Primary Outcomes

Measure: Dose Escalation and Cancer Treatment Expansions: Number of Participants Reporting one or More Treatment Emergent Adverse Events (TEAEs)

Time: Up to 36 months

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Measure: Dose Escalation and Cancer Treatment Expansions: Number of Participants With Dose Limiting Toxicities (DLTs)

Time: Up to 36 months

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Measure: Dose Escalation and Cancer Treatment Expansions: Number of Participants With one or More Serious Adverse Events (SAEs)

Time: Up to 36 months

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Measure: Dose Escalation and Cancer Treatment Expansions: Number of Participants With one or More TEAEs Leading to Dose Modifications and Treatment Discontinuations

Time: Up to 36 months

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Measure: Dose Escalation and Cancer Treatment Expansions: Number of Participants With Greater Than or Equal to (>=) Grade 3 TEAEs

Time: Up to 36 months

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Measure: Dose Escalation and Cancer Treatment Expansions: Number of Participants With Clinically Significant Laboratory Values

Time: Up to 36 months

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Measure: Dose Escalation and Cancer Treatment Expansions: Number of Participants With Clinically Significant Vital Sign Measurements

Time: Up to 36 months

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Description: CRS will be graded as per American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading for CRS.

Measure: Dose Escalation and Cancer Treatment Expansions: Number of Participants who Experience Cytokine Release Syndrome CRS)

Time: Up to 36 months

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Measure: COVID-19 Expansion: Number of Participants With >=2 log Reduction From Baseline in Viral Load or Below Level of Detection (Negative) in Nasopharyngeal or Oropharyngeal Samples

Time: Up to 9 months

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Secondary Outcomes

Measure: Dose Escalation and Cancer Treatment Expansions, Cmax: Maximum Observed Plasma Concentration for TAK-981

Time: Cycle 1 Day 1 pre-dose and at multiple time points (up to 48 hours) post dose; Cycle 1 Day 8 pre-dose and at multiple time points (up to 24 hours) post dose (Cycle length is equal to [=] 21 days)

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Measure: Dose Escalation and Cancer Treatment Expansions, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-981

Time: Cycle 1 Day 1 pre-dose and at multiple time points (up to 48 hours) post dose; Cycle 1 Day 8 pre-dose and at multiple time points (up to 24 hours) post dose (Cycle length =21 days)

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Measure: Dose Escalation and Cancer Treatment Expansions, AUCt: Area Under the Plasma Concentration-time Curve from Time 0 to Time t Over the Dosing Interval for TAK-981

Time: Cycle 1 Day 1 pre-dose and at multiple time points (up to 48 hours) post dose; Cycle 1 Day 8 pre-dose and at multiple time points (up to 24 hours) post dose (Cycle length =21 days)

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Measure: Dose Escalation and Cancer Treatment Expansions, AUC∞: Area Under the Plasma Concentration-time Curve from Time 0 to Infinity for TAK-981

Time: Cycle 1 Day 1 pre-dose and at multiple time points (up to 48 hours) post dose; Cycle 1 Day 8 pre-dose and at multiple time points (up to 24 hours) post dose (Cycle length =21 days)

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Measure: Dose Escalation and Cancer Treatment Expansions, Terminal Disposition Phase Half-life (t1/2z) for TAK-981

Time: Cycle 1 Day 1 pre-dose and at multiple time points (up to 48 hours) post dose; Cycle 1 Day 8 pre-dose and at multiple time points (up to 24 hours) post dose (Cycle length =21 days)

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Measure: Dose Escalation and Cancer Treatment Expansions, Total Clearance After Intravenous Administration (CL) for TAK-981

Time: Cycle 1 Day 1 pre-dose and at multiple time points (up to 48 hours) post dose; Cycle 1 Day 8 pre-dose and at multiple time points (up to 24 hours) post dose (Cycle length =21 days)

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Measure: Dose Escalation and Cancer Treatment Expansions, Volume of Distribution at Steady State After Intravenous Administration (Vss) for TAK-981

Time: Cycle 1 Day 1 pre-dose and at multiple time points (up to 48 hours) post dose; Cycle 1 Day 8 pre-dose and at multiple time points (up to 24 hours) post dose (Cycle length =21 days)

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Description: ORR is defined as percentage of participants who achieve complete response (CR) and partial response (PR) through the study (approximately 3 years), as determined by the investigator according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST V1.1) for participants with solid tumors and Response Evaluation Criteria in Lymphoma (RECIL) for participants with lymphoma.

Measure: Dose Escalation and Cancer Treatment Expansions: Overall Response Rate (ORR)

Time: From the first dose until best response is achieved (up to approximately 3 years)

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Description: DOR will be determined by the investigator according to RECIST V1.1 for participants with solid tumors and RECIL for participants with lymphoma.

Measure: Dose Escalation and Cancer Treatment Expansions: Duration of Response (DOR)

Time: From the time of documentation of tumor response to the first recorded occurrence of disease progression (PD) or death from any cause (whichever occurs first), through end of study (up to approximately 3 years)

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Description: DCR is defined as percentage of participants who achieve stable disease (SD) or better greater than (>) 6 weeks during the study in response-evaluable population, as determined by the investigator according to RECIST V1.1 for participants with solid tumors and RECIL for participants with lymphoma.

Measure: Dose Escalation and Cancer Treatment Expansions: Disease Control Rate (DCR)

Time: From the first dose until best response is achieved (up to approximately 3 years)

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Description: PFS will be determined by the investigator according to RECIST V1.1 for participants with solid tumors and RECIL for participants with lymphoma.

Measure: Dose Escalation and Cancer Treatment Expansions: Progression-free Survival (PFS)

Time: From the date of the first dose administration to the date of first documentation of PD or death due to any cause whichever occurs first, through the end of the study (up to approximately 3 years)

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Description: TTR will be determined by the investigator according to RECIST V1.1 for participants with solid tumors and RECIL for participants with lymphoma.

Measure: Dose Escalation and Cancer Treatment Expansions: Time to Response (TTR)

Time: From the date of first study drug administration to the date of first documented PR or better (up to approximately 3 years)

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Measure: Dose Escalation and Cancer Treatment Expansions: Percentage of Participants at Each Dose Level Demonstrating Adduct Formation in Post-dose Skin or Tumor Biopsies

Time: Up to Cycle 1 (approximately 3 weeks) (Cycle length =21 days)

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Measure: Dose Escalation and Cancer Treatment Expansions: Percent Change in Small Ubiquitin-like Modifier (SUMO) 2/3 Signal With Pre and Post-dose Skin or Tumor Biopsies at Each Dose Level

Time: Up to Cycle 1 (approximately 3 weeks) (Cycle length =21 days)

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Measure: COVID-19 Expansion: Number of Participants Reporting one or More TEAEs

Time: Up to 9 months

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Description: Severity Grades will be evaluated as per National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE), version 5.0.

Measure: COVID-19 Expansion: Number of Participants Based on Severity of TEAEs

Time: Up to 9 months

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Measure: COVID-19 Expansion: Number of Participants Based on Duration of TEAEs

Time: Up to 9 months

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Description: CRS will be graded as per ASTCT Consensus Grading for CRS.

Measure: COVID-19 Expansion: Number of Participants who Experience CRS

Time: Up to 9 months

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Description: NEWS determines the degree of illness of participants and prompts critical care intervention. It will be based on the score allocated to respiratory rate, peripheral capillary oxygen saturation, any supplemental oxygen, temperature, systolic blood pressure, heart rate and level of consciousness.

Measure: COVID-19 Expansion: Change from Baseline in National Early Warning Score (NEWS)

Time: Up to 9 months

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Description: Percentage of participants will be reported based on severity rating on a 6-point ordinal scale, which will include: 1 (death); 2 (hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation, hospitalized); 3 (on non-invasive ventilation or high flow oxygen devices); 4 (hospitalized, requiring supplemental oxygen); 5 (hospitalized, not requiring supplemental oxygen); and 6 (not hospitalized).

Measure: COVID-19 Expansion: Percentage of Participants Reporting Each Hospitalization Severity Rating

Time: Up to 9 months

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Description: Change from Baseline in SARS-CoV-2 viral Load in nasopharyngeal or oropharyngeal samples will be determined by viral response. The nasopharyngeal swab will be collected from both nostrils or from the same nostril every time.

Measure: COVID-19 Expansion: Change From Baseline in SARS-CoV-2 Viral Load in Nasopharyngeal or Oropharyngeal Samples

Time: Up to 9 months

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Measure: COVID-19 Expansion: Percentage of Participants Requiring Oxygen Supplementation; Assisted or Positive Pressure Non-invasive Ventilation; and Invasive Ventilation, on Days 3, 5, 8, 11, 15, and 30

Time: Days 3, 5, 8, 11, 15, and 30

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Measure: COVID-19 Expansion: Percentage of Participants That met Intensive Care Unit (ICU) Criteria

Time: Up to 9 months

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Measure: COVID-19 Expansion: Duration of Hospitalization

Time: Up to 9 months

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Description: Time from the first dose of TAK-981 to viral load negativity (below level of detection).

Measure: COVID-19 Expansion: Time to Viral Ribonucleic Acid (RNA) Negativity in Nasopharyngeal or Oropharyngeal Samples

Time: Up to 9 months

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Description: Time from first dose of TAK-981 to participant's discharge or to NEWS score <=3. NEWS determines the degree of illness of participants and prompts critical care intervention. It will be based on the score allocated to respiratory rate, peripheral capillary oxygen saturation, any supplemental oxygen, temperature, systolic blood pressure, heart rate and level of consciousness.

Measure: COVID-19 Expansion: Time to Discharge or to a NEWS of Less Than or Equal to (<=) 3 and Maintained for 24 Hours

Time: Up to 9 months

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Measure: COVID-19 Expansion: Number of Deaths in Hospital due to any Cause in First 30 Days and in 90 Days

Time: Days 30 and 90

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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

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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: 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: Percentage of subjects reporting each severity rating on a 7-point ordinal scale

Time: Day 15

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Secondary Outcomes

Description: Time to an improvement of one category from admission on an ordinal scale. Time to an improvement of two categories from admission on an ordinal scale. Time to discharge (categories 1 or 2 of ordinal scale) from admission. Subject clinical status on an ordinal scale at days 3, 5, 8, 11, and 29. Mean change in the ranking on an ordinal scale from baseline to days 3, 5, 8, 11, 15 and 29 from baseline.

Measure: Percentage of subjects reporting each severity rating on a 7-point on an ordinal scale

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

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Description: • Change from baseline to days 3, 5, 8, 11, 15, and 29 in NEWS.

Measure: The time to discharge or to a NEWS of ≤ 2 and maintained for 24 hours, whichever occurs first.

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

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

Time: 29 days

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Measure: Incidence of new oxygen use, non-invasive ventilation or high flow oxygen devices during the trial.

Time: 29 days

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Measure: Duration of new oxygen use, non-invasive ventilation or high flow oxygen devices during the trial.

Time: 29 days

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Measure: Ventilator free days in the first 28 days

Time: 29 days

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Measure: Incidence of new mechanical ventilation use during the trial.

Time: 29 days

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Description: • Duration of hospitalization (days).

Measure: Hospitalization

Time: 29 days

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Description: Rate of mortality

Measure: Mortality

Time: In hospital, Day 28, Day 90

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Measure: Cumulative incidence of serious adverse events (SAEs)

Time: 29 days

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Measure: Cumulative incidence of Grade 3 and 4 adverse events (AEs)

Time: 29 days

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Measure: Number of participants with a discontinuation or temporary suspension of study drugs (for any reason)

Time: 29 days

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Measure: Changes from baseline in blood white cell count

Time: 29 days

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Measure: Changes from baseline in haemoglobin

Time: 29 days

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Measure: Changes from baseline in platelets

Time: 29 days

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Measure: Changes from baseline in creatinine

Time: 29 days

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Measure: Changes from baseline in blood electrolytes (including kaliemia)

Time: 29 days

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Measure: Changes from baseline in prothrombine time

Time: 29 days

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Measure: Changes from baseline in international normalized ratio (INR)

Time: 29 days

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Measure: Changes from baseline in glucose

Time: 29 days

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Measure: Changes from baseline in total bilirubin

Time: 29 days

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Measure: Changes from baseline in alanine aminotransferase (ALT)

Time: 29 days

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Measure: Changes from baseline in aspartate aminotransferase (AST)

Time: 29 days

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Other Outcomes

Measure: Percent of subjects with SARS-CoV-2 detectable in nasopharyngeal sample

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

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Measure: Quantitative SARS-CoV-2 virus in nasopharyngeal sample

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

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Measure: Quantitative SARS-CoV-2 virus in blood

Time: Days 3, 5, 8 and 11

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Description: On Day 1, plasma concentration 4 hours after the first administration (peak), and before the second administration (trough at H12) On Days 3, 5, 8 and 11, trough plasma concentration (before dose administration) while hospitalized

Measure: Plasma concentration of lopinavir

Time: Days 1, 3, 5, 8 and 11

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Description: On Day 1, plasma concentration 4 hours after the first administration (peak), and before the second administration (trough at H12) On Days 3, 5, 8 and 11, trough plasma concentration (before dose administration) while hospitalized

Measure: Plasma concentration of hydroxychloroquine

Time: Days 1, 3, 5, 8 and 11

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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)

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

Measure: World Health Organization (WHO) ordinal scale measured at 14 days after enrollment

Time: Day 14

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Secondary Outcomes

Measure: Rates of death during the index hospitalization

Time: Index hospitalization, up to 46 days

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Measure: Number of days on mechanical ventilation for patients who were on mechanical ventilation at baseline

Time: Baseline

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Measure: Proportion of patients not receiving mechanical ventilation at baseline who progress to requiring mechanical ventilation during the index hospitalization

Time: Index hospitalization, up to 46 days

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

Measure: WHO ordinal scale measured at 28 days after enrollment

Time: Day 28

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Measure: Hospital length of stay in days for the index hospitalization

Time: Index hospitalization, up to 46 days

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Measure: Rates of all-cause study medication discontinuation

Time: Index hospitalization, up to 46 days

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Measure: Rates of severe adverse events

Time: Day 14

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Primary Outcomes

Description: Number of participants in each arm who expire.

Measure: Death

Time: up to day 60

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Description: Number of participants in each arm who are hospitalized and requiring mechanical ventilation and/or high flow nasal cannula and/or ICU/CCU admission (or equivalent) and/or ECMO.

Measure: Hospitalized, requiring mechanical ventilation and/or high flow nasal cannula and/or ICU/CCU admission (or equivalent) and/or ECMO

Time: up to day 60

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Description: Number of participants in each arm who are hospitalized and requiring supplemental oxygen, not requiring ICU/CCU level care (or interventions listed under Outcome 2).

Measure: Hospitalized, requiring supplemental oxygen, not requiring ICU/CCU level care (or interventions listed under Outcome 2)

Time: up to day 60

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Description: Number of participants in each arm who develop grade 3 and 4 adverse events during the study period.

Measure: Cumulative incidence of grade 3 and 4 adverse events

Time: up to day 60

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Description: Number of participants in each arm who develop serious adverse events during the study period.

Measure: Number of participants with serious adverse events

Time: up to day 60

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Description: Number of participants in each arm who develop symptomatic hypotension (systolic blood pressure <90 mmHg) or hypotension requiring cessation of prazosin.

Measure: Incidence of symptomatic hypotension or hypotension requiring cessation of prazosin

Time: up to day 60

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Secondary Outcomes

Description: Number of participants with laboratory abnormalities in peripheral blood (Lymphopenia, leukocytosis, anemia, thrombocytopenia, creatinine, AST/ALT, troponin I, pro-BNP, D-dimer, ferritin, interleukin (IL-6), soluble IL-2 receptor.

Measure: Number of participants with laboratory abnormalities in peripheral blood

Time: up to day 60

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Description: Number of days with laboratory abnormalities in peripheral blood (Lymphopenia, leukocytosis, anemia, thrombocytopenia, creatinine, AST/ALT, troponin I, pro-BNP, D-dimer, ferritin, interleukin (IL-6), soluble IL-2 receptor.

Measure: Duration of laboratory abnormalities in peripheral blood

Time: up to day 60

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Description: Number of participants with laboratory abnormalities in fractionated plasma catecholamines and plasma metanephrines.

Measure: Number of participants with laboratory abnormalities in plasma

Time: up to day 60

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Description: Number of days with laboratory abnormalities in fractionated plasma catecholamines and plasma metanephrines.

Measure: Duration of laboratory abnormalities in plasma

Time: up to day 60

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Primary Outcomes

Description: At least 3 parameters are met including CRP and/or Ferritin among: CRP: decrease > 50% Ferritinemia: decrease > 1/3 Serum creatinine: decrease > 1/3 AST/ALT: decrease > 50% Eosinophils > 50 /mm3 Lymphocytes > 1000 /mm3

Measure: Biological criteria

Time: 7 days from enrolment

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Secondary Outcomes

Description: Number of days without mechanical ventilation

Measure: Duration of oxygen therapy (days)

Time: 28 days from enrolment

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Description: Number of patients included in stage 2b

Measure: Number of intensive care units admissions

Time: 28 days from enrolment

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Description: Number of days in intensive care units for patients managed in intensive care units

Measure: Number of days in intensive care units

Time: 28 days from enrolment

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Description: Mortality rate

Measure: Mortality rate

Time: 28 days from enrolment

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Description: Total number of days in hospital

Measure: Total number of days in hospital

Time: 28 days from enrolment

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Description: Organ failure score modification (Sepsis-related Organ Failure Assessment (SOFA) score); Sofa score's minimum and maximum values are 0 and 24, the lowest score corresponds to a better outcome.

Measure: Organ failure score modification (Sepsis-related Organ Failure Assessment (SOFA) score)

Time: 28 days from enrolment

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Description: Number of bacterial and/or fungal sepsis

Measure: Number of bacterial and/or fungal sepsis

Time: 28 days from enrolment

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Primary Outcomes

Description: Percentage of patients death due to lung involvement due to SARS-CoV-2 virus infection at 28 days of treatment

Measure: Mortality due to lung involvement due to SARS-CoV-2 virus infection at 28 days of treatment

Time: 28 days

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Secondary Outcomes

Description: Percentage of patients death due to lung involvement due to SARS-CoV-2 virus infection at 14 days of treatment

Measure: Mortality due to lung involvement due to SARS-CoV-2 virus infection at 14 days of treatment

Time: 14 days

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Description: Percentage of patients death due to any cause at 28 days of treatment

Measure: Mortality from any cause at 28 days

Time: 28 days

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Description: Number of days without mechanical respirator and without vasopressor treatment for 28 days

Measure: Days without mechanical respirator and without vasopressor treatment for 28 days

Time: 28 days

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Description: Percentage of patients alive without mechanical ventilation and without vasopressors on day 28

Measure: Patients alive without mechanical ventilation and without vasopressors on day 28

Time: 28 days

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Description: Percentage of patients alive and without mechanical ventilation on day 14

Measure: Patients alive and without mechanical ventilation on day 14

Time: 14 days

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Description: Percentage of patients alive and without mechanical ventilation on day 28

Measure: Patients alive and without mechanical ventilation on day 28

Time: 28 days

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Description: Percentage of patients alive and without vasopressors on day 28

Measure: Patients alive and without vasopressors on day 28

Time: 28 days

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Description: Number of days without vasopressors for 28 days

Measure: Days without vasopressors for 28 days

Time: 28 days

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Description: Percentage of patients cured at 15 days

Measure: Patients cured at 15 days

Time: 15 days

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Description: Percentage of patients with each adverse event

Measure: Incidence of Treatment-Emergent Adverse Events

Time: 1 year

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Primary Outcomes

Description: Participants are alive and free of respiratory failure if they are in category 1, 2, 3 or 4 from the GlaxoSmithKline (GSK) modified version ordinal scale adapted from World Health Organization (WHO) scale 2020. The 8-point scale is as follows: 1) Non-hospitalized, no limitation of activity; 2) Non-hospitalized, limitation of activity; 3) Hospitalized, no oxygen therapy; 4) Hospitalized, low-flow oxygen by mask or nasal prongs; 5) Hospitalized, high-flow oxygen (≥15L/min), continuous positive airway pressure (CPAP), bilevel positive airway pressure (BIPAP), non-invasive ventilation; 6) Hospitalized, intubation and mechanical ventilation; 7) Hospitalized, mechanical ventilation plus additional organ support; 8) Death.

Measure: Proportion of participants alive and free of respiratory failure at Day 28

Time: Day 28

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Secondary Outcomes

Description: Number of deaths due to all causes will be assessed.

Measure: Number of deaths due to all causes at Day 60

Time: Day 60

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Description: Time to death due to all causes will be assessed.

Measure: Time to number of deaths due to all causes up to Day 60

Time: Up to Day 60

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Description: Participants alive and free of respiratory failure if they are in category 1, 2, 3 or 4 from the GlaxoSmithKline (GSK) modified version ordinal scale adapted from World Health Organization (WHO) scale 2020. The 8-point scale is as follows: 1) Non-hospitalized, no limitation of activity; 2) Non-hospitalized, limitation of activity; 3) Hospitalized, no oxygen therapy; 4) Hospitalized, low-flow oxygen by mask or nasal prongs; 5) Hospitalized, high-flow oxygen (≥15L/min), continuous positive airway pressure (CPAP), bilevel positive airway pressure (BIPAP), non-invasive ventilation; 6) Hospitalized, intubation and mechanical ventilation; 7) Hospitalized, mechanical ventilation plus additional organ support; 8) Death.

Measure: Proportion of participants alive and free of respiratory failure at Days 7, 14, 42 and 60

Time: Days 7, 14, 42, and 60

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Description: Time will be recorded from dosing to recovery from respiratory failure. Participants are in respiratory failure if they are in category 5 or above from the GlaxoSmithKline (GSK) modified version ordinal scale adapted from World Health Organization (WHO) scale 2020. The 8-point scale is as follows: 1) Non-hospitalized, no limitation of activity; 2) Non-hospitalized, limitation of activity; 3) Hospitalized, no oxygen therapy; 4) Hospitalized, low-flow oxygen by mask or nasal prongs; 5) Hospitalized, high-flow oxygen (≥15L/min), continuous positive airway pressure (CPAP), bilevel positive airway pressure (BIPAP), non-invasive ventilation; 6) Hospitalized, intubation and mechanical ventilation; 7) Hospitalized, mechanical ventilation plus additional organ support; 8) Death.

Measure: Time to recovery from respiratory failure

Time: Up to Day 28

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Description: Participants are independent of supplementary oxygen if they are in category 1, 2 or 3 from the GlaxoSmithKline (GSK) modified version ordinal scale adapted from World Health Organization (WHO) scale 2020. The 8-point scale is as follows: 1) Non-hospitalized, no limitation of activity; 2) Non-hospitalized, limitation of activity; 3) Hospitalized, no oxygen therapy; 4) Hospitalized, low-flow oxygen by mask or nasal prongs; 5) Hospitalized, high-flow oxygen (≥15L/min), continuous positive airway pressure (CPAP), bilevel positive airway pressure (BIPAP), non-invasive ventilation; 6) Hospitalized, intubation and mechanical ventilation; 7) Hospitalized, mechanical ventilation plus additional organ support; 8) Death.

Measure: Proportion of participants alive and independent of supplementary oxygen at Days 7, 14, 28, 42, and 60

Time: Days 7, 14, 28, 42, and 60

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Description: Participants are independent of supplementary oxygen if they are in category 1, 2 or 3 from the GlaxoSmithKline (GSK) modified version ordinal scale adapted from World Health Organization (WHO) scale 2020. The 8-point scale is as follows: 1) Non-hospitalized, no limitation of activity; 2) Non-hospitalized, limitation of activity; 3) Hospitalized, no oxygen therapy; 4) Hospitalized, low-flow oxygen by mask or nasal prongs; 5) Hospitalized, high-flow oxygen (≥15L/min), continuous positive airway pressure (CPAP), bilevel positive airway pressure (BIPAP), non-invasive ventilation; 6) Hospitalized, intubation and mechanical ventilation; 7) Hospitalized, mechanical ventilation plus additional organ support; 8) Death.

Measure: Time to last dependence on supplementary oxygen

Time: Up to Day 28

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Description: For participants not in ICU at time of dosing, the proportion of participants admitted to the ICU prior to Day 28.

Measure: Proportion of participants admitted to Intensive Care Unit (ICU)

Time: Up to Day 28

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Description: Defined as the time from dosing to when the participant is discharged from the ICU.

Measure: Time to final ICU discharge

Time: Up to Day 28

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Description: Time from dosing to when a participant is discharged from the hospital.

Measure: Time to final hospital discharge

Time: Up to Day 28

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Description: AEs and SAEs will be collected.

Measure: Number of participants with Adverse events (AEs) and Serious adverse events (SAEs)

Time: Up to Day 60

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Primary Outcomes

Description: The number of patients with the clinical improvement is defined as an improvement of two points (from the status at baseline) on an ordinal scale of clinical improvement on day 28 or discharge from hospital ( whatever occurs earlier) Death Hospitalized with Invasive mechanical ventilation plus additional organ support - ECMO / pressors / RRT Hospitalized with intubation and mechanical ventilation Hospitalized on non-invasive ventilation or high flow oxygen. Hospitalized on a mask or nasal prongs. Hospitalized no oxygen therapy. Ambulatory, with limitation of activities. Ambulatory, no limitation of activities. I. No clinical or virological evidence of infection.

Measure: The changes of COVID Ordinal Outcomes Scale

Time: baseline vs Day 14, day 28

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Description: Percentage of the patients with clinical recovery which is defined as a normalisation of fever, respiratory rate, and oxygen saturation, and improvement of cough, sustained for at least 72 hours, or live hospital discharge, whichever comes first. Normalization and improvement criteria: Fever - <37°C, Respiratory rate - ≤24/minute on room air, Oxygen saturation - >94% on room air, Cough - mild or absent on a patient reported scale of severe, moderate, mild, absent.

Measure: Percentage of the patients with Clinical Recovery

Time: baseline vs day 7, day 14, day 28

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Description: The evaluation of changes in modified Borg dyspnea scale. From 0 to 10 units.A lower score means a better clinical result (0 is the absence of dyspnea, and 10 - is maximal dyspnea). Minimal clinically important difference is 1 unit.

Measure: The changes of the Borg's scale

Time: Baseline vs day 7, day 14, day 28

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Secondary Outcomes

Description: Change in C-reactive protein (CRP) level from baseline in mg/ml. A lower level of CRP means a better clinical result.

Measure: CRP level

Time: baseline, day 7, Day 14, Day 28

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Description: Change in blood absolute lymphocyte count from baseline. A higher number of lymphocytes means a better clinical result.

Measure: Lymphocyte count

Time: baseline, day 7, Day 14, Day 28

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Description: Change in blood D-dimer level from baseline. A lower level of D-dimer means a better clinical result.

Measure: D-dimer

Time: baseline, day 7, Day 14, Day 28

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Description: Change in peripheral blood IL-6 level from baseline. A lower level of IL-6 means a better clinical result.

Measure: IL-6

Time: baseline, day 7, Day 14, Day 28

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Description: Percentage of patients without artificial lung ventilation during the study. A lower percentage of patients means a better clinical result.

Measure: Percentage of patients without artificial lung ventilation

Time: baseline, day 7, Day 14, Day 28

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Primary Outcomes

Description: Proportion of all-cause mortality

Measure: All-cause mortality

Time: up to 28 days

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Secondary Outcomes

Description: Mean length of stay in intensive care unit

Measure: Length of stay in intensive care unit

Time: up to 28 days

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Description: Mean duration of mechanical ventilation

Measure: Duration of mechanical ventilation

Time: up to 28 days

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Description: Mean change from baseline using time series analysis

Measure: Body temperature (degree in Celsius)

Time: Day 1, 3, 5, and 7 after administration of therapy

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Description: Mean change from baseline using time series analysis

Measure: The Sequential Organ Failure Assessment (SOFA) Score

Time: Day 1, 3, 5, and 7 after administration of therapy

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Description: Mean change from baseline using time series analysis

Measure: PAO2/FIO2 ratio

Time: Day 1, 3, 5, and 7 after administration of therapy

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Description: Mean change from baseline using time series analysis

Measure: C-Reactive Protein (CRP) in mg/L

Time: Day 1, 3, 5, and 7 after administration of therapy

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Description: Mean change from baseline using time series analysis

Measure: D-Dimer in ng/mL

Time: Day 1, 3, 5, and 7 after administration of therapy

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Description: Mean change from baseline using time series analysis

Measure: Procalcitonin in ng/mL

Time: Day 1, 3, 5, and 7 after administration of therapy

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Description: Mean change from baseline using time series analysis

Measure: Interleukin 6 (IL-6) in pg/mL

Time: Day 1, 3, 5, and 7 after administration of therapy

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Description: Number of participants with allergic/ anaphylaxis transfusion reaction

Measure: Allergic/ anaphylaxis transfusion reaction

Time: 24 hours post-transfusion

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Description: Number of participants with Hemolytic transfusion reaction

Measure: Hemolytic transfusion reaction

Time: 24 hours post-transfusion

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Description: Number of participants with Transfusion Related Acute Lung Injury

Measure: Transfusion Related Acute Lung Injury

Time: 24 hours post-transfusion

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Description: Number of participants with Transfusion associated Circulatory Overload

Measure: Transfusion associated Circulatory Overload

Time: 24 hours post-transfusion

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Primary Outcomes

Description: Number of days taken for occurrence of one of the following events: 1. Death 2. Mechanical ventilation 3. Extracorporeal membrane oxygenation (ECMO) 4. Cardiovascular organ support (balloon pump or inotropes) 5. Renal failure (estimated creatinine clearance (by Cockcroft-Gault formula) <15 ml /min/1.73m^2), haemofiltration or dialysis

Measure: Time to incidence of the composite endpoint of: Death, Mechanical ventilation, ECMO, Cardiovascular organ support, or Renal failure

Time: up to Day 14

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Secondary Outcomes

Description: The clinical status of the patients is assessed using 7-point ordinal scale as follows: 1 = Death, 2 = Mechanical ventilation, 3 = Non-invasive or high flow oxygen, 4 = Low flow oxygen, 5 = Hospitalised - no oxygen, 6 = Discharged - normal activities not resumed, 7 = Discharged - normal activities resumed

Measure: Change in clinical status as assessed on 7-point ordinal scale compared to baseline

Time: 14 days

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Description: The proportion of patients in each treatment arm that experience adverse events of special interest, defined as: venous thromboembolism, new infections requiring antimicrobials

Measure: Proportion of patients with adverse events of special interest in each treatment arm

Time: 14 days

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Description: The time taken to achieve blood oxygen saturation levels above 94% in patients on room air, measured in hours/days

Measure: Time to Sp02 >94% on room air

Time: 14 days

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Description: The amount of time between a patient's first positive SARS-CoV2 PCR test and a patient's first negative SARS-CoV2 PCR test, measured in days

Measure: Time to first negative SARS-CoV2 PCR

Time: 14 days

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Description: The duration of oxygen therapy given to a patient, measured in days

Measure: Duration of oxygen therapy

Time: 14 days

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Description: The duration of hospitalisation of a patient, measured in days

Measure: Duration of hospitalisation

Time: 14 days

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Description: The number of deaths recorded at 28 days irrespective of the cause

Measure: All cause mortality at day 28

Time: 28 Days

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Description: The time to clinical improvement for a patient, defined as: >2 point improvement from Day 1 on the 7-point ordinal scale, measured in days

Measure: Time to clinical improvement

Time: 14 days

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Primary Outcomes

Description: Number of days taken for occurrence of one of the following events: 1. Death 2. Mechanical ventilation 3. Extracorporeal membrane oxygenation (ECMO) 4. Cardiovascular organ support (balloon pump or inotropes/vassopressors) 5. Renal failure (estimated creatinine clearance (by Cockcroft-Gault formula) <15 ml /min/1.73m^2), haemofiltration or dialysis

Measure: Time to incidence of the composite endpoint of: Death, Mechanical ventilation, ECMO, Cardiovascular organ support, or Renal failure

Time: up to Day 14

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Secondary Outcomes

Description: Change in patient blood levels of IL-6 compared to baseline, measured in pg/mL

Measure: Change in biomarkers thought to be associated with progression of COVID-19 compared to baseline: IL-6

Time: 14 days

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Description: Change in patient blood levels of ferritin compared to baseline, measured in ng/mL

Measure: Change in biomarkers thought to be associated with progression of COVID-19 compared to baseline: ferritin

Time: 14 days

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Description: Change in patient blood levels of CRP compared to baseline, measured in mg/L

Measure: Change in biomarkers thought to be associated with progression of COVID-19 compared to baseline: c-reactive protein (CRP)

Time: 14 days

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Description: Change in patient blood levels of D-dimer compared to baseline, measured in ng/mL

Measure: Change in biomarkers thought to be associated with progression of COVID-19 compared to baseline: D-dimer

Time: 14 days

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Description: Change in patient blood levels of neutrophil/lymphocyte ratio compared to baseline

Measure: Change in biomarkers thought to be associated with progression of COVID-19 compared to baseline: neutrophil/lymphocyte ratio

Time: 14 days

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Description: Change in patient blood levels of lactate dehydrogenase (LDH) compared to baseline, measured in U/L

Measure: Change in biomarkers thought to be associated with progression of COVID-19 compared to baseline: lactate dehydrogenase (LDH)

Time: 14 days

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Description: The clinical status of the patients is assessed using 7-point ordinal scale as follows: 1 = Death, 2 = Mechanical ventilation, 3 = Non-invasive or high flow oxygen, 4 = Low flow oxygen, 5 = Hospitalised - no oxygen, 6 = Discharged - normal activities not resumed, 7 = Discharged - normal activities resumed

Measure: Change in clinical status as assessed on 7-point ordinal scale compared to baseline

Time: 14 days

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Description: Number of days taken for occurrence of each of the following events: 1. Death 2. Mechanical ventilation 3. Extracorporeal membrane oxygenation (ECMO) 4. Cardiovascular organ support (balloon pump or inotropes/vassopressors) 5. Renal failure (estimated creatinine clearance (by Cockcroft-Gault formula) <15 ml /min/1.73m^2), haemofiltration or dialysis

Measure: Time to each of the individual endpoints of the composite primary outcome measure

Time: 14 days

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Description: The proportion of patients in each treatment arm that experience adverse events of special interest, defined as: Diabetic ketoacidosis in patients on Ambrisentan & Dapagliflozin, New peripheral oedema in patients on Ambrisentan & Dapagliflozin arm

Measure: Proportion of patients with adverse events of special interest in each treatment arm

Time: 14 days

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Description: The time taken to achieve blood oxygen saturation levels above 94% in patients on room air, measured in hours/days (chronically hypoxic individuals will be excluded from this analysis)

Measure: Time to Sp02 >94% on room air

Time: 14 days

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Description: The amount of time between a patient's first positive SARS-CoV2 PCR test and a patient's first negative SARS-CoV2 PCR test, measured in days

Measure: Time to first negative SARS-CoV2 PCR

Time: 14 days

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Description: The duration of oxygen therapy given to a patient, measured in days

Measure: Duration of oxygen therapy

Time: 14 days

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Description: The duration of hospitalisation of a patient, measured in days

Measure: Duration of hospitalisation

Time: 14 days

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Description: The number of deaths recorded at 28 days irrespective of the cause

Measure: All-cause mortality at day 28

Time: 28 days

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Description: The time to clinical improvement for a patient, defined as: >2 point improvement from Day 1 on the 7-point ordinal scale, measured in days

Measure: Time to clinical improvement

Time: 14 days

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Primary Outcomes

Description: Clinical improvement until hospital discharge

Measure: Daily Patient progression assessed with the World Health Organization-adapted 6-points ordinal scale

Time: through whole duration of the hospitalization, an average of 14 days

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Secondary Outcomes

Description: Titrated every second with automated oxygen titration device (FreeO2)

Measure: The mean oxygen flow required to maintain the oxygen saturation (SpO2) target at 92%

Time: First 7 days of the trial

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Measure: Rate of non invasive ventilation (NIV) / high flow nasal therapy (HFNT) use

Time: through whole duration of the hospitalization, an average of 14 days

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Measure: Rate of intubation

Time: through whole duration of the hospitalization, an average of 14 days

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Measure: Ventilator-free days at day 28

Time: through whole duration of the hospitalization, an average of 14 days

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Measure: Rate of ICU admission/length of stay/mortality

Time: through whole duration of the hospitalization, an average of 14 days

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Description: Sepsis-related organ failure assessment (SOFA), national early warning score (NEWS2), early warning score for oxygen therapy (EWS.O2), decrease of at least 2 points on the 6-point ordinal scale

Measure: Severity index measurement

Time: through whole duration of the hospitalization, an average of 14 days

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Primary Outcomes

Description: Change in composite COVID ordinal scale at day 15. Ordinal scale: 1) not hospitalized with resumption of normal activities; 2) not hospitalized, but unable to resume normal activities; 3) hospitalized, not requiring oxygen; 4) hospitalized, requiring oxygen; 5) hospitalized, requiring high-flow oxygen therapy, or noninvasive ventilation; 6) hospitalized, requiring invasive ventilation; 7) ventilation plus additional organ support such as pressors, renal replacement therapy and ECMO and 8) death. COVID Ordinal Scale ranges from 1 to 8, with score 1 on the scale corresponds to an ambulatory patient with minimal symptoms and score 8 on the scale corresponds to death.

Measure: Covid (Coronavirus Disease-19) Ordinal Scale

Time: 15 days

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Secondary Outcomes

Description: All-cause mortality assessed on day 15.

Measure: Mortality

Time: 15 days

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Description: All-cause mortality assessed on day 28.

Measure: Mortality

Time: 28 days

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Description: Supplemental Oxygen-free days

Measure: Supplemental Oxygen

Time: 28 days

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Description: Invasive-ventilator-free days

Measure: Invasive-ventilator

Time: 28 days

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Description: ICU-free days

Measure: ICU stay

Time: 28 days

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Description: Hospital-free days

Measure: Hospital stay

Time: 28 days

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Description: Decrease in the markers D-dimer/ Ferritin/ C-reactive protein

Measure: Inflammatory markers

Time: 15 days

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Description: Thromboembolic complications including stroke

Measure: Thromboembolic complications

Time: 28 days

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Description: COVID ordinal scale

Measure: COVID ordinal scale

Time: 28 days

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Primary Outcomes

Measure: Change in oxygenation parameter of P(A-a)O2 gradient by Day 6

Time: 1-6 days

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Measure: Percent of patients who have been intubated by Day 14

Time: 1-14 days

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Secondary Outcomes

Description: The 8 point ordinal scale will be used, where 0 is not hospitalized, no clinical or virological evidence of infection, and 8 is death.

Measure: Change in ordinal scale

Time: 1-28 days

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Measure: All cause 28-day mortality

Time: 1-28 days

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Measure: Number of patients with treatment-emergent serious adverse events or clinically significant adverse drug reactions (ADRs)

Time: 1-58 days

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Primary Outcomes

Description: number of days living without mechanical ventilation at D28

Measure: Ventilation free days at D28

Time: 28 days

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Primary Outcomes

Description: Primary outcome of the study is the number of patients alive without mechanical ventilation at day 15 after hospitalization.

Measure: Patients requiring mechanical ventilation or death

Time: No mechanical ventilation at day 15 after hospitalization.

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Secondary Outcomes

Description: 0. Uninfected. Non viral RNA detected Ambulatory, Asymptomatic, viral RNA detected Ambulatory, Symptomatic, Independent Ambulatory, Symptomatic, Assistance needed Hospitalized, mild disease, No oxygen therapy needed Hospitalized, mild disease, Oxygen by mask of nasal prongs Hospitalized, severe disease, Oxygen by NIV or High flow Hospitalized, severe disease, Intubation and mechanical ventilation (pO2/FiO2>=150 OR SpO2/FIO2>=200) Hospitalized, severe disease, Mechanical ventilation (pO2/FiO2<150 OR SpO2/FIO2<200) OR vasopressors (norepinephrine >0.3 microg/kg/min) Hospitalized, severe disease, Mechanical ventilation pO2/FiO2<150 AND vasopressors (norepinephrine >0.3 microg/kg/min), OR Dialysis OR ECMO Death, Dead

Measure: Clinical status of subject at day 15 and day 30 (on a 10-point "WHO progression" ordinal scale)

Time: day 15 and day 30

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Primary Outcomes

Description: Plasma viscosity will be measured in centipoise (cP). The normal range is 1.4 - 1.8 cP and measurements above this range indicate increased viscosity.

Measure: Change in Plasma Viscosity

Time: Baseline (Study Day 1 prior to TPE), up to Day 4 (within 24 hours of last TPE)

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Secondary Outcomes

Description: The number of participants dying from any cause will be compared between study arms.

Measure: All Cause Mortality

Time: Up to Day 31

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Description: The number of bleeding and thromboembolic complications will be compared between study arms. This endpoint is a composite outcome including any acute bleeding requiring transfusion support, venous thrombosis (deep vein thrombosis or pulmonary embolism), arterial clots (myocardial infarction, stroke, limb ischemia), renal replacement therapy or catheter line related clots.

Measure: Bleeding and Thromboembolic Complications

Time: Up to Day 31

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Description: Time to treatment failure will be assessed in hours and is defined as plasma viscosity > 3.5 cP and/or the participant is a candidate for TPE as salvage therapy, as assessed by clinical team.

Measure: Time to Treatment Failure

Time: Up to Day 31

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Description: The number of days spent in the ICU will be compared between study arms.

Measure: Duration of ICU Stay

Time: Up to Day 31

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Description: The number of days spent in the hospital will be compared between study arms.

Measure: Duration of Hospital Stay

Time: Up to Day 31

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Description: The number of participants in each study arm discharged to home or to a long-term acute care hospital, versus palliative care or death.

Measure: Discharge Disposition

Time: Up to Day 31

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Description: The clinical status of participants will be assessed with a single-item, 12-point ordinal scale. A score of 1 indicates no evidence of infection and the severity of the clinical status increases as the number of necessary interventions increases to the final score of 12, which is death.

Measure: Change in Clinical Status

Time: Days 6, 10, 17, and 31

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Description: Body temperature will be assessed in degrees Celsius.

Measure: Change in Body Temperature

Time: Days 6, 10, 17, and 31

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Description: Systolic blood pressure will be assessed in millimeters of mercury (mm Hg).

Measure: Change in Systolic Blood Pressure

Time: Days 6, 10, 17, and 31

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Description: Diastolic blood pressure will be assessed in millimeters of mercury (mm Hg).

Measure: Change in Diastolic Blood Pressure

Time: Days 6, 10, 17, and 31

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Description: Heart rate will be assessed as beats per minute.

Measure: Change in Heart Rate

Time: Days 6, 10, 17, and 31

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Description: Respiratory rate will be assessed as breaths per minute.

Measure: Change in Respiratory Rate

Time: Days 6, 10, 17, and 31

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Description: The number of days participants are on a ventilator will be compared between study arms.

Measure: Change in Ventilator Days

Time: Days 6, 10, 17, and 31

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Description: The oxygen percent delivered with a ventilator that is needed to maintain blood oxygen levels will be compared between study arms.

Measure: Change in Ventilator Oxygen Percent (FiO2)

Time: Days 6, 10, 17, and 31

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Description: PEEP during ventilator use is measured in centimeters of water (cmH2O) and is the pressure in the lungs above atmospheric pressure, at the end of an exhalation. Higher PEEP (10 cmH2O or greater) may be associated with improved mortality, compared with PEEP below 10 cmH2O.

Measure: Change in Positive End-Expiratory Pressure (PEEP)

Time: Days 6, 10, 17, and 31

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Description: Whether or not breathing assistance from vasopressors is needed will be compared between study arms.

Measure: Change in Vasopressor Requirements

Time: Days 6, 10, 17, and 31

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Description: Whether or not breathing assistance from an RRT is needed will be compared between study arms.

Measure: Change in Need for Treatment from a Registered Respiratory Therapist (RRT)

Time: Days 6, 10, 17, and 31

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Description: The Sequential Organ Failure Assessment (SOFA) score is a method of predicting mortality that is based on the degree of dysfunction of six organ systems (respiratory, nervous, cardiovascular, liver, coagulation, and kidneys). Each organ system is scored between 0 and 4, where 0 indicates normal function and 4 indicates a high degree of dysfunction.Total scores range from 0 to 24. A score of 0-6 is associated with a mortality rate of less than 10% while a score between 16 and 24 is associated with a greater than 90% mortality rate.

Measure: Change in Sequential Organ Failure Assessment (SOFA) Score

Time: Days 6, 10, 17, and 31

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Description: The PaO2/FiO2 ratio is decreased with hypoxia. A value of less than 200 indicates acute respiratory distress syndrome (ARDS).

Measure: Change in Partial Pressure of Arterial Oxygen (PaO2)/Percentage of Inspired Oxygen (FiO2) Ratio

Time: Days 6, 10, 17, and 31

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Description: Ventilatory ratio will be documented. The formula for the ventilatory is [minute ventilation (ml/min) × PaCO2 (mm Hg)]/(predicted body weight × 100 × 37.5).

Measure: Change in Ventilatory Ratio

Time: Days 6, 10, 17, and 31

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Description: The normal range for WBC is 3,400 to 6,600 cells per microliter (cells/mL) of blood. A high WBC occurs when inflammation or infection is present.

Measure: Change in White Blood Count (WBC)

Time: Days 6, 10, 17, and 31

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Description: Hemoglobin is measured in grams per deciliter (grams/dL). A normal Hb count for males is 13.2 to 16.6 grams/dL and a normal count for females is 11.6 to 15 grams/dL. A patient has anemia when their hemoglobin is low.

Measure: Change in Hemoglobin (Hb)

Time: Days 6, 10, 17, and 31

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Description: A measure of hematocrit is the volume of red blood cells in the total blood volume. Normal hematocrit for males is 40 to 54% and a normal measurement for females is 36 to 48%

Measure: Change in Hematocrit (Hct)

Time: Days 6, 10, 17, and 31

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Description: A normal platelet is 150,000 to 450,000 platelets per microliter of blood. An excess of platelets in the blood can be caused by inflammation or infection.

Measure: Change in Platelet Count

Time: Days 6, 10, 17, and 31

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Description: MVP is a measurement of platelet size. Platelet size tends to be increased when platelet count is high. Typical platelet volume is 9.4 to 12.3 femtoliters (fL).

Measure: Change in Mean Platelet Volume (MVP)

Time: Days 6, 10, 17, and 31

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Description: The normal range for BUN is 7 to 20 milligrams per deciliter (mg/dL) of blood. A high BUN value indicates that kidneys are not functioning well.

Measure: Change in Blood Urea Nitrogen (BUN)

Time: Days 6, 10, 17, and 31

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Description: The normal range for creatinine is 0.84 to 1.21 mg/dL of blood. High serum creatinine indicates that kidneys are not functioning well.

Measure: Change in Creatinine

Time: Days 6, 10, 17, and 31

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Description: For adults, normal values for total bilirubin are around 1.2 mg/dL of blood. High bilirubin indicates that the liver is not functioning well.

Measure: Change in Bilirubin

Time: Days 6, 10, 17, and 31

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Description: The normal range for total protein is 6.0 to 8.3 g/dL of blood. High levels of total protein can occur with inflammation or infection while low levels may indicate kidney or liver problems, or malnutrition.

Measure: Change in Total Protein

Time: Days 6, 10, 17, and 31

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Description: The normal range for albumin is 3.4 to 5.4 g/dL of blood. High albumin may indicate acute infection while low albumin can indicate malnutrition or liver disease.

Measure: Change in Albumin

Time: Days 6, 10, 17, and 31

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Description: A normal value for CRP (with a standard test) is less than 10 milligrams per liter (mg/L) of blood. CRP increases with inflammation, which could be attributed to an infection, chronic inflammatory disease or heart disease.

Measure: Change in C-reactive Protein (CRP)

Time: Days 6, 10, 17, and 31

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Description: A normal value for IL-6 is 1.8 picograms per milliliter (pg/mL) or less. IL-6 is increased in patients with infections or chronic inflammation.

Measure: Change in Interleukin 6 (IL-6)

Time: Days 6, 10, 17, and 31

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Description: Prothrombin time is a measurement of the time it takes (in seconds) for blood to clot. A normal value is 10 to 14 seconds.

Measure: Change in Prothrombin Time (PT)

Time: Days 6, 10, 17, and 31

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Description: An INR of around 1.1 is considered normal. Lower INR can means that blood is clotting faster than desired while higher INR indicates that blood is clotting slower than normal.

Measure: Change in International Normalized Ratio (INR)

Time: Days 6, 10, 17, and 31

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Description: The aPTT test is a measurement of blood clotting time. Normal values for aPTT are around 30 to 40 seconds. Higher aPTT values can indicate a bleeding risk.

Measure: Change in Activated Partial Thromboplastin Time (aPTT)

Time: Days 6, 10, 17, and 31

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Description: The anti-factor Xa assay measures plasma heparin and is useful with monitoring anticoagulation therapy. Interpretation of the resulting values depends on the anticoagulation medication used as well as the dosing schedule and indication. Patients not taking heparin should have an anti-Xa value of 0 units per milliliter (U/mL).

Measure: Change in Anti-factor Xa (anti-Xa)

Time: Days 6, 10, 17, and 31

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Description: Fibrinogen is a protein that helps with the formation of blood clots. For adults, the normal range of fibrinogen is 200 to 400 mg/dL. Fibrinogen can be increased in patients with liver, kidney, or inflammatory diseases. The risk of developing a thromboembolism is increased with chronically high levels of fibrinogen.

Measure: Change in Fibrinogen

Time: Days 6, 10, 17, and 31

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Description: The D-dimer blood test is a method of screening for deep vein thrombosis or pulmonary embolism. A normal D-dimer value is less than 0.50 micrograms per milliliter (mcg/mL) of blood. High levels of D-dimer can occur when a patient has a major blood clot, infection, or liver disease.

Measure: Change in D-dimer

Time: Days 6, 10, 17, and 31

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Primary Outcomes

Description: Number of patients have clinical improvement as described by WHO and Bangladesh local guideline with 7 days.. Body temperature remains normal for at least 3 days (ear temperature is lower than 37.5 °C). Respiratory symptoms are significantly improved. Lung imaging shows obvious improvement in lesions. There is no co-morbidities or complications which require hospitalization. SpO2, >93% without assisted oxygen inhalation.

Measure: Number of Patients With Early Clinical Improvement

Time: 7 days

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Description: Number of the patients required more than 12 days for clinical improvement as defined above.

Measure: Number of Participants With Late Clinical Recovery

Time: 12 days

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Secondary Outcomes

Description: Number of patients deteriorating to next level of severity, like moderate, severe and death. That is from mild illness at presentation with subsequent follow up developed moderate, severe illness or death. Like wise from moderate illness at presentation developed severe illness or death. Mild illness: These patients usually present with symptoms of an upper respiratory tract viral infection, including mild fever, cough (dry), sore throat, nasal congestion, malaise, headache, muscle pain, or malaise. Signs and symptoms of a more serious disease, such as dyspnea, are not present Moderate illness: Respiratory symptoms such as cough and shortness of breath (or tachypnea in children) are present without signs of severe pneumonia. Severe illness:severe dyspnea, respiratory distress, tachypnea (> 30 breaths/min), and hypoxia (SpO2 < 90% on room air).

Measure: Number of Patients Having Clinical Deterioration.

Time: 1 month

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Description: Number of Patients remain positive for RT-PCR of Covid-19 at day 14 after the day of initial positivity.

Measure: Number of Patients Remain Persistently Positive for RT-PCR of Covid-19

Time: 14 days

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Primary Outcomes

Description: Rate of clinical status improvement by categorical ordinal scale of clinical status improvement by 2 or more categories by Day 10 WHO Ordinal Scale for Clinical Improvement (WHO-OSCI), 0 - uninfected (There are no clinical and virological signs of infection), 8 - dead, higher scores mean a worse outcome

Measure: Rate of Clinical Status Improvement

Time: By Visit 3, approximately 10 days

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Description: Time (in days) to improvement in clinical status by WHO categorical ordinal scale of clinical status improvement.

Measure: Time to Clinical Improvement

Time: 28 days

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Secondary Outcomes

Description: Percentage of patients with elimination (clearance) of COVID-19 according to PCR data by day 10 (negative PCR results).

Measure: Rate of Viral Elimination by Day 10

Time: 10 days

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Description: Time (in days) before the end of fever (body temperature < 37.2 ° C for 3 consecutive days without antipyretic medication).

Measure: Time Before the End of Fever

Time: 28 days

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Description: Assessment of lung injury (degree of damage by "empirical" visual scale and % of patients) according to CT data comparing to baseline. The number of patients in whom by the end of therapy there was an improvement in the condition of the lungs (a decrease in the volume of the lesion according to CT)

Measure: Change in the Level of Lung Damage According to CT

Time: Days 15, 21, 28

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Description: Percentage of patients transferred to intensive care unit (% of patients).

Measure: Rate of Transfer to the Intensive Care Unit

Time: 28 Days

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Description: Percentage of cases with non-invasive lung ventilation (% of patients).

Measure: Rate of the Use of Non-invasive Lung Ventilation

Time: 28 Days

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Description: Percentage of cases with mechanical lung ventilation (% of patients)

Measure: Rate of the Use of Mechanical Ventilation

Time: 28 Days

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Description: Incidence of fatal cases (% of patients)

Measure: Mortality

Time: 28 Days

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Primary Outcomes

Description: Total number of days alive and not on a ventilator in the first 28 days after enrollment

Measure: 28-day ventilator-free days (VFDs)

Time: Calculated at study day 28 or death (whichever occurs first)

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Secondary Outcomes

Description: Total number of days alive and not admitted to the ICU in the first 28 days after

Measure: 28-day ICU-free days

Time: Calculated at study day 28 or death (whichever occurs first)

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Description: 28-day, 60-day, and 90-day mortality

Measure: Survival

Time: calculated at 28, 60, and 90 days

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Description: SOFA score excluding neurologic component - based on PaO2/FiO2 (0-4), BP and pressor requirement (0-4), bilirubin level (0-4), platelet count (0-4), and creatinine (0-14) with total composite score 0-20

Measure: non neurologic Sequential Organ Failure (SOFA) scores

Time: At enrollment and study days 1, 2, 3, 4, 7, and 28

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Description: Pulse ox reading

Measure: Oxygen saturation (SpO2)

Time: Measured at enrollment, every 2 hours on enrollment day, then once on day 2, 3, 4, 7 and 28

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Description: On ventilator-imitated breath; measured at enrollment, every 4 hours on enrollment day, then Measured at randomization and daily on study days 1, 2, 3, 4, and 7 or until extubation whichever occurs firstinitiated breath

Measure: Plateau airway pressure

Time: Measured at randomization and daily as close to 0800 as possible on study days 1 2, 3, 4, and 7 or until extubation whichever occurs first

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Description: Measured from ventilator during machine initiated breath

Measure: Mean airway pressure

Time: Measured at randomization and daily as close to 0800 as possible on study days 1 2, 3, 4, and 7 or until extubation whichever occurs first

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Description: Plateau pressure - PEEP (machine initiated breath)

Measure: Airway driving pressure

Time: Measured at randomization and daily as close to 0800 as possible on study days 1 2, 3, 4, and 7 or until extubation whichever occurs first

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Description: Mean airway pressure x 100 x FiO2/SpO2

Measure: Oxygen saturation index

Time: Measured at randomization and daily as close to 0800 as possible on study days 1 2, 3, 4, and 7 or until extubation whichever occurs first

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Description: Measured continuously from iv catheter, urinary catheter, or esophageal probe.

Measure: Core temperature

Time: Measured continuously and recorded at randomization and then every 2 hours through study day 4

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Description: 24 hour urine volume

Measure: Urine output

Time: Daily on study day 1, 2, 3, 4, and 7

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Description: 7 ml of blood collected in serum separator tubes; assay preformed in clinical lab

Measure: comprehensive metabolic panel blood test (includes sodium, potassium, chloride, bicarb, BUN, creatinine, glucose, albumin, total protein, AST, SLT, alkaline phosphatase, and bilirubin)

Time: At randomization and each morning on study days 1, 2, 3, 4, and 7

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Description: 7 ml of blood collected in purple top tube; assay preformed in clinical lab

Measure: Complete blood count with differential count and platelet count

Time: At randomization and each morning on study days 1, 2, 3, 4, and 7

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Description: 12 ml blood draw in two green top tubes

Measure: Plasma biomarkers measured by immunoassay and including IL-1ß, IL-6, IL-8, IL-18, surfactant protein D, soluble ICAM-1, MMP8, and soluble TNF receptor-I)

Time: Collected at randomization and as close to 0800 as possible on study days 1 2, 3, 4, and 7 or until extubation whichever occurs first

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Description: performed in clinical lab

Measure: Serum electrolytes

Time: Performed each evening on study days 1, 2, and 3

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Description: POC blood glucose testing performed at bedside

Measure: Fingerstick blood glucose level

Time: every 6 hour from randomization through study day 3

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Primary Outcomes

Measure: All-cause mortality

Time: Day 14

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Measure: Number and proportion of patients requiring invasive ventilation

Time: Day 14

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Measure: Number and proportion of patients requiring non-invasive ventilation (CPAP and high flow nasal oxygen)

Time: Day 14

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Secondary Outcomes

Measure: All-cause mortality

Time: Day 28

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Measure: Number and proportion of patients requiring invasive ventilation or extracorporeal membrane oxygenation (ECMO)

Time: Day 14, 28

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Measure: Number and proportion of patients requiring non-invasive ventilation including continuous positive airway pressure (CPAP) or high flow nasal oxygen

Time: Day 14, 28

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Measure: Number and proportion of patients requiring renal replacement therapy

Time: Day 14, 28

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Measure: Number and proportion of patients experiencing venous thromboembolism events

Time: Day 14, 28

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Measure: Length of stay

Time: Day 14, 28

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Measure: Number and proportion of serious adverse events and discontinuations

Time: Day 14, 28

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Description: Scale range from 0 (uninfected) to 9 (dead)

Measure: Absolute change in pneumonia severity on the modified WHO COVID-19 Ordinal Scale

Time: Day 14, 28

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