Correlated Drug Terms (82)

---

	Name (Synonyms)	Correlation
drug192	Anakinra Wiki	0.20
drug3511	ventilatory support with oxygen therapy Wiki	0.17
drug2897	Therapeutic Plasma exchange Wiki	0.17
drug2120	Piperacillin-tazobactam Wiki	0.17
drug1094	Favipiravir Combined With Tocilizumab Wiki	0.17
drug2999	Ultra-Low-dose radiotherapy Wiki	0.17
drug1290	Hydroxychloroquine + lopinavir/ritonavir Wiki	0.17
drug1325	Hydroxychloroquine, Azithromycin Wiki	0.17
drug1465	Intranasal heparin sodium (porcine) Wiki	0.17
drug1324	Hydroxychloroquine sulfate &Azithromycin Wiki	0.17
drug779	Corticosteroid injection Wiki	0.17
drug303	Avdoralimab Wiki	0.17
drug1442	Interferon-β1a Wiki	0.17
drug196	Anakinra Prefilled Syringe Wiki	0.17
drug2261	Protocolised mechanical ventilation strategy Wiki	0.17
drug1116	Fixed-duration Hydrocortisone Wiki	0.17
drug761	Convalescent Serum Wiki	0.17
drug623	Ceftaroline Wiki	0.17
drug1674	Maintenance or reduction of immunosuppression Wiki	0.17
drug561	COVID-19 exposure Wiki	0.17
drug2734	Standard-of-care treatment Wiki	0.17
drug2868	Ten-days oseltamivir Wiki	0.17
drug3418	pre_dinner Yoga-based breathing support Wiki	0.17
drug1329	Hydroxychloroquine, Doxycycline Wiki	0.17
drug658	Chloroquine analog (GNS651) Wiki	0.17
drug739	Continuous renal replacement therapy Wiki	0.17
drug3351	morning Yoga-based breathing support Wiki	0.17
drug189	Amoxicillin-clavulanate Wiki	0.17
drug1117	Fixed-duration higher dose Hydrocortisone Wiki	0.17
drug1467	Intravenous Immune Globulin Wiki	0.17
drug1670	Macrolide administered for 3-5 days Wiki	0.17
drug1773	Monalizumab Wiki	0.17
drug1326	Hydroxychloroquine, Clindamycin Wiki	0.17
drug2622	Shock-dependent hydrocortisone Wiki	0.17
drug1438	Interferon-Alpha2B Wiki	0.17
drug1328	Hydroxychloroquine, Clindamycin, Primaquine - low dose. Wiki	0.17
drug2121	Piperacillin/tazobactam Wiki	0.17
drug1734	Mesenchymal stem cell therapy Wiki	0.17
drug1327	Hydroxychloroquine, Clindamycin, Primaquine - high dose. Wiki	0.17
drug625	Cell therapy protocol 1 Wiki	0.17
drug1113	Five-days oseltamivir Wiki	0.17
drug624	Ceftriaxone Wiki	0.17
drug1111	Fisetin Wiki	0.17
drug1671	Macrolide administered for up to 14 days Wiki	0.17
drug2381	Recombinant Bacterial ACE2 receptors -like enzyme of B38-CAP (rbACE2) Wiki	0.17
drug2084	Pembrolizumab (MK-3475) Wiki	0.17
drug1551	Lactoferrin (Apolactoferrin) Wiki	0.17
drug2827	Taking biological samples Wiki	0.17
drug2937	Tocilizumab Prefilled Syringe Wiki	0.17
drug2156	Placebo of excipient(s) will be administered Wiki	0.17
drug626	Cell therapy protocol 2 Wiki	0.17
drug3419	pre_lunch Yoga-based breathing support Wiki	0.17
drug1786	Moxifloxacin or Levofloxacin Wiki	0.17
drug2898	Therapeutic anticoagulation Wiki	0.12
drug3029	Usual Care Wiki	0.12
drug2625	Siltuximab Wiki	0.12
drug778	Corticosteroid Wiki	0.12
drug1623	Low molecular weight heparin Wiki	0.12
drug1596	Lopinavir-Ritonavir Wiki	0.12
drug2633	Simvastatin Wiki	0.12
drug2413	Remdesivir Wiki	0.12
drug1605	Lopinavir/ritonavir Wiki	0.11
drug394	Best Practice Wiki	0.10
drug2683	Standard Medical Treatment Wiki	0.10
drug1883	Nivolumab Wiki	0.10
drug1885	No Intervention Wiki	0.10
drug1743	Methylprednisolone Wiki	0.10
drug313	Azithromycin Wiki	0.09
drug1977	Online Survey Wiki	0.09
drug763	Convalescent plasma Wiki	0.08
drug2707	Standard of care Wiki	0.08
drug2562	Sarilumab Wiki	0.08
drug870	Dexamethasone Wiki	0.07
drug1284	Hydroxychloroquine Wiki	0.07
drug1607	Losartan Wiki	0.06
drug703	Colchicine Wiki	0.06
drug3085	Vitamin C Wiki	0.05
drug2122	Placebo Wiki	0.05
drug2176	Placebos Wiki	0.04
drug1087	Favipiravir Wiki	0.04
drug752	Convalescent Plasma Wiki	0.04
drug2698	Standard of Care Wiki	0.03

Correlated MeSH Terms (31)

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	Name (Synonyms)	Correlation
D055501	Macrophage Activation Syndrome NIH	0.17
D030341	Nidovirales Infections NIH	0.12
D011014	Pneumonia NIH	0.12
D009202	Cardiomyopathies NIH	0.10
D009362	Neoplasm Metastasis NIH	0.09
D003324	Coronary Artery Disease NIH	0.09
D011618	Psychotic Disorders NIH	0.08
D003333	Coronaviridae Infections NIH	0.08
D012327	RNA Virus Infections NIH	0.08
D018352	Coronavirus Infections NIH	0.08
D009369	Neoplasms, NIH	0.07
D045169	Severe Acute Respiratory Syndrome NIH	0.07
D007676	Kidney Failure, Chronic NIH	0.07
D029424	Pulmonary Disease, Chronic Obstructive NIH	0.06
D014777	Virus Diseases NIH	0.06
D008173	Lung Diseases, Obstructive NIH	0.06
D007239	Infection NIH	0.05
D020521	Stroke NIH	0.05
D055371	Acute Lung Injury NIH	0.05
D012127	Respiratory Distress Syndrome, Newborn NIH	0.05
D012128	Respiratory Distress Syndrome, Adult NIH	0.04
D018450	Disease Progression NIH	0.04
D011024	Pneumonia, Viral NIH	0.04
D003141	Communicable Diseases NIH	0.04
D012140	Respiratory Tract Diseases NIH	0.04
D013577	Syndrome NIH	0.04
D001523	Mental Disorders NIH	0.04
D007249	Inflammation NIH	0.03
D012141	Respiratory Tract Infections NIH	0.03
D002318	Cardiovascular Diseases NIH	0.03
D016638	Critical Illness NIH	0.02

Correlated HPO Terms (10)

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	Name (Synonyms)	Correlation
HP:0002090	Pneumonia HPO	0.12
HP:0001638	Cardiomyopathy HPO	0.10
HP:0001677	Coronary artery atherosclerosis HPO	0.09
HP:0000709	Psychosis HPO	0.08
HP:0002664	Neoplasm HPO	0.07
HP:0006510	Chronic pulmonary obstruction HPO	0.06
HP:0006536	Pulmonary obstruction HPO	0.06
HP:0001297	Stroke HPO	0.05
HP:0011947	Respiratory tract infection HPO	0.03
HP:0001626	Abnormality of the cardiovascular system HPO	0.03

Primary Outcomes

Measure: All-cause mortality

Time: Day 90

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Description: Primary end-point for patients with suspected or proven COVID-19 pandemic infection

Measure: Days alive and not receiving organ support in ICU

Time: Day 21

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Secondary Outcomes

Measure: ICU Mortality

Time: Day 90

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Measure: ICU length of stay

Time: Day 90

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Measure: Hospital length of stay

Time: Day 90

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Measure: Ventilator free days

Time: Day 28

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Measure: Organ failure free days

Time: Day 28

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Measure: All-cause mortality

Time: 6 months

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Description: EQ5D-5L and WHODAS 2.0 (not completed in all regions)

Measure: Health-related Quality of life assessment

Time: 6 months

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Measure: Proportion of intubated patients who receive a tracheostomy

Time: Day 28

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Description: Characterised as home, rehabilitation hospital, nursing home or long-term care facility, or another acute hospital

Measure: Destination at time of hospital discharge

Time: Free text Day 90

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Measure: Readmission to the index ICU during the index hospitalization

Time: Day 90

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Measure: World Health Organisation 8-point ordinal scale outcome

Time: Hospital discharge

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Other Outcomes

Description: Antibiotic Domain specific outcome

Measure: Occurrence of multi-resistant organism colonisation/infection

Time: Day 90, censored at hospital discharge

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Description: Antibiotic Domain specific outcome

Measure: Occurrence clostridium difficile

Time: Day 90, censored at hospital discharge

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Description: Macrolide Duration domain specific outcome, and COVID-19 Antiviral Domain specific outcome.

Measure: Occurrence of serious ventricular arrhythmia (including ventricular fibrillation) or sudden unexpected death

Time: Day 90, censored at hospital discharge

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Description: Antiviral Domain specific outcome. Only required at selected sites.

Measure: Change from baseline influenza virus levels in upper and lower respiratory tract specimens

Time: Day 3, up to Day 7

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Description: COVID-19 Antiviral Domain and COVID-19 Immune Modulation Domain specific endpoint

Measure: Serial detection of SARS-CoV-2 in upper or lower respiratory tract specimens (using only specimens collected for routine clinical testing)

Time: Day 90, censored at hospital discharge

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Primary Outcomes

Description: This is a composite outcome measure. Criteria for fever normalization: Temperature < 36.6 °C armpit, < 37.2 °C oral sustained for at least 72 hours and criteria for oxygen normalization: peripheral capillary oxygen saturation (Sp02) > 94% sustained for at least 72 hours.

Measure: Proportion of Participants With Normalization of Fever and Oxygen Saturation Through Day 14

Time: First dose date up to 14 days

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Secondary Outcomes

Description: Measured in days

Measure: Duration of hospitalization

Time: Up to 28 days

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Description: Criteria for: Temperature < 36.6 °C armpit, < 37.2 °C oral, or < 37.8 °C rectal sustained for at least 72 hours.

Measure: Proportion of Participants With Normalization of Fever Through Day 14

Time: First dose date up to 14 days

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Description: Blood routine test

Measure: Change from baseline in white blood cell and differential count

Time: Day 1 through Day 28

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Description: Oropharyngeal or anal swabs

Measure: Time to first negative in 2019 novel Corona virus RT-PCR test

Time: Up to 28 days

---

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

Measure: All-cause mortality

Time: up to 12 weeks

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Description: Serum hsCRP

Measure: Change from baseline in hsCRP

Time: Day 1 through Day 28

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Description: Serum inflammatory cytokines

Measure: Change from baseline in cytokines IL-1β, IL-10, sIL-2R, IL-6, IL-8 and TNF-α

Time: Day 1 through Day 28

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Description: Flow cytometry for peripheral whole blood

Measure: Change from baseline in proportion of CD4+CD3/CD8+CD3 T cells

Time: Day 1 through Day 28 (if applicable)

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Primary Outcomes

Description: Definition of clinical cure: The viral load of the respiratory specimen was negative for two consecutive times (the interval between the two tests was greater than or equal to one day), the lung image improved, and the body temperature returned to normal for more than 3 days, and the clinical manifestation improved.

Measure: Clinical cure rate

Time: 3 months

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Secondary Outcomes

Measure: Viral nucleic acid test negative conversion rate and days from positive to negative

Time: 14 days after taking medicine

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Measure: Duration of fever

Time: 14 days after taking medicine

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Measure: Lung imaging improvement time

Time: 14 days after taking medicine

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Measure: Mortality rate because of Corona Virus Disease 2019

Time: 3 months

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Measure: Rate of non-invasive or invasive mechanical ventilation when respiratory failure occurs

Time: 3 months

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Measure: Mean in-hospital time

Time: 3 months

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Primary Outcomes

Description: rate of patients with no need in increase of FiO2 to maintain stable SO2 and no need of intubation

Measure: arrest in deterioration of pulmonary function

Time: 7days

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Description: rate of patients with change of oxygen saturation >3 percentage points or >10% or decrease in FiO2 need or reduction in pulmonary consolidations >30% at HR CT-scan

Measure: improving in pulmonary function

Time: 7 days

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Secondary Outcomes

Description: rate of patients needed of intubation

Measure: need of oro-tracheal intubation

Time: +7 days

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Description: rate of patients dead

Measure: death

Time: 14days

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Primary Outcomes

Description: defined as the time from randomization to either an improvement of two points on a six-category ordinal scale or discharge from the hospital: 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: Time to Clinical Improvement

Time: at day 15

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Secondary Outcomes

Description: defined as independece from supplemental oxygen

Measure: Time to improvement in oxygenation

Time: during hospital admission (up to 28 days)

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Description: defined by Pa02/FiO2 ratio while breading room air

Measure: Mean change in oxygenation

Time: day 1, day 15 or hospital discharge, whichever is first

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Measure: Number of days with hypoxia

Time: during hospital admission (up to 28 days)

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Measure: Number of days of supplemental oxygen use

Time: during hospital admission (up to 28 days)

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Measure: Time to absence fever for more than 48h without antipyretics

Time: during hospital admission (up to 28 days)

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Measure: Number of days with fever

Time: during hospital admission (up to 28 days)

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Measure: Time to halving of CRP levels compared to peak value during trial

Time: during hospital admission (up to 28 days)

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Measure: Time to halving of ferritin levels compared to peak value during trial

Time: during hospital admission (up to 28 days)

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Measure: Incidence of AEs (Adverse Events)

Time: during hospital admission (up to 28 days)

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Measure: Incidence of SAEs (Serious Adverse Events)

Time: during hospital admission (up to 28 days)

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Measure: Duration of hospital stay

Time: during hospital admission (up to 28 days)

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Measure: Duration of hospital stay in survivors

Time: during hospital admission (up to 28 days)

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Description: SOFA score: 0 (best) - 24 (worse)

Measure: Mean change of SOFA score (Sequential Organ Failure Assessment) between day 1 and day 7

Time: Day 1, day 7or hospital discharge, whichever is first

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Description: SOFA score: 0 (best) - 24 (worse)

Measure: Mean change of SOFA score between day 1 and day 15

Time: day 1, day 15 or hospital discharge, whichever is first

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Description: 6-point ordinal scale: 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: Percentage of patients reporting each severity rating on a 6-point ordinal scale in relation to serum IL-1

Time: at day 15 or hospital discharge, whichever is first

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Description: 6-point ordinal scale: 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: Percentage of patients reporting each severity rating on a 6-point ordinal scale in relation to serum IL-6

Time: at day 15 or hospital discharge, whichever is first

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Measure: Incidence of nosocomial bacterial or invasive fungal infection

Time: during hospital admission (up to 28 days)

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Description: defined by Hs (Hemophagocytic Syndrome) score

Measure: incidence of secondary haemophagocytic lymphohistiocytosis

Time: during hospital admission (up to 28 days)

---

Description: defined by Hs score

Measure: Incidence of secondary haemophagocytic lymphohistiocytosisscore in relation to serum IL-1

Time: during hospital admission (up to 28 days)

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Description: defined by Hs score

Measure: Incidence of secondary haemophagocytic lymphohistiocytosis in relation to serum IL-6

Time: during hospital admission (up to 28 days)

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Measure: Time to first use of high-flow oxygen devices, non-invasive or invasive mechanical ventilation in non-ventilated patients

Time: during hospital admission (up to 28 days)

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Measure: Time to first use of salvage systemic steroids in ventilated patients

Time: during hospital admission (up to 28 days)

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Measure: Number of ventilator free days

Time: during hospital admission (up to 28 days)

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Measure: Duration of mechanical ventilation in ventilated patients

Time: during hospital admission (up to 28 days)

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Measure: Duration of ICU stay in patients that enrolled in trial while already on invasive or non-invasive mechanical ventilation

Time: during hospital admission (up to 28 days)

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Measure: Time to progression to ARDS in ventilated patients, according to the adapted Berlin criteria

Time: during hospital admission (up to 28 days)

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Measure: Time to progression to ARDS in ventilated patients according to IL-1

Time: during hospital admission (up to 28 days)

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Measure: Time to progression to ARDS in ventilated patients according to IL-6

Time: during hospital admission (up to 28 days)

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Measure: All-cause mortality rate (excluding group that entered during ventilation)

Time: during hospital admission (up to 28 days)

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Measure: Percentage of patients in clinical status on 6-point Ordinal Scale

Time: at 10-20 weeks follow-up

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Measure: Incidence of lung function abnormalities

Time: at 10-20 weeks follow-up

---

Measure: Incidence of lung fibrosis on chest CT scan

Time: at 10-20 weeks follow-up

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Measure: All-cause mortality rate

Time: at 10-20 weeks follow-up

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Primary Outcomes

Description: Tmax Response: Resolution of fever (from Tmax > 38C in 24H period to Tmax < 38C in following 24H period, with Tmax measured by commonly accepted clinical methods [forehead, tympanic, oral, axillary, rectal]). Maximum temperature within 24-hour period of time (0:00-23:59) on the day prior to, day of, and every 24 hours after tocilizumab administration. The primary endpoint is absence of Tmax greater than or equal to 38ºC in the 24-hour period following tocilizumab administration.

Measure: Clinical response

Time: Assessed for the 24 hour period after tocilizumab administration

---

Description: CRP normalization rate: Calculated as the ratio of the number of patients who achieve normal CRP value following tocilizumab administration and total number of patients who receive tocilizumab. Time to CRP normalization: Calculated as the number of hours between tocilizumab administration and first normal CRP value.

Measure: Biochemical response

Time: Assessed every 24 hours during patient's hospitalization, up to 4 weeks after tocilizumab administration

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Secondary Outcomes

Description: 28-Day Overall Survival is defined as the status of the patient at the end of 28 days, beginning from the time of the first dose of tocilizumab.

Measure: Overall survival

Time: 28 days

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Description: This will be defined as the percentage of patients who are discharged in stable condition compared to the percentage of patients who die in the hospital. Patients who are discharged to hospice will be excluded from this calculation.

Measure: Survival to hospital discharge

Time: Hospitalization, up to 4 weeks after tocilizumab administration

---

Description: This will be a binary outcome defined by worsening COVID-19 pneumonitis resulting in transition from clinical Group A or Group B COVID-19 pneumonitis to critical COVID-19 pneumonitis during the course of the patient's COVID-19 infection. This diagnosis will be determined by treating physicians on the basis of worsening pulmonary infiltrates on chest imaging as well as clinical deterioration marked by persistent fever, rising supplemental oxygen requirement, declining PaO2/FiO2 ratio, and the need for intensive care such as mechanical ventilation or vasopressor/inotrope medication(s).

Measure: Progression of COVID-19 pneumonitis

Time: Hospitalization, up to 4 weeks after tocilizumab administration

---

Description: This will be a binary outcome defined as worsening COVID-19 disease resulting in the use of non-invasive (BiPap, heated high-flow nasal cannula) or invasive positive pressure ventilation during the course of the patient's COVID-19 infection. For patients admitted to the hospital using non-invasive mechanical ventilation, the utilization of mechanical ventilation will count toward this metric, as well. Calculated as the ratio of the number of patients who require non-invasive or invasive positive pressure ventilation during hospitalization and total number of patients who receive tocilizumab.

Measure: Rate of non-elective mechanical ventilation

Time: Hospitalization, up to 4 weeks after tocilizumab administration

---

Description: This will be a continuous outcome defined by the amount of time between initiation and cessation of mechanical ventilation (invasive and non-invasive).

Measure: Duration of mechanical ventilation

Time: Hospitalization, up to 4 weeks after tocilizumab administration

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Description: This will be a continuous outcome defined by the amount of time between tocilizumab dose administration and the initiation of mechanical ventilation. This will be treated as a time-to-event with possible censoring.

Measure: Time to mechanical ventilation

Time: Assessed over hospitalization, up to 4 weeks after tocilizumab administration

---

Description: This will be a binary outcome defined as utilization of any vasopressor or inotropic medication during the course of the patient's COVID-19 infection. Calculated as the ratio of the number of patients who require vasopressor or inotrope medication during hospitalization and total number of patients who receive tocilizumab.

Measure: Rate of vasopressor/inotrope utilization

Time: Hospitalization, up to 4 weeks after tocilizumab administration

---

Description: This will be a continuous outcome defined by the amount of time between initiation of first and cessation of last vasopressor or inotrope medication(s).

Measure: Duration of vasopressor/inotrope utilization

Time: Hospitalization, up to 4 weeks after tocilizumab administration

---

Description: This will be a continuous outcome defined by the amount of time between first tocilizumab dose administration and the initiation of vasopressor or inotropic medication(s). This will be treated as a time-to-event with possible censoring.

Measure: Time to vasopressor or inotropic utilization

Time: Assessed over hospitalization, up to 4 weeks after tocilizumab administration

---

Description: Number of ICU days is defined as the time period when a patient is admitted to the ICU (defined as the timestamp on the first vital signs collected in an ICU) until they are transferred from the ICU to a non-ICU setting such as a general acute care bed (defined as the timestamp on the first vital signs collected outside an ICU, excepting any "off the floor" vital signs charted from operating rooms or procedure or imaging suites). Death in the ICU will be a competing risk.

Measure: Number of ICU days

Time: Hospitalization, up to 4 weeks after tocilizumab administration

---

Description: Duration of increased supplemental oxygen requirement from baseline is defined as the time period (number of days) during which the participant requires supplemental oxygen in excess of his/her baseline supplemental oxygen requirement. The supplemental oxygen requirement is defined as the highest liters-per-minute flow of supplemental oxygen required by the patient each day over the course of the hospitalization.

Measure: Duration of Increased Supplemental Oxygen Requirement from Baseline

Time: Assessed over hospitalization, up to 4 weeks after tocilizumab administration

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Primary Outcomes

Description: Tmax Response: Resolution of fever (from Tmax > 38C in 24H period to Tmax < 38C in following 24H period, with Tmax measured by commonly accepted clinical methods [forehead, tympanic, oral, axillary, rectal]). Maximum temperature within 24-hour period of time (0:00-23:59) on the day prior to, day of, and every 24 hours after tocilizumab administration. The primary endpoint is absence of Tmax greater than or equal to 38ºC in the 24-hour period following tocilizumab administration.

Measure: Clinical response

Time: Assessed for the 24 hour period after tocilizumab administration

---

Description: CRP normalization rate: Calculated as the ratio of the number of patients who achieve normal CRP value following tocilizumab administration and total number of patients who receive tocilizumab. Time to CRP normalization: Calculated as the number of hours between tocilizumab administration and first normal CRP value.

Measure: Biochemical response

Time: Assessed every 24 hours during patient's hospitalization, up to 4 weeks after tocilizumab administration

---

Secondary Outcomes

Description: 28-Day Overall Survival is defined as the status of the patient at the end of 28 days, beginning from the time of the first dose of tocilizumab.

Measure: Overall survival

Time: 28 days

---

Description: This will be defined as the percentage of patients who are discharged in stable condition compared to the percentage of patients who die in the hospital. Patients who are discharged to hospice will be excluded from this calculation.

Measure: Survival to hospital discharge

Time: Hospitalization, up to 4 weeks after tocilizumab administration

---

Description: This will be a binary outcome defined by worsening COVID-19 pneumonitis resulting in transition from clinical Group A or Group B COVID-19 pneumonitis to critical COVID-19 pneumonitis during the course of the patient's COVID-19 infection. This diagnosis will be determined by treating physicians on the basis of worsening pulmonary infiltrates on chest imaging as well as clinical deterioration marked by persistent fever, rising supplemental oxygen requirement, declining PaO2/FiO2 ratio, and the need for intensive care such as mechanical ventilation or vasopressor/inotrope medication(s).

Measure: Progression of COVID-19 pneumonitis

Time: Hospitalization, up to 4 weeks after tocilizumab administration

---

Description: This will be a binary outcome defined as worsening COVID-19 disease resulting in the use of non-invasive (BiPap, heated high-flow nasal cannula) or invasive positive pressure ventilation during the course of the patient's COVID-19 infection. For patients admitted to the hospital using non-invasive mechanical ventilation, the utilization of mechanical ventilation will count toward this metric, as well. Calculated as the ratio of the number of patients who require non-invasive or invasive positive pressure ventilation during hospitalization and total number of patients who receive tocilizumab.

Measure: Rate of non-elective mechanical ventilation

Time: Hospitalization, up to 4 weeks after tocilizumab administration

---

Description: This will be a continuous outcome defined by the amount of time between initiation and cessation of mechanical ventilation (invasive and non-invasive).

Measure: Duration of mechanical ventilation

Time: Hospitalization, up to 4 weeks after tocilizumab administration

---

Description: This will be a continuous outcome defined by the amount of time between tocilizumab dose administration and the initiation of mechanical ventilation. This will be treated as a time-to-event with possible censoring.

Measure: Time to mechanical ventilation

Time: Assessed over hospitalization, up to 4 weeks after tocilizumab administration

---

Description: This will be a binary outcome defined as utilization of any vasopressor or inotropic medication during the course of the patient's COVID-19 infection. Calculated as the ratio of the number of patients who require vasopressor or inotrope medication during hospitalization and total number of patients who receive tocilizumab.

Measure: Rate of vasopressor/inotrope utilization

Time: Hospitalization, up to 4 weeks after tocilizumab administration

---

Description: This will be a continuous outcome defined by the amount of time between initiation of first and cessation of last vasopressor or inotrope medication(s).

Measure: Duration of vasopressor/inotrope utilization

Time: Hospitalization, up to 4 weeks after tocilizumab administration

---

Description: This will be a continuous outcome defined by the amount of time between first tocilizumab dose administration and the initiation of vasopressor or inotropic medication(s). This will be treated as a time-to-event with possible censoring.

Measure: Time to vasopressor or inotropic utilization

Time: Assessed over hospitalization, up to 4 weeks after tocilizumab administration

---

Description: Number of ICU days is defined as the time period when a patient is admitted to the ICU (defined as the timestamp on the first vital signs collected in an ICU) until they are transferred from the ICU to a non-ICU setting such as a general acute care bed (defined as the timestamp on the first vital signs collected outside an ICU, excepting any "off the floor" vital signs charted from operating rooms or procedure or imaging suites). Death in the ICU will be a competing risk.

Measure: Number of ICU days

Time: Hospitalization, up to 4 weeks after tocilizumab administration

---

Description: Duration of increased supplemental oxygen requirement from baseline is defined as the time period (number of days) during which the participant requires supplemental oxygen in excess of his/her baseline supplemental oxygen requirement. The supplemental oxygen requirement is defined as the highest liters-per-minute flow of supplemental oxygen required by the patient each day over the course of the hospitalization.

Measure: Duration of Increased Supplemental Oxygen Requirement from Baseline

Time: Assessed over hospitalization, up to 4 weeks after tocilizumab administration

---

Primary Outcomes

Description: Group 1. Survival without needs of ventilator utilization (including non invasive ventilation and high flow) at day 14. Thus, events considered are needing ventilator utilization (including Non Invasive Ventilation, NIV or high flow), or death. New DNR order (if given after the inclusion of the patient) will be considered as an event at the date of the DNR.

Measure: Survival without needs of ventilator utilization at day 14. Group 1

Time: 14 days

---

Description: Group 1. Proportion of patients alive without non-invasive ventilation of high low at day 4 (WHO progression scale ≤ 5). A patient with new DNR order at day 4 will be considered as with a score > 5. WHO progression scale: Uninfected; non viral RNA detected: 0 Asymptomatic; viral RNA detected: 1 Symptomatic; Independent: 2 Symptomatic; Assistance needed: 3 Hospitalized; No oxygen therapy: 4 Hospitalized; oxygen by mask or nasal prongs: 5 Hospitalized; oxygen by NIV or High flow: 6 Intubation and Mechanical ventilation, pO2/FIO2>=150 OR SpO2/FIO2>=200: 7 Mechanical ventilation, (pO2/FIO2<150 OR SpO2/FIO2<200) OR vasopressors (norepinephrine >0.3 microg/kg/min): 8 Mechanical ventilation, pO2/FIO2<150 AND vasopressors (norepinephrine >0.3 microg/kg/min), OR Dialysis OR ECMO: 9 Dead: 10

Measure: WHO progression scale <=5 at day 4. Group 1.

Time: 4 days

---

Description: Group 2. Cumulative incidence of successful tracheal extubation (defined as duration extubation > 48h) at day 14 if patients have been intubated before day 14 ; or removal of NIV or high flow (for > 48h) if they were included under oxygen by NIV or High flow (score 6) and remained without intubation. Death or new DNR order (if given after the inclusion of the patient) will be considered as a competing event.

Measure: Cumulative incidence of successful tracheal extubation (defined as duration extubation > 48h) at day 14. Group 2.

Time: 14 days

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

Measure: WHO progression scale at day 4. Group 2.

Time: 4 days

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Secondary Outcomes

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

Measure: WHO progression scale

Time: 7 and 14 days

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Description: Overall survival

Measure: Survival

Time: 14, 28 and 90 days

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Measure: 28-day ventilator free-days

Time: 28 days

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Description: arterial blood pH of <7.25 with a partial pressure of arterial carbon dioxide [Paco2] of ≥60 mm Hg for >6 hours

Measure: respiratory acidosis at day 4

Time: 4 days

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Description: evolution of PaO2/FiO2 ratio

Measure: PaO2/FiO2 ratio

Time: day 1 to day 14

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Description: time to oxygen supply independency

Measure: time to oxygen supply independency

Time: 14 days

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Description: duration of hospitalization

Measure: duration of hospitalization

Time: 90 days

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Description: time to negative viral excretion

Measure: time to negative viral excretion

Time: 90 days

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Description: time to ICU discharge

Measure: time to ICU discharge

Time: 90 days

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Description: time to hospital discharge

Measure: time to hospital discharge

Time: 90 days

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Primary Outcomes

Measure: In-hospital mortality

Time: Through hospitalization, an average of 2 weeks

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Measure: Need for mechanical ventilation in the Intensive Care Unit

Time: Through hospitalization, an average of 2 weeks

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Primary Outcomes

Description: 28-day survival rate, defined by the proportion of patients still alive 28 days after randomization. The 28-day survival rate will be described in each arm of each cohort.

Measure: 28-day survival rate

Time: 28 days from randomization

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Secondary Outcomes

Description: Time to clinical improvement defined as the time from randomization to an improvement of two points (from the status at randomization) on a seven-category ordinal scale (WHO-ISARIC) or live discharge from the hospital, whichever comes first.

Measure: Time to clinical improvement

Time: 28 days from randomization

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Description: Clinical status will be assessed using a 7-point ordinal scale : Not hospitalized, no limitations on activities Not hospitalized, limitation on activities; Hospitalized, not requiring supplemental oxygen; Hospitalized, requiring supplemental oxygen; Hospitalized, on non-invasive ventilation or high flow oxygen devices; Hospitalized, on invasive mechanical ventilation or ECMO; Death.

Measure: Clinical status

Time: Day 7, Day 14, Day 28

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Description: Mean change in clinical status from baseline will be assessed using a 7-point ordinal scale.

Measure: Mean change in clinical status from baseline to days

Time: Day 7, Day 14, Day 28

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Description: Overall survival will be defined by the time from date of randomization until date of death, regardless of the cause. Any patient not known to have died at the time of analysis will be censored based on the last recorded date on which the patient was known to be alive.

Measure: Overall survival

Time: 3 months (i.e. at the the time of last patient last visit)

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Description: The length of stay in Intensive Care Unit (from the date of admission in the Unit to the date of discharge).

Measure: Length of stay in Intensive Care Unit

Time: 3 months (i.e. at the the time of last patient last visit)

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Description: The duration of mechanical ventilation or high flow oxygen devices (from the date of intubation to the stop date of mechanical ventilation or high flow oxygen)

Measure: Duration of mechanical ventilation or high flow oxygen devices

Time: 3 months (i.e. at the the time of last patient last visit)

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Description: The duration of hospitalization (from the date of hospitalization to the date of definitive discharge for live patients)

Measure: Duration of hospitalization

Time: 3 months (i.e. at the the time of last patient last visit)

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Measure: Rate of throat swab negativation

Time: Day 7, Day 14, Day 28

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Measure: Quantitative SARS-CoV-2 virus in throat swab and blood samples

Time: Day 7, Day 14, Day 28

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Measure: Rate of secondary infection by other documented pathogens

Time: Day 7, Day 14, Day 28 (if available)

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Description: Changes from baseline in neutrophils count (G/L)

Measure: Biological parameters

Time: 3 months (i.e. at the the time of last patient last visit)

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Description: Treatment-Emergent Adverse Events, Serious Adverse Events, Suspected Unexpected Serious Adverse Reactions, New Safety Issues described using the NCI-CTC AE classification v5. Number of participants with a discontinuation or temporary suspension of study drugs (for any reason).

Measure: Number of participants with treatment-related adverse events as assessed by CTCAE v5.0

Time: 3 months (i.e. at the the time of last patient last visit)

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Description: Incremental Cost-Effectiveness Ratios (ICERs) expressed in cost per Life Year Gained.

Measure: Cost-Effectiveness Analyses (CEA)

Time: 3 months (i.e. at the the time of last patient last visit)

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Description: Changes from baseline in lymphocytes count (G/L)

Measure: Biological parameters

Time: 3 months (i.e. at the the time of last patient last visit)

---

Description: Changes from baseline in platelets count (G/L)

Measure: Biological parameters

Time: 3 months (i.e. at the the time of last patient last visit)

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Description: Changes from baseline in hemoglobin count (g/dL)

Measure: Biological parameters

Time: 3 months (i.e. at the the time of last patient last visit)

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Description: Changes from baseline in CRP count (mg/L)

Measure: Biological parameters

Time: 3 months (i.e. at the the time of last patient last visit)

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Description: Changes from baseline in pro-inflammatory cytokine (IL6)

Measure: Biological parameters

Time: 3 months (i.e. at the the time of last patient last visit)

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Primary Outcomes

Description: Assessed by hospital records

Measure: Percentage of patients with normalization of SpO2 ≥96% on room air (measured without any respiratory support for at least 15 minutes

Time: through day 14 after study treatment initiation

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Secondary Outcomes

Description: Assessed by hospital records

Measure: Proportion of patients discharged from the emergency department and classified as low risk

Time: through End of Study, defined as 90 ± 14 days after study entry

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Description: Assessed by hospital records

Measure: Number of days of patient hospitalization

Time: through End of Study, defined as 90 ± 14 days after study entry

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Description: The clinical status will be assessed by the SOFA scores

Measure: Change from baseline in organ failure parameters

Time: Days 1, 3, 5, 7, 14 (+/- 1 day) and 28 (+/- 2 days) or until discharge whatever it comes first.

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Description: Determined as percentage of dead patients

Measure: Proportion of mortality rate

Time: through End of Study, defined as 90 ± 14 days after study entry

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Description: Determined as: Time to invasive mechanical ventilation (if not previously initiated); Time to independence from non-invasive mechanical ventilation; Time to independence from oxygen therapy.

Measure: Analysis of the remission of respiratory symptoms

Time: through End of Study, defined as 90 ± 14 days after study entry

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Description: by using the same imaging technique (chest X-ray or thoracic CT scan)

Measure: Evaluation of the radiological response

Time: at days 1 and 28 (+/- 2 days)

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Description: determined using oropharyngeal or anal swabs

Measure: Time to first negative in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RT-PCR test

Time: within 28 days from study inclusion

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Description: Baseline defined as the value collected at day 1, 2 hours before treatment administration

Measure: Change from baseline of absolute lymphocyte count (ALC),white blood cell count and white blood cell differential count

Time: days 3, 5, 7, 10, 14 and 28 after administration of study drug

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Description: Baseline defined as the value collected at day 1, 2 hours before treatment administration

Measure: Change from baseline of hemoglobin

Time: days 3, 5, 7, 10, 14 and 28 after administration of study drug

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Description: Baseline defined as the value collected at day 1, 2 hours before treatment administration

Measure: Change from baseline of platelets

Time: days 3, 5, 7, 10, 14 and 28 after administration of study drug

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Description: Baseline defined as the value collected at day 1, 2 hours before treatment administration

Measure: Change from baseline of activated partial thromboplastin time (aPTT)

Time: days 3, 5, 7, 10, 14 and 28 after administration of study drug

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Description: Baseline defined as the value collected at day 1, 2 hours before treatment administration

Measure: Change from baseline of Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST)

Time: days 3, 5, 7, 10, 14 and 28 after administration of study drug

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Description: Baseline defined as the value collected at day 1, 2 hours before treatment administration

Measure: Change from baseline of creatinine

Time: days 3, 5, 7, 10, 14 and 28 after administration of study drug

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Description: Baseline defined as the value collected at day 1, 2 hours before treatment administration

Measure: Change from baseline of glucose

Time: days 3, 5, 7, 10, 14 and 28 after administration of study drug

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Description: Baseline defined as the value collected at day 1, 2 hours before treatment administration

Measure: Change from baseline of total bilirubin

Time: days 3, 5, 7, 10, 14 and 28 after administration of study drug

---

Description: Baseline defined as the value collected at day 1, 2 hours before treatment administration

Measure: Change from baseline of albumin

Time: days 3, 5, 7, 10, 14 and 28 after administration of study drug

---

Description: Evaluated using the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v.5.0), SOFA scores.

Measure: Incidence of adverse events (AEs), incidence of prespecified AEs (safety and tolerability)

Time: Up to End of Study, defined as 90 ± 14 days after study entry

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Primary Outcomes

Description: At least 25% decrease between baseline sequential organ failure assessment SOFA score and measured sequential organ failure assessment SOFA score at Study Day 8

Measure: Change of baseline total sequential organ failure assessment (SOFA) score

Time: Visit study day 8

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Description: Resolution of all criteria of lower respiratory tract involvemed that led to study inclusion (except findings from imaging studies) at Study Day 8

Measure: Improvement of lung involvement measurements

Time: Visit study day 8

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Description: At least 50% increase of pO2/FiO2 ratio between baseline and study visit Day 8

Measure: Increase of pO2/FiO2 ratio

Time: Visit Study Day 8

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Secondary Outcomes

Description: Change of total sequential organ failure assessment (SOFA) score between baseline and study visit day 8 will be compared with historical comparators from Hellenic Sepsis Study Group Database (Sequential organ failure assessment range 0-24, high score associated with worst outcome)

Measure: Comparison of change of baseline total sequential organ failure assessment (SOFA) score in enrolled subjects towards historical comparators

Time: Screening, Day 8

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Description: Change of lung involvement measurements between baseline and study visit day 8 will be compared with historical comparators from Hellenic Sepsis Study Group Database

Measure: Comparison of change of lung involvement measurements in enrolled subjects towards historical comparators

Time: Screening, Day 8

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Description: Comparison of increase in pO2/FiO2 ratio towards historical comparators from Hellenic Sepsis Study Group Database

Measure: Comparison of pO2/FiO2 ratio in enrolled subjects towards historical comparators

Time: Screening, Day 8

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Description: Change of Sequential organ failure assessment (SOFA) score on day 28 (Sequential organ failure assessment range 0-24, high score associated with worst outcome)

Measure: Change of sequential organ failure assessment (SOFA) score

Time: Day 28

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Description: Mortality on day 28

Measure: Rate of Mortality

Time: Day 28

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Description: Mortality on day 90

Measure: Rate of Mortality

Time: Day 90

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Description: Cytokine stimulation from peripheral blood mononuclear cells will be compared between days 0 and 4

Measure: Cytokine stimulation

Time: Screening, Day 4

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Description: Gene expression of peripheral blood mononuclear cells will be compared between days 0 and 4

Measure: Gene expression

Time: Screening, Day 4

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Description: Change of serum/plasma proteins between days 0 and 4

Measure: Serum/plasma proteins

Time: Screening, Day 4

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Description: Classification of immune function of screened patients who are not enrolled in study drug since they are not characterized with MAS or immune dysregulation

Measure: Classification of the immune function

Time: Screening

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Primary Outcomes

Measure: The proportion of patients requiring mechanical ventilation

Time: Through study completion, and average of 6 months

---

Measure: Mean days of ventilation

Time: Through study completion, and average of 6 months

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Secondary Outcomes

Measure: The proportion of patients requiring ICU admission

Time: Through study completion, and average of 6 months

---

Measure: Overall 28-day survival

Time: 28 day from baseline

---

Measure: Change in symptom severity assessed by the World Health Organization (WHO) Coronavirus Disease 2019 (COVID19) ordinal scale measured daily up to 7 days from baseline

Time: 7 days from baseline

---

Measure: Duration of hospital and ICU stay

Time: Through study completion, and average of 6 months

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Primary Outcomes

Description: Entry into Intensive Care with invasive mechanical ventilation or death from any cause or clinical aggravation documented by the finding of a PaO2 / FiO2 ratio <150mm / Hg confirmed by a second arterial blood gas (ABG) measurement within four hours

Measure: Entry into Intensive Care with invasive mechanical ventilation or death from any cause or clinical aggravation

Time: two weeks from participants' allocation to study arm

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Secondary Outcomes

Description: Death

Measure: Death from any cause

Time: Two weeks from participants' allocation to study arm

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Description: Adverse events (AE) classified according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) scale

Measure: Tocilizumab toxicity

Time: Two weeks from participants' allocation to study arm

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Description: Levels of ferritin, lactate dehydrogenase and D-dimer and their correlation with the effectiveness of the treatment

Measure: Levels of interleukin-6 and C-reactive protein (CRP) and their correlation with the effectiveness of the treatment

Time: Two weeks from participants' allocation to study arm

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Description: Changes from baseline of the PaO2 / FiO2 ratio

Measure: Evaluate the progress of the PaO2 / FiO2 ratio

Time: Two weeks from participants' allocation to study arm

---

Description: Changes from baseline of the lymphocyte count

Measure: Evaluate the trend over time of the lymphocyte count

Time: Two weeks from participants' allocation to study arm

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Primary Outcomes

Description: Measured improvement in tissue as measured using FMTVDM

Measure: Improvement in FMTVDM Measurement with nuclear imaging.

Time: 72 hours

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Secondary Outcomes

Description: Extubation

Measure: Ventilator status

Time: 7 days

---

Description: Self explanatory

Measure: Survival status

Time: 30 days

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Primary Outcomes

Description: The time to event will be the time from administration of the investigational agent (or from randomization if the investigational agent was not administered) to the time of initiation of mechanical ventilation for subjects who are intubated and to the time of death for subjects who die prior to intubation. All subjects who do not have either event by the end of the follow-up period will be censored at 28 days.

Measure: Time to mechanical ventilation or death

Time: 28 days

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Secondary Outcomes

Description: Time to improvement will be assessed by changes in subjects' status, ranked on the ordinal scale: Discharged (or "ready for discharge" as evidenced by normal body temperature and respiratory rate, and stable oxygen saturation on ambient air or <= 2L supplemental oxygen) Non-ICU hospital ward (or "ready for hospital ward") not requiring supplemental oxygen Non-ICU hospital ward (or "ready for hospital ward") requiring supplemental oxygen ICU or non-ICU hospital ward, requiring non-invasive ventilation or high-flow oxygen ICU, requiring intubation and mechanical ventilation ICU, requiring ECMO or mechanical ventilation and additional organ support (e.g. vasopressors, renal replacement therapy) Death Higher scores indicate a worse outcome.

Measure: Time to improvement

Time: 28 days

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Description: Time to progression will be measured from the time the investigational medication is administered until the time of progression to non-invasive ventilation or high-flow oxygen. We will compare the groups using a stratified log-rank test and estimate the hazard ratio comparing the groups using a stratified Cox proportional hazards model. For patients requiring non-invasive ventilation or high-flow oxygen at baseline, their time to intubation or death will be assessed for this comparison.

Measure: Time to progression to non-invasive ventilation or high-flow oxygen, defined as >6L

Time: 28 days

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Description: The raw ordinal scale scores at days 4, 7, 14, 21, and 28 in subjects treated with tocilizumab therapy versus controls will be compared at each time point using a random intercept proportional odds logistic regression model. This model will be used to model all measurements together to estimate the differences between the treatment groups at each time point.

Measure: Raw ordinal scale scores at days 4, 7, 14, 21, and 28.

Time: Days 4, 7, 14, 21, and 28

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Description: Time to absence of the need for supplemental oxygen will be measured from time of investigational treatment administration. We will use the same approach as that employed for the comparison of time to clinical improvement. Only subjects on supplemental oxygen at the time of randomization will contribute to this analysis. Subjects who die will be censored at 29 days, and the groups will be compared using a stratified log-rank test and stratified Cox proportional hazards model.

Measure: Time to absence of the need for supplemental oxygen

Time: 28 days

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Description: The duration of supplemental oxygen will be compared between the groups. For this analysis, we will include all subjects in the analysis by assigning all subjects who did not receive supplemental oxygen a value of 0. Subjects who died following supplemental oxygen will be given a value of the number of days from when supplemental oxygen began until the end of the follow-up period. The groups will be compared using a Wilcoxon rank sum test.

Measure: Duration of supplemental oxygen

Time: 28 days

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Description: For time to improvement in the NEWS2 score to ≤ 2 or discharge from the hospital, we will use the same approach as time to clinical improvement. Subjects who die will be censored at the end of the study to indicate that they did not have an improvement event by the end of the study. The groups will be compared using a stratified log-rank test and stratified Cox proportional hazards model.

Measure: Time to improvement in NEWS2 score to ≤ 2 or discharge from the hospital.

Time: 28 days

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Description: Time to death will be measured from the time the investigational medication is administered until the time of the subject's death. We will compare the groups using a stratified log-rank test and estimate the hazard ratio comparing the groups using a stratified Cox proportional hazards model.

Measure: Time to death

Time: 28 days

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Description: Mortality at 28 days will be compared using a Mantel-Haenszel test to allow stratification on study site. The relative risk will be estimated using the Mantel-Haenszel method. If we have missing mortality data on any subjects, we will estimate the proportion of subjects who died in each treatment group using the estimate from the Kaplan-Meier curve in each group. Then, we will compare the two groups using the approaches described in Klein et al (citation: Klein JP, Logan B, Harhoff M, Anderson PK. Analyzing survival curves at a fixed point in time. Statistics in Medicine. 2007;26:4505-4519.)

Measure: Mortality at 28 days

Time: 28 days

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Description: Time to intubation will be measured from time of investigational treatment administration to the time of intubation. For this analysis, death will be treated as a competing risk. The analysis will compare the cause-specific hazard in the treatment groups using a Cox proportional hazards model. We will also compare the cumulative incidence functions between groups using the approach of Fine and Gray.

Measure: Time to intubation

Time: 28 days

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Description: The duration of mechanical ventilation will be compared between the groups using two approaches. First, we will include all subjects in the analysis by assigning all subjects who were not intubated a value of 0. Subjects who died following intubation will be given a value of the number of days from when mechanical ventilation began until the end of the follow-up period. The groups will be compared using a Wilcoxon rank sum test. Second, we will analyze only subjects who were intubated and compare the time on mechanical ventilation using a stratified log-rank test. Subjects who die without being taken off the ventilator will be censored at a duration of mechanical ventilation longer than the longest time.

Measure: Duration of mechanical ventilation

Time: 28 days

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Description: The proportion of subjects requiring ICU admission between baseline and 28 days will be measured as the number of subjects requiring ICU admission over their hospitalization over the number of evaluable subjects (i.e., the number of subjects not in the ICU at the time of investigational treatment administration). The groups will be compared using a Mantel-Haenszel test to allow stratification on study site. The relative risk will be estimated using the Mantel-Haenszel method.

Measure: Proportion of subjects requiring ICU admission

Time: 28 days

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Description: The time to discharge from the hospital in subjects, measured from the time of investigational treatment administration to time of discharge, will be compared using a stratified log-rank test. Subjects who die will be censored at Day 29 to indicate that they never left the hospital during the study.

Measure: Time to discharge

Time: 28 days

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Description: Safety and tolerability, defined as adverse events graded by CTCAE v5.0, will be compared using a Mantel-Haenszel test to allow stratification on study site. The relative risk will be estimated using the Mantel-Haenszel method.

Measure: Safety and tolerability

Time: 28 days

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Primary Outcomes

Description: The 7-day length of invasive MV for each arm will be estimated with 95% confidence intervals (CIs) using the exact binomial distribution. Their difference by the arms will be tested by Cochran-Mantel-Haenszel (CMH) test stratified by the age group and Sequential Organ Failure Assessment (SOFA) score at significance level of 0.05.

Measure: 7-day length of invasive mechanical ventilation (MV)

Time: Up to 7 days

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Description: Defined as death within 30-day after randomization. The 30-day mortality rate for each arm will be estimated with 95% CIs using the exact binomial distribution. Their difference by the arms will be tested CMH test stratified by the age group and SOFA score at significance level of 0.05.

Measure: 30-day mortality rate

Time: Up to 30-day after randomization

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Secondary Outcomes

Description: The rate of ICU transfer for each arm will be estimated with 95% CIs using the exact binomial distribution. Their difference by the arms will be tested CMH test stratified by the age group and SOFA score at significance level of 0.05.

Measure: Rate of intensive care (ICU) transfer

Time: Up to 2 years

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Description: The rate of invasive mechanical ventilation for each arm will be estimated with 95% CIs using the exact binomial distribution. Their difference by the arms will be tested CMH test stratified by the age group and SOFA score at significance level of 0.05.

Measure: Rate of invasive mechanical ventilation

Time: Up to 2 years

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Description: The rate of tracheostomy for each arm will be estimated with 95% CIs using the exact binomial distribution. Their difference by the arms will be tested CMH test stratified by the age group and SOFA score at significance level of 0.05.

Measure: Rate of tracheostomy

Time: Up to 2 years

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Description: Will first be described by median and inter-quartile, and then compared between two arms by Wilcoxon Sum-Rank test

Measure: Length of ICU stay

Time: Up to 2 years

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Measure: Length of hospital stay

Time: Up 2 years

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Primary Outcomes

Description: Until removal of mechanical ventilation, Control of hemoglobin, hematocrit, platelet , and leukocytes levels.

Measure: Hematic biometry

Time: 24 hours

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Description: Until removal of mechanical ventilation. Control of glucose, uric acid, cholesterol, urea, triglycerides, and creatinine.

Measure: Blood chemistry

Time: 24 hours

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Description: Until removal of mechanical ventilation. Control metabolic and repiratory alcalosis or acidosis.

Measure: Blood gas

Time: 24 hours

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Description: Until removal of mechanical ventilation, Control of hemoglobin, hematocrit, platelet , and leukocytes levels.

Measure: Hematic biometry

Time: 48 hours

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Description: Until removal of mechanical ventilation. Control of glucose, uric acid, cholesterol, urea, triglycerides, and creatinine.

Measure: Blood chemistry

Time: 48 hours

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Description: Until removal of mechanical ventilation. Control metabolic and repiratory alcalosis or acidosis.

Measure: blood gas

Time: 48 hours

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Description: Until removal of mechanical ventilation, Control of hemoglobin, hematocrit, platelet , and leukocytes levels.

Measure: Hematic biometry

Time: 72 hours

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Description: Until removal of mechanical ventilation. Control of glucose, uric acid, cholesterol, urea, triglycerides, and creatinine.

Measure: Blood chemistry

Time: 72 hours

---

Description: Until removal of mechanical ventilation. Control metabolic and repiratory alcalosis or acidosis.

Measure: blood gas

Time: 72 hours

---

Description: Until removal of mechanical ventilation, Control of hemoglobin, hematocrit, platelet , and leukocytes levels.

Measure: Hematic biometry

Time: 7 days

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Description: Until removal of mechanical ventilation. Control of glucose, uric acid, cholesterol, urea, triglycerides, and creatinine.

Measure: Blood chemistry

Time: 7 days

---

Description: Until removal of mechanical ventilation. Control metabolic and repiratory alcalosis or acidosis.

Measure: blood gas

Time: 7 days

---

Description: Until removal of mechanical ventilation, Control of hemoglobin, hematocrit, platelet , and leukocytes levels.

Measure: Hematic biometry

Time: 14 days

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Description: Until removal of mechanical ventilation. Control of glucose, uric acid, cholesterol, urea, triglycerides, and creatinine.

Measure: Blood chemistry

Time: 14 days

---

Description: Until removal of mechanical ventilation. Control metabolic and repiratory alcalosis or acidosis.

Measure: blood gas

Time: 14 days

---

Description: Until removal of mechanical ventilation. Monitoring for signs of pneumonia imaging.

Measure: thorax radiography

Time: 24 hours

---

Description: Until removal of mechanical ventilation. Monitoring for signs of pneumonia imaging.

Measure: thorax radiography

Time: 7 days

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Description: Until removal of mechanical ventilation. Monitoring for signs of pneumonia imaging.

Measure: thorax radiography

Time: 14 days

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Primary Outcomes

Measure: Clinical outcome as evaluated by the 7-category Clinical Status Ordinal Scale

Time: At least 60 days, up to 1 year

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Primary Outcomes

Measure: Cumulative Proportion of Participants Requiring Mechanical Ventilation by Day 28

Time: Up to Day 28

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Secondary Outcomes

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

Time: Up to Day 28

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Measure: Time to Clinical Failure, Defined as the Time to Death, Mechanical Ventilation, ICU Admission, or Withdrawal (whichever occurs first)

Time: Up to Day 28

---

Measure: Mortality Rate by Day 28

Time: Up to Day 28

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Measure: Time to Hospital Discharge or "Ready for Discharge" (as evidenced by normal body temperature and respiratory rate, and stable oxygen saturation on ambient air or >/= 2 liters (L) supplemental oxygen)

Time: Up to Day 28

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Measure: Percentage of Participants with Adverse Events

Time: Up to Day 60

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Measure: Percentage of Participants with any Post-Treatment Bacterial and/or Fungal Infection

Time: Up to Day 60

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Measure: Incidence of Post-Treatment Acute Kidney injury (defined by 50% increase of creatinine from baseline)

Time: Up to Day 60

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Primary Outcomes

Description: The primary endpoint for this cohort is progression of respiratory failure (binary yes/no while hospitalized). Progression of respiratory failure will be defined as a sustained increase in oxygen requirement (FiO2) or need for intubation/mechanical ventilation.

Measure: Progression of respiratory failure or death

Time: 14 days

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Primary Outcomes

Description: One-month mortality rate .

Measure: Survival

Time: One-month

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Primary Outcomes

Description: For each pairwise comparison with the 'no additional treatment' arm, the primary objective is to provide reliable estimates of the effect of study treatments on all-cause mortality.

Measure: All-cause mortality

Time: Within 28 days after randomisation

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Secondary Outcomes

Description: To assess the effects of study treatment on number of days stay in hospital

Measure: Duration of hospital stay

Time: Within 28 days and up to 6 months after the main randomisation

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Description: Among patients not on mechanical ventilation at baseline, the number of patients with a composite endpoint of death or need for mechanical ventilation or ECMO.

Measure: Composite endpoint of death or need for mechanical ventilation or ECMO

Time: Within 28 days and up to 6 months after the main randomisation

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Other Outcomes

Description: To assess the effects of study treatment on number of patients who needed ventilation and the number of days it was required

Measure: Need for (and duration of) ventilation

Time: Within 28 days and up to 6 months after the main randomisation

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Description: To assess the effects of study treatment on number of patients who needed renal replacement therapy

Measure: Need for renal replacement

Time: Within 28 days and up to 6 months after the main randomisation

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Description: To assess the effects of study treatment on number of patients who develop new major cardiac arrythmias

Measure: Development of new major cardiac arrythmias

Time: Within 28 days and up to 6 months after the main randomisation

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Primary Outcomes

Description: To evaluate the efficacy of ultra low-dose pulmonary RT through clinical evaluation.It was performed by oxygen therapy status assessment after RT treatment. Improvement criteria is considered as an oxygen therapy de-escalation (more to less need for support: Ventimask (VMK) with reservoir >VMK >Nasal Cannula-(NC).)

Measure: Oxygen Therapy Status at Day 2

Time: At 2 after RT

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Description: To evaluate the efficacy of ultra low-dose pulmonary RT through clinical evaluation. .It was performed by oxygen saturation (Sat02 %) status assessment after RT treatment. Improvement criteria is considered as a Sat02 with/without oxygen therapy >93% (Pulse oximeter measurement)

Measure: Oxygen Saturation (Sat02; Pulse oximeter measurement) at Day 2

Time: At 2 days after RT

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Secondary Outcomes

Description: Pa02 / Fi02 > 300 mmHg

Measure: Blood Gas Analysis at Day 2

Time: At 2 days after RT

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Description: Achievement of normal range value in 1 or more of the inflammatory and immunological parameters (lymphocytes, IL-6, D-dimer, ferritin, LDH, C Reactive Protein (CRP) and fibrinogen)

Measure: Blood Test at Day 2

Time: At 2 days after RT

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Description: To evaluate the efficacy of ultra low-dose pulmonary RT through clinical evaluation.It was performed by oxygen therapy status assessment after RT treatment. Improvement criteria is considered as an oxygen therapy de-escalation (more to less need for support: Ventimask (VMK) with reservoir >VMK >Nasal Cannula-(NC).)

Measure: Oxygen Therapy Status at Day 5

Time: At 5 after RT

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Description: To evaluate the efficacy of ultra low-dose pulmonary RT through clinical evaluation. .It was performed by oxygen saturation (Sat02 %) status assessment after RT treatment. Improvement criteria is considered as a Sat02 with/without oxygen therapy >93% (Pulse oximeter measurement)

Measure: Oxygen Saturation (Sat02; Pulse oximeter measurement) at Day 5

Time: At 5 days after RT

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Description: Achievement of normal range value in 1 or more of the inflammatory and immunological parameters (lymphocytes, IL-6, D-dimer, ferritin, LDH, C Reactive Protein (CRP) and fibrinogen)

Measure: Blood Test at Day 5

Time: At 5 days after RT

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Description: To evaluate the efficacy of ultra low-dose pulmonary RT through clinical evaluation.It was performed by oxygen therapy status assessment after RT treatment. Improvement criteria is considered as an oxygen therapy de-escalation (more to less need for support: Ventimask (VMK) with reservoir >VMK >Nasal Cannula-(NC).)

Measure: Oxygen Therapy Status at Day 7

Time: At 7 after RT

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Description: To evaluate the efficacy of ultra low-dose pulmonary RT through clinical evaluation. .It was performed by oxygen saturation (Sat02 %) status assessment after RT treatment. Improvement criteria is considered as a Sat02 with/without oxygen therapy >93% (Pulse oximeter measurement)

Measure: Oxygen Saturation (Sat02; Pulse oximeter measurement) at Day 7

Time: At 7 days after RT

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Description: Achievement of normal range value in 1 or more of the inflammatory and immunological parameters (lymphocytes, IL-6, D-dimer, ferritin, LDH, C Reactive Protein (CRP) and fibrinogen)

Measure: Blood Test at Day 7

Time: At 7 days after RT

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Description: To evaluate the efficacy of ultra low-dose pulmonary RT through radiological evaluation.It was performed by thoracic CT scan after RT treatment . It is considered a radiological improvement the decrease of the Total Severity Score (TSS) from the baseline in > or = 1 point. NOTE: The score values ranged from 0 to 4 according to the sum of the percentage involvement of each of the 5 lung lobes. The total severity score (TSS), was reached by summing the overall involvement in the lung (0-20 points)

Measure: Change from baseline Total Severity Score (TSS) analyzed in a thoracic CT scan at Day 7

Time: At 7 days after RT

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Description: Recovery time after RT administration until hospital discharge or death (<48h; 2-7 days; >7 days; clinical worsening or death)

Measure: Recovery time

Time: From RT administration until hospital discharge or death

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Description: COVID-19 negativization test

Measure: COVID-19 status

Time: At 7 days after RT

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Description: To evaluate the efficacy of ultra low-dose pulmonary RT through radiological evaluation.It was performed by thoracic CT scan after RT treatment . It is considered a radiological improvement the decrease of the Total Severity Score (TSS) from the baseline in > or = 1 point. NOTE: The score values ranged from 0 to 4 according to the sum of the percentage involvement of each of the 5 lung lobes. The total severity score (TSS), was reached by summing the overall involvement in the lung (0-20 points)

Measure: Change from baseline Total Severity Score (TSS) analyzed in a thoracic CT scan al Month 1

Time: At 1 month after RT

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Description: Toxicity was assessed and rated according to the NIH Common Terminology Criteria for Adverse Events (CTCAE version 5.0) and RTOG scales.

Measure: Acute Toxicity

Time: 1-3 months after RT

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Primary Outcomes

Description: Evaluation of clinical status of patients on day 15 after randomization, defined by the Ordinal Scale of 7 points (score ranges from 1 to 7, with 7 being the worst score)

Measure: Evaluation of clinical status

Time: Day 15 of the trial

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Secondary Outcomes

Description: All-cause mortality from randomization to day 28

Measure: All-cause mortality

Time: 29 days after the randomization

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Description: Deaths that occur during hospital admission.

Measure: Hospital Mortality

Time: 29 days after the randomization

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Description: Improvement of SOFA scale of patients at day 8, 15 and 29 after randomization

Measure: Improvement of Sequential Sepsis-related Organ Failure Assessment (SOFA) scale

Time: 29 days after the randomization (evaluations at D8 and D15)

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Description: Evaluation of clinical status of patients on the day 8, 22 and 29 after randomization, defined by the Ordinal Scale of 7 points (score ranges from 1 to 7, with 7 being the worst score)

Measure: Evaluation of clinical status

Time: 29 days after the randomization (evaluations at D8 and D29)

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Description: Days alive and free from mechanical ventilation since randomization

Measure: Ventilator free days

Time: 29 days after the randomization

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Description: Days from randomization to independence of oxygen support

Measure: Time until oxygen support independence

Time: 29 days after the randomization

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Description: Number of patients that were not at mechanical ventilation at randomization and that required that support.

Measure: Need of mechanical ventilation support

Time: 29 days after the randomization

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Description: Number of days to mechanical ventilation for patients that were not receiving it at randomization. For patients that were not in mechanical ventilation at randomization: number of days until that support was required.

Measure: Days to mechanical ventilation support.

Time: 29 days after the randomization

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Description: Lenght of hospitalization stay in survivors (in days)

Measure: Duration of hospitalization

Time: 29 days after the randomization

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Description: Incidence of other infections (aside from SARS-CoV 2)

Measure: Other infections

Time: 29 days after the randomization

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Description: Incidence of thromboembolic events in patients with COVID-19

Measure: Incidence of thromboembolic events

Time: 29 days after the randomization

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Description: Evaluation of adverse events, as well as serious and unexpected adverse events

Measure: Incidence of adverse events

Time: 29 days after the randomization (specific evaluations at D8, D15 and D29)

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Other Outcomes

Description: Correlation of inflammatory tests and cytokines with clinical outcomes: clinical status (ordinal scale), time to oxygen support independence, ventilator free days, need of mechanical ventilation and mortality

Measure: Correlation of inflammatory tests and cytokines with clinical outcomes

Time: 29 days after the randomization

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Description: Evaluation the kinetics of hemostasia exams, inflammatory tests, cytokines, flow cytometry of blood cells, CBC, renal and liver exams

Measure: Exploratory evaluation of laboratory exams during hospitalization

Time: 29 days after the randomization

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Description: Evaluation of viral clearance of SARS-CoV2 using RT-PCR analysis of nasopharyngeal swab

Measure: Evaluation of viral clearance of SARS-CoV2

Time: Day 8 and 15 after randomization

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Primary Outcomes

Measure: Clinical Status as Assessed by the Investigator Using a 7-Category Ordinal Scale of Clinical Status on Day 28

Time: Day 28

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Secondary Outcomes

Measure: Time to Clinical Improvement (TTCI) Defined as Time from Randomization to National Early Warning Score 2 (NEWS2) Score of Time: Up to Day 28

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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 Day 28

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Measure: Clinical Status as Assessed by the Investigator Using a 7-Category Ordinal Scale of Clinical Status on Days 7, 14, and 21

Time: Days 7, 14, and 21

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Measure: Proportion of Participants Requiring Initiation of Mechanical Ventilation Post-baseline

Time: Up to Day 28

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Measure: Ventilator-Free Days from Randomization to Day 28

Time: Up to Day 28

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Measure: Proportion of Participants Requiring Initiation of Intensive Care Unit (ICU) Care Post-baseline

Time: Up to Day 28

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Measure: Duration of ICU Stay in Days

Time: Up to Day 28

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Description: For participants entering the study already in ICU or on mechanical ventilation, clinical failure is defined as a one-category worsening on the ordinal scale, withdrawal or death.

Measure: Time to Clinical Failure, Defined as the Time from Randomization to the First Occurrence of Death, Mechanical Ventilation, ICU Admission, or Withdrawal (whichever occurs first)

Time: Up to Day 28

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Measure: Mortality Rate on Days 7, 14, 21, 28, and 60

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

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Measure: Time to Recovery, Defined as Time from Randomization to the Time when a Category of 2, Non-ICU Hospital Ward (or "Ready for Hospital Ward") not Requiring Supplemental Oxygen, or Better is Observed

Time: Up to Day 28

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Measure: Time from Randomization to Hospital Discharge or "Ready for Discharge" (as Evidenced by Normal Body Temperature and Respiratory Rate, and Stable Oxygen Saturation on Ambient Air or Time: Up to Day 28

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Measure: Duration of Supplemental Oxygen Use

Time: Up to Day 28

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Other Outcomes

Measure: Percentage of Participants with Adverse Events (AEs)

Time: Up to Day 28

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Measure: Proportion of Participants with any Post-Treatment Infection

Time: Up to Day 28

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Measure: Plasma Concentration of Remdesivir

Time: Up to Day 28

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Primary Outcomes

Description: Clinical Status 7-point ordinal scale: Not hospitalized, no limitations on activities Not hospitalized, limitation on activities Hospitalized, not requiring supplemental oxygen Hospitalized, requiring supplemental oxygen Hospitalized, on non-invasive ventilation or high flow oxygen devices Hospitalized, on invasive mechanical ventilation or ECMO Death

Measure: Clinical status (on a 7-point ordinal scale) at day 28

Time: up to day 28

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Secondary Outcomes

Description: ii. Time to clinical improvement, defined as a National Early Warning Score (NEWS) of < 2 maintained for 24 hours iii. Time to clinical improvement of at least 2 categories relative to baseline on a 7-category ordinal scale of clinical status

Measure: Clinical improvement

Time: up to day 28

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Description: iv. Incidence of mechanical ventilation v. Ventilator-free days

Measure: Mechanical Ventilation

Time: up to day 28

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Description: vi. Duration of time on supplemental oxygen

Measure: Oxygenation

Time: up to day 28

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Primary Outcomes

Description: Mortality status of participants

Measure: All-cause mortality

Time: Assessed at 30 days post treatment

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Secondary Outcomes

Description: Uninfected, ambulatory, hospitalized: mild disease, hospitalized: severe disease, death

Measure: Ordinal Scale for evaluating subject clinical status at days 3, 8, 15, 30, 60 post treatment.

Time: Assessed at days 3, 8, 15, 30, 60 post treatment

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Primary Outcomes

Description: Calculate the mean time of intubation

Measure: To calulate the time of intubation

Time: through study completion, and average of 1 month

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Description: Calculate the mean time with oxygen therapy

Measure: To calculate the time with oxygen therapy

Time: through study completion, and average of 1 month

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Description: Calculate the mean time with Non-invasive mechanical ventilation

Measure: To calculate the time with Non-invasive mechanical ventilation

Time: through study completion, and average of 1 month

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Description: Number of patients deaths of the total of patients included

Measure: To evaluate mortality rate

Time: through study completion, and average of 1 month

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Secondary Outcomes

Description: To calculate the mean ofPaO2/FiO2

Measure: To calculate respiratory function parameters

Time: through study completion, and average of 1 month

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Description: To calculate the mean of levels of oxygen saturation

Measure: To calculate respiratory function parameters

Time: through study completion, and average of 1 month

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Description: To calculate the mean of SaO2/FiO2

Measure: To calculate respiratory function parameters

Time: through study completion, and average of 1 month

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Description: Evaluate the lung extension of pneumonia

Measure: To evaluate radiological lung extension

Time: through study completion, and average of 1 month

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Description: Evaluate the type of lung affection

Measure: To evaluate radiological evolution

Time: through study completion, and average of 1 month

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Description: Days of hospitalization in survivors and/or days at ICU throughout the study

Measure: To describe the duration of hospitalization and ICU use

Time: through study completion, and average of 1 month

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Description: Percentage of patients with extracorporeal membrane oxygenation

Measure: To evaluate the requirement of additional organ support

Time: through study completion, and average of 1 month

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Description: Percentage of patients with molecular adsorbent recirculating system

Measure: To evaluate the requirement of additional organ support

Time: through study completion, and average of 1 month

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Description: Percentage of patients with dialysis

Measure: To evaluate the requirement of additional organ support

Time: through study completion, and average of 1 month

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Description: Percentage of patients with other support therapy

Measure: To evaluate the requirement of additional organ support

Time: through study completion, and average of 1 month

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Description: Analyze the levels of IL-6

Measure: To evaluate the effect of IV tocilizumab on the serum levels of inflammatory markers

Time: through study completion, and average of 1 month

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Description: Incidence of adverse events

Measure: To calculate the number of adverse events in patients with COVID-19 pneumonia treated with Tocilizumab

Time: through study completion, and average of 1 month

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Description: Incidence of adverse events by dose of Tocilizumab

Measure: To calculate the number of adverse events in patients with COVID-19 pneumonia treated with Tocilizumab

Time: through study completion, and average of 1 month

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Description: To evaluate the time to RT-PCR virus negativity

Measure: To assess time to reverse-transcriptase polymerase chain reaction (RT-PCR) virus negativity

Time: through study completion, and average of 1 month

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Description: Analyze the levels of CRP

Measure: To evaluate the effect of IV tocilizumab on the serum levels of inflammatory

Time: through study completion, and average of 1 month

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Description: Analyze the levels of procalcitonin (PCT)

Measure: To evaluate the effect of IV tocilizumab on the serum levels of inflammatory

Time: through study completion, and average of 1 month

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Description: Analyze the levels of ID-dimer

Measure: To evaluate the effect of IV tocilizumab on the serum levels of inflammatory

Time: through study completion, and average of 1 month

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Description: Analyze the levels of ferritin

Measure: To evaluate the effect of IV tocilizumab on the serum levels of inflammatory

Time: through study completion, and average of 1 month

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Description: Indicende of serious adverse events

Measure: To calculate the number of serious adverse events in patients with COVID-19 pneumonia treated with Tocilizumab

Time: through study completion, and average of 1 month

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Description: Indicende of serious adverse events based on dose of Tocilizumab

Measure: To calculate the number of serious adverse events in patients with COVID-19 pneumonia treated with Tocilizumab

Time: through study completion, and average of 1 month

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Description: Indicende of adverse events of special interest based on dose of Tocilizumab

Measure: To calculate the number of adverse events of special interest in patients with COVID-19 pneumonia treated with Tocilizumab

Time: through study completion, and average of 1 month

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Description: Number of patients deaths of the total of patients included based on dose of Tocilizumab

Measure: To evaluate mortality rate

Time: through study completion, and average of 1 month

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Description: Time with intubation, oxygen therapy and Non-invasive mechanical ventilation based on dose of Tocilizumab

Measure: To evaluate respiratory function

Time: through study completion, and average of 1 month

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Description: Number of patients deaths of the total of patients included based on severity of disease at the start of the study treatment

Measure: To evaluate mortality rate

Time: through study completion, and average of 1 month

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Description: Number of patients deaths of the total of patients included based on presence of cytokine storm syndrome at the start of treatment

Measure: To evaluate mortality rate

Time: through study completion, and average of 1 month

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Description: Time with intubation, oxygen therapy and Non-invasive mechanical ventilation based on severity of disease at the start of the study treatment

Measure: To evaluate respiratory function

Time: through study completion, and average of 1 month

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Description: Time with intubation, oxygen therapy and Non-invasive mechanical ventilation based on presence of cytokine storm syndrome at the start of treatment

Measure: To evaluate respiratory function

Time: through study completion, and average of 1 month

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Primary Outcomes

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

Measure: Survival without needs of ventilator utilization at day 14

Time: day 14

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Secondary Outcomes

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

Measure: WHO progression scale at day 7 and 14

Time: day 7 and day 14

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Description: Overall survival

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

Time: 14, 28, 60 and 90 days

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Description: Cumulative incidence of discharge alive

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

Time: 14 and 28 days

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

Measure: Survival without needs of mechanical ventilation at day 1

Time: day 1

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Description: Cumulative incidence of oxygen supply independency

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

Time: 14 and 28 days

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Primary Outcomes

Description: Day of recovery is defined as the first day on which the patient achieves one of the following two categories from the seven-point ordinal scale: 6) Hospitalized, not requiring supplemental oxygen or ongoing medical care or 7) Not hospitalized. Time to recovery is the number of days from randomization to achievement of this status. Note that the ordinal scale is measured once daily, with the patient's worst clinical status during the 24-hour time period (0:00-23:59) being documented.

Measure: Time to Recovery

Time: 28 days

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Secondary Outcomes

Description: This will be defined as the percentage of patients in a given arm of the study achieving one of the above two categories on the ordinal scale on day 7. Note that the ordinal scale is measured once daily, with the patient's worst clinical status during the 24-hour time period (0:00-23:59) being documented.

Measure: Achievement of Recovery

Time: 7 days

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Description: This will be defined as the percentage of patients in a given arm of the study who are alive thirty days following randomization. Patients who are discharged to hospice will be counted as deceased on the day of discharge. Patients who are transitioned to inpatient hospice or inpatient comfort measures only will be counted as deceased on the day of transition.

Measure: Overall Survival

Time: 28 days

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Description: This will be defined as the number of days that pass between the day of a patient's randomization and his or her discharge from the hospital.

Measure: Hospital Length of Stay

Time: Up to 1 year

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Description: Maximum temperature within 24-hour periods of time immediately prior to, immediately following, and then every 24 hours thereafter randomization. The primary endpoint is a measured Tmax in the 24-hour period immediately following randomization that is lower than the measured Tmax in the 24-hour period immediately preceding randomization.

Measure: Clinical Response: Maximum Temperature (Tmax) Response

Time: 24 hours

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Description: This will be a binary outcome defined as worsening COVID-19 disease resulting in the use of invasive mechanical ventilation during the course of the patient's COVID-19 infection.

Measure: Clinical Response: Rate of Non-Elective Invasive Mechanical Ventilation

Time: Up to 28 days

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Description: This will be a continuous outcome defined by the amount of time between initiation and cessation of non-elective invasive mechanical ventilation.

Measure: Clinical Response: Duration of Non-Elective Invasive Mechanical Ventilation

Time: Up to 28 days

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Description: This will be a continuous outcome defined by the amount of time between randomization and the initiation of non-elective invasive mechanical ventilation. This will be treated as a time-to-event with possible censoring.

Measure: Clinical Response: Time to Non-Elective Invasive Mechanical Ventilation

Time: Up to 28 days

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Description: This will be a binary outcome defined as utilization of any vasopressor or inotropic medication.

Measure: Clinical Response: Rate of Vasopressor/Inotrope Utilization

Time: Up to 28 days

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Description: This will be a continuous outcome defined by the amount of time between initiation of first and cessation of last vasopressor medications.

Measure: Clinical Response: Duration of Vasopressor/Inotrope Utilization

Time: Up to 28 days

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Description: This will be a continuous outcome defined by the amount of time between randomization and the initiation of any vasopressor or inotropic medication. This will be treated as a time-to-event with possible censoring.

Measure: Clinical Response: Time to Vasopressor/Inotrope Utilization

Time: Up to 28 days

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Description: This will be an ordinal outcome defined by the number of days counted from randomization over which the participant requires supplemental oxygen in excess over his/her baseline supplemental oxygen requirement. The supplemental oxygen requirement is defined as the highest liters-per-minute flow of supplemental oxygen required by the patient each day over the course of the hospitalization.

Measure: Clinical Response: Duration of Increased Supplemental Oxygen from Baseline

Time: 28 days

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Description: This will be a binary outcome defined as the presence or absence of a decline in CRP of ≥ 25% from baseline CRP in the 27 +/- 3 hours after tocilizumab administration, as compared to pre-treatment baseline.

Measure: Biochemical Response: C-reactive Protein Response Rate

Time: 24 hours

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Description: This will be defined as the percentage of patients in a study arm who develop serious non-COVID-19 viral, bacterial, or fungal infections (e.g., bloodstream infection, hospital-acquired pneumonia, ventilator-associated pneumonia, opportunistic infection) following randomization and up to the 28-day assessment of overall survival.

Measure: Safety: Rate of Secondary Infection

Time: 28 days

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Primary Outcomes

Description: Day of recovery is defined as the first day on which the patient achieves one of the following two categories from the seven-point ordinal scale: 6) Hospitalized, not requiring supplemental oxygen or ongoing medical care or 7) Not hospitalized. Time to recovery is the number of days from randomization to achievement of this status. Note that the ordinal scale is measured once daily, with the patient's worst clinical status during the 24-hour time period (0:00-23:59) being documented.

Measure: Time to Recovery

Time: 28 days

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Secondary Outcomes

Description: This will be defined as the percentage of patients in a given arm of the study achieving one of the above two categories on the ordinal scale on day 7. Note that the ordinal scale is measured once daily, with the patient's worst clinical status during the 24-hour time period (0:00-23:59) being documented.

Measure: Achievement of Recovery

Time: 7 days

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Description: This will be defined as the percentage of patients in a given arm of the study who are alive thirty days following randomization. Patients who are discharged to hospice will be counted as deceased on the day of discharge. Patients who are transitioned to inpatient hospice or inpatient comfort measures only will be counted as deceased on the day of transition.

Measure: Overall Survival

Time: 28 days

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Description: This will be defined as the number of days that pass between the day of a patient's randomization and his or her discharge from the hospital.

Measure: Hospital Length of Stay

Time: Up to 1 year

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Description: Maximum temperature within 24-hour periods of time immediately prior to, immediately following, and then every 24 hours thereafter randomization. The primary endpoint is a measured Tmax in the 24-hour period immediately following randomization that is lower than the measured Tmax in the 24-hour period immediately preceding randomization.

Measure: Clinical Response: Maximum Temperature (Tmax) Response

Time: 24 hours

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Description: This will be a binary outcome defined as worsening COVID-19 disease resulting in the use of invasive mechanical ventilation during the course of the patient's COVID-19 infection.

Measure: Clinical Response: Rate of Non-Elective Invasive Mechanical Ventilation

Time: Up to 28 days

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Description: This will be a continuous outcome defined by the amount of time between initiation and cessation of non-elective invasive mechanical ventilation.

Measure: Clinical Response: Duration of Non-Elective Invasive Mechanical Ventilation

Time: Up to 28 days

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Description: This will be a continuous outcome defined by the amount of time between randomization and the initiation of non-elective invasive mechanical ventilation. This will be treated as a time-to-event with possible censoring.

Measure: Clinical Response: Time to Non-Elective Invasive Mechanical Ventilation

Time: Up to 28 days

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Description: This will be a binary outcome defined as utilization of any vasopressor or inotropic medication.

Measure: Clinical Response: Rate of Vasopressor/Inotrope Utilization

Time: Up to 28 days

---

Description: This will be a continuous outcome defined by the amount of time between initiation of first and cessation of last vasopressor medications.

Measure: Clinical Response: Duration of Vasopressor/Inotrope Utilization

Time: Up to 28 days

---

Description: This will be a continuous outcome defined by the amount of time between randomization and the initiation of any vasopressor or inotropic medication. This will be treated as a time-to-event with possible censoring.

Measure: Clinical Response: Time to Vasopressor/Inotrope Utilization

Time: Up to 28 days

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Description: This will be an ordinal outcome defined by the number of days counted from randomization over which the participant requires supplemental oxygen in excess over his/her baseline supplemental oxygen requirement. The supplemental oxygen requirement is defined as the highest liters-per-minute flow of supplemental oxygen required by the patient each day over the course of the hospitalization.

Measure: Clinical Response: Duration of Increased Supplemental Oxygen from Baseline

Time: 28 days

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Description: This will be a binary outcome defined as the presence or absence of a decline in CRP of ≥ 25% from baseline CRP in the 27 +/- 3 hours after tocilizumab administration, as compared to pre-treatment baseline.

Measure: Biochemical Response: C-reactive Protein Response Rate

Time: 24 hours

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Description: This will be defined as the percentage of patients in a study arm who develop serious non-COVID-19 viral, bacterial, or fungal infections (e.g., bloodstream infection, hospital-acquired pneumonia, ventilator-associated pneumonia, opportunistic infection) following randomization and up to the 28-day assessment of overall survival.

Measure: Safety: Rate of Secondary Infection

Time: 28 days

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Primary Outcomes

Description: death or recovery

Measure: survival

Time: 28 days

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Secondary Outcomes

Description: duration in days

Measure: duration of hospitalization

Time: 28 days

---

Description: duration in days to normalize symptoms and laboratory parameters

Measure: Time to resolution of cytokine release storm

Time: 28 days

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Description: Time in days to turn PCR negative

Measure: Time of viral clearance

Time: 45 days

---

Description: incidence of Post Covid lung fibrosis

Measure: Complications

Time: 90 days

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HP:0006510: Chronic pulmonary obstruction

Genes 30

CYBB CYBC1 JMJD1C CYBA NCF1 NFKB1 HMOX1 GLA SEC24C WIPF1 DNAAF4 MMP1 HIRA NCF2 RREB1 HLA-DPB1 HLA-DPA1 PTPN22 CTLA4 GP1BB ARVCF TBX1 SERPINA1 TBX1 UFD1 COMT PRTN3 NCF4 WAS MYH7

Protein Mutations 2

A118G G551D

SNP 6

rs1051730 rs1800470 rs1828591 rs25331 rs4129267 rs7103572

HP:0001677: Coronary artery atherosclerosis

Genes 51

ZNF687 ACTA2 SERPIND1 LOX KCNJ5 LDLR SMAD4 ESR1 PRKG1 ABCA1 SMAD3 ABCC6 MFAP5 SMPD1 CYP7A1 ABCG8 LMNA ACTA2 CEP19 LMNA LOX TGFBR2 ELN APOE XYLT1 ABCA1 LDLRAP1 MYLK TGFB3 LMNA PCSK9 APOB APOB MAT2A FBN1 PPARG ZMPSTE24 LMNA LMNA LMNA TGFBR1 TGFB2 ABCG5 LMNA XYLT2 FOXE3 MYH11 MYH11 LIPC ABCG8 MYH11

Protein Mutations 1

C825T

SNP 19

rs10153820 rs1143623 rs1143633 rs1143634 rs12041331 rs16944 rs16969968 rs17561 rs1761667 rs2043211 rs20432111 rs2305619 rs4612666 rs4848306 rs6434222 rs7586970 rs7903146 rs8069645 rs8176528

HP:0002664: Neoplasm

Genes 1515

EPCAM BAP1 CYLD WT1 CTBP1 GLI3 CTNNB1 ELMO2 ATRX TERT EDN3 MTAP TSC2 RAD51 BLNK KCNAB2 WDPCP SPINK1 ARID1B PTEN STK11 XPA PTH1R TCF4 EPCAM NF1 GPC3 ERCC3 MC1R CASP10 PDGFRA RPL5 CDH1 BRIP1 RUNX1 KRAS SFTPC GPR35 MYLK STS DYNC2LI1 RAG2 CBL FOXE1 STAT3 TTC37 ABL1 NSD1 ATM KCNH1 GPR101 IGH KRT17 SUFU TERT KRAS GPC3 CYP11B2 MLH3 PTCH1 FAH MSH2 EXT1 CCND1 MSH3 ATP7A SEC23A PHOX2B HAX1 MYD88 LMO1 PIK3CA PRLR AXIN1 TCF4 RUNX1 AKT1 ERBB2 REST DCLRE1C SERPINA1 ERCC3 TMC6 RASA1 MSH3 TRNL1 CALR HRAS INS RNF113A SETBP1 CDH1 SLC37A4 TFAP2A CDH1 PTCH1 KIT PTEN IL1RN MLH3 MUTYH PTEN KIT GBA BCL2 KCNH1 GINS1 ESCO2 TET2 SLX4 DICER1 PALB2 NEK1 ESCO2 COL7A1 PTCH2 WT1 WRN GCM2 BRD4 BRAF TREX1 THPO SUFU NRAS CDC73 POU6F2 GNAS DAXX BUB3 RSPO1 MNX1 ERCC2 RPS28 ANTXR2 CTNNB1 POT1 FANCA KDM6B RET MST1 NOTCH3 FGFR1 KRAS LYST CHIC2 TMC6 MET KRT10 UROD SLC25A11 ARSA EVC2 TEK XRCC2 CASP8 ASCL1 IL1B TERF2IP DICER1 MPL OFD1 RHBDF2 DICER1 MDM2 WT1 MMP1 CDKN2A FGF8 NR4A3 FGFR2 OCRL TP53 ERCC2 SUFU ERCC4 ALX4 TINF2 DCLRE1C SRY SRP72 NF2 GNAS LETM1 TP53 FANCB TAL1 TDGF1 BRCA1 LEMD3 NF2 BRAF NUP214 RAD21 COL18A1 SDHD ICOS CEP57 BAP1 FANCM PTPRJ FANCE SLC22A18 PIK3R1 JAK2 FLT4 SMO WIPF1 DLST NF2 RAD50 MEN1 CHEK2 GPC4 WDPCP CYP2A6 HBB GANAB XRCC4 TET2 ATP7B EP300 DIS3L2 HFE CARD14 OFD1 ALX3 VANGL1 BAP1 SDHB EXTL3 PIK3CA GATA2 ALX3 BCL10 KIT WAS FGFR2 RMRP TWIST1 BMPR1B DIS3L2 ERCC3 FOXP1 SMAD4 CALR APC PCGF2 USP8 DMPK NRAS DKC1 BRCA1 ADAR BCR RSPO1 SLC45A2 GJC2 TNFRSF4 AKT1 IFIH1 MSH6 DICER1 PAX6 TGFBR2 SRY KLHDC8B CPLX1 MSH6 AIP PMS1 CREBBP ERCC2 CTSA APC MMP1 SH2B3 PKD1 TRNF SEC23B DNAJC21 STK11 BCR HBB MITF IGLL1 ALX4 MDH2 AKT1 SCN4A SDHAF2 PRKN PLA2G2A RNF43 DNMT3A TERT NSD2 RMRP FANCG BRCA2 CAT TP53 BMPR1A MAD2L2 SIX6 DDB2 GREM1 KRT17 PAX4 RPS17 TRPV3 ERCC4 C11ORF95 APC IL12RB1 BRIP1 PPM1D SDHB NODAL HNF1A FLT4 MSH6 ERCC6 BTK SLC26A4 SEMA3C AR NEK1 TERC RPL35A RPS20 CDKN1C SF3B1 TERC PTEN RFWD3 BRCA2 KCNQ1OT1 RPL10 ACTG2 MAGT1 ALK BLM H19 LEMD3 RPL31 MLLT10 PYGL RPL15 IRF1 CR2 MITF PTEN MYC PTPN11 TUBB TCF4 KCNQ1 NFKB2 ALX1 HLA-DRB1 APC EWSR1 NBN CDKN2A ERCC4 GCK DLL1 SLC25A11 PDGFB L2HGDH PRKCD CTC1 PIK3CA SUFU RPL27 KIF1B SRC CIB1 RECQL4 CDKN2B MSH3 BRCA2 PALB2 PDE6D SDHC SDHD CCL2 CHEK2 PMVK XPC STK11 PIK3CA MVD DHCR7 KIT GPC6 KARS1 MNX1 VHL TUBB NAB2 KEAP1 TSC1 NQO2 APC SDHB VHL TCTN3 RECQL4 PMS2 RAD51C STAG3 SNAI2 MAP3K8 SETBP1 SDHB NPM1 RAD51C RARA ERBB2 ERCC5 ATRX CHEK2 KRAS BRCA1 TFAP2A SLCO2A1 PHOX2B PTEN COL2A1 PIGL PDGFRA APC CPLANE1 AURKA SDHD LAMA3 VHL RPS26 GFI1B CDKN1B PRDM16 AXIN2 FZD2 AP2S1 LZTR1 TP53 TP53 GNA14 CTNNB1 MSTO1 PIK3CA RPS29 CALR DHX37 MYF6 SDHC MALT1 ELANE SDHD SLC26A4 MAP3K1 GDNF MSH2 SDHC TGFBR1 RUNX1 CREB1 CDKN2A TSC2 KRAS TNFRSF10B LMNA WWOX PHOX2B EDN3 RPS10 RSPRY1 TRIM37 RET MEN1 BCL10 MSH2 TNFRSF13C FOXE1 FANCC H19-ICR BLM ERCC6 LIG4 BDNF LMOD1 NF2 TMEM107 CYLD GJB2 EXT1 CTSC PHOX2B RAD51D RASGRP1 RB1 TGFBR2 SRY MYH8 KRAS TINF2 RECQL4 H19 PRF1 GDNF MXI1 SMPD1 WT1 HRAS COL1A1 PDGFRB FAS FANCD2 NF1 DISP1 PDGFRL IKBKG BIN1 BRCA2 ADA POLE AXIN2 SEMA4A KRAS NRAS PALB2 CHEK2 ASCL1 POLE TLR2 PIK3CA MINPP1 SOS1 CYLD CTLA4 POT1 ASXL1 CDC73 APC SAMD9L WT1 TRAF7 GATA4 PIK3CA DYNC2LI1 ATP7A CBFB MST1R GCGR MPL COL4A5 SMAD4 CDKN1A SDHD TRIM28 POLH GPR101 PIK3CA FLCN GPR143 RB1 SBDS SLC12A3 KLF6 ICOS GNB1 PIGA TYROBP GFI1 RAD51 SLC26A2 MC1R TREM2 SFTPA2 JAG1 BAP1 EGFR IGH KIT PLCB4 NLRP1 HNF1B ZFHX3 EPHB2 KLLN OCA2 WT1 FAH FH TERT SRD5A3 LIG4 NFKB1 RNF43 KIT STAT1 IFNG BMPR1A ERCC3 TBX18 TET2 MAP2K1 EXT2 HRAS RTEL1 FGFR3 PTEN CTNNB1 MAP2K2 MEN1 APC CLCNKB AKT1 ESCO2 CDC73 MS4A1 BRAF CRKL NUTM1 CDK4 NTHL1 ETV6 TET2 SQSTM1 FAM20C PIGL SEC23A ATM PALB2 TYR SRSF2 EXT2 GJB2 DNMT3A HRAS TCOF1 CHEK2 CDH1 FH DKC1 POLE PIK3CA PTCH2 AKT1 PAX3 FH ADAMTS3 APC PMS1 RAD51C PLCD1 PUF60 DIS3L2 CDH23 SCN9A FOXC2 SMARCB1 CDKN2A VANGL2 ENG SH2D1A SDHB SOX9 BRAF SDHA PGM3 ERCC2 GJB2 TBC1D24 CHD7 MPL DHH PTCH1 CALR IL12A TNFRSF13B CD28 MLH1 PTPN12 OFD1 MLH3 REST CCDC22 APPL1 COL14A1 IGH PSENEN IL2RG MC1R SMARCA4 CYLD KIF11 PHKG2 JAK2 COL2A1 AXIN2 FLNA WNT5A TYR EP300 GLI3 EXT2 MGAT2 KCNE3 ECE1 PARN IDH2 TSC1 ARL6IP6 FGFR3 SMAD4 HMBS SLC6A17 PRKAR1A BAP1 KDSR DHCR24 CXCR4 DDX41 GABRD RET NR0B1 DMRT3 CCND1 GDF5 POU6F2 CTLA4 TBXT FANCA NRTN PHKA2 KIT ITK RNASEH2A PERP CDC73 OFD1 CYP2D6 RET MEN1 CD27 PARN FUZ RPS19 MSH2 SMARCE1 TNFSF12 ZSWIM6 TERT RHOH NF1 BUB1B SLX4 LIG4 PDGFRL TNFSF15 OPCML APC PRKCD SETD2 RPS19 BRCA1 FAT4 ANTXR1 WNT10A SUFU TP63 EFL1 IL7 MN1 DOCK8 CDC73 SSX1 TMEM231 MPLKIP VHL MINPP1 BIRC3 PDX1 STS PSAP HNF1A JAK2 FANCL POT1 GNAS TERT CD79A KLF11 WRN MAPRE2 LIG4 CYSLTR2 DNM2 SH3GL1 KIT FOXH1 RELA KRAS PRKAR1A ERBB3 FGFR2 H19 TJP2 CD81 PNP MSH6 WT1 THPO ATP6V1B2 GNAQ BRCA1 WRAP53 ERCC3 CHRNG KRT14 TSC1 DLC1 CTNNB1 FGFRL1 SDHC GDNF HABP2 NRAS ATR TRNK BMPR1A TERT BRAF AKT1 XPC FGFR3 NUP214 TRIP13 SMARCD2 ZSWIM6 PIEZO2 EVC IL6 HRAS GPC4 TNFRSF13B PALLD CDKN2A POLR1D TP53 FOXO1 BRCA2 FIBP CDH23 RB1CC1 B3GALT6 FLT3 GJA1 SH2B3 MRAP MTOR AR FOXI1 TP53 GNAQ KRT6B MYD88 KRT16 TP53 NF1 MYSM1 MGMT KIT NF1 GPC4 GCM2 SIX3 PIK3CA RAD21 HRAS PMS2 ASCC1 BRCA2 GAS1 FASLG SDHD NRAS C2CD3 KDR SDHA SMAD4 SOX2 NBEAL2 SRGAP1 AGGF1 ATM AKT1 RPGRIP1L NOD2 BAX BRCA2 H19-ICR TGIF1 MAPK1 ESR1 EXT1 RPL11 KRAS BCL10 SKI LAMB3 XIAP SDHC HABP2 TRNS1 CCM2 FIBP PIK3CA TRIM28 HRAS SCN10A NF1 WT1 CPLANE1 HFE F5 C2CD3 GNPTAB TBX2 KLF6 GATA2 VEGFC RNASEH2B CBL SEMA3D ARMC5 CXCR4 JAK2 IGF2 FGFR2 NRAS UBE2T ARHGAP26 SCN11A MEN1 LMX1B F13A1 BCR COMP EDN1 SDHC ACTB GDNF CDKN2C ASPSCR1 NAGS PDGFRB PALB2 DLEC1 BCL10 STAR GNA11 PORCN RNR1 FLCN SPIB WT1 RET SDHB SLC22A18 ERCC4 CDKN2A CTHRC1 DLST OGG1 POLD1 DCC IL2RG REST SRP54 RAF1 TSC1 SRP54 IDH1 ACD KIT ACAN NSD2 TOP2A CASP10 DVL1 PTPN11 CASP10 STIM1 KRT9 AR CIB1 GNAS AR VAMP7 MRE11 GFI1 RPS14 BCL10 CACNA1S TP53 VANGL1 SKIV2L PTCH2 G6PC LRP5 PDGFRB BARD1 RPS27 RPS7 GNAS ENPP1 STAT6 ACVR1 MTM1 NEUROD1 TNFRSF13C PKD2 RUNX1 STK11 FGF3 TRIP13 SIX1 BRCA2 LAMC2 NELFA DVL3 GJB4 NSUN2 CDKN1B CTNNB1 POLR1C GJB3 SMARCB1 SBDS LMNA KRAS TRNH ECM1 STK4 ANTXR2 SOS1 BAP1 MSX2 DICER1 SDHB ACD WRAP53 BRCA1 ATP7A BUB1B RYR1 RET BRCA2 TP53 DPM1 BRCA2 BCR POLD1 TCIRG1 PTPN11 HOXD13 CR2 TARS1 JAK2 BMP2 MUTYH FLT3 TRNS2 MTMR14 NR5A1 ABCA5 RET AHCY TSC2 KIT KCNQ1OT1 RNF6 RAD54L HNF1A HMMR RNF139 WWOX TCTN3 BRAF FCN3 RNASEH2C AIP PRKN SF3B1 MSH6 NSD1 PTCH2 CCBE1 RECQL4 PMS2 ERCC2 HNF4A MMEL1 BUB1 TET2 TRPS1 ABCC6 RET IRF5 CDKN2B PDGFB USP9X TAL2 INTU GNAS HDAC4 MFN2 DYNC2H1 PIK3CA PLAG1 ATM MAX FAS PIK3CA CYP11B1 CCND1 H19-ICR PTCH1 MUTYH ABL1 ODC1 FGFR2 COL7A1 MSR1 BRCA1 RB1 TNFRSF1B COL7A1 FLT4 GPC3 TGFBR2 ATRX RAG1 PRCC BRAF TNFRSF1B FANCE RAD54L CBL SDHB TERT SDHD RPS24 FASLG MET KRT17 GATA1 ERBB2 FGFR1 KAT6B ABCA5 SDHAF2 SLC25A13 NOP10 GATA2 RFWD3 PDGFRA SPRTN MLH1 NKX2-1 IGF2R CD19 MAP3K1 TREX1 TRNP ZFPM2 CTNNB1 TRNQ WWOX IGHM MYH11 TMEM127 CDON NF2 SAMD9 PTEN RNASEL IDH2 HNF4A GTF2H5 GLI3 HRAS LPP DDB2 KIT PIK3CA PDCD10 HSPG2 HFE RPL26 BRIP1 ASXL1 SDHD CEBPA ACVRL1 NRAS CD19 GNAQ TET2 TCTN3 SMARCB1 FLCN ABCB11 BLK RAD54B SDHC FH AKT1 ANTXR1 FANCF HNF1B EXOC6B SAMHD1 SHOX MYO1H COL11A2 KCNJ10 TRIP13 CC2D2A LZTS1 SEC23B GPR101 DOCK8 BRCA2 NBN SLC26A2 SPRED1 VHL KRT1 LIN28B GTF2E2 NRAS ZIC2 SNAI2 SH3KBP1 SHOX BCL6 NTHL1 RHBDF2 CD28 MCM4 CCND1 FANCG SMARCAD1 GATA2 RERE YY1 ASXL1 IL7R TMEM67 C1S TAF1 FGFR3 NBN KRAS KIF1B AIP KCNJ11 LETM1 FANCI MLH1 MBTPS2 NRAS NEK9 GNAI3 APC2 EYA1 ZAP70 EXT2 BUB1 SSX2 LIG4 CARMIL2 SLC17A9 TMC8 PCNA EPAS1 TFE3 BRCA2 DHH MAP2K1 CASP8 CDK4 PDGFB RTEL1 EWSR1 PTEN VHL GJB6 NDP RNF6 TNPO3 TGFBR2 TXNRD2 PNP TAF15 TRNK SMO NOTCH1 LRRC8A RASA1 TSC2 ABCC8 PRKAR1A BAX IDH1 SLC22A18 ADA FAN1 TG PTEN BMPR1A MSTO1 ERCC5 IRF1 MLH1 NRAS MLH1 PICALM FANCD2 SF3B1 BICC1 RPS15A TERT KLLN ELANE FAM149B1 GATA1 SASH1 INPP5E TP53 WT1 BMPR1A PTPN11 PTPN11 MYCN XPA EDNRB TP53 FLI1 GDF2 PHB BMPER FGFR3 PTEN MCC EXT1 MC2R KCNN3 DNASE1L3 DHCR7 RASGRP1 SHH NPM1 SLC26A2 SLC37A4 IGF2 RPL18 SH2B3 PTCH1 BRAF PAX7 INHBA BMPR1A KIF7 XRCC3 IGF2 POU2AF1 DNAJC21 CYP26C1 RB1 MPL REST KIAA0753 DNMT3A ERCC6 MUC5B MLH3 ASXL1 MPL NOTCH3 KCNJ10 SMARCE1 TSR2 RPL10 KRT1 SLC25A13 WT1 NNT TP53 GNA11 GLI1 BARD1 FLCN COL7A1 SRP54 GLI2 EDN3 PTPN3 WT1 TMEM127 CD79B GATA2 TERC FN1 EIF2AK4 RAD51 WASHC5 SAMD9L AIP TP53 AAGAB RB1 TP53 KRT5 ADA2 HSPA9 PIK3CA SRSF2 PHF21A IDH1 KRAS KRAS CHEK2 BUB1B RET FANCC TP53 WHCR RAD54B NUMA1 SDHB HMBS TMEM216 SMAD4 MAFA MSH2 RPL35 CDKN1B IGF2 PPP2R1B CD70 CEL MAD1L1 MAX ALK GPC3 FERMT1 KIF1B TCF3 POLH PIK3R1 USF3 FDPS MYC DNAJC21 TNFSF12 HACE1 CDH1 SDHA ND5 NHP2 PIK3CA RPS14 NBN WNT10A ING1 CASR SUFU FGFR3 HPGD BTK ENG DCC CASP8 PHOX2B STAC3 USB1 KRIT1 PHOX2B TET2 SMAD4 JAK2 BCHE APC MVK SMAD7 SMO DKC1 SMARCB1 VHL F13B TINF2 USP8 FGFR1 FOXI1 TET2 CD96 TET2 JAK2 KRAS