure: Incidence of Cardiovascular disease

Time: 30 months

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Description: Based on self-reporting and Norwegian Registries

Measure: Incidence of cardiovascular mortality

Time: 6 months

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Description: Based on self-reporting and Norwegian Registries

Measure: Incidence of cardiovascular mortality

Time: 30 months

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Description: Based on self-reporting and Norwegian Registries

Measure: Incidence of cancer

Time: 6 months

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Description: Based on self-reporting and Norwegian Registries

Measure: Incidence of cancer

Time: 30 months

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Description: Based on self-reporting and Norwegian Registries

Measure: Incidence of cancer mortality

Time: 6 months

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Description: Based on self-reporting and Norwegian Registries

Measure: Incidence of cancer mortality

Time: 30 months

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Description: Based on self-reporting and Norwegian Registries

Measure: All-cause mortality

Time: 6 months

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Description: Based on self-reporting and Norwegian Registries

Measure: All-cause mortality

Time: 30 months

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Description: Based on self-reporting and Norwegian Registries

Measure: Incidence of fracture of the hip or forearm

Time: 6 months

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Description: Based on self-reporting and Norwegian Registries

Measure: Incidence of fracture of the hip or forearm

Time: 30 months

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Description: Based on self-reporting and Norwegian Registries

Measure: Incident dementia

Time: 6 months

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Description: Based on self-reporting and Norwegian Registries

Measure: Incident dementia

Time: 30 months

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Description: The number of participants with first time SARS-CoV-2 positive nasopharyngeal and or pharyngeal swabs (or any other sample used for detection of current disease) analyzed by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) nucleic acid amplification test or antigen tests used by accredited Norwegian microbiology laboratories in the period from one week after the start of cod liver oil/placebo taking to the end of this period together with any of the following: A) Self-reported dyspnea and fever concurrent (within four weeks) with the positive test OR B) hospitalization caused by Covid-19 concurrent (within four weeks) with the positive test OR C) death where the Covid-19 infection was wholly or partly responsible as judged by the death certificate (see endpoint in the protocol)

Measure: Number of participants diagnosed with serious Covid-19

Time: 12 months

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Description: The number of participants diagnosed with first time SARS-CoV-2 positive nasopharyngeal and or pharyngeal swabs (or any other sample used for detection of current disease) analyzed by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) nucleic acid amplification test or antigen tests used by accredited Norwegian microbiology laboratories from one week after the start of cod liver oil/placebo taking.

Measure: Number of participants diagnosed with new Covid-19

Time: 12 months

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Description: An airway sample positive for a respiratory pathogen* (either PCR or culture). *Influenza virus (A and B), parainfluenzavirus (1,2,3), metapneumovirus, rhinovirus, coronavirus (non-SARS), Respiratory Syncytial virus, Haemophilus Influenzae, Moraxella Catharralis, Streptococcus Pneumonia, Beta-hemolytic streptococci, Mycoplasma pneumonia, Chlamydophila pneumonia, Enterovirus, Bordetella pertussis. The list can be expanded based on the analyses performed in Norwegian Microbiology laboratories.

Measure: Laboratory confirmed respiratory tract infection

Time: 12 months

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Description: The number of episodes with any two of the following symptoms: fever, cough, nasal congestion or sore throat

Measure: Self-reported airway infection

Time: 12 months

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Description: Number of participants with self-reported adverse events

Measure: Number of participants with self-reported cod liver oil related adverse events

Time: 12 months

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Description: Number of participants hospitalized for major diseases or death in the cod liver oil versus placebo group in Norwegian registries

Measure: Number of participants with cod liver oil related adverse events

Time: 12 months

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Primary Outcomes

Description: 28-day all-cause mortality

Measure: 28-day all-cause mortality

Time: Day 28

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Secondary Outcomes

Description: Time to 7-category ordinal scale of clinical status improvement (T7COSCSI)

Measure: Time to 7-category ordinal scale of clinical status improvement (T7COSCSI)

Time: Up to 60 days

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Description: Ventilator-free days (VFDs) within 28 days

Measure: Ventilator-free days (VFDs) within 28 days

Time: Up to 28 days

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Description: Organ failure-free days (OFFD)

Measure: Organ failure-free days (OFFD)

Time: Up to 60 days

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Description: Intensive care unit length of stay (ICU LOS)

Measure: Intensive care unit length of stay (ICU LOS)

Time: Up to 60 days

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Description: Hospital length of stay (HLOS)

Measure: Hospital length of stay (HLOS)

Time: Up to 60 days

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Description: In-hospital all-cause mortality (IHACM)

Measure: In-hospital all-cause mortality (IHACM)

Time: Up to 60 days

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Description: 60-day all-cause mortality (60DACM)

Measure: 60-day all-cause mortality (60DACM)

Time: Up to 60 days

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Description: Time to oxygenation improvement (TOI)

Measure: Time to oxygenation improvement (TOI)

Time: Up to 60 days

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Description: Duration of supplemental oxygen (DSO)

Measure: Duration of supplemental oxygen (DSO)

Time: Up to 60 days

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Description: Chest radiographic improvement (CRI)

Measure: Chest radiographic improvement (CRI)

Time: Up to 60 days

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Description: Time to National Early Warning Score 2 improvement (TNEWS2I)

Measure: Time to National Early Warning Score 2 improvement (TNEWS2I)

Time: Up to 60 days

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Description: Treatment-emergent adverse events (TEAEs)

Measure: Treatment-emergent adverse events (TEAEs)

Time: Up to 60 days

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Description: Plasma siltuximab concentrations (PSCs)

Measure: Plasma siltuximab concentrations (PSCs)

Time: Up to 60 days

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Description: Anti-siltuximab antibodies (ASA)

Measure: Anti-siltuximab antibodies (ASA)

Time: Up to 60 days

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