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 not develop serious respiratory failure SRF until day 14. Patients dying before study visit of day 14 are considered non-achieving the primary endpoint.

Measure: The ratio of patients who will not 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 historical comparators from Hellenic Sepsis Study Group Database

Measure: Comparison of the rate of patients who will not develop serious respiratory failure (SRF) until day 14 with historical comparators from Hellenic Sepsis Study Group Database

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 cytokine stimulation from peripheral blood mononuclear cells of enrolled subjects will be compared between days 1 and 7

Measure: Change of cytokine production 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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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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