Correlated Drug Terms (162)

---

	Name (Synonyms)	Correlation
drug242	DAS181 Wiki	0.21
drug480	Losartan Wiki	0.20
drug360	Hydroxychloroquine Wiki	0.19
drug169	Camostat Mesilate Wiki	0.18
drug650	Presatovir Wiki	0.16
drug872	UC-MSCs Wiki	0.16
drug855	Tocilizumab (TCZ) Wiki	0.15
drug386	Hydroxychloroquine Sulfate Regular dose Wiki	0.15
drug597	PUL-042 Inhalation Solution Wiki	0.15
drug184	ChAdOx1 MERS Wiki	0.15
drug385	Hydroxychloroquine Sulfate Loading Dose Wiki	0.15
drug805	Suspension of heat killed (autoclaved) Mycobacterium w Wiki	0.12
drug82	Azithromycin Wiki	0.11
drug247	Dapagliflozin 10 MG Wiki	0.10
drug523	MuscleSound Ultrasound Wiki	0.10
drug664	Pyridostigmine Bromide Wiki	0.10
drug401	Hydroxychloroquine, Doxycycline Wiki	0.10
drug295	Exercise brochure Wiki	0.10
drug434	Intermediate dose thromboprophylaxis Wiki	0.10
drug510	Mid dose chloroquine or hydroxychloroquine Wiki	0.10
drug706	Routine care for COVID-19 patients Wiki	0.10
drug399	Hydroxychloroquine, Clindamycin, Primaquine - high dose. Wiki	0.10
drug98	BNT162a1 Wiki	0.10
drug348	High does chloroquine or hydroxychloroquine Wiki	0.10
drug636	Plasma Donation Wiki	0.10
drug458	Leflunomide Wiki	0.10
drug124	Biosensor Wiki	0.10
drug976	mRNA-1273 Wiki	0.10
drug319	Galidesivir Wiki	0.10
drug452	Ketamine Wiki	0.10
drug548	Nintedanib 150 MG Wiki	0.10
drug729	Saliva Wiki	0.10
drug673	Quick Defense Wiki	0.10
drug336	HCQ+AZT Wiki	0.10
drug774	Standard of Care thromboprophylaxis Wiki	0.10
drug430	Interferon-Alpha2B Wiki	0.10
drug604	Peginterferon Lambda-1a Wiki	0.10
drug1001	pathogen reduced SARS-CoV-2 convalescent plasma Wiki	0.10
drug817	TJ003234 Wiki	0.10
drug688	Recombinant novel coronavirus vaccine (Adenovirus type 5 vector) Wiki	0.10
drug590	PD-1 blocking antibody+standard treatment Wiki	0.10
drug694	Remestemcel-L® Wiki	0.10
drug891	Vazegepant (BHV-3500) Wiki	0.10
drug537	Naltrexone Wiki	0.10
drug520	Multifrequency Bioimpedance Spectroscopy Wiki	0.10
drug551	Nitazoxanide Tablets Wiki	0.10
drug954	favipiravir tablets+chloroquine phosphatetablets tablets Wiki	0.10
drug91	BCG Wiki	0.10
drug170	Canakinumab Wiki	0.10
drug898	Views and experiences of health care professionals working in intensive care units during the COVID-19 pandemic Wiki	0.10
drug444	Isotonic saline 0.9% Wiki	0.10
drug1039	vaccine BCG Wiki	0.10
drug77	Aviptadil (VIP) Wiki	0.10
drug519	MultiStem Wiki	0.10
drug374	Hydroxychloroquine SAR321068 Wiki	0.10
drug271	Duodenal biopsy Wiki	0.10
drug323	Gimsilumab Wiki	0.10
drug978	meplazumab for injection Wiki	0.10
drug39	Almitrine Wiki	0.10
drug1029	standard treatment Wiki	0.10
drug99	BNT162b1 Wiki	0.10
drug3	- Synthetic anti-malarial drugs Wiki	0.10
drug859	Tradipitant Wiki	0.10
drug472	Lopinavir / ritonavir tablets combined with Xiyanping injection Wiki	0.10
drug244	DAS181 OL Wiki	0.10
drug80	Ayurveda Wiki	0.10
drug56	Any drug used to treat Covid-19 Wiki	0.10
drug665	Q-NRG Metobolic Cart Device Wiki	0.10
drug85	Azithromycin 500 milligram (mg) oral Tablet Wiki	0.10
drug989	no intervention Wiki	0.10
drug180	Cell therapy protocol 1 Wiki	0.10
drug485	MRx-4DP0004 Wiki	0.10
drug201	Clazakizumab 25 mg Wiki	0.10
drug200	Clazakizumab 12.5 mg Wiki	0.10
drug400	Hydroxychloroquine, Clindamycin, Primaquine - low dose. Wiki	0.10
drug332	HCQ Wiki	0.10
drug928	bacTRL-Spike Wiki	0.10
drug153	COVID-19 barrier box Wiki	0.10
drug250	Data collection and rhinopharyngeal swab Wiki	0.10
drug210	ColdZyme® mouth spray Wiki	0.10
drug228	Convalescent Serum Wiki	0.10
drug239	Cytokine Adsorption Wiki	0.10
drug483	Low-dose chloroquine/hydroxychloroquine Wiki	0.10
drug815	TD-0903 Wiki	0.10
drug451	Kerecis Oral and Nasal Spray Wiki	0.10
drug27	AZ Wiki	0.10
drug488	MVA-MERS-S_DF1 - High Dose Wiki	0.10
drug306	Favipiravir tablets Wiki	0.10
drug329	HB-adMSC Wiki	0.10
drug643	Povidone-Iodine 2% Wiki	0.10
drug751	Sirolimus 1 MG/ML Wiki	0.10
drug101	BNT162c2 Wiki	0.10
drug829	Telmisartan 40mg Wiki	0.10
drug331	HC Wiki	0.10
drug474	Lopinavir 200Mg/Ritonavir 50Mg Tab Wiki	0.10
drug450	JNJ-53718678 Wiki	0.10
drug422	Inhaled beclomethasone Wiki	0.10
drug95	BLD-2660 Wiki	0.10
drug687	Recombinant human interferon α1β Wiki	0.10
drug51	Angiotensin-Converting Enzyme Inhibitors (ACE-I) and Angiotensin II Receptor Blockers (ARB) Wiki	0.10
drug676	REGN3051 Wiki	0.10
drug212	Combination of Lopinavir /Ritonavir and Interferon beta-1b Wiki	0.10
drug811	T89 Wiki	0.10
drug100	BNT162b2 Wiki	0.10
drug849	Thymosin+standard treatment Wiki	0.10
drug1005	plasma therapy using convalescent plasma with antibody against SARS-CoV-2 Wiki	0.10
drug733	Sarilumab SAR153191 Wiki	0.10
drug749	Simvastatin Wiki	0.10
drug675	REGN3048 Wiki	0.10
drug489	MVA-MERS-S_DF1 - Low Dose Wiki	0.10
drug312	Fluvoxamine Wiki	0.10
drug686	Recombinant human angiotensin-converting enzyme 2 (rhACE2) Wiki	0.10
drug642	Povidone-Iodine 0.5% Wiki	0.10
drug42	Aluminum hydroxide Wiki	0.10
drug96	BM-MSCs Wiki	0.10
drug1021	serum inflammatory biomarkers Wiki	0.10
drug714	SARS-CoV Wiki	0.10
drug397	Hydroxychloroquine, Azithromycin Wiki	0.10
drug181	Cell therapy protocol 2 Wiki	0.10
drug63	Aspirin Wiki	0.10
drug355	Human immunoglobulin Wiki	0.10
drug290	Ergoferon Wiki	0.10
drug144	CD24Fc Wiki	0.10
drug840	Therapeutic Anticoagulation Wiki	0.10
drug398	Hydroxychloroquine, Clindamycin Wiki	0.10
drug689	Recombinase aided amplification (RAA) assay Wiki	0.10
drug536	Nafamostat Mesilate Wiki	0.10
drug727	Saline containing 1% Human serum albumin（solution of MSC） Wiki	0.10
drug479	Lopinavir/ritonavir treatment Wiki	0.10
drug243	DAS181 COVID-19 Wiki	0.10
drug379	Hydroxychloroquine Sulfate 200 MG Wiki	0.10
drug190	Chloroquine Wiki	0.08
drug455	L-ascorbic acid Wiki	0.07
drug269	Doxycycline Wiki	0.07
drug738	Selinexor Wiki	0.07
drug276	Eculizumab Wiki	0.07
drug486	MSCs Wiki	0.07
drug504	Mesenchymal Stromal Cells Wiki	0.07
drug330	HB-adMSCs Wiki	0.07
drug195	Chloroquine or Hydroxychloroquine Wiki	0.07
drug691	Remdesivir Wiki	0.06
drug151	COVID-19 RT-PCR Wiki	0.06
drug925	anti-SARS-CoV-2 convalescent plasma Wiki	0.06
drug92	BCG Vaccine Wiki	0.06
drug554	Nitric Oxide Gas Wiki	0.06
drug60	Ascorbic Acid Wiki	0.06
drug359	Hydrocortisone Wiki	0.06
drug220	Control Wiki	0.05
drug826	Telerehabilitation Wiki	0.05
drug883	Usual Care Wiki	0.05
drug668	Questionnaire Wiki	0.05
drug707	Ruxolitinib Wiki	0.05
drug627	Placebo oral tablet Wiki	0.05
drug900	Vitamin C Wiki	0.05
drug732	Sarilumab Wiki	0.04
drug304	Favipiravir Wiki	0.04
drug225	Convalescent Plasma Wiki	0.04
drug507	Methylprednisolone Wiki	0.04
drug558	No intervention Wiki	0.04
drug375	Hydroxychloroquine Sulfate Wiki	0.03
drug632	Placebos Wiki	0.03
drug854	Tocilizumab Wiki	0.03

Correlated MeSH Terms (32)

---

	Name (Synonyms)	Correlation
D018352	Coronavirus Infections NIH	0.27
D007239	Infection NIH	0.22
D003141	Communicable Diseases NIH	0.22
D055371	Acute Lung Injury NIH	0.20
D014777	Virus Diseases NIH	0.18
D012128	Respiratory Distress Syndrome, Adult NIH	0.18
D045169	Severe Acute Respiratory Syndrome NIH	0.17
D012127	Respiratory Distress Syndrome, Newborn NIH	0.16
D055370	Lung Injury NIH	0.13
D009164	Mycobacterium Infections NIH	0.12
D011014	Pneumonia NIH	0.11
D020141	Hemostatic Disorders NIH	0.10
D018357	Respiratory Syncytial Virus Infections NIH	0.10
D017250	Caliciviridae Infections NIH	0.10
D001778	Blood Coagulation Disorders NIH	0.10
D007049	Iatrogenic Disease NIH	0.10
D013577	Syndrome NIH	0.10
D014947	Wounds and Injuries NIH	0.08
D012141	Respiratory Tract Infections NIH	0.08
D005334	Fever NIH	0.07
D003139	Common Cold NIH	0.07
D058070	Asymptomatic Diseases NIH	0.07
D015004	Yellow Fever NIH	0.07
D000257	Adenoviridae Infections NIH	0.07
D053120	Respiratory Aspiration NIH	0.07
D011658	Pulmonary Fibrosis NIH	0.06
D004417	Dyspnea NIH	0.06
D018184	Paramyxoviridae Infections NIH	0.06
D058186	Acute Kidney Injury NIH	0.05
D018450	Disease Progression NIH	0.04
D007251	Influenza, Human NIH	0.04
D016638	Critical Illness NIH	0.03

Correlated HPO Terms (3)

---

	Name (Synonyms)	Correlation
HP:0002090	Pneumonia HPO	0.10
HP:0011947	Respiratory tract infection HPO	0.08
HP:0001945	Fever HPO	0.07

Primary Outcomes

Measure: Frequency and description of serious adverse events (SAEs).

Time: 5 months after receipt of the booster dose of vaccine.

---

Measure: Frequency of significant increases in serum antibody to CoV S protein in Enzyme Linked Immunosorbent Assay (ELISA) and in neutralization tests, and increases in Geometric Mean Titers (GMT)s in sera.

Time: Screening, 1 and 5 months after the booster dose of vaccine.

---

Measure: Frequency and severity of solicited injection site and systemic signs and symptoms and unsolicited adverse events (AE) / SAEs.

Time: 1 month after receipt of the first and second doses of vaccine.

---

Secondary Outcomes

Measure: Frequency of significant serum antibody increases and increases in Geometric Mean Titers (GMT)s, as measured in neutralizing antibody tests and an ELISA against SARS-CoV S protein.

Time: Collected just before the first vaccination and at 1 month (just before booster).

---

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

---

Primary Outcomes

Description: The time-weighted average change, often referred to as the DAVG, provides the average viral burden change from baseline. The mean values presented were calculated using the ANCOVA model and are adjusted for baseline value and stratification factor.

Measure: Time-Weighted Average Change in Nasal Respiratory Syncytial Virus (RSV ) Viral Load From Baseline (Day 1) to Day 9

Time: Baseline; Day 9

---

Description: A Lower Respiratory Tract Complication (LRTC) was defined as one of the below as determined by the adjudication committee: Primary RSV lower respiratory tract infection (LRTI) Secondary bacterial LRTI LRTI due to unusual pathogens Lower respiratory tract complication of unknown etiology

Measure: Percentage of Participants Who Developed a Lower Respiratory Tract Complication

Time: Up to Day 28

---

Secondary Outcomes

Description: Participants were considered to have an event if either condition is met: Participant develops a respiratory failure (of any cause) requiring mechanical ventilation (invasive or noninvasive) or; Participant dies prior to or on Day 28

Measure: Percentage of Participants Who Developed Respiratory Failure (of Any Cause) Requiring Mechanical Ventilation (Invasive or Noninvasive) or All-cause Mortality

Time: Up to Day 28

---

Primary Outcomes

Description: The time-weighted average change, often referred to as the DAVG, provides the average viral burden change from baseline. The mean values presented were calculated using the ANCOVA model and are adjusted for baseline value and stratification factors.

Measure: Time-weighted Average Change in Nasal Respiratory Syncytial Viral (RSV) Load From Baseline to Day 9

Time: Baseline to Day 9

---

Secondary Outcomes

Measure: Number of Supplemental O2-Free Days Through Day 28

Time: Up to Day 28

---

Measure: Percentage of Participants Developing Respiratory Failure Requiring Mechanical Ventilation Through Day 28

Time: Up to Day 28

---

Measure: Percentage of All-Cause Mortality Among Participants Through Day 28

Time: Up to Day 28

---

Primary Outcomes

Measure: Freedom from new or progressive chronic lung allograft dysfunction

Time: 180 days

---

Measure: Death

Time: 180 days

---

Secondary Outcomes

Measure: Respiratory virus symptom score

Time: 7 days

---

Measure: Acute rejection

Time: 180 days

---

Measure: Lymphocytic bronchiolitis

Time: 180 days

---

Measure: Donor-specific antibodies

Time: 180 days

---

Measure: Chronic lung allograft dysfunction

Time: 365 days

---

Primary Outcomes

Measure: Day 28 all causes mortality

Time: at day 28

---

Description: For the sub-group of patients included with COVID19, failure is defined as death or need of respiratory support (mechanical ventilation or high-flow oxygen therapy);

Measure: Day 21 failure

Time: at day 21

---

Secondary Outcomes

Measure: In patients non-invasively ventilated at inclusion, proportion of patients needing endotracheal intubation

Time: Participants will be followed for the duration of hospital stay, for a maximum of 28 days

---

Measure: In patients non-ventilated at inclusion, proportion of patients requiring non-invasive ventilation

Time: Participants will be followed for the duration of hospital stay, for a maximum of 28 days

---

Measure: In patients non-ventilated at inclusion, proportion of patients needing endotracheal intubation

Time: Participants will be followed for the duration of hospital stay, for a maximum of 28 days

---

Measure: Day 28 ventilator-free-days

Time: between 0 and day 28

---

Measure: Number of patients with vasopressor therapy initiation from inclusion to day 28

Time: between 0 and day 28

---

Measure: Day 28 vasopressor-free-days

Time: between 0 and day 28

---

Measure: ICU and/or intermediate care unit LOS

Time: Participants will be followed for the duration of hospital stay, for a maximum of 28 days

---

Measure: All-causes mortality at day 90

Time: at day 90

---

Measure: SF-36 Health Survey at day 90

Time: at day 90

---

Measure: Biomarkers: procalcitonin at baseline, day 3 and day 7

Time: at inclusion, day 3 and day 7

---

Measure: Biomarkers: C-reactive protein at baseline, day 3 and day 7

Time: at inclusion, day 3 and day 7

---

Measure: Biomarkers: plasmatic concentration of pro-inflammatory cytokines (IL-6, IL-20, IL-22, IL-22BP, HBD2, TNF) at baseline, day 3 and day 7

Time: at inclusion, day 3 and day 7

---

Measure: P/F ratio measured daily from baseline to day 7, at the end of treatment, at the end of ICU-stay and/or day 28

Time: measured daily from baseline to day 7, at the end of treatment i.e 14 days after the start of treatment, at the end of ICU-stay (for a maximum of 28 days) and/or day 28

---

Measure: SOFA calculated daily from baseline to day 7, at the end of treatment, at the end of ICU-stay and/or day 28

Time: calculated daily from baseline to day 7, at the end of treatment (i.e 14 days after the start of treatment), at the end of ICU-stay (for a maximum of 28 days) and/or day 28

---

Measure: Proportion of patients experiencing secondary infection during their ICU-stay

Time: Participants will be followed for the duration of hospital stay, for a maximum of 28 days

---

Measure: Proportion of patients experiencing gastrointestinal bleeding during their ICU-stay

Time: Participants will be followed for the duration of hospital stay, for a maximum of 28 days

---

Measure: Daily amount of insulin administered to the patient from day 1 to day 7

Time: Patients will be followed from day 1 to day 7

---

Measure: Weight-gain at baseline and day 7

Time: Patients will be followed at baseline and day 7

---

Other Outcomes

Description: Sub-group of patients included with COVID19

Measure: P/F ratio measured daily from Day1 to Day7, at Day 14 and at Day 21 and/or at the end of ICU-stay

Time: from day 1 to day 7, at day 14 and day 21 and/or at the end of ICU-stay

---

Description: Sub-group of patients included with COVID19

Measure: Proportion of patients needing endotracheal intubation

Time: at day 21

---

Description: Sub-group of patients included with COVID19

Measure: Proportion of patients experiencing secondary infection during their ICU-stay

Time: From baseline to day 21

---

Primary Outcomes

Description: Reduction in viral load in the URT(Upper Respiratory Tract), after challenge with rhinovirus, in relation to placebo

Measure: Reduction in viral load in the URT

Time: 7 days

---

Secondary Outcomes

Description: Reduction of number of days having a total symptom severity score of 6 or higher using a 5-graded Jackson scale, in relation to placebo.

Measure: Prevention of symptomatic URTI (Upper Respiratory Tract Infection)

Time: 11 days

---

Description: Asymptomatic URTI will be assessed by quantification of viral load at peak day (day with highest viral load measured by oropharyngeal swab).

Measure: Prevention of asymptomatic URTI.

Time: 11 days

---

Description: The number of days with cold is defined as the sum of all days with a total score of ≥ 6 according to the modified method of Jackson.

Measure: Fewer days with symptomatic URTI

Time: 11 days

---

Description: The number of days with asymptomatic URTI is defined as the sum of all days with a viral load significantly different from the baseline.

Measure: Fewer days with asymptomatic URTI.

Time: 11 days

---

Description: Nasal samples will be analysed for the quantity of IL-6 (Interleukin 6), IL-8 and IFNα (Interferon alpha).

Measure: Lower level of proinflammatory proteins

Time: 11 days

---

Measure: Lower daily total symptom score

Time: 11 days

---

Measure: Lower daily score of individual symptoms

Time: 11 days

---

Primary Outcomes

Measure: Time-Weighted Average Change in Viral Load From Day 1/Baseline Through Day 7 in Participants in the Full Analysis Set

Time: Up to 7 days

---

Measure: Time-Weighted Average Change in Viral Load From Day 1/Baseline Through Day 7 in a Subset of Participants in the Full Analysis Set Whose Duration of RSV Symptoms Prior to the First Dose of Study Drug is ≤ Median

Time: Up to 7 days

---

Secondary Outcomes

Description: The Flu-PRO is a patient-reported outcome questionnaire utilized as a standardized method for evaluating symptoms of influenza. Flu-PRO Score was calculated as the mean of 38 individual scores. Individual scores ranged from 0 (no symptoms) to 4 (worst symptoms) for the 5-point severity scale and 0 (never) to 4 or more times (always) for the 5-point frequency scale. The mean values presented were calculated using the ANCOVA model and are adjusted for baseline value and stratification factor.

Measure: Time-Weighted Average Change in FLU-PRO Score From Day 1/Baseline Through Day 7

Time: Up to 7 days

---

Description: FEV1 is defined as forced expiratory volume in the first second.

Measure: Percent Change From Study Baseline in FEV1% Predicted Value

Time: Baseline; Day 28

---

Primary Outcomes

Measure: 90-day mortality

Time: 90-day

---

Secondary Outcomes

Measure: Organ support-free days (e.g., supplemental O2, ventilator, extracorporeal membrane oxygenation (ECMO), renal replacement and vasopressors)

Time: 28 days

---

Measure: RT-PCR cycle threshold value in the lower respiratory samples

Time: At randomization and every 3 days afterwards, until 3 consecutive samples are negative or reaching a maximum of 90 days

---

Measure: Sequential organ failure assessment (SOFA) scores

Time: Days 1, 3, 5, 7, 14, and 28

---

Measure: Length of stay in ICU

Time: Up to one year from enrollment

---

Measure: Length of stay in hospital

Time: Up to one year from enrollment

---

Measure: Duration of mechanical ventilation

Time: Up to one year from enrollment

---

Description: Infections will be reported as per the NHSN 2016 definitions, as number of events per devise day or ICU day as appropriate.

Measure: Hospital-acquired infections as assessed by the NHSN 2016 definitions

Time: Up to one year from enrollment

---

Measure: Serial chest radiograph findings

Time: 28 day

---

Measure: Number of Patients with Adverse drug reactions related to the treatment

Time: From enrollment to 28 day

---

Measure: Karnofsky Performance Scale

Time: 90-day

---

Measure: ICU mortality

Time: Up to one year from enrollment

---

Measure: Hospital mortality

Time: Up to one year from enrollment

---

Measure: 28-day mortality

Time: 28-day

---

Primary Outcomes

Description: Based on patient diary data. Criteria of alleviation of all ARVI symptoms: oral temperature ≤37.5С for 24 hours (without subsequent increase within the observation period) + absence of ARVI symptoms /presence of ARVI symptoms with ≤3-point of the total score (TS) according to the 4-point scale (0 = no symptom; 1 = mild symptom; 2 = moderate symptom; 3 = severe symptom, for each flu-like nonspecific and respiratory symptom).

Measure: Time to Alleviation of All ARVI Symptoms.

Time: 14 days of observation.

---

Secondary Outcomes

Description: Based on patient diary data. Oral temperature ≤37.5С for 24 hours (without subsequent increase within the observation period).

Measure: Time to Normalization of Body Temperature.

Time: 14 days of observation.

---

Description: Based on patient diary data. Absence of flu-like nonspecific symptoms/presence of one mild flu-like nonspecific symptom.

Measure: Time to Alleviation of Flu-like Nonspecific Symptoms.

Time: 14 days of observation.

---

Description: Based on patient diary data. Absence of respiratory symptoms/presence of one mild respiratory symptom.

Measure: Time to Alleviation of Respiratory Symptoms.

Time: 14 days of observation.

---

Description: Based on patient diary data. The total score (TS) ranges from 0 to 30 consisting of 4 flu-like nonspecific (decreased activity/weakness, poor appetite/refusal to eat, sick appearance, sleep disturbance) and 6 respiratory (runny nose, stuffy nose/nasal congestion, sneezing, hoarseness, sore throat, cough) symptoms according to the 4-point scale for each symptom (0 = no symptom; 1 = mild symptom; 2 = moderate symptom; 3 = severe symptom). The higher values represent a worse outcome.

Measure: Flu-like Nonspecific and Respiratory Symptoms Total Score (TS) for Days 2-6.

Time: On days 2-6 of the observation period.

---

Description: Based on the area under the curve of TS for days 2-6, according to the patient diary. The total score (TS) will be calculated based on the severity of each ARVI symptom (sum of 11 symptoms = body temperature, flu-like nonspecific symptoms (4 symptoms) and respiratory symptoms (6 symptoms) according to the 4-point scale (0 = no symptom; 1 = mild symptom; 2 = moderate symptom; 3 = severe symptom). To calculate TS the absolute oral temperature values, measured in degrees Celsius, will be converted into relative units (or points), given the following gradations: ≤37.5С = 0 point; 37.6-38.1C = 1 point; 38.2-38.8C = 2 points; ≥38.90С = 3 points. For total score minimum and maximum scores are 0 and 33, where higher values represent worse outcome.

Measure: ARVI Severity.

Time: On days 2-6 of the observation period.

---

Description: Based on patient diary data. Criteria of recovery/alleviation of all ARVI symptoms: oral temperature ≤37.5С for 24 hours (without subsequent increase within the observation period) + absence of ARVI symptoms /presence of ARVI symptoms with ≤3-point of the total score (TS) according to the 4-point scale for each flu-like nonspecific and respiratory symptom (0 = no symptom; 1 = mild symptom; 2 = moderate symptom; 3 = severe symptom, for each flu-like nonspecific and respiratory symptom).

Measure: Percentage of Recovered Patients.

Time: On days 2-6 of the observation period.

---

Description: Based on patient diary data. The number of intakes of prescribed antipyretics.

Measure: Rates of Antipyretics Use Per Patient.

Time: On days 1- 5 of the treatment period.

---

Description: Based on patient diary data. The disease worsening: ARVI complications, including those requiring antibiotics; hospitalization).

Measure: Percentage of Patients With Worsening of Illness.

Time: 14 days of observation peiod.

---

Primary Outcomes

Measure: Changes from baseline in abbreviated physical examination

Time: Days 1-2

---

Measure: Changes from baseline in clinical safety laboratory values

Time: From Day 2 up to Day 121

---

Measure: Changes from baseline in Electrocardiogram (ECG) parameters

Time: 15 mins after infusion

---

Measure: Changes from baseline in Electrocardiogram (ECG) parameters

Time: 24 hrs after infusion

---

Measure: Changes from baseline in symptom-directed physical examination

Time: From Day 1 up to Day 121

---

Measure: Changes from baseline in vital signs

Time: From Day 1 up to Day 121

---

Measure: The incidence of Adverse Events

Time: From Day 1 up to Day 121

---

Measure: The incidence of treatment-emergent Serious Adverse Events

Time: From Day 1 up to Day 121

---

Measure: The severity of Adverse Events assessed by toxicity grading criteria

Time: From Day 1 up to Day 121

---

Measure: The severity of treatment-emergent Serious Adverse Events assessed by toxicity grading criteria

Time: From Day 1 up to Day 121

---

Measure: The type of treatment-emergent Serious Adverse Events

Time: From Day 1 up to Day 121

---

Secondary Outcomes

Measure: AUC for each dose of REGN3048 measured using validated Enzyme Linked Immunosorbent Assays (ELISAs)

Time: From Day 1 up to Day 121

---

Measure: AUC for each dose of REGN3051 measured using validated Enzyme Linked Immunosorbent Assays (ELISAs)

Time: From Day 1 up to Day 121

---

Measure: AUC(0-infinity) for each dose of REGN3048 measured using validated Enzyme Linked Immunosorbent Assays (ELISAs)

Time: From Day 1 up to Day 121

---

Measure: AUC(0-infinity) for each dose of REGN3051 measured using validated Enzyme Linked Immunosorbent Assays (ELISAs)

Time: From Day 1 up to Day 121

---

Measure: CL for each dose of REGN3048 measured using validated Enzyme Linked Immunosorbent Assays (ELISAs)

Time: From Day 1 up to Day 121

---

Measure: CL for each dose of REGN3051 measured using validated Enzyme Linked Immunosorbent Assays (ELISAs)

Time: From Day 1 up to Day 121

---

Measure: CMAX for each dose of REGN3048 measured using validated Enzyme Linked Immunosorbent Assays (ELISAs)

Time: From Day 1 up to Day 121

---

Measure: CMAX for each dose of REGN3051 measured using validated Enzyme Linked Immunosorbent Assays (ELISAs)

Time: From Day 1 up to Day 121

---

Measure: K(e) for each dose of REGN3048 measured using validated Enzyme Linked Immunosorbent Assays (ELISAs)

Time: From Day 1 up to Day 121

---

Measure: K(e) for each dose of REGN3051 measured using validated Enzyme Linked Immunosorbent Assays (ELISAs)

Time: From Day 1 up to Day 121

---

Measure: t(1/2) for each dose of REGN3048 measured using validated Enzyme Linked Immunosorbent Assays (ELISAs)

Time: From Day 1 up to Day 121

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Measure: t(1/2) for each dose of REGN3051 measured using validated Enzyme Linked Immunosorbent Assays (ELISAs)

Time: From Day 1 up to Day 121

---

Measure: The change from baseline of antibodies against REGN3048 and REGN3051 (anti-drug antibodies, ADA), as measured in serum using validated bridging assays

Time: Day 121

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Measure: The change from baseline of antibodies against REGN3048 and REGN3051 (anti-drug antibodies, ADA), as measured in serum using validated bridging assays

Time: Day 57

---

Measure: TMAX for each dose of REGN3048 measured using validated Enzyme Linked Immunosorbent Assays (ELISAs)

Time: From Day 1 up to Day 121

---

Measure: TMAX for each dose of REGN3051 measured using validated Enzyme Linked Immunosorbent Assays (ELISAs)

Time: From Day 1 up to Day 121

---

Measure: V(ss) for each dose of REGN3048 measured using validated Enzyme Linked Immunosorbent Assays (ELISAs)

Time: From Day 1 up to Day 121

---

Measure: V(ss) for each dose of REGN3051 measured using validated Enzyme Linked Immunosorbent Assays (ELISAs)

Time: From Day 1 up to Day 121

---

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

---

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

Time: by Day 21

---

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

---

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

Time: by Days 14, 21, 28 and 35

---

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

Time: through Day 35

---

Measure: Total number of inpatient days (main study)

Time: up to Day 35

---

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

Time: at Day 28

---

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

Time: at Day 35

---

Measure: All-cause mortality rate (main study)

Time: at Day 35

---

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

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

---

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

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

---

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

---

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

Measure: number of subjects with treatment emergent adverse events and serious adverse events

Time: absolute number through the end of the study, approximately 56 days

---

Measure: number of subjects with change in laboratory parameters

Time: absolute number and change from baseline through the end of the study, approximately 56 days

---

Measure: exposure of galidesivir as measured by plasma concentrations

Time: 24 hours post dose on Day 1 through 12 hours post dose on Day 7

---

Secondary Outcomes

Measure: yellow fever virus (YFV) titer (Group A)

Time: change in YFV titer from baseline through Day 21

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Measure: antiviral effect on SARS-CoV-2 in the respiratory tract - COVID-19 (Group B)

Time: change in SARS-CoV-2 from baseline through Day 21

---

Measure: changes in clinical status using 8-point ordinal scale in COVID-19 (Group B)

Time: through Day 21

---

Measure: changes from baseline and time to improvement using NEWS in COVID-19 (Group B)

Time: through Day21

---

Measure: mortality

Time: mortality at Day 56

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Primary Outcomes

Description: The proportion of participants who develop RSV LRTI through Visit Day 28 per the Endpoint Adjudication Committee (EAC) assessment will be reported.

Measure: Proportion of Participants who Develop Respiratory Syncytial Virus (RSV) Lower Respiratory Tract Infection (LRTI)

Time: Up to Day 28

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Secondary Outcomes

Description: The proportion of participants who develop RSV-associated LRTC through Visit Day 28 per the EAC's assessment will be reported.

Measure: Proportion of Participants who Develop RSV-associated Lower Respiratory Tract Complication (LRTC)

Time: Up to Day 28

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Description: An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship.

Measure: Number of Participants with Adverse Events (AEs)

Time: Up to 49 Days

---

Description: Percentage of participants with abnormal clinical laboratory findings will be reported.

Measure: Percentage of Participants with Abnormal Clinical Laboratory Findings

Time: Up to 49 days

---

Description: Percentage of participants with abnormal ECGs findings will be reported.

Measure: Percentage of Participants with Abnormal Electrocardiograms (ECGs) Findings

Time: Up to 49 days

---

Description: Percentage of participants with abnormal vital signs findings will be reported.

Measure: Percentage of Participants with Abnormal Vital Signs Findings

Time: Up to 49 days

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Description: The proportion of participants progressing to respiratory failure (of any cause) requiring mechanical ventilation (invasive or noninvasive) and/or death, in participants who develop RSV LRTI or RSV-associated LRTC per the EAC's assessment will be reported.

Measure: Proportion of Participants Progressing to Respiratory Failure (of any Cause) Requiring Mechanical Ventilation (Invasive or Noninvasive) and/or Death, in Participants who Develop RSV LRTI or RSV-associated LRTC per the EAC's Assessment

Time: Up to 49 days

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Description: Proportion of participants progressing to respiratory failure (of any cause) requiring mechanical ventilation (invasive or noninvasive) and/or death, (all-cause mortality) will be reported.

Measure: Proportion of Participants Progressing to Respiratory Failure (of any Cause) Requiring Mechanical Ventilation (Invasive or Noninvasive) and/or Death, (all-cause Mortality)

Time: Up to 49 days

---

Description: Proportion of participants progressing to death (all-cause mortality), in participants who develop RSV LRTI or RSV-associated LRTC per the EAC's assessment will be reported.

Measure: Proportion of Participants Progressing to Death (All-cause Mortality), in Participants who Develop RSV LRTI or RSV-associated LRTC per the EAC's Assessment

Time: Up to 49 days

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Description: Proportion of participants progressing to death (all-cause mortality) will be reported.

Measure: Proportion of Participants Progressing to Death (All-cause Mortality)

Time: Up to 49 days

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Description: Proportion of participants progressing to respiratory failure (of any cause) requiring mechanical ventilation (invasive or noninvasive), in participants who develop RSV LRTI or RSV-associated LRTC per the EAC's assessment will be reported.

Measure: Proportion of Participants Progressing to Respiratory Failure (of any Cause) Requiring Mechanical Ventilation (Invasive or Noninvasive), in Participants who Develop RSV LRTI or RSV-associated LRTC per the EAC's Assessment

Time: Up to 49 days

---

Description: Proportion of participants progressing to respiratory failure (of any cause) requiring mechanical ventilation (invasive or noninvasive) will be reported.

Measure: Proportion of Participants Progressing to Respiratory Failure (of any Cause) Requiring Mechanical Ventilation (Invasive or Noninvasive)

Time: Up to 49 days

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Description: Number of supplemental O2 free days will be reported.

Measure: Number of Supplemental Oxygen (O2) Free Days Through Day 28

Time: Through Day 28

---

Description: Incidence of supplemental oxygen requirement in participants will be reported.

Measure: Incidence of Supplemental Oxygen Requirement

Time: Up to 28 days

---

Description: Duration of supplemental oxygen requirement in participants will be reported.

Measure: Duration of Supplemental Oxygen

Time: Up to 28 days

---

Description: Change from baseline in respiratory rate as measured by the investigator during scheduled visits will be reported.

Measure: Change from Baseline in Respiratory Rate

Time: Baseline up to 49 days

---

Description: Change from baseline in heart rate as measured by the investigator during scheduled visits will be reported.

Measure: Change from Baseline in Heart Rate

Time: Baseline up to 49 days

---

Description: Change from baseline in SpO2 as measured by the investigator during scheduled visits will be reported.

Measure: Change from Baseline in Peripheral Capillary Oxygen Saturation (SpO2)

Time: Baseline up to 49 days

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Description: Change from baseline in body temperature as measured by the investigator during scheduled visits will be reported.

Measure: Change from Baseline in Body Temperature

Time: Baseline up to 49 days

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Description: Proportion of participants hospitalized (of participants who were not hospitalized at baseline) will be reported.

Measure: Proportion of Participants Hospitalized (of Participants who Were not Hospitalized at Baseline)

Time: Up to 49 days

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Description: Proportion of participants re-hospitalized (of participants who were hospitalized at baseline and discharged during the study and of participants who were not hospitalized at baseline, required hospitalization, and were discharged during the study) will be reported.

Measure: Proportion of Participants Re-hospitalized

Time: Up to 49 days

---

Description: Total length of hospital stay (time in hospital from first dosing) will be reported.

Measure: Total Length of Hospital Stay

Time: Up to 49 days

---

Description: Total time in the ICU (time in ICU from first dosing) will be reported.

Measure: Total Time in the Intensive Care Unit (ICU)

Time: Up to 49 days

---

Description: Incidence of Grade 3 and Grade 4 AEs will be assessed by system organ class where Grade 3: Severe and Grade 4: Life-threatening.

Measure: Incidence of Grade 3 and Grade 4 Adverse Events (AEs)

Time: Up to 49 days

---

Description: Incidence of respiratory AEs will be reported.

Measure: Incidence of Respiratory AEs

Time: Up to 49 days

---

Description: Incidence of thoracic-related AEs will be reported.

Measure: Incidence of Thoracic-related AEs

Time: Up to 49 days

---

Description: Incidence of antibiotic use in participants who develop and in those who do not develop RSV LRTI or RSV-associated LRTC per the EAC's assessment will be reported.

Measure: Incidence of Antibiotic use in Participants who Develop and in Those who do not Develop RSV LRTI or RSV-Associated LRTC per the EAC's Assessment

Time: Up to 49 days

---

Description: Time to resolution of symptoms, assessed through an instrument for participant-reported symptoms (RiiQ Symptom Scale) will be reported.

Measure: Time to Resolution of Symptoms as Assessed by Respiratory Infection Intensity and Impact Questionnaire (RiiQ) Symptom Scale

Time: Up to 49 days

---

Description: Change from baseline in severity of symptoms reported by participants in the RiiQ symptom scale through Day 28 will be reported.

Measure: Change from Baseline in Severity of Symptoms Reported by Participants in the RiiQ Symptom Scale Through Day 28

Time: Baseline up to Day 28

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Description: Time to resolution of respiratory illness, through the PGI-S Scale, will be reported.

Measure: Time to Resolution of Respiratory Illness as Assessed by Patient Global Impression of Severity (PGI-S) Scale

Time: Up to 49 days

---

Description: Change from baseline in PGI-H scale through Day 28 will be reported.

Measure: Change from Baseline in Patient Global Impression of Health (PGI-H) Scale Through Day 28

Time: Baseline up to Day 28

---

Description: Change from baseline in PGI-C scale through Day 28 will be reported.

Measure: Change from Baseline in Patient Global Impression of Change (PGI-C) Scale Through Day 28

Time: Baseline up to Day 28

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Description: AUC (0-24h) is defined as area under the plasma concentration-time curve from time 0 to 24 hours postdose.

Measure: Area Under the Plasma Concentration-time Curve from Time Zero to 24 Hours Postdose (AUC [0-24]) of JNJ-53718678

Time: Up to 24 hours postdose (on Days 1 and 8)

---

Description: Ctrough is defined as the observed plasma concentration before dosing or at the end of the dosing interval.

Measure: Trough Plasma Concentration (Ctrough) of JNJ-53718678

Time: Predose on Days 1 and 8

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Description: Cmax is defined as the maximum observed plasma concentration of JNJ-53718678 in the dosing interval.

Measure: Maximum Observed Plasma Concentration (Cmax) of JNJ-53718678

Time: Predose; 0.5, 1, 1.5, 2, 4, 8, 24 hours postdose (on Days 1 and 8)

---

Description: The potential association of plasma concentration-time data of JNJ-53718678 with antiviral activity (RSV viral kinetics) will be analyzed. Association will be analyzed using (non)-linear mixed-effects models in a tabular and/or graphical display.

Measure: Association of Plasma Concentration-time Data of JNJ-53718678 and Antiviral Activity

Time: Up to 49 days

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Description: The potential association of plasma concentration-time data of JNJ-53718678 with selected safety (including AEs and laboratory abnormalities) parameters will be analyzed. Association will be analyzed using (non)-linear mixed-effects models in a tabular and/or graphical display.

Measure: Association of Plasma Concentration-time Data of JNJ-53718678 and Safety Parameters

Time: Up to 49 days

---

Description: The potential association of plasma concentration-time data of JNJ-53718678 with clinical outcomes (proportion of participants developing LRTI) will be analyzed. Association will be analyzed using (non)-linear mixed-effects models in a tabular and/or graphical display.

Measure: Association of Plasma Concentration-time Data of JNJ-53718678 and Clinical Outcomes

Time: Up to 49 days

---

Description: RSV viral load and change from baseline over time will be measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay in the mid-turbinate nasal swab specimens.

Measure: RSV Viral Load and Change from Baseline Over Time

Time: Baseline up to Day 28

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Description: RSV viral load AUC will be determined by quantitative qRT-PCR assay of nasal swabs.

Measure: RSV Viral Load AUC from Immediately Prior to First Dose of Study Drug (Baseline) Through Days 8, 11, 15, 22 and 28

Time: Baseline up to Days 8, 11, 15, 22 and 28

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Description: Time to undetectable RSV viral load (per the detection limit of the assay used in the study) will be reported.

Measure: Time to Undetectable RSV Viral Load

Time: Up to 49 days

---

Description: Proportion of participants with undetectable RSV viral load at each time point throughout the study will be reported.

Measure: Proportion of Participants with Undetectable RSV Viral Load at Each Timepoint

Time: Up to 49 days

---

Description: Change from baseline for the HRQOL assessment as assessed through the EQ-5D-5L through Day 28 will be reported.

Measure: Change from Baseline for the Health-related Quality of Life (HRQOL) as Assessed by 5-level EuroQol 5-Dimension (EQ-5D-5L) Through Day 28

Time: Baseline up to Day 28

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Description: Change from baseline for the HRQOL assessment as assessed through RiiQ impact scales through Day 28 will be reported.

Measure: Change from Baseline for the HRQOL as Assessed by RiiQ Impact Scales Through Day 28

Time: Baseline up to Day 28

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Description: Change from baseline in the RSV F gene sequence will be reported.

Measure: Change from Baseline in the RSV F Gene Sequence

Time: Baseline up to 49 days

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Primary Outcomes

Description: Safety and reactogenicity will be assesssed by observation, questionaire and diary. Changes from baseline for safety laboratory measures will be monitored. Occurence of SAE will be collected throughout the entire study duration.

Measure: Frequency of adverse events associated with MVA-MERS-S_DF-1.

Time: day 1, 14, 29, 42, 56, 84, 168, 336, 364

---

Measure: Frequency and severity of local injection site reactogenicity signs and symptoms

Time: day 1, 14, 29, 42, 84, 336

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Secondary Outcomes

Description: Magnitude of MERS-S-specific antibody re-sponses (ELISA and neutralization assays) monitored in a centralized approved laboratory

Measure: Immunogenicity

Time: day 0, 14, 28, 42, 56, 70, 84, 168, 336, 364 (dependent on vaccination scheme)

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Primary Outcomes

Description: Evaluation of Pneumonia Improvement

Measure: Pneumonia severity index

Time: From Baseline (0W) to 12 week after treatment

---

Description: Evaluation of Pneumonia Improvement

Measure: Oxygenation index (PaO2/FiO2)

Time: From Baseline (0W) to 12 week after treatment

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Secondary Outcomes

Description: Incidence of acute and chronic treatment-related adverse events in patients with novel coronavirus severe pneumonia receiving UC-MSCs infusion as assessed.

Measure: Side effects in the UC-MSCs treatment group

Time: From Baseline (0W) to 96 week after treatment

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Description: Marker for efficacy of treatment

Measure: 28-days survival

Time: Day 28

---

Description: Markers of organ function（Score each criterion on a scale of 0 to 4, and the higher the score, the worse the prognosis.）

Measure: Sequential organ failure assessment

Time: Day 28

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Description: Markers of Infection

Measure: C-reactive protein

Time: From Baseline (0W) to 12 week after treatment

---

Description: Markers of Infection

Measure: Procalcitonin

Time: From Baseline (0W) to 12 week after treatment

---

Description: Marker of Immunological function

Measure: Lymphocyte count

Time: From Baseline (0W) to 12 week after treatment

---

Description: Marker of Immunological function

Measure: CD3+, CD4+ and CD8+ T celll count

Time: From Baseline (0W) to 12 week after treatment

---

Description: Marker of Immunological function

Measure: CD4+/CD8+ratio

Time: From Baseline (0W) to 12 week after treatment

---

Primary Outcomes

Description: Day of recovery is defined as the first day on which the subject satisfies one of the following three categories from the ordinal scale: 1) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 3) Not hospitalized, no limitations on activities.

Measure: Time to recovery

Time: Day 1 through Day 29

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Secondary Outcomes

Measure: Change from baseline in alanine transaminase (ALT)

Time: Day 1 through Day 29

---

Measure: Change from baseline in aspartate transaminase (AST)

Time: Day 1 through Day 29

---

Measure: Change from baseline in creatinine

Time: Day 1 through Day 29

---

Measure: Change from baseline in glucose

Time: Day 1 through Day 29

---

Measure: Change from baseline in hemoglobin

Time: Day 1 through Day 29

---

Measure: Change from baseline in platelets

Time: Day 1 through Day 29

---

Measure: Change from baseline in prothrombin time (PT)

Time: Day 1 through Day 29

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Measure: Change from baseline in total bilirubin

Time: Day 1 through Day 29

---

Measure: Change from baseline in white blood cell count (WBC) with differential

Time: Day 1 through Day 29

---

Description: The NEW score has demonstrated an ability to discriminate patients at risk of poor outcomes. This score is based on 7 clinical parameters (respiration rate, oxygen saturation, any supplemental oxygen, temperature, systolic blood pressure, heart rate, level of consciousness). The NEW Score is being used as an efficacy measure.

Measure: Change in National Early Warning Score (NEWS) from baseline

Time: Day 1 through Day 29

---

Description: The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7) Not hospitalized, limitation on activities and/or requiring home oxygen; 8) Not hospitalized, no limitations on activities.

Measure: Clinical status using ordinal scale

Time: Day 3 through Day 29

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Description: Grade 3 AEs are defined as events that interrupt usual activities of daily living, or significantly affects clinical status, or may require intensive therapeutic intervention. Severe events are usually incapacitating. Grade 4 AEs are defined as events that are potentially life threatening.

Measure: Cumulative incidence of Grade 3 and 4 clinical and/or laboratory adverse events (AEs)

Time: Day 1 through Day 29

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Description: An SAE is defined as an AE or suspected adverse reaction is considered serious if, in the view of either the investigator or the sponsor, it results in death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect.

Measure: Cumulative incidence of serious adverse events (SAEs)

Time: Day 1 through Day 29

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Description: For any reason.

Measure: Discontinuation or temporary suspension of investigational therapeutics

Time: Day 1 through Day 10

---

Description: Measured in days.

Measure: Duration of hospitalization

Time: Day 1 through Day 29

---

Description: Measured in days.

Measure: Duration of new non-invasive ventilation or high flow oxygen use

Time: Day 1 through Day 29

---

Description: Measured in days.

Measure: Duration of new oxygen use

Time: Day 1 through Day 29

---

Description: Measured in days.

Measure: Duration of new ventilator or extracorporeal membrane oxygenation (ECMO) use

Time: Day 1 through Day 29

---

Measure: Incidence of new non-invasive ventilation or high flow oxygen use

Time: Day 1 through Day 29

---

Measure: Incidence of new oxygen use

Time: Day 1 through Day 29

---

Measure: Incidence of new ventilator or extracorporeal membrane oxygenation (ECMO) use

Time: Day 1 through Day 29

---

Description: The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7) Not hospitalized, limitation on activities and/or requiring home oxygen; 8) Not hospitalized, no limitations on activities.

Measure: Mean change in the ordinal scale

Time: Day 1 through Day 29

---

Description: The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7) Not hospitalized, limitation on activities and/or requiring home oxygen; 8) Not hospitalized, no limitations on activities.

Measure: Percentage of subjects reporting each severity rating on an 8-point ordinal scale

Time: Day 15

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Description: Date and cause of death (if applicable).

Measure: Subject 14-day mortality

Time: Day 1 through Day 15

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Description: Date and cause of death (if applicable).

Measure: Subject 29-day mortality

Time: Day 1 through Day 29

---

Description: The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7) Not hospitalized, limitation on activities and/or requiring home oxygen; 8) Not hospitalized, no limitations on activities.

Measure: Time to an improvement of one category using an ordinal scale

Time: Day 1 through Day 29

---

Description: The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7) Not hospitalized, limitation on activities and/or requiring home oxygen; 8) Not hospitalized, no limitations on activities.

Measure: Time to an improvement of two categories using an ordinal scale

Time: Day 1 through Day 29

---

Description: The NEW score has demonstrated an ability to discriminate patients at risk of poor outcomes. This score is based on 7 clinical parameters (respiration rate, oxygen saturation, any supplemental oxygen, temperature, systolic blood pressure, heart rate, level of consciousness). The NEW Score is being used as an efficacy measure.

Measure: Time to discharge or to a National Early Warning Score (NEWS) of Time: Day 1 through Day 29

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Primary Outcomes

Description: Evaluation of Pneumonia change

Measure: Size of lesion area by chest imaging

Time: At baseline, Day 1, Week 1, Week 2, Week 4, Week 8

---

Description: Evaluation of Pneumonia change

Measure: Blood oxygen saturation

Time: At baseline, Day 1, Week 1, Week 2, Week 4, Week 8

---

Secondary Outcomes

Description: Marker for efficacy of treatment

Measure: Rate of mortality within 28-days

Time: At baseline, Day 1, Week 1, Week 2, Week 4, Week 8

---

Description: 0-4 score, the higher the score is, the poor of the prognosis will be.

Measure: Sequential organ failure assessment

Time: At baseline, Day 1, Week 1, Week 2, Week 4, Week 8

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Description: Number of participants with treatment-related adverse events

Measure: Side effects in the UC-MSCs treatment group

Time: At baseline, Day 1, Week 1, Week 2, Week 4, Week 8

---

Description: Markers of the heart function

Measure: Electrocardiogram, the changes of ST-T interval mostly

Time: At baseline, Day 1, Week 1, Week 2, Week 4, Week 8

---

Description: Markers of infection

Measure: Concentration of C-reactive protein C-reactive protein, immunoglobulin

Time: At baseline, Day 1, Week 1, Week 2, Week 4, Week 8

---

Description: Marker of Immunology and inflammation

Measure: CD4+ and CD8+ T cells count

Time: At baseline, Day 1, Week 1, Week 2, Week 4, Week 8

---

Description: Marker of Immunology and inflammation

Measure: Concentration of the blood cytokine (IL-1β, IL-6, IL-8,IL-10,TNF-α)

Time: At baseline, Day 1, Week 1, Week 2, Week 4, Week 8

---

Description: Markers of the heart function

Measure: Concentration of the myocardial enzymes

Time: At baseline, Day 1, Week 1, Week 2, Week 4, Week 8

---

Primary Outcomes

Description: Percent of subjects who have returned to room air

Measure: Percent of subjects who have returned to room air

Time: 7 days

---

Description: Percent change of subjects return to baseline oxygen requirement by Day 7 compared to Day 1

Measure: Percent change of subjects return to baseline oxygen requirement

Time: 7 days

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Primary Outcomes

Description: Number of symptomatic COVID-19 infections will be compared between the chloroquine or hydroxychloroquine and placebo groups

Measure: Number of symptomatic COVID-19 infections

Time: Approximately 90 days

---

Secondary Outcomes

Description: Symptoms severity of COVID-19 will be compared between the two groups using a respiratory severity score.

Measure: Symptoms severity of COVID-19

Time: Approximately 90 days

---

Description: Number of asymptomatic cases of COVID-19 will be determined by comparing serology in all participants at time of enrolment and at the end of follow up.

Measure: Number of asymptomatic cases of COVID-19

Time: Approximately 90 days

---

Description: Number of symptomatic acute respiratory illnesses will be compared between the chloroquine or hydroxychloroquine and placebo groups.

Measure: Number of symptomatic acute respiratory illnesses

Time: Approximately 90 days

---

Description: Severity of symptomatic acute respiratory illnesses will be compared between the chloroquine or hydroxychloroquine and placebo groups.

Measure: Severity of symptomatic acute respiratory illnesses

Time: Approximately 90 days

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Other Outcomes

Description: Genetic loci and levels of biochemical components will be correlated with frequency of COVID-19, Acute Respiratory Infection and disease severity.

Measure: Genetic loci and levels of biochemical components will be correlated with frequency of COVID-19, ARI and disease severity.

Time: Approximately 90 days

---

Description: Number of days lost to work in relation to the treatment arm

Measure: Assess the impact of chloroquine or hydroxychloroquine prophylaxis on number of days lost to work during the pandemic.

Time: Approximately 90 days

---

Description: The trial will collect data on monetary costs associated with the use of healthcare resources and determine the effects between treatment groups.

Measure: Assess the impact of chloroquine or hydroxychloroquine prophylaxis on healthcare costs

Time: Approximately 90 days

---

Description: The trial will collect data on health-related quality of life using the quality of life questionnaire (EQ-5D-3L) to determine the effects between treatment groups.

Measure: Assess the impact of chloroquine or hydroxychloroquine prophylaxis on quality of life measures using the quality of life questionnaire (EQ-5D-3L)

Time: Approximately 90 days

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Primary Outcomes

Description: Number of participants at 14 days post enrollment with active COVID19 disease.

Measure: Incidence of COVID19 Disease among those who are asymptomatic at baseline

Time: 14 days

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Description: Repeated Measure mixed regression model of change in: Visual Analog Scale 0-10 score of rating overall symptom severity (0 = no symptoms; 10 = most severe)

Measure: Overall change in disease severity over 14 days among those who are symptomatic at baseline

Time: 14 days

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Secondary Outcomes

Description: Outcome reported as the number of participants in each arm who require hospitalization for COVID19-related disease.

Measure: Incidence of Hospitalization

Time: 14 days

---

Description: Outcome reported as the number of participants in each arm who expire due to COVID-19-related disease.

Measure: Incidence of Death

Time: 90 days

---

Description: Outcome reported as the number of participants in each arm who have confirmed SARS-CoV-2 infection.

Measure: Incidence of Confirmed SARS-CoV-2 Detection

Time: 14 days

---

Description: Outcome reported as the number of participants in each arm who self-report symptoms compatible with COVID19 infection.

Measure: Incidence of Symptoms Compatible with COVID19 (possible disease)

Time: 90 days

---

Description: Outcome reported as the number of participants in each arm who discontinue or withdraw medication use for any reason.

Measure: Incidence of All-Cause Study Medicine Discontinuation or Withdrawal

Time: 14 days

---

Description: Visual Analog Scale 0-10 score of rating overall symptom severity (0 = no symptoms; 10 = most severe)

Measure: Overall symptom severity at 5 and 14 days

Time: 5 and 14 days

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Description: Participants will self-report disease severity status as one of the following 3 options; no COVID19 illness (score of 1), COVID19 illness with no hospitalization (score of 2), or COVID19 illness with hospitalization or death (score of 3). Increased scale score indicates greater disease severity. Outcome is reported as the percent of participants who fall into each category per arm.

Measure: Ordinal Scale of COVID19 Disease Severity at 14 days among those who are symptomatic at trial entry

Time: 14 days

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Primary Outcomes

Description: Outcome reported as the number of participants per arm admitted to inpatient hospital care due to COVID-19-related disease within 15 days of randomization. Currently, there is a pre-planned pooled analysis with a national trial network under development.

Measure: Hospital Admission

Time: 15 days

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Secondary Outcomes

Description: The PROMIS Dyspnea (shortness of breath) item banks and pools assess self-reported Functional Limitations, Severity, Activity Motivation, Activity Requirements, Airborne Exposure, Assistant Devices Resources, Characteristics, Emotional Response, Task Avoidance and Time Extension as they related to dyspnea. In the 33-item Functional Limitations bank, 33 daily activities are rated in terms of degree of difficulty while engaging in the activity over the past 7 days (0 = no difficulty, 1 = a little difficulty, 2 = some difficulty, 3 = much difficulty). Total scores range from 0 to 99, with higher scores reflecting greater functional limitations.

Measure: Change in PROMIS Dyspnea Functional Limitations

Time: baseline, 10 days

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Description: The PROMIS Dyspnea (shortness of breath) item banks and pools assess self-reported Functional Limitations, Severity, Activity Motivation, Activity Requirements, Airborne Exposure, Assistant Devices Resources, Characteristics, Emotional Response, Task Avoidance and Time Extension as they related to dyspnea. The 33-item Severity bank assesses the severity of difficulty breathing during various specific activities (the same 33 activities assessed in Dyspnea Functional Limitations). Each activity is rated in terms of degree of dyspnea (0 = no shortness of breath, 1 = mildly short of breath, 2 = moderately short of breath, 3 = severely short of breath) while engaging in the activity over the past 7 days. Total scores range from 0 to 99 with higher scores reflecting greater levels of dyspnea during daily activity.

Measure: Change in PROMIS Dyspnea Severity

Time: baseline, 10 days

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Description: Participants will report their maximum daily oral temperature to the study team. Outcome is reported as the mean maximum daily body temperature (in degrees Celsius) over 10 days.

Measure: Daily Maximum Temperature

Time: 10 days

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Description: Outcome is reported as the mean number of emergency department and clinic presentations combined per participant in each arm.

Measure: Emergency Department/Clinic Presentations

Time: 28 days

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Description: Outcome reported as the number of participants in each arm who fall into each of 7 categories. Lower scores indicate greater condition severity. The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen; 6) Not hospitalized, limitation on activities; 7) Not hospitalized, no limitations on activities.

Measure: Disease Severity Rating Day 7

Time: 7 days

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Description: Outcome reported as the number of participants in each arm who fall into each of 7 categories. Lower scores indicate greater condition severity. The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen; 6) Not hospitalized, limitation on activities; 7) Not hospitalized, no limitations on activities.

Measure: Disease Severity Rating Day 15

Time: 15 days

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Description: Outcome reported as the number of participants in each arm who fall into each of 7 categories. Lower scores indicate greater condition severity. The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen; 6) Not hospitalized, limitation on activities; 7) Not hospitalized, no limitations on activities.

Measure: Disease Severity Rating Day 28

Time: 28 days

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Description: Participants will collect oropharyngeal swabs every third day for the duration of study participation. Viral load is measured as number of viral genetic copies per mL.

Measure: Viral Load by Oropharyngeal Swab Day 9

Time: 9 days

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Description: Participants will collect oropharyngeal swabs every third day for the duration of study participation. Viral load is measured as number of viral genetic copies per mL.

Measure: Viral Load by Oropharyngeal Swab Day 15

Time: 15 days

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Description: Outcome reported as the mean number of days participants in each arm did not require ventilator use.

Measure: Ventilator-Free Days

Time: 28 days

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Description: Outcome reported as the mean number of days participants in each arm did not require therapeutic oxygen use.

Measure: Therapeutic Oxygen-Free Days

Time: 28 days

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Description: Outcome reported as the percent of participants in each arm who require hospital admission by day 15 following randomization.

Measure: Need for Hospital Admission at 15 Days

Time: 15 days

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Description: Outcome reported as the percent of participants in each arm who require oxygen therapy by day 15 following randomization.

Measure: Need for Oxygen Therapy at 15 Days

Time: 15 days

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Primary Outcomes

Description: Outcome calculated from the partial pressure of oxygen or peripheral saturation of oxygen by pulse oximetry divided by the fraction of inspired oxygen (PaO2 or SaO2 : FiO2 ratio). PaO2 is preferentially used if available. A correction is applied for endotracheal intubation and/or positive end-expiratory pressure. Patients discharged prior to day 7 will have a home pulse oximeter send home for measurement of the day 7 value, and will be adjusted for home O2 use, if applicable. Patients who died will be applied a penalty with a P/F ratio of 0.

Measure: Difference in Estimated (PEEP adjusted) P/F Ratio at 7 days

Time: 7 days

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Secondary Outcomes

Description: Outcome reported as the mean number of daily hypotensive episodes (MAP < 65 mmHg) prompting intervention (indicated by a fluid bolus >=500 mL) per participant in each arm.

Measure: Daily Hypotensive Episodes

Time: 10 days

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Description: Outcome reported as the number of participants in each arm requiring the use of vasopressors for hypotension.

Measure: Hypotension Requiring Vasopressors

Time: 10 days

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Description: Outcome reported as the number of participants in each arm who experience acute kidney injury as defined by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines: Increase in serum creatinine by 0.3mg/dL or more within 48 hours OR Increase in serum creatinine to 1.5 times baseline or more within the last 7 days OR Urine output less than 0.5 mL/kg/h for 6 hours.

Measure: Acute Kidney Injury

Time: 10 days

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Description: The SOFA assessment is used to track a person's risk status during stay in the Intensive Care Unit (ICU). The score is based on six different scores, one each for the respiratory, cardiovascular, hepatic, coagulation, renal, and neurological systems. Each organ system is assigned a point value from 0 (normal) to 4 (high degree of dysfunction/failure). Total score is calculated by entering patient data into a SOFA calculator, a widely-available software. Total scores range from 0-24, with higher scores indicating greater chance of mortality.

Measure: Sequential Organ Failure Assessment (SOFA) Total Score

Time: 10 days

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Description: Oxygen saturation (percent) is measured by pulse oximeter. Fraction of inspired oxygen (FiO2) (unitless) is the volumetric fraction of oxygen to other gases in respiratory support. The F/S ratio is unitless.

Measure: Oxygen Saturation / Fractional Inhaled Oxygen (F/S)

Time: 10 days

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Description: Outcome reported as the number of participants who have expired at 28 days post enrollment.

Measure: 28-Day Mortality

Time: 28 days

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Description: Outcome reported as the number of participants who have expired at 90 days post enrollment.

Measure: 90-Day Mortality

Time: 90 days

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Description: Outcome reported as the number of participants in each arm who require admission to the Intensive Care Unit (ICU).

Measure: ICU Admission

Time: 10 days

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Description: Outcome reported as the mean number of days participants in each arm did not require mechanical ventilation during an in-patient hospital admission.

Measure: Number of Ventilator-Free Days

Time: 10 days

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Description: Outcome reported as the mean number of days participants in each arm did not require therapeutic oxygen usage during an in-patient hospital admission.

Measure: Number of Therapeutic Oxygen-Free Days

Time: 10 days

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Description: Outcome reported as the mean number of days participants in each arm did not require vasopressor usage during an in-patient hospital admission.

Measure: Number of Vasopressor-Free Days

Time: 10 days

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Description: Outcome reported as the mean length of stay (in days) in the Intensive Care Unit (ICU) for participants in each arm.

Measure: Length of ICU Stay

Time: 10 days

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Description: Outcome reported as the mean length of in-patient hospital stay (in days) for participants in each arm.

Measure: Length of Hospital Stay

Time: 10 days

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Description: Outcome reported as the number of participants requiring BiPAP OR high flow nasal cannula OR mechanical ventilation OR extracorporeal membranous oxygenation (ECMO) utilization during in-patient hospital care in each arm.

Measure: Incidence of Respiratory Failure

Time: 10 days

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Description: The PROMIS Dyspnea (shortness of breath) item banks and pools assess self-reported Functional Limitations, Severity, Activity Motivation, Activity Requirements, Airborne Exposure, Assistant Devices Resources, Characteristics, Emotional Response, Task Avoidance and Time Extension as they related to dyspnea. In the 33-item Functional Limitations bank, 33 daily activities are rated in terms of degree of difficulty while engaging in the activity over the past 7 days (0 = no difficulty, 1 = a little difficulty, 2 = some difficulty, 3 = much difficulty). Total scores range from 0 to 99, with higher scores reflecting greater functional limitations.

Measure: Change in PROMIS Dyspnea Functional Limitations

Time: 10 days

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Description: The PROMIS Dyspnea (shortness of breath) item banks and pools assess self-reported Functional Limitations, Severity, Activity Motivation, Activity Requirements, Airborne Exposure, Assistant Devices Resources, Characteristics, Emotional Response, Task Avoidance and Time Extension as they related to dyspnea. The 33-item Severity bank assesses the severity of difficulty breathing during various specific activities (the same 33 activities assessed in Dyspnea Functional Limitations). Each activity is rated in terms of degree of dyspnea (0 = no shortness of breath, 1 = mildly short of breath, 2 = moderately short of breath, 3 = severely short of breath) while engaging in the activity over the past 7 days. Total scores range from 0 to 99 with higher scores reflecting greater levels of dyspnea during daily activity.

Measure: Change in PROMIS Dyspnea Severity

Time: 10 days

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Description: Outcome reported as the number of participants in each arm who fall into each of 7 categories. Lower scores indicate greater condition severity. The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen; 6) Not hospitalized, limitation on activities; 7) Not hospitalized, no limitations on activities.

Measure: Disease Severity Rating

Time: 10 days

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Description: Nasopharyngeal swabs will be collected every third day for the duration of study participation. Viral load is measured as number of viral genetic copies per mL.

Measure: Viral Load by Nasopharyngeal Swab Day 9

Time: 9 days

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Description: Nasopharyngeal swabs will be collected every third day for the duration of study participation. Viral load is measured as number of viral genetic copies per mL.

Measure: Viral Load by Nasopharyngeal Swab Day 15

Time: 15 days

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Description: Blood will be collected every third day for viral load assessment for the duration of study participation. Viral load is measured as number of viral genetic copies per mL.

Measure: Viral Load by Blood Day 9

Time: 9 days

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Description: Blood will be collected every third day for viral load assessment for the duration of study participation. Viral load is measured as number of viral genetic copies per mL.

Measure: Viral Load by Blood Day 15

Time: 15 days

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Primary Outcomes

Description: To determine the efficacy of PUL-042 Inhalation Solution in decreasing the severity of COVID-19 in subjects: 1) who have documented SARS-CoV-2 infection and, 2) who do not require supplemental oxygen (Ordinal Scale for Clinical Improvement 3 or less) at the time of enrollment. The primary endpoint is the severity of COVID-19 as measured by the maximum difference from the baseline value in the Ordinal Scale for Clinical Improvement within 10 days from the start of the experimental therapy.

Measure: Severity of COVID-19

Time: 10 days

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Secondary Outcomes

Description: SARS-Co-V-2 positivity up to 28 days from the start of experimental therapy

Measure: SARS-CoV-2 infection

Time: 28 days

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Description: The severity of COVID-19 as measured by the maximum difference from the baseline value in the Ordinal Scale for Clinical Improvement within 28 days from the start of the experimental therapy.

Measure: Severity of COVID-19 over 28 days

Time: 28 days

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Description: The requirement for ICU admission within 28 days from the start of the experimental therapy.

Measure: ICU admission

Time: 28 days

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Description: The requirement for mechanical ventilation within 28 days from the start of the experimental therapy.

Measure: Mechanical Ventilation

Time: 28 days

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Description: All cause mortality at 28 days from the start of experimental therapy

Measure: Mortality

Time: 28 days

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Primary Outcomes

Description: To determine the efficacy of PUL-042 Inhalation Solution in the prevention of viral infection with SARS-CoV-2 and progression to COVID-19 in subjects: 1) who have repeated exposure to individuals with SARS-CoV-2 infection and, 2) are asymptomatic at enrollment. The primary endpoint is the severity of COVID-19 as measured by the maximum difference from the baseline value in the Ordinal Scale for Symptom Improvement within 14 days from the start of experimental therapy.

Measure: Severity of COVID-19

Time: 14 days

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Secondary Outcomes

Description: Positive test for SARS-CoV-2 infection 14 days from the start of experimental therapy in subjects who test negative for SARS-CoV-2 at the pre-treatment visit

Measure: Incidence of SARS-CoV-2 infection

Time: 14 days

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Description: The severity of COVID-19 as measured by the maximum difference from the baseline value in the Ordinal Scale for Symptom Improvement within 28 days from the start of experimental therapy.

Measure: Severity of COVID-19

Time: 28 days

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Description: The requirement for ICU admission within 28 days from the start of experimental therapy.

Measure: ICU admission

Time: 28 days

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Description: The requirement for mechanical ventilation within 28 days from the start of experimental therapy.

Measure: Mechanical ventilation

Time: 28 days

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Description: All cause mortality at 28 days from the start of experimental therapy.

Measure: Mortality

Time: 28 days

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Primary Outcomes

Description: Phase 2 Only

Measure: Percent change in C-reactive protein (CRP) levels

Time: Day 4

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Description: Phase 3 Only 7-point Ordinal Scale: Death; Hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); Hospitalized, requiring non-invasive ventilation or high flow oxygen devices; Hospitalized, requiring supplemental oxygen; Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care Not hospitalized

Measure: Time to improvement (2 points) in clinical status assessment using the 7-point ordinal scale in patients with serum IL-6 levels greater than the upper limit of normal

Time: Up to day 29

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Secondary Outcomes

Description: Phase 2 Only

Measure: Time to improvement (2 points) in clinical status assessment on the 7-point ordinal scale in severe or critical patients with serum IL-6 levels greater than the upper limit of normal

Time: Up to day 29

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Description: Phase 2 Only

Measure: Time to improvement (2 points) in clinical status assessment on the 7-point ordinal scale reporting in severe or critical patients with all IL-6 levels

Time: Up to day 29

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Description: Resolution of fever defined as postbaseline body temperature <37.2°C (oral), or <37.6°C (rectal or tympanic) or <36.8°C (temporal or axillary) Documented fever defined as ≥38°C (oral), ≥38.4°C (rectal or tympanic), or ≥37.6°C (temporal or axillary)

Measure: Time to resolution of fever for at least 48 hours without antipyretics in patients with documented fever

Time: Up to day 29

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Description: Defined as postbaseline body temperature <37.2°C (oral), or <37.6°C (rectal or tympanic) or <36.8°C (temporal or axillary)

Measure: Time to resolution of fever for at least 48 hours without antipyretics by clinical severity

Time: Up to day 29

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Description: Defined as postbaseline body temperature <37.2°C (oral), or <37.6°C (rectal or tympanic) or <36.8°C (temporal or axillary)

Measure: Time to resolution of fever for at least 48 hours without antipyretics by baseline IL-6 levels

Time: Up to day 29

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Description: Improvement in oxygenation defined as increase in SpO2/FiO2 of 50 or greater compared to the nadir SpO2/FiO2

Measure: Time to improvement in oxygenation for at least 48 hours

Time: Up to day 29

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Description: Defined as increase in SpO2/FiO2 of 50 or greater compared to the nadir SpO2/FiO2

Measure: Time to improvement in oxygenation for at least 48 hours by clinical severity

Time: Up to day 29

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Description: Defined as increase in SpO2/FiO2 of 50 or greater compared to the nadir SpO2/FiO2

Measure: Time to improvement in oxygenation for at least 48 hours by baseline IL-6 levels

Time: Up to day 29

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Description: Resolution of fever defined as postbaseline body temperature <37.2°C (oral), or <37.6°C (rectal or tympanic) or <36.8°C (temporal or axillary) Improvement in oxygenation defined as increase in SpO2/FiO2 of 50 or greater compared to the nadir SpO2/FiO2

Measure: Time to resolution of fever and improvement in oxygenation for at least 48 hours

Time: Up to day 29

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Measure: Mean change in the 7-point ordinal scale

Time: Up to day 29

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Measure: Percentage of patients in each clinical status category using the 7-point ordinal scale

Time: Up to day 29

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Description: NEWS2 consists of: Physiological Parameters: Respiration rate (per minute), SpO2 Scale 1 (%), SpO2 Scale 2 (%), Use of Air or oxygen, Systolic blood pressure (mmHg), Pulse (per minute), Consciousness, Temperature (°C)

Measure: Time to discharge or to a National Early Warning Score 2 (NEWS2) of ≤2 and maintained for 24 hours

Time: Up to day 29

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Measure: Change from baseline in NEWS2 scoring system

Time: Up to day 29

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Description: Defined as ≥38°C (oral), ≥38.4°C (rectal or tympanic) or ≥37.6°C (temporal or axillary)

Measure: Number of days with fever

Time: Up to day 29

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Measure: Proportion of patients alive, off oxygen

Time: Day 29

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Measure: Number of days of resting respiratory rate >24 breaths/min

Time: Up to day 29

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Measure: Number of days with hypoxemia

Time: Up to day 29

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Measure: Number of days of supplemental oxygen use

Time: Up to day 29

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Measure: Time to saturation ≥94% on room air

Time: Up to day 29

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Measure: Number of ventilator free days in the first 28 days

Time: Baseline to day 29

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Measure: Number of patients requiring initiation of mechanical ventilation

Time: Up to day 29

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Measure: Number of patients requiring non-invasive ventilation

Time: Up to day 29

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Measure: Number of patients requiring the use of high flow nasal cannula

Time: Up to day 29

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Measure: Number of patients admitted into an intensive care unit (ICU)

Time: Up to day 29

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Measure: Number of days of hospitalization among survivors

Time: Up to day 29

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Measure: Number of deaths due to any cause

Time: Up to day 60

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Description: Phase 3 Only

Measure: Change in serum CRP levels

Time: Up to day 29

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Measure: Incidence of serious adverse events

Time: Up to Day 29

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Measure: Incidence of Grade 4 neutropenia (ANC <500/mm3)

Time: Up to day 29

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Measure: Incidence of severe or life-threatening bacterial, invasive fungal, or opportunistic infection

Time: Up to day 29

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Measure: Incidence of severe or life-threatening bacterial, invasive fungal, or opportunistic infection in patients with Grade 4 neutropenia

Time: Up to day 29

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Measure: Incidence of hypersensitivity reactions

Time: Up to day 29

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Measure: Incidence of infusion reactions

Time: Up to day 29

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Measure: Incidence of gastrointestinal perforation

Time: Up to day 29

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Measure: White blood cell count

Time: Up to day 29 if still hospitalized

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Measure: Hemoglobin levels

Time: Up to day 29 if still hospitalized

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Measure: Platelet count

Time: Up to day 29 if still hospitalized

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Measure: Creatinine levels

Time: Up to day 29 if still hospitalized

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Measure: Total bilirubin level

Time: Up to day 29 if still hospitalized

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Measure: Alanine aminotransferase (ALT) level

Time: Up to day 29 if still hospitalized

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Measure: Aspartate aminotransferase (AST) level

Time: Up to day 29 if still hospitalized

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Primary Outcomes

Description: Time to improve in clinical status: the time (days) required from the start of treatment to the improvement of clinical status "severe" to "moderate/mild"; or improvement from "scale 3 or 4" to "scale 5 or higher" based on NIAID ordinal scales.

Measure: Improvement of COVID-19 disease status

Time: 14 days

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Description: Time for disease progression from NIAID scale 3 or 4 to scale 2 or 1, and patients need to be on invasive mechanical ventilation, or ESMO, or death.

Measure: Disease progression of COVID-19

Time: 28 days

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Secondary Outcomes

Description: All cause of death

Measure: All cause of death

Time: 28 days

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Description: Conversion rate of clinical status on days 8 (proportion of subjects who changed from "severe" to "moderate or mild", or the improvement from "scale 3 or 4" to "scale 5 or higher" on NIAID ordinal scale)

Measure: Conversion rate of clinical status at Day 8

Time: 7 days

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Description: Conversion rate of clinical status on days 15 (proportion of subjects who changed from "severe" to "moderate or mild", or the improvement from "scale 3 or 4" to "scale 5 or higher" on NIAID ordinal scale)

Measure: Conversion rate of clinical status at Day 15

Time: 14 days

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Description: The discharge time or NEWS2 (National Early Warning Score 2) of ≤2 is maintained for 24 hours

Measure: Hospital discharge time

Time: 28 days

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Description: Duration of mechanical ventilation (IMV, NIV) (days)

Measure: Duration of mechanical ventilation

Time: 28 days

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Description: Duration of pressors (days)

Measure: Duration of pressors

Time: 28 days

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Description: Duration of extracorporeal membrane oxygenation (days)

Measure: Duration of ECMO

Time: 28 days

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Description: Duration of oxygen therapy (oxygen inhalation by nasal cannula or mask) (days)

Measure: Duration of oxygen therapy

Time: 28 days

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Description: Length of hospital stay (days)

Measure: Length of hospital stay

Time: 28 days

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Description: Changes of absolute lymphocyte count in peripheral blood

Measure: Absolute lymphocyte count

Time: 28 days

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Primary Outcomes

Description: Time of improvement or recovery of respiratory symptoms

Measure: Time of Improvement or recovery of respiratory symptoms

Time: 10 days during the intervention period

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Description: Number of days from positive to negative for test of swab or sputum virus nucleic acid

Measure: Number of days virus nucleic acid shedding

Time: 10 days during the intervention period

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Description: Frequency of improvement or recovery of respiratory symptoms

Measure: Frequency of Improvement or recovery of respiratory symptoms

Time: 10 days during the intervention period

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Secondary Outcomes

Description: Duration of fever after recruitment

Measure: Duration of fever

Time: 10 days during the intervention period

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Description: Disease is defined as severe if it meets any of the following criteria: 1.Respiratory rate ≥30/min; 2. Oxygen saturation ≤93%; 3. Arterial partial oxygen pressure (PaO2)/oxygen absorption concentration (FiO2) ≤300 mmHg (1 mmHg=0.133 kPa)

Measure: Frequencies of progression to severe illness

Time: 10 days during the intervention period

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Description: Time of improvement of pulmonary imaging

Measure: Time of improvement of pulmonary imaging

Time: 10 days during the intervention period

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Description: Peripheral blood c-reactive protein concentration

Measure: Peripheral blood c-reactive protein concentration

Time: day-1,3,7,14 after the intervention period

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Description: Absolute value of peripheral blood lymphocytes

Measure: Absolute value of peripheral blood lymphocytes

Time: day-1,3,7,14 after the intervention period

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Description: percentage of peripheral blood lymphocytes

Measure: percentage of peripheral blood lymphocytes

Time: day-1,3,7,14 after the intervention period

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Primary Outcomes

Measure: Clinical Status Assessed Using a 7-Category Ordinal Scale

Time: Day 28

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Secondary Outcomes

Measure: Time to Clinical Improvement (TTCI), Defined as a National Early Warning Score 2 (NEWS2) of Time: Up to 60 days

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Measure: Time to Improvement of at Least 2 Categories Relative to Baseline on a 7-Category Ordinal Scale of Clinical Status

Time: Up to 60 days

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Measure: Incidence of Mechanical Ventilation

Time: Up to 60 days

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Measure: Ventilator-Free Days to Day 28

Time: Up to Day 28

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Measure: Incidence of Intensive Care Unit (ICU) Stay

Time: Up to 60 days

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Measure: Duration of ICU Stay

Time: Up to 60 days

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Measure: Time to Clinical Failure

Time: From first dose to time of death, mechanical ventilation, ICU admission, or study withdrawal (whichever occurs first, for up to 60 days). If already in ICU on ventilation, failure = a one-category worsening on the ordinal scale, withdrawal, or death

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Measure: Mortality Rate

Time: Days 7, 14, 21, 28, and 60

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Measure: Time to Hospital Discharge

Time: Up to 60 days

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Measure: Duration of Time on Supplemental Oxygen

Time: Up to 60 days

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Measure: Percentage of Participants with Adverse Events

Time: Up to 60 days

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Measure: COVID-19 (SARS-CoV-2) Viral Load Over Time

Time: Up to 60 days

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Measure: Time to Reverse-Transcriptase Polymerase Chain Reaction (RT-PCR) Virus Negativity

Time: Up to 60 days

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Measure: Proportion of Participants with Post-Treatment Infection

Time: Up to 60 days

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Measure: Serum Concentration of IL-6

Time: Up to 60 days

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Measure: Serum Concentration of sIL-6R

Time: Up to 60 days

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Measure: Serum Concentration of Ferritin

Time: Up to 60 days

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Measure: Serum Concentration of C-Reactive Protein (CRP)

Time: Up to 60 days

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Measure: Serum Concentration of TCZ

Time: Up to 60 days

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Primary Outcomes

Measure: Number of death from any cause, or the need for intubation and mechanical ventilation during the 14 days following inclusion and start of treatment.

Time: Day 14

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Secondary Outcomes

Measure: Number of death from any cause, or the need for intubation and mechanical ventilation during the 28 days following inclusion and start of treatment.

Time: Day 28

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Description: WHO Ordinal Scale for Clinical Improvement ranges from 0 to 8, higher score meaning poorer outcome

Measure: Clinical evolution on the WHO Ordinal Scale for Clinical Improvement for COVID-19 between day 0 and day 14

Time: Day 14

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Description: WHO Ordinal Scale for Clinical Improvement ranges from 0 to 8, higher score meaning poorer outcome

Measure: Clinical evolution on the WHO Ordinal Scale for Clinical Improvement for COVID-19 between day 0 and day 28.

Time: Day 28

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Measure: Number of all-cause mortality at day 14

Time: Day 14

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Measure: Number of all-cause mortality at day 28

Time: Day 28

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Measure: Rate of positive SARS-CoV-2 RT-PCR on nasopharyngeal samples at day 5

Time: Day 5

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Measure: Rate of positive SARS-CoV-2 RT-PCR on nasopharyngeal samples at day 10

Time: Day 10

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Measure: The rate of venous thromboembolic events at day 28, documented and confirmed by an adjudication committee.

Time: Day 28

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Measure: Number of all-cause mortality at day 28 in patients aged 75 and older

Time: day 28

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Measure: Clinical evolution on the WHO OSCI scale for COVID-19 between day 0 and day 28 for patients aged 75 or older

Time: day 28

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Measure: Rate of severe adverse events at day 28

Time: day 28

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Measure: Number of all-cause mortality at day 14 in patients aged 75 and older

Time: day 14

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Primary Outcomes

Measure: Time to improvement on a 7-point ordinal scale as compared to baseline

Time: 14 days or discharge

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Secondary Outcomes

Measure: Treatment and prevention of inflammatory lung injury as measured by change in baseline of interleukin-6 (IL-6)

Time: 14 days or discharge

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Measure: Rate of Decline of COVID-19 viral load assessed by RT-PCR from nasopharyngeal samples

Time: 14 days or discharge

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Measure: In-hospital mortality

Time: 14 days or discharge

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Measure: Mean change in NEWS2 score from baseline

Time: 14 days or discharge

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Measure: Understand the effect of genetics for treatment response through whole genome sequence of the participant and the COVID-19 virus

Time: 14 days or discharge

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Measure: Reduction from baseline of NRS for cough

Time: 14 days or discharge

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Measure: Reduction from baseline of NRS for nausea

Time: 14 days or discharge

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Measure: Time to normalization of fever for at least 48 hours

Time: 14 days or discharge

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Measure: Time to improvement in oxygenation for at least 48 hours

Time: 14 days or discharge

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Primary Outcomes

Description: Resolution of fever is defined as body temperature: ≤36.6 C (axilla) or ≤37.2 C (oral), or ≤37.8 C (rectal or tympanic).

Measure: Phase 2: Time to resolution of fever for at least 48 hours without antipyretics or until discharge, whichever is sooner

Time: Baseline to Day 29

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Description: The ordinal scale is an assessment of the clinical status. Score ranges 1-7. Lower score is worse.

Measure: Phase 3: The percentage of patients reporting each severity rating on the 7-point ordinal scale

Time: Baseline to Day 15

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Secondary Outcomes

Description: Increase in SpO2/FiO2 of 50 or greater compared to the nadir SpO2/FiO2 for at least 48 hours. SpO2 is oxygen saturation and FiO2 is the fraction of inspired oxygen.

Measure: Phase 2: The time to improvement in oxygenation

Time: Baseline to Day 29

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Description: The ordinal scale is an assessment of the clinical status. Score ranges 1-7. Lower score is worse.

Measure: Phase 2: Mean change in 7-point ordinal scale from baseline to Day 15

Time: Baseline to Day 15

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Description: The ordinal scale is an assessment of the clinical status. Score ranges 1-7. Lower score is worse.

Measure: Phase 2: Clinical status using the 7-point ordinal scale at Day 15

Time: Baseline to Day 15

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Description: The ordinal scale is an assessment of the clinical status. Score ranges 1-7. Lower score is worse.

Measure: Phase 2: Time to improvement of two categories from admission using the 7-point ordinal scale

Time: Baseline to Day 29

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Description: Defined as body temperature (≤36.6°C [axilla], or ≤37.2 °C [oral], or ≤37.8°C [rectal or tympanic]) for at least 48 hours without antipyretics or until discharge, whichever is sooner.

Measure: Phase 2 and 3 : Time to resolution of fever

Time: Baseline to Day 29

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Description: Increase in SpO2/FiO2 of 50 or greater compared to the nadir SpO2/FiO2) for at least 48 hours, or until discharge, whichever is sooner. SpO2 is oxygen saturation and FiO2 is the fraction of inspired oxygen.

Measure: Phase 2 and 3 : Time to improvement in oxygenation

Time: Baseline to Day 29

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Description: Resolution of both fever and improvement in oxygenation. Resolution of fever is defined as body temperature (≤36.6°C [axilla], or ≤37.2 °C [oral], or ≤37.8°C [rectal or tympanic]) for at least 48 hours without antipyretics or until discharge, whichever is sooner. Improvement in oxygenation is increase in SpO2/FiO2 of 50 or greater compared to the nadir SpO2/FiO2) for at least 48 hours, or until discharge, whichever is sooner. SpO2 is oxygen saturation and FiO2 is the fraction of inspired oxygen.

Measure: Phase 2 and 3: Time to resolution of fever and improvement in oxygenation

Time: Baseline to Day 29

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Description: The National Early Warning Score (NEWS2) is used to standardize the assessment of acute-illness severity, track the clinical condition of patients, and to alert clinical teams to patient deterioration. Score ranges from 0-20. A higher score is worse.

Measure: Phase 2 and 3:Time to change in NEWS2 from baseline

Time: Baseline to Day 29

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Description: The NEWS2 is used to standardize the assessment of acute-illness severity, track the clinical condition of patients, and to alert clinical teams to patient deterioration. Score ranges from 0-20. A higher score is worse.

Measure: Phase 2 and 3: Time to NEWS2 of <2 and maintained for 24 hours

Time: Baseline to Day 29

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Description: The NEWS2 is used to standardize the assessment of acute-illness severity, track the clinical condition of patients, and to alert clinical teams to patient deterioration. Score ranges from 0-20. A higher score is worse.

Measure: Phase 2 and 3: Mean change from baseline to days 3, 5, 8, 11, 15, and 29 in NEWS2

Time: Baseline to days 3, 5, 8, 11, 15, and 29

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Description: Fever is defined as >37.4°C (axilla), or >38.0 °C (oral), or >38.4°C (rectal or tympanic) based on maximum value observed during a 24 period.

Measure: Phase 2 and 3:Days with fever

Time: Baseline to Day 29

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Description: Supplemental oxygen is defined as oxygen administration by nasal cannula, simple face mask, or other similar oxygen delivery device.

Measure: Phase 2 and 3: Alive off supplemental oxygen at day 29

Time: Baseline to Day 29

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Measure: Phase 2 and 3: Days of resting respiratory rate >24 breaths/min

Time: Baseline to Day 29

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Description: Hypoxemia is defined as SpO2 <93% on room air, or requiring supplemental oxygen, or mechanical ventilatory support.

Measure: Phase 2 and 3:Days of hypoxemia

Time: Baseline to Day 29

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Description: Supplemental oxygen is defined as oxygen administration by nasal cannula, simple face mask, or other similar oxygen delivery device.

Measure: Phase 2 and 3: Days of supplemental oxygen use

Time: Baseline to Day 29

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Measure: Phase 2 and 3: Time to saturation ≥94% on room air

Time: Baseline to Day 29

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Measure: Phase 2 and 3: Ventilator free days in the first 28 days (to day 29)

Time: Baseline to Day 29

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Description: For those not requiring these interventions at baseline.

Measure: Phase 2 and 3: The number of patients with Initiation of mechanical ventilation, non-invasive ventilation, or use of high flow nasal cannula

Time: Baseline to Day 60

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Measure: Phase 2 and 3: Proportion of patients requiring rescue medication during the 28-day period

Time: Baseline to Day 28

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Description: For patients are not in ICU at baseline

Measure: Phase 2 and 3: The number of patients transferred to the ICU or the need to transfer to the ICU (if the ICU is not available)

Time: Baseline to Day 60

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Measure: Phase 2 and 3: Days of hospitalization among survivors

Time: Baseline to Day 60

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Measure: Phase 2 and 3: Incidence of death

Time: Baseline to Day 60

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Description: The ordinal scale is an assessment of the clinical status. Score ranges 1-7. Lower score is worse.

Measure: Phase 3: Mean change in the 7-point ordinal scale from baseline to days 3, 5, 8, 11, 15, and 29 (or until discharge)

Time: baseline to days 3, 5, 8, 11, 15, and 29 (or until discharge)

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Description: The ordinal scale is an assessment of the clinical status. Scores range 1-7. Lower score is worse.

Measure: Phase 3: Clinical status using the 7-point ordinal scale at days 3, 5, 8, 11,15, and 29

Time: Days 3, 5, 8, 11,15, and 29

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Description: The ordinal scale is an assessment of the clinical status. Score ranges 1-7. Lower score is worse.

Measure: Phase 3: Time to improvement of two categories from admission using the 7-point ordinal scale

Time: Baseline to Day 29

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Measure: Phase 2 and 3: Incidence of serious adverse events

Time: Baseline to Day 60

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Measure: Phase 2 and 3: The incidence of major or opportunistic bacterial or fungal infections

Time: Baseline to Day 60

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Measure: Phase 2 and 3: The incidence of major or opportunistic bacterial or fungal infections in patients with grade 4 neutropenia

Time: Baseline to Day 60

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Measure: Phase 2 and 3: The incidence of hypersensitivity reactions, infusion reactions, gastrointestinal perforation

Time: Baseline to Day 60

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Measure: The number of patients with clinically significant laboratory abnormalities

Time: Baseline to Day 60

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Primary Outcomes

Description: Number of days of unplanned absenteeism for any reason

Measure: Health Care Workers absenteeism

Time: Maximum of 180 days

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Secondary Outcomes

Measure: the cumulative incidence of documented COVID-19

Time: Maximum of 180 days

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Measure: the cumulative incidence of Hospital Admission due to documented COVID-19

Time: Maximum of 180 days

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Measure: the number of days of unplanned absenteeism, because of documented COVID-19

Time: Maximum of 180 days

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Measure: the cumulative incidence of self-reported acute respiratory symptoms or fever

Time: Maximum of 180 days

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Measure: the cumulative incidence of death due to documented COVID-19

Time: Maximum of 180 days

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Measure: the cumulative incidence of Intensive Care Admission due to documented COVID-19

Time: Maximum of 180 days

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Description: Exploratory

Measure: the number of days of absenteeism, because of imposed quarantine as a result of exposure to COVID-19

Time: Maximum of 180 days

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Description: Exploratory

Measure: the number of days of absenteeism, because of imposed quarantine as a result of having acute respiratory symptoms, fever or documented COVID-19

Time: Maximum of 180 days

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Description: Exploratory

Measure: the number of days of unplanned absenteeism because of self-reported acute respiratory symptoms

Time: Maximum of 180 days

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Description: Exploratory

Measure: the number of days of self-reported fever (≥38 gr C)

Time: Maximum of 180 days

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Description: Exploratory

Measure: the cumulative incidence of self-reported fever (≥38 gr C)

Time: Maximum of 180 days

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Description: Exploratory

Measure: the number of days of self-reported acute respiratory symptoms

Time: Maximum of 180 days

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Description: Exploratory

Measure: the cumulative incidence of self-reported acute respiratory symptoms

Time: Maximum of 180 days

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Description: Exploratory

Measure: the cumulative incidence of death for any reason

Time: Maximum of 180 days

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Description: Exploratory

Measure: the cumulative incidence of Intensive Care Admission for any reason

Time: Maximum of 180 days

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Description: Exploratory

Measure: the cumulative incidence of Hospital Admission for any reason

Time: Maximum of 180 days

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Description: Exploratory

Measure: • the cumulative incidence and magnitude of plasma/serum antibodies (IgA,M,G) and SARS-CoV-2-specific antibodies at 12 weeks after vaccination and at the end of the study period

Time: Maximum of 180 days

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Primary Outcomes

Description: Outcome reported as the percent of participants in each arm who are COVID-19-free at the end of study treatment.

Measure: COVID-19-free survival

Time: up to 12 weeks

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Secondary Outcomes

Description: Outcome reported as the percent of participants in each arm who have a confirmed SARS-CoV-2 infection during study treatment.

Measure: Incidence of confirmed SARS-CoV-2 detection

Time: up to 12 weeks

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Description: Outcome reported as the percent of participants in each arm who report COVID-19-related symptoms during study treatment.

Measure: Incidence of possible COVID-19 symptoms

Time: up to 12 weeks

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Description: Outcome reported as the percent of participants in each arm who discontinue study medication use for any reason during treatment.

Measure: Incidence of all-cause study medicine discontinuation

Time: up to 12 weeks

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Description: Participants will self-report COVID-19 status on an ordinal scale as follows: No illness (score=1), Illness with outpatient observation (score=2), Hospitalization (or post-hospital discharge) (score=3), or Hospitalization with ICU stay or death (score=4). Possible scores range from 1-4 with higher scores indicating greater disease severity.

Measure: Ordinal Scale of COVID-19 Disease maximum severity if COVID-19 diagnosed at study end

Time: up to 12 weeks

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Description: Outcome reported as the percent of participants in each arm who are hospitalized or expire due to COVID-19 during study treatment.

Measure: Incidence of Hospitalization for COVID-19 or death

Time: up to 12 weeks

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Description: Outcome reported as the percent of participants in each arm who experience medication-related side effects during study treatment.

Measure: Incidence of study medication-related side effects

Time: up to 12 weeks

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Primary Outcomes

Description: Time to first of two consecutive negative respiratory secretions obtained by nasopharyngeal and/or oropharyngeal and/or salivary swabs tests for SARS-CoV-2 by qRT-PCR.

Measure: Duration of Viral shedding of SARS-CoV-2 by qRT-PCR

Time: 28 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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Primary Outcomes

Description: Viral load assessed by PCR from a nasopharyngeal swab

Measure: Change from baseline to Day 3 in nasopharyngeal SARS-CoV-2 viral load (if quantitative PCR is available)

Time: Baseline to Day 3

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Description: Viral load assessed by PCR from a nasopharyngeal swab - 2. Viral load assessed by PCR from a nasopharyngeal swab

Measure: Number of participants by PCR result status (positive or negative) (if quantitative PCR is not available)

Time: Baseline to Day 3

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Secondary Outcomes

Description: Viral load assessed by PCR from a nasopharyngeal swab

Measure: Change from baseline to Day 5 in nasopharyngeal SARS-CoV-2 viral load

Time: Baseline to Day 5

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Description: Viral load assessed by PCR from a nasopharyngeal swab

Measure: Number of participants by PCR result status (positive or negative)

Time: Baseline to end of study (Day14)

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Description: COVID-19 symptoms (feverishness, sore throat, cough, shortness of breath, myalgias) will be scored by the participant on a 4-point scale ( 0 =none; 1 = mild; 2 = moderate; 3 = severe)

Measure: Number of participants with COVID-19 symptoms by severity

Time: Baseline to end of study (Day14)

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Description: COVID-19 symptoms (feverishness, sore throat, cough, shortness of breath, myalgias) will be scored by the participant on a 4-point scale ( 0 =none; 1 = mild; 2 = moderate; 3 = severe). Resolution of a symptom is defined as when a symptom previously scored ≥ 1 on the scale is scored as 0

Measure: Time to resolution of COVID-19 Symptoms

Time: Baseline to end of study (Day14)

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Description: Resolution of fever defined as the first day of 2 consecutive daily temperatures < 37.7 C

Measure: Time to resolution of fever

Time: Baseline to end of study (Day14)

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Description: Resolution of fever defined as the first day of 2 consecutive daily temperatures < 37.7 C

Measure: Percentage of participants with resolution of fever

Time: Baseline to end of study (Day14)

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Measure: Percentage of participants hospitalized

Time: Baseline to end of study (Day14)

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Measure: Number of participants with Adverse Events

Time: Baseline to end of study (Day14)

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Primary Outcomes

Description: Clinical diagnosis of COVID-19 with limitation of activities (WHO Severity Scale 2-8)

Measure: Symptomatic COVID-19

Time: 3 months

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Description: i) Uninfected - no clinical or virological evidence of infection (Score = 0) ii) Ambulatory - no limitation of activities (score=1) or with limitation (Score=2) iii) Hospitalized - mild no oxygen (Score=3) or with oxygen (Score=4) iv) Hospitalized severe - Scores 5-7* v) Dead * Score 5 is non-invasive ventilation or high flow oxygen; Score 6 is intubation with mechanical ventilation; Score 7 is intubation with additional organ support (e.g. pressors, renal replacement therapy, extra corporeal membrane oxygenation [ECMO]) These outcome definitions are based on WHO R&D Blueprint consensus definitions for COVID-19.

Measure: Peak severity of COVID-19 over the study period

Time: 3 months

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Primary Outcomes

Description: Adverse events (specifically including incidence of gastrointestinal-associated events) following administration of oral bacTRL-Spike

Measure: Frequency of Adverse Events

Time: Up to12 months post-vaccination

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Secondary Outcomes

Description: Antibody against SARS-CoV-2 Spike protein

Measure: SARS-CoV-2 antibodies

Time: Baseline (pre-vaccination), and 1, 3 and 12 months post-vaccination

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Description: Incidence and clinical phenotype of confirmed and probable COVID-19 infection among vaccinated participants, based on current public health definitions

Measure: Incidence of COVID-19 infection

Time: Up to 12 months post-vaccination

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Description: Isolation of viable bacTRL-Spike from stool post-vaccination

Measure: bacTRL-Spike in stool post-vaccination

Time: Days 7, 14, 21, and 1 and 3 months post-vaccination

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Description: Collection of biological samples for future studies to understand immunity against SARS-CoV-2.

Measure: Seroconversion of circulating anti-Spike IgG antibodies & stability of serum IgG titers

Time: Up to 12 months post-vaccination

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Description: Collection of biological samples for future studies to understand immunity against SARS-CoV-2.

Measure: Effectiveness of intestinal colonization of the probiotic-based bacTRL-Spike oral vaccine

Time: Up to 12 months post-vaccination

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Primary Outcomes

Measure: Number of patients with ICU admission

Time: 7 days after randomisation

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Measure: Number of patients with intubation

Time: 14 days after randomisation

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Measure: Number of patients with death

Time: 28 days after randomisation

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Secondary Outcomes

Description: Assessed by the 8-point WHO scale

Measure: Illness severity

Time: At days 2, 7, 14, 28 after randomisation

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Description: Clinical improvement is defined as a ≥ 2-point improvement in the 8-point WHO scale

Measure: Number of patients with clinical improvement

Time: At days 2, 7, 14, 28 after randomisation

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Description: Clinical improvement is defined as a ≥ 2-point improvement in the 8-point WHO scale

Measure: Time to clinical improvement (days)

Time: Up to day 28 after randomisation

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Measure: Duration of hospitalization (days)

Time: Up to day 28 after randomisation

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Measure: Time to ICU admission (days)

Time: Up to day 28 after randomisation

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Measure: Duration of ICU stay

Time: Up to day 28 after randomisation

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Measure: Time to intubation

Time: Up to day 28 after randomisation

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Measure: Duration of mechanical ventilation (days)

Time: Up to day 28 after randomisation

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Other Outcomes

Measure: Number of deaths

Time: Within 28 days after randomisation

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Measure: Number of patients with ICU admission

Time: Within 28 days after randomisation

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Measure: Number of patients with intubation

Time: Within 28 days after randomisation

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Description: Events of special interest are defined as secondary infections, acute kidney failure, hepatic, and cardiac failure

Measure: Number of patients with events of special interest

Time: Within 28 days after randomisation

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Measure: Number of patients with SAEs considered by the investigator to be at least probably related to the IMP

Time: Within 28 days after randomisation

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Primary Outcomes

Description: The duration from start of treatment (Favipiravir or placebo) to normalization of pyrexia, respiratory rate and SPO2 and relief of cough (where there are relevant abnormal symptoms at enrolment) that is maintained for at least 72 hours.

Measure: Time from randomization to clinical recovery

Time: 90 days

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Secondary Outcomes

Description: 1. Time from randomization to negativity in RT-PCR nucleic acid test for 2019-nCov within 28 days of randomization;

Measure: Time from randomization to negativity in RT-PCR nucleic acid test

Time: 28 days

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Description: Incidence of deterioration/aggravation of pneumonia (defined as SPO2≤93% or PaO2/FiO2 ≤300 mmHg or distressed RR≥30/min without oxygen inhalation and requiring oxygen therapy or more advanced breath support) within 28 days of randomization;

Measure: Incidence of deterioration/aggravation of pneumonia

Time: 28 days

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Description: Time from randomization to resolution of pyrexia (defined the same as for the primary efficacy variable; applicable to subjects with pyrexia at enrolment) within 28 days of randomization;

Measure: Time from randomization to resolution of pyrexia

Time: 28 days

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Description: Time from randomization to relief of cough (defined the same as for the primary efficacy variable; applicable to subjects with cough at enrolment) within 28 days of randomization; It is recommended that the severity of cough be graded as per NCI-CTCAE v5.0: Mild: Requires non-prescription treatment; Moderate: Requires medication treatment; limits instrumental activities of daily living; Severe: Limits self-care activities of daily living

Measure: Time from randomization to relief of cough

Time: 28 days

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Description: Time from randomization to relief of dyspnoea (defined as subject-perceived improvement or resolution of dyspnoea; applicable to subjects with dyspnoea at enrolment) within 28 days of randomization;

Measure: Time from randomization to relief of dyspnoea

Time: 28 days

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Description: 6. Rate of auxiliary oxygen therapy or non-invasive ventilation within 28 days of randomization

Measure: Rate of auxiliary oxygen therapy

Time: 28 days

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Description: ICU admission rate within 28 days of randomization

Measure: ICU admission rate

Time: 28 days

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Description: All-cause mortality within 28 days of randomization

Measure: Mortality

Time: 28 days

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Primary Outcomes

Description: Changes in forced vital capacity (FVC) after treatment compared to baseline.

Measure: Changes in forced vital capacity (FVC)

Time: 8 weeks

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Secondary Outcomes

Description: Changes incarbon monoxide dispersion (DLco%) after treatment compared to baseline.

Measure: Changes in carbon monoxide dispersion (DLco%)

Time: 8 weeks

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Description: Changes in the six-minute walk test (6MWT) after treatment compared to baseline.

Measure: Changes in the six-minute walk test (6MWT)

Time: 8 weeks

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Description: Changes in High resolution CT score after treatment compared to baseline.The minimum and maximum values are 0 and 25 , and higher scores mean a worse outcome. As for the score, it is the expected value and will be determined according to the actual result

Measure: Changes in High resolution CT score

Time: 8 weeks

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Primary Outcomes

Measure: Not hospitalized

Time: day 14 from baseline

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Secondary Outcomes

Measure: Time to improvement of 2 categories from admission on a 7-point ordinal scale

Time: day 14

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Measure: Proportion of participants in each group with normalization of fever

Time: day 7 and day 14

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Measure: Proportion of participants in each group with oxygen saturation > 94% on room air for >24h

Time: day 7 and day 14

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Measure: Time to fever normalization (if febrile at baseline)

Time: within 14 days

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Measure: Time to first negative SARS-CoV-2 PCR in NP swap (if pos. at baseline)

Time: within 14 days

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Measure: Time to first negative SARS-CoV-2 PCR in lower respiratory tract specimens (sputum, bronchoalveolar lavage, tracheal aspirate) (if positive at baseline)

Time: within 14 days

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Measure: Duration of oxygen therapy

Time: within 28 days

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Measure: Proportion of participants in each group with need for mechanical ventilation

Time: within 28 days

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Measure: Duration of hospitalization

Time: within 28 days

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Measure: All cause mortality

Time: day 28

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Primary Outcomes

Description: Improvement and recovery time of inflammatory and immune factors

Measure: The immune function (TNF-α 、IL-1β、IL-6、TGF-β、IL-8、PCT、CRP)

Time: Observe the immune function of the participants within 4 weeks

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Description: Evaluation of Pneumonia change

Measure: Blood oxygen saturation

Time: Monitor blood oxygen saturation of the participants within 4 weeks

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Secondary Outcomes

Description: Marker for efficacy of treatment

Measure: Rate of mortality within 28-days

Time: At baseline, Day 1, Day 2, Day 7, Week 2, Week 3, Week 4

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Description: Evaluation of Pneumonia change

Measure: Size of lesion area by chest imaging

Time: At baseline, Day 1, Day 2, Day 7, Week 2, Week 3, Week 4

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Description: Marker of Immunology and inflammation

Measure: CD4+ and CD8+ T cells count

Time: At baseline, Day 1, Day 2, Day 7, Week 2, Week 3, Week 4

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Description: Degree of infection

Measure: Peripheral blood count recovery time

Time: At baseline, Day 1, Day 2, Day 7, Week 2, Week 3, Week 4

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Description: Indirect response to lung function

Measure: Duration of respiratory symptoms (fever, dry cough, difficulty breathing, etc.)

Time: At baseline, Day 1, Day 2, Day 7, Week 2, Week 3, Week 4

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Description: Clearance time of COVID-19 in participant

Measure: COVID-19 nucleic acid negative time

Time: At baseline, Day 1, Day 2, Day 7, Week 2, Week 3, Week 4

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Primary Outcomes

Description: Composite percentage of patients alive and not on end-of-life pathway who are free of mechanical ventilation at day 14.

Measure: Proportion of alive patients free off mechanical ventilation

Time: 14 days after enrolment

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Secondary Outcomes

Description: Composite percentage of patients alive and not on end-of-life pathway who are free of mechanical ventilation at day 14 in the subgroup of patients without the need of mechanical ventilation at baseline.

Measure: Proportion of patients who avoided the need of mechanical ventilation

Time: 14 days

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Description: Length of stay in intensive care unit

Measure: ICU LOS

Time: 28 days

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Description: Proportion of patients who died by day 28

Measure: Mortality28

Time: 28 days

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Description: Proportion of patients who died by day 90

Measure: Mortality90

Time: 90 days

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Primary Outcomes

Measure: Difference in time to resolution of clinical signs and symptoms of mild COVID-19 treated with hydroxychloroquine or placebo as assessed by daily self-assessment

Time: 28±2 days

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Secondary Outcomes

Measure: Difference between hydroxychloroquine- and placebotreated patients on an ordinal outcome scale until Day 28 (death, admission to intensive care, hospitalization, continuing disease, recovered)

Time: 28±2 days

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Measure: All-cause mortality within 28 days

Time: 28±2 days

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Other Outcomes

Measure: Proportion of patients with negative COVID-19 PCR test at day 14 in per protocol population as per throat swab

Time: 28±2 days

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Measure: Change in COVID-19 virus load from baseline to day 14

Time: 28±2 days

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Primary Outcomes

Description: 8-category ordinal scale

Measure: Proportion (%) of subjects experiencing deterioration in clinical status

Time: Changes from baseline on Day 14

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Description: Per CTCAE

Measure: Treatment Emergent Adverse Events

Time: Up to 30 days after drug administration

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Secondary Outcomes

Description: 8-category ordinal scale

Measure: Proportion (%) of subjects experiencing deterioration in clinical status

Time: Changes from baseline on Day 7 and Day 30

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Description: 8-category ordinal scale: 8, Death; 7, ventilation in addition to extracorporeal membrane oxygen (ECMO), continuous renal replacement therapy (CRRT) or pressors; 6, Intubation and mechanical ventilation; 5, non-invasive mechanical ventilation (NIV) or high-flow oxygen; 4,Oxygen by mask or nasal prongs; 3, Hospitalization without oxygen supplementation; 2, Limitation of activities, discharge from hospital; and 1, No limitation of activities, discharge from hospital

Measure: Clinical status

Time: On Day 7, Day 14 and Day 30

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Description: 8-category ordinal scale: 8, Death; 7, ventilation in addition to extracorporeal membrane oxygen (ECMO), continuous renal replacement therapy (CRRT) or pressors; 6, Intubation and mechanical ventilation; 5, non-invasive mechanical ventilation (NIV) or high-flow oxygen; 4,Oxygen by mask or nasal prongs; 3, Hospitalization without oxygen supplementation; 2, Limitation of activities, discharge from hospital; and 1, No limitation of activities, discharge from hospital

Measure: Improvement in clinical status

Time: On Day 7, Day 14 and Day 30

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Description: The score is based on six different scores, one each for the respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems. A higher score predicts a worse clinical outcome.

Measure: Sequential Organ Failure Assessment (SOFA) score

Time: On Day 7 and Day 14

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Measure: Change from baseline in PaO2/ FiO2

Time: On Day 7 and Day 14

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Description: Defined as SpO2≥94% sustained minimum 24 hours

Measure: Length of time to normalization of oxygen saturation

Time: Up to 30 days after drug administration

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Measure: Change from baseline in percentage of subjects requiring mechanical ventilation

Time: On Day 7 and Day 14

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Measure: Change from baseline in Glucocorticoid use

Time: On Day 7 and Day 14

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Measure: Mortality rate from any cause

Time: Up to 30 days after drug administration

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Measure: Length of hospitalization

Time: Up to 30 days after drug administration

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Measure: Change from baseline in D-dimer

Time: On Day 7 and Day 14

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Measure: Serum concentration of TJ003234

Time: Day 1 predose, Day 1 End of Infusion, Day 7 and Day 14

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Measure: Incidence and titer of anti-drug antibodies (ADA)

Time: Day 1 predose, Day 14

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Primary Outcomes

Measure: Occurrence of adverse reactions

Time: 0-14 days post vaccination

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Measure: Anti SARS-CoV-2 S antibody response(ELISA)

Time: 28 days post vaccination

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Measure: Neutralizing antibody response to SARS-CoV-2

Time: 28 days post vaccination

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Secondary Outcomes

Measure: Occurrence of adverse events

Time: 0-28 days post vaccination

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Measure: Occurrence of serious adverse reaction

Time: 0-6 months post vaccination

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Measure: Anti SARS-CoV-2 S antibody response(ELISA)

Time: 14 days, 6 months post vaccination

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Measure: Neutralizing antibody response to SARS-CoV-2

Time: 6 months post vaccination

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Measure: Neutralizing antibody response to Ad5-vector

Time: 28 days, 6 months post vaccination

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Primary Outcomes

Description: Viral clearance defined as time to sustained SARS-CoV-2-specific RNA copy number ≤100, measured by real time reverse-transcription polymerase chain reaction RT-PCR in throat swabs.

Measure: Effect of HCQ on in vivo viral clearance

Time: 6 months

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Other Outcomes

Measure: In-hospital mortality

Time: 60 days

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Measure: All-cause mortality

Time: 60 days

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Measure: Proportion requiring non-invasive or invasive ventilation

Time: 6 months

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Measure: Proportion admitted to ICU

Time: 6 months

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Measure: Duration of hospitalization

Time: 6 months

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Measure: Reduction in viral RNA load in upper respiratory tract specimen as assessed by area under viral load curve

Time: 6 months

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Measure: Reduction in viral RNA load in upper respiratory tract specimen defined as decline of RNA load by 2 log-levels or to below detection level

Time: 6 months

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Primary Outcomes

Description: Clinical worsening is defined meeting both of the following: (1) presence of dyspnea and/or hospitalization for shortness of breath or pneumonia, plus (2) decrease in O2 saturation (<92%) on room air and/or supplemental oxygen requirement in order to keep O2 saturation >92%.

Measure: Time to clinical worsening

Time: RCT (approximately 15 days)

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Secondary Outcomes

Description: (1) moderate severity of illness as defined by O2 saturation <92% but no supplemental oxygen requirement; (2) O2 saturation plus supplemental oxygen requirement; (3) O2 saturation <92% plus hospitalization (related to dyspnea/hypoxia); (4) the above, plus ventilator support requirement; (5) the above, plus ventilator support for at least 3 days; (6) death.

Measure: clinical deterioration on a Likert-type scale (1-6)

Time: RCT (approximately 15 days)

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Description: (1) requiring supplemental oxygen; (2) requiring hospitalization; (3) requiring ventilator support.

Measure: clinical deterioration measured by number of days

Time: RCT (approximately 15 days)

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Description: Outcomes will be collected daily, with symptomatic data collected approximately twice daily. The most severe symptom at baseline will be the focus.

Measure: Symptomatic severity on a likert scale (0-10 where 0= none and 10=very severe)

Time: RCT (approximately 15 days)

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Primary Outcomes

Description: Composite of death, Need for mechanical ventilation, or an increase of 2 or more points in the SOFA score

Measure: Critical condition or death

Time: 28 days

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Description: Kinetics of circulating IL-6

Measure: IL-6

Time: 14 days in-hospital, hospital discharge, or death

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Primary Outcomes

Measure: Incidence of serious adverse events associated with clazakizumab or placebo

Time: 60 days

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Secondary Outcomes

Measure: Incidence of intubation

Time: 14 days

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Measure: Time to extubation

Time: 14 days

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Measure: Length of ICU stay

Time: 14 days

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Measure: Number of patients who present a decrease in C-reactive protein

Time: 14 days

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Description: Assessed at 28 and 60 days

Measure: Patient survival

Time: 60 days

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Primary Outcomes

Description: Documented days free off mechanical ventilation the first 28 days post enrollment

Measure: Number of ventilator-free days

Time: Up to 28 days

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Secondary Outcomes

Description: Mortality at 28-days by all causes

Measure: All-cause-mortality

Time: Up to 28 days

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Description: Number of days free of acute inflammation (defined as CRP >= 10 mg/L)

Measure: Acute-inflammation-free days

Time: Up to 28 days

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Description: Number of days that the participant is free of organ failure in ALL of the following organ systems: Cardiovascular, Respiratory, Neurological, Liver, Bone marrow organ, Renal

Measure: Organ-failure-free days

Time: Up to 1 year

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Primary Outcomes

Description: Evaluation of pneumonia improvement

Measure: Changes of oxygenation index (PaO2/FiO2)

Time: At baseline, 6 hour, Day 1, Day 3,Week 1, Week 2, Week 4, Month 6.

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Description: Proportion of participants with treatment-related adverse events

Measure: Side effects in the BM-MSCs treatment group

Time: Baseline through 6 months

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Secondary Outcomes

Description: Improvement of clinical symptoms including duration of fever, respiratory destress, pneumonia, cough, sneezing, diarrhea.

Measure: Clinical outcome

Time: At baseline, 6 hour, Day 1, Day 3,Week 1, Week 2, Week 4, Month 6.

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Description: days of the patients in hospital

Measure: Hospital stay

Time: Baseline through 6 months

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Description: Evaluation of pneumonia improvement

Measure: CT Scan

Time: At baseline, 6 hour, Day 1, Day 3,Week 1, Week 2, Week 4, Month 6.

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Description: (deep sputum / pharyngeal swab / nasal swab / anal swab / tear fluid / stomach fluid / feces / blood or alveolar lavage fluid)

Measure: Changes in viral load

Time: At baseline, 6 hour, Day 1, Day 3,Week 1, Week 2, Week 4, Month 6.

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Description: Immunological status

Measure: Changes of CD4+, CD8+ cells count and concentration of cytokines

Time: At baseline, 6 hour, Day 1, Day 3,Week 1, Week 2, Week 4, Month 6.

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Description: Marker for efficacy

Measure: Rate of mortality within 28-days

Time: From baseline to day 28

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Description: Markers of Infection

Measure: Changes of C-reactive protein

Time: At baseline, 6 hour, Day 1, Day 3,Week 1, Week 2, Week 4, Month 6.

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Primary Outcomes

Description: Efficacy will be measured by examining the percentage of subjects reported as being in each category of a 6-point, ordinal, severity rating scale at Day 15. The severity ratings are: Death Hospitalized, on invasive mechanical ventilation or ECMO Hospitalized, on non-invasive ventilation or high flow oxygen devices Hospitalized, requiring supplemental oxygen Hospitalized, not requiring supplemental oxygen Not hospitalized

Measure: To evaluate the safety and efficacy of vazegepant compared with placebo in patients hospitalized with COVID-19 infection requiring supplemental oxygen.

Time: Baseline to Day 15

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Secondary Outcomes

Measure: The number of unique subjects alive and off of oxygen. These are subjects in categories 5 or 6 of the 6-point ordinal scale being used as the primary endpoint.

Time: Baseline to Day 29

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Measure: A subject requiring initiation of mechanical ventilation, non-invasive ventilation, or a high flow nasal cannula is a subject that has any eCRF showing the use of any such device on any day.

Time: Baseline to Day 60

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Measure: The number of unique subjects admitted to an ICU verse those not admitted.

Time: Baseline to Day 60

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Measure: Subjects are alive and respiratory-failure free if they are categorized as being in categories 3, 4, 5 or 6 of the 6-point ordinal scale being used as the primary endpoint.

Time: Baseline to Day 60

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Measure: Subjects are alive and free of either mechanical ventilation or non-invasive ventilation if they are categorized as being in categories 4, 5 or 6 of the 6-point ordinal scale being used as the primary endpoint.

Time: Baseline to Day 60

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Measure: Efficacy on Day 29 will be evaluated using the same 6-point severity scales that is used at Day 15.

Time: Baseline at Day 15 and at Day 29

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Measure: Time to improvement of one category on the 6-point severity scale will be determined as the number of days from baseline to the first day that an eCRF indicates a one category improvement in the scale.

Time: Baseline to Day 60

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Measure: A 48-hour improvement in SpO2/FiO2 consists of two consecutive days where the case report forms show a clinically meaningful increase from baseline.

Time: Baseline to Day 60

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Measure: The time to improvement in the in the NEWS2 scale will be determined as the number of days from baseline to the first eCRF that shows an improvement.

Time: Baseline to Day 29

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Measure: A score < 2 for 24 hours on the NEWS2 scale consists of a day where all of the reported NEWS2 scores are < 2.

Time: Baseline to Day 29

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Measure: The change in NEWS2 scores will be determined as the change from baseline at Day 15 and at Day 29.

Time: Baseline at Day 15 and at Day 29.

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Measure: The number of unique subjects alive and off of oxygen.

Time: Baseline to Day 60

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Measure: A day with a resting respiratory rate > 24 is a day in which all eCRFs collected for a subject indicate observed respiratory rates > 24 breaths per minute.

Time: Baseline to Day 29

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Measure: A day with supplemental oxygen is one in which any case report form collected on that day indicates the use of any amount of supplemental oxygen.

Time: Baseline to Day 29

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Measure: Time to saturation greater than or equal to 90% on room air is measured by the number of days from baseline to the first day on which an eCRF indicates saturation greater than or equal to 90% without any supplemental oxygenation.

Time: Baseline to Day 60

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Measure: A ventilator free day is a day in which all of the eCRFs collected indicate that the subject was not using a ventilator.

Time: Baseline to Day 29

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Measure: SOFA scores will be determined from eCRFs. Values will be determined for subjects at admission to an ICU and for all subjects still in an ICU at the end of the study (Day 29).

Time: Baseline to Day 29

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Measure: The number of days of hospitalization will be determined from eCRFs. A hospitalization day is any day that it is shown that a subject spent at least spent part of the day in a hospital.

Time: First day of hospital admission to discharge from hospital (evaluated from Baseline to Day 60)

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Measure: Time to fever resolution, without antipyretics, during two contiguous days .

Time: Screening to 48 hours fever free

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Measure: The number of deaths, SAEs, severe AEs and Grade 3 or 4 laboratory abnormalities will be tabulated as the number of unique subjects meeting those criteria.

Time: Screening to Day 60

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Measure: The incidence of severe or life-threatening bacterial, invasive fungal, or opportunistic infections will be tabulated as the number of unique subjects, reported in eCRFs, as having these conditions at any point in the study

Time: Screening to day 60

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Measure: The incidence of intranasal administration reactions will be tabulated, from eCRFs, as the number of unique subjects having such a condition at any point in the study.

Time: Baseline to Day 60

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Measure: The percentage of subjects who develop significant renal disease.

Time: Baseline to Day 60

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Measure: The percentage of subjects discharged to home on supplemental oxygen will determined from the unique number of subjects have eCRF pages indicating they were discharged to home while still on supplemental oxygen.

Time: Baseline to Day 60

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Primary Outcomes

Description: Percentage of patients who become RT-PCR negative with two RT-PCR tests performed at day 6 and day 7

Measure: RT-PCR negative status

Time: 6-7 days

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Secondary Outcomes

Description: Time to progression to next stage of SARS-CoV-2 disease severity index

Measure: Progression of symptoms

Time: 7 days

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Description: Time to onset of fever (temperature greater than 100 degree F), cough, or shortness of breath (respiratory rate >22 per minute).

Measure: Development of Symptoms

Time: 7 days

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Description: Drug related adverse events as determined by data safety and monitoring board (DSMB)

Measure: Adverse events

Time: 7 days

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Primary Outcomes

Description: PCR will be done to evaluate the change in viral load

Measure: Viral load

Time: day 1, 4, 7, 14 and 21

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Secondary Outcomes

Description: Time to wean off oxygen supplementation

Measure: Evolution of acute respiratory syndrome

Time: 21 days

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Description: WHO Ordinal Scale for Clinical Improvement that measures illness severity over time (0=uninfected; ambulatory, no limitation of activities=1; ambulatory, limitation of activities=2, hospitalized no oxygen therapy=3; hospitalized oxygen by mask or nasal prongs=4; hospitalized non invasive ventilation or high-flow oxygen=5; hospitalized intubation or mechanical ventilation=6; hospitalized ventilation + additional organ support=7; death=8)

Measure: Change in Clinical Condition

Time: 21 days

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Description: Time to be discharged from hospital

Measure: Hospital discharge

Time: 21 days

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Description: Evaluation of change in acute respiratory syndrome

Measure: Rate of mortality within 21-days

Time: 21 days

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Description: Evaluation of change in acute respiratory syndrome

Measure: Need of mechanical ventilation

Time: 21 days

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Primary Outcomes

Measure: Percentage of Participants with at Least a 2 Point Improvement in the Ordinal Scale

Time: Baseline to Day 14

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Secondary Outcomes

Measure: Time to Clinical Improvement (TTCI)

Time: Up to Day 28

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Measure: Number of Participants with Overall Death Rate

Time: Day 14, Day 28

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Measure: Number of Participants With Rate of Mechanical Ventilation

Time: Up to Day 28

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Measure: Time to Mechanical Ventilation

Time: Up to Day 28

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Measure: Overall survival

Time: Up to Day 28

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Measure: Time to Improvement (2 points) in Clinical Measures Using the Ordinal Scale

Time: Baseline, Day 28

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Measure: Time to Intensive Care Unit (ICU) Admission

Time: Up to Day 28

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Measure: Rate of Intensive Care Unit (ICU) Admission

Time: Up to Day 28

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Measure: Length of Stay in Hospital

Time: Up to Day 28

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Measure: Percentage of Participants Discharged from Hospital

Time: Up to Day 28

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Measure: Length of Stay in Intensive Care Unit (ICU)

Time: Up to Day 28

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Measure: Duration of Oxygen Supplementation

Time: Up to Day 28

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Measure: Duration of Mechanical Ventilation

Time: Up to Day 28

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Description: The ViVi or Vienna Vaccine Safety Initiative Disease Severity Score ranges from 0 to 22 with the disease severity indicated by increasing score. It is used to score disease severity and risk in patients with influenza-like illness and/or other forms of acute respiratory infections (e.g. RSV, adenovirus metapneumovirus, rhinovirus and other respiratory viral pathogens), including in infants and children. The Investigator will ask yes/no questions to the patient, and the mobile application will automatically calculate the score.

Measure: Change in Vienna Vaccine Safety Initiative (ViVI) Disease Severity Score

Time: Up to Day 28

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Measure: Time to Clinical Improvement in Participants ≤ 70 Years Old

Time: Up to Day 28

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Measure: Time to Clinical Improvement in Participants > 70 Years Old

Time: Up to Day 28

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Measure: Time to Clinical Improvement in Participants with Pre-existing Diseases

Time: Up to Day 28

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Measure: Change in Oxygenation Index

Time: Up to Day 28

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Measure: Time to Improvement of One Point Using WHO Ordinal Scale Improvement

Time: Up to Day 28

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Measure: Percentage of Participants Experiencing WHO Ordinal Scale Improvement of >1 point

Time: Up to Day 28

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Measure: Change from Baseline in C-reactive protein (CRP) Levels

Time: Up to Day 28

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Measure: Change from Baseline in Ferritin Levels

Time: Up to Day 28

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Measure: Change from Baseline in Lactate Dehydrogenase (LDH) Levels

Time: Up to Day 28

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Measure: Changes from Baseline in Blood Plasma Cytokines Levels

Time: Up to Day 28

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Measure: Number of Participants with Adverse Events (AE)

Time: From start of study drug administration up to Day 28

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Primary Outcomes

Description: Sum of the days the patient did not receive VM, but if death occurs before D28, the score is zero

Measure: Ventilator-free days

Time: 28 days

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Secondary Outcomes

Measure: Mortality

Time: 28 and 90 days

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Description: Used to determine the extent of a person's organ function or rate of failure, from 0 to 24, with severity increasing the higher the score

Measure: Sequential Organ Failure Assessment Score

Time: Days 1, 3, 7, 14, 21 and 28

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Description: Ratio of arterial oxygen partial pressure (PaO2 in mmHg) to fractional inspired oxygen (FiO2 expressed as a fraction, not a percentage)

Measure: P/F ratio

Time: Days 1, 3, 7, 14, 21 and 28

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Measure: Lung compliance

Time: Days 1, 3, 7, 14, 21 and 28

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Description: Severity scoring of lung oedema on the chest radiograph

Measure: Radiological score

Time: Days 1, 3, 7, 14, 21 and 28

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Description: Concentration in mg/L

Measure: Biological efficacy endpoints - C-reactive protein

Time: Days 1, 3, 7, 14, 21 and 28

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Description: Concentration in microgram/L

Measure: Biological efficacy endpoints - Procalcitonin

Time: Days 1, 3, 7, 14, 21 and 28

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Description: Number of CD4 HLA-DR+ and CD38+, CD8 lymphocytes

Measure: Immunological profile

Time: Up to 28 days

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Description: Use of corticosteroids, antiretroviral, chloroquine

Measure: Number of patients using other treatments for COVID-19 related ARDS

Time: Up to 28 days

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Measure: Occurrence of deep vein thrombosis or pulmonary embolism

Time: 28 days

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Measure: Total duration of mechanical ventilation, ventilatory weaning and curarisation

Time: 28 days

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Description: Divided in 3 stages, with higher severity of kidney injury in higher stages

Measure: Kidney Disease: Improving Global Outcomes (KDIGO) score and need for dialysis

Time: 28 days

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Description: Kidney failure, hypersensitivity with cutaneous or hemodynamic manifestations, aseptic meningitis, hemolytic anemia, leuko-neutropenia, transfusion related acute lung injury (TRALI)

Measure: Occurrence of adverse event related to immunoglobulins

Time: 28 days

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Description: Medical research council sum score on awakening

Measure: Occurrence of critical illness neuromyopathy

Time: Up to 28 days

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Description: Radiological and clinical context associated with a bacteriological sampling in culture of tracheal secretions, bronchiolar-alveolar lavage or a protected distal sampling

Measure: Occurrence of ventilator-acquired pneumonia

Time: Up to 28 days

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Primary Outcomes

Description: Respiratory decompensation New or worsening congestive HF Requirement for vasopressor therapy and/or inotropic or mechanical circulatory support Ventricular tachycardia or fibrillation lasting at least 30 seconds and/or associated with hemodynamic instability or pulseless electrical activity, or resuscitated cardiac arrest Initiation of renal replacement therapy

Measure: Time to first occurrence of either death from any cause or new/worsened organ dysfunction through 30 days of follow up, defined as at least one of the following:

Time: Randomization through Day 30

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Secondary Outcomes

Description: Time to death from any cause Time to new/worsened organ dysfunction (as defined in the primary outcome measure) Clinical status at Day 30 for patients still hospitalized and without any worsening organ dysfunction (using points 3 to 5 of a 7-point ordinal scale) Time to hospital discharge

Measure: Hierarchical composite outcome measures:

Time: Randomization through Day 30

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Description: Time to hospital discharge

Measure: Time to hospital discharge

Time: Randomization through Day 30

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Description: Total number of days alive, out of hospital, and/or free from mechanical ventilation

Measure: Total number of days alive, out of hospital, and/or free from mechanical ventilation

Time: Randomization through Day 30

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Description: Total number of days alive, not in the ICU, and free from mechanical ventilation (as defined in the primary outcome measure)

Measure: Total number of days alive, not in the ICU, and free from mechanical ventilation (as defined in the primary outcome measure)

Time: Randomization through Day 30

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Description: Time to death from any cause

Measure: Time to death from any cause

Time: Randomization through Day 30

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Description: Time to new/worsened organ dysfunction

Measure: Time to new/worsened organ dysfunction

Time: Randomization through Day 30

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Description: Time to acute kidney injury (defined as doubling of s-Creatinine compared to baseline)

Measure: Time to acute kidney injury (defined as doubling of s-Creatinine compared to baseline)

Time: Randomization through Day 30

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Primary Outcomes

Description: Number and severity of treatment emergent adverse events

Measure: Safety and Tolerability of SAD of TD-0903: Adverse Events

Time: Day 1 to Day 8

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Description: Number and severity of treatment emergent adverse events

Measure: Safety and Tolerability of MAD of TD-0903: Adverse Events

Time: Day 1 to Day 14

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Secondary Outcomes

Description: Multiple PK variables of TD-0903 will be assessed during SAD and may include, but are not limited to: Area under the plasma concentration-time curve (AUC)

Measure: Pharmacokinetics (PK) of TD-0903 when given as a Single Ascending Dose (SAD): AUC

Time: Day 1 through Day 4

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Description: Multiple PK variables of TD-0903 will be assessed during SAD and may include, but are not limited to: Maximum observed concentration (Cmax)

Measure: Pharmacokinetics (PK) of TD-0903 when given as a Single Ascending Dose (SAD): Cmax

Time: Day 1 through Day 4

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Description: Multiple PK variables of TD-0903 will be assessed during SAD and may include, but are not limited to: Time to reach maximum observed concentration (Tmax)

Measure: Pharmacokinetics (PK) of TD-0903 when given as a Single Ascending Dose (SAD): Tmax

Time: Day 1 through Day 4

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Description: Multiple PK variables of TD-0903 will be assessed during MAD and may include, but are not limited to: Area under the plasma concentration-time curve (AUC)

Measure: Pharmacokinetics (PK) of TD-0903 when given as a Multiple Ascending Dose (MAD): AUC

Time: Day 1 through Day 9

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Description: Multiple PK variables of TD-0903 will be assessed during MAD and may include, but are not limited to: Maximum observed concentration (Cmax)

Measure: Pharmacokinetics (PK) of TD-0903 when given as a Multiple Ascending Dose (MAD): Cmax

Time: Day 1 through Day 9

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Description: Multiple PK variables of TD-0903 will be assessed during MAD and may include, but are not limited to: Time to reach maximum observed concentration (Tmax)

Measure: Pharmacokinetics (PK) of TD-0903 when given as a Multiple Ascending Dose (MAD): Tmax

Time: Day 1 through Day 9

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Primary Outcomes

Description: Percentage of patients who become RT-PCR negative with two RT-PCR tests performed at day 6 and day 7

Measure: RT-PCR result

Time: 6th and 7th day

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Secondary Outcomes

Description: Time to progression to next stage of SARS-CoV-2 disease severity index

Measure: Progression of symptoms

Time: 7 days

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Description: Death

Measure: Mortality

Time: 30 days

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