Adaptive COVID-19 Treatment Trial 3 (ACTT-3)

Study Overview
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Brief Summary
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ACTT-3 will evaluate the combination of interferon beta-1a and remdesivir compared to remdesivir alone. Subjects will be assessed daily while hospitalized. If the subjects are discharged from the hospital, they will have a study visit at Days 15, 22, and 29. For discharged subjects, it is preferred that the Day 15 and 29 visits are in person to obtain safety laboratory tests and oropharyngeal (OP) swab and blood (serum only) samples for secondary research as well as clinical outcome data. However, infection control or other restrictions may limit the ability of the subject to return to the clinic. In this case, these visits may be conducted by phone, and only clinical data will be obtained. The Day 22 visit does not have laboratory tests or collection of samples and is conducted by phone. The primary outcome is time to recovery by Day 29.

Detailed Description
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This study is an adaptive randomized double-blind placebo-controlled trial to evaluate the safety and efficacy of novel therapeutic agents in hospitalized adults diagnosed with COVID-19. The study is a multicenter trial that will be conducted in up to approximately 100 sites globally. The study will compare different investigational therapeutic agents to a control arm. New arms can be introduced according to scientific and public health needs. There will be interim monitoring to allow early stopping for futility, efficacy, or safety. If one therapy proves to be efficacious, then this treatment may become the control arm for comparison(s) with new experimental treatment(s). Any such change would be accompanied by an updated sample size. This adaptive platform is used to rapidly evaluate different therapeutics in a population of those hospitalized with moderate to severe COVID-19. The platform will provide a common framework sharing a similar population, design, endpoints, and safety oversight. New stages with new therapeutics can be introduced. One independent Data and Safety Monitoring Board (DSMB) will actively monitor interim data in all stages to make recommendations about early study closure or changes to study arms. ACTT-3 will evaluate the combination of interferon beta-1a and remdesivir compared to remdesivir alone. Subjects will be assessed daily while hospitalized. If the subjects are discharged from the hospital, they will have a study visit at Days 15, 22, and 29. For discharged subjects, it is preferred that the Day 15 and 29 visits are in person to obtain safety laboratory tests and oropharyngeal (OP) swab and blood (serum only) samples for secondary research as well as clinical outcome data. However, infection control or other restrictions may limit the ability of the subject to return to the clinic. In this case, these visits may be conducted by phone, and only clinical data will be obtained. The Day 22 visit does not have laboratory tests or collection of samples and is conducted by phone. All subjects will undergo a series of efficacy, safety, and laboratory assessments. Safety laboratory tests and blood (serum and plasma) research samples and oropharyngeal (OP) swabs will be obtained on Days 1 (prior to infusion) and Days 3, 5, 8, and 11 (while hospitalized). OP swabs and blood (serum only) plus safety laboratory tests will be collected on Day 15 and 29 (if the subject attends an in-person visit or are still hospitalized). The primary outcome is time to recovery by Day 29 for patients with baseline ordinal score 4, 5 and 6. A key secondary outcome evaluates treatment-related improvements in the 8-point ordinal scale at Day 15. Each stage may prioritize different secondary endpoints for the purpose of multiple comparison analyses. Contacts: 20-0006 Central Contact Telephone: 1 (301) 7617948 Email: DMIDClinicalTrials@niaid.nih.gov

Official Title
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A Multicenter, Adaptive, Randomized Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for the Treatment of COVID-19 in Hospitalized Adults (ACTT-3)

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Interferon beta-1a
* Other: Placebo
* Drug: Remdesivir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Admitted to a hospital with symptoms suggestive of COVID-19. Subject (or legally authorized representative) provides informed consent prior to initiation of any study procedures. Subject (or legally authorized representative) understands and agrees to comply with planned study procedures. Male or non-pregnant female adult > / = 18 years of age at time of enrollment. Has laboratory-confirmed SARS-CoV-2 infection as determined by polymerase chain reaction (PCR) or other commercial or public health assay in any respiratory specimen or saliva, as documented by either of the following: PCR or other assay positive in sample collected < 72 hours prior to randomization; OR PCR or other assay positive in sample collected >/= 72 hours but < 7 days prior to randomization AND progressive disease suggestive of ongoing SARS-CoV-2 infection. Note: if written documentation of the positive test result is not available at enrollment (e.g., report from other institution), the subject may be enrolled but the PCR should be repeated at the time of enrollment. Illness of any duration, and at least one of the following: Radiographic infiltrates by imaging (chest x-ray, CT scan, etc.), OR SpO2 < / = 94% on room air, OR Requiring supplemental oxygen. Women of childbearing potential must agree to either abstinence or use at least one primary form of contraception not including hormonal contraception from the time of screening through Day 29. Agrees to not participate in another clinical trial (both pharmacologic and other types of interventions) for the treatment of COVID-19 through Day 29. Exclusion Criteria: Anticipated discharge from the hospital or transfer to another hospital which is not a study site within 72 hours. Subject meets criteria for ordinal scale category 6 or 7 at the time of screening. Subject has a positive test for influenza virus during this current hospital admission. Subjects with an estimated glomerular filtration rate (eGFR) < 30 mL/min are excluded unless in the opinion of the PI, the potential benefit of receiving remdesivir outweighs the potential risk of study participation. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 times the upper limits of normal. Total white cell blood cell count (WBC) <1500 cells/microliter. Platelet count <50,000/microliter. History of chronic liver disease (e.g., jaundice, ascites, hepatic encephalopathy, history of bleeding esophageal or gastric varices). No laboratory testing is needed. Pregnancy or breast feeding (lactating women who agree to discard breast milk from Day 1 until three weeks after the last study product is given are not excluded). Allergy to any study medication including history of hypersensitivity to natural or recombinant interferon beta or human albumin. Patient has a chronic or acute medical condition or is taking a medication that cannot be discontinued at enrollment, that in the judgement of the PI, places them at unacceptable risk for a poor clinical outcome if they were to participate in the study. Received three or more doses of remdesivir, including the loading dose, outside of the study for COVID-19. Received convalescent plasma or intravenous immunoglobulin [IVIg] for the treatment of COVID-19. Received any interferon product within two weeks of screening, either for the treatment of COVID-19 or for a chronic medical condition (e.g., multiple sclerosis, HCV infection). Received any of the following in the two weeks prior to screening as treatment of COVID-19: Small molecule tyrosine kinase inhibitors (e.g. baricitinib, imatinib, gefitinib, acalabrutinib, etc.); Monoclonal antibodies targeting cytokines (e.g., TNF inhibitors, anti-interleukin-1 [IL-1], anti-IL-6 [tocilizumab or sarilumab], etc.); Monoclonal antibodies targeting T-cells or B-cells as treatment for COVID-19. Prior enrollment in ACTT-3.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Remdesivir plus Interferon Beta-1a<br>200 mg of Remdesivir administered intravenously on Day 1, followed by a 100 mg once-daily maintenance dose of Remdesivir while hospitalized for up to a 10-day total course and 44 mcg of interferon beta-1a administered by a 0.5 mL subcutaneous injection on Days 1, 3, 5, and 7 while hospitalized for a total of 4 doses. | Drug: Interferon beta-1a<br>* Rebif (R) is a purified 166 amino acid human interferon beta glycoprotein with an amino acid sequence identical to natural fibroblast derived human interferon beta. Each 0.5 mL prefilled syringe contains 44 mcg of interferon beta-1a, 4 mg human albumin, USP; 27.3 mg mannitol, USP; 0.4 mg sodium acetate; and water for injection, USP.<br>Drug: Remdesivir<br>* Drug Remdesivir is a single diastereomer monophosphoramidate prodrug designed for the intracellular delivery of a modified adenine nucleoside analog GS-441524. In addition to the active ingredient, the lyophilized formulation of Remdesivir contains the following inactive ingredients: water for injection, sulfobutylether beta-cyclodextrin sodium (SBECD), and hydrochloric acid and/or sodium hydroxide.<br>|
| Placebo Comparator: Remdesivir plus Placebo<br>200 mg of Remdesivir administered intravenously on Day 1, followed by a 100 mg once-daily maintenance dose of Remdesivir while hospitalized for up to a 10-day total course and a 0.5 mL placebo injection administered subcutaneously on Days 1, 3, 5, and 7 while hospitalized for a total of 4 doses. | Other: Placebo<br>* The interferon beta-1a placebo contains either 0.5 mL 0.9% normal saline or 0.5 mL sterile water for injection.<br>Drug: Remdesivir<br>* Drug Remdesivir is a single diastereomer monophosphoramidate prodrug designed for the intracellular delivery of a modified adenine nucleoside analog GS-441524. In addition to the active ingredient, the lyophilized formulation of Remdesivir contains the following inactive ingredients: water for injection, sulfobutylether beta-cyclodextrin sodium (SBECD), and hydrochloric acid and/or sodium hydroxide.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Recovery for Participants With Baseline Ordinal Score 4, 5 and 6 | Day of recovery is defined as the first day on which the subject satisfies one of the following three categories from the ordinal scale: 1) Not hospitalized, no limitations on activities; 2) Not hospitalized, but new or increased limitation on activities and/or new or increased requirement for home oxygen; 3) Hospitalized, not requiring supplemental oxygen and no longer requires ongoing medical care. | Day 1 through Day 29 | 
| Time to Recovery for Participants With Baseline Ordinal Score 4, 5 and 6 by Race | Day of recovery is defined as the first day on which the subject satisfies one of the following three categories from the ordinal scale: 1) Not hospitalized, no limitations on activities; 2) Not hospitalized, but new or increased limitation on activities and/or new or increased requirement for home oxygen; 3) Hospitalized, not requiring supplemental oxygen and no longer requires ongoing medical care. | Day 1 through Day 29 | 
| Time to Recovery for Participants With Baseline Ordinal Score 4, 5 and 6 by Ethnicity | Day of recovery is defined as the first day on which the subject satisfies one of the following three categories from the ordinal scale: 1) Not hospitalized, no limitations on activities; 2) Not hospitalized, but new or increased limitation on activities and/or new or increased requirement for home oxygen; 3) Hospitalized, not requiring supplemental oxygen and no longer requires ongoing medical care. | Day 1 through Day 29 | 
| Time to Recovery for Participants With Baseline Ordinal Score 4, 5 and 6 by Sex | Day of recovery is defined as the first day on which the subject satisfies one of the following three categories from the ordinal scale: 1) Not hospitalized, no limitations on activities; 2) Not hospitalized, but new or increased limitation on activities and/or new or increased requirement for home oxygen; 3) Hospitalized, not requiring supplemental oxygen and no longer requires ongoing medical care. | Day 1 through Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Alanine Aminotransferase (ALT) | Blood to evaluate ALT was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge. The measure was assessed by baseline ordinal scale category (categories 4 and 5 versus category 6). | Days 1, 3, 5, 8, 11, 15 and 29 | 
| Change From Baseline in Aspartate Aminotransferase (AST) | Blood to evaluate AST was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge. The measure was assessed by baseline ordinal scale category (categories 4 and 5 versus category 6). | Days 1, 3, 5, 8, 11, 15 and 29 | 
| Change From Baseline in C-reactive Protein (CRP) | Blood to evaluate CRP was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge. The measure was assessed by baseline ordinal scale category (categories 4 and 5 versus category 6). | Days 1, 3, 5, 8, 11, 15 and 29 | 
| Change From Baseline in Creatinine | Blood to evaluate serum creatinine was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge. The measure was assessed by baseline ordinal scale category (categories 4 and 5 versus category 6). | Days 1, 3, 5, 8, 11, 15 and 29 | 
| Change From Baseline in D-dimer Concentration | Blood to evaluate d-dimer concentration was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge. | Days 1, 3, 5, 8, 11, 15, and 29 | 
| Change From Baseline in Hemoglobin | Blood to evaluate hemoglobin was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge. The outcome was assessed by baseline ordinal scale category (categories 4 and 5 versus category 6). | Days 1, 3, 5, 8, 11, 15 and 29 | 
| Change From Baseline in Prothrombin International Normalized Ratio (INR) | Blood to evaluate INR was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge. The outcome was assessed by baseline ordinal scale category (categories 4 and 5 versus category 6). | Days 1, 3, 5, 8, 11, 15 and 29 | 
| Change From Baseline in Platelets | Blood to evaluate platelets was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge. The outcome was assessed overall and by baseline ordinal scale category (categories 4 and 5 versus category 6). | Days 1, 3, 5, 8, 11, 15 and 29 | 
| Change From Baseline in Total Bilirubin | Blood to evaluate total bilirubin was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge. The outcome was assessed by baseline ordinal scale category (categories 4 and 5 versus category 6). | Days 1, 3, 5, 8, 11, 15 and 29 | 
| Change From Baseline in White Blood Cell Count (WBC) | Blood to evaluate WBC was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge. The outcome was assessed by baseline ordinal scale category (categories 4 and 5 versus category 6). | Days 1, 3, 5, 8, 11, 15 and 29 | 
| Change From Baseline in Neutrophils | Blood to evaluate neutrophils was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge. The outcome was assessed by baseline ordinal scale category (categories 4 and 5 versus category 6). | Days 1, 3, 5, 8, 11, 15 and 29 | 
| Change From Baseline in Lymphoctyes | Blood to evaluate lymphocytes was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge. The outcome was assessed by baseline ordinal scale category (categories 4 and 5 versus category 6). | Days 1, 3, 5, 8, 11, 15 and 29 | 
| Change From Baseline in Monocytes | Blood to evaluate monocytes was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge. The outcome was assessed by baseline ordinal scale category (categories 4 and 5 versus category 6). | Days 1, 3, 5, 8, 11, 15 and 29 | 
| Change From Baseline in Basophils | Blood to evaluate basophils was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge. The outcome was assessed by baseline ordinal scale category (categories 4 and 5 versus category 6). | Days 1, 3, 5, 8, 11, 15 and 29 | 
| Change From Baseline in Eosinophils | Blood to evaluate eosinophils was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge. The outcome was assessed by baseline ordinal scale category (categories 4 and 5 versus category 6). | Days 1, 3, 5, 8, 11, 15 and 29 | 
| Change in National Early Warning Score (NEWS) From Baseline | The NEW score has demonstrated an ability to discriminate patients at risk of poor outcomes. This score is based on 7 clinical parameters (respiration rate, oxygen saturation, any supplemental oxygen, temperature, systolic blood pressure, heart rate, level of consciousness). The NEW Score is being used as an efficacy measure. The minimum score is 0, representing the better outcome, and the maximum value is 19, representing the worse outcome. | Days 1, 3, 5, 8, 11, 15, 22, and 29 | 
| Percentage of Participants Reporting Grade 3 and 4 Clinical and/or Laboratory Adverse Events (AEs) | Grade 3 AEs are defined as events that interrupt usual activities of daily living, or significantly affects clinical status, or may require intensive therapeutic intervention. Severe events are usually incapacitating. Grade 4 AEs are defined as events that are potentially life threatening. | Day 1 through Day 29 | 
| Percentage of Participants Reporting Serious Adverse Events (SAEs) | An SAE is defined as an AE or suspected adverse reaction is considered serious if, in the view of either the investigator or the sponsor, it results in death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. | Day 1 through Day 29 | 
| Duration of Hospitalization | Duration of hospitalization was determined two ways. The first includes imputations for participants who died. The second method is restricted to participants who did not die. | Day 1 through Day 29 | 
| Duration of Invasive Mechanical Ventilation | Duration of invasive ventilation was measured in days among participants who required invasive ventilation, determined two ways. The first includes imputations for participants who died. The second method is restricted to participants who did not die | Day 1 through Day 29 | 
| Duration of New Non-invasive Ventilation or High Flow Oxygen Use | Duration of new non-invasive ventilation or high flow oxygen use was measured in days among participants who were not on non-invasive ventilation or high-flow oxygen use at baseline, determined two ways. The first includes imputations for participants who died. The second method is restricted to participants who did not die | Day 1 through Day 29 | 
| Duration of New Oxygen Use | Duration of new oxygen use was measured in days among participants who were not on oxygen at baseline, determined two ways. The first includes imputations for participants who died. The second method is restricted to participants who did not die | Day 1 through Day 29 | 
| Duration of New Ventilator or Extracorporeal Membrane Oxygenation (ECMO) Use | Duration of new ventilator or ECMO use was measured in days among participants who were not on a ventilator or ECMO at baseline, determined two ways. The first includes imputations for participants who died. The second method is restricted to participants who did not die. | Day 1 through Day 29 | 
| Duration of Non Invasive Ventilation or High Flow Oxygen Use | Duration of non invasive ventilation or high flow oxygen use was measured in days, determined two ways. The first includes imputations for participants who died. The second method is restricted to participants who did not die. | Day 1 through Day 29 | 
| Duration of Oxygen Use | Duration of oxygen use was measured in days among participants who were on oxygen in based, calculated in two ways. The first includes imputations for participants who died. The second method is restricted to participants who did not die. | Day 1 through Day 29 | 
| Number of Participants With Discontinuation or Temporary Suspension of Study Product Administration | Discontinuation or temporary suspension of study product administration, including participants who died or were discharged, was evaluated by baseline ordinal scale category (categories 4 and 5 versus category 6). | Day 1 through Day 10 | 
| Proportion of Participants With New Non-invasive Ventilation or High Flow Oxygen Use | Proportion of participants with new non-invasive ventilation or high flow oxygen use was assessed as for participants in Ordinal Score 4 and 5. | Day 1 through Day 29 | 
| Proportion of Participants With New Oxygen Use | Incidence of new oxygen use was assessed as for participants in Ordinal Score 4 and 5 who were not on oxygen at baseline. | Day 1 through Day 29 | 
| Proportion of Participants With New Ventilator or Extracorporeal Membrane Oxygenation (ECMO) Use | Incidence of new ventilator or extracorporeal membrane oxygenation (ECMO) use was assessed among participants not on ventilator or extracorporeal membrane oxygenation (ECMO) use at baseline. | Day 1 through Day 29 | 
| Mean Change From Baseline in the Ordinal Scale | 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) Not hospitalized, no limitations on activities; 2) Not hospitalized, but new or increased limitation on activities and/or new or increased requirement for home oxygen; 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 5) Hospitalized, requiring supplemental oxygen; 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 8) Death. A positive change indicates a worsening and a negative change is an improvement. | Day 1, 3, 5, 8, 11, 15, 22, and 29 | 
| Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 15 for Participants With Baseline Ordinal Score 4 and 5 | The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities. Data was imputed using last observation carried forward or worst possible score based on hospitalization status (2 if not hospitalized, 7 if hospitalized) when there was a change in hospitalization status since last score. Deaths were imputed as an 8. | Day 15 | 
| Percentage of Participants Reporting Each Severity Rating on an 8 Point Ordinal Scale at Day 1 | The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities. | Day 1 | 
| Percentage of Participants Reporting Each Severity Rating on an 8 Point Ordinal Scale at Day 3 | The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities. | Day 3 | 
| Percentage of Participants Reporting Each Severity Rating on an 8 Point Ordinal Scale at Day 5 | The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities. | Day 5 | 
| Percentage of Participants Reporting Each Severity Rating on an 8 Point Ordinal Scale at Day 8 | The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities. | Day 8 | 
| Percentage of Participants Reporting Each Severity Rating on an 8 Point Ordinal Scale at Day 11 | The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities. | Day 11 | 
| Percentage of Participants Reporting Each Severity Rating on an 8 Point Ordinal Scale at Day 15 | The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities. | Day 15 | 
| Percentage of Participants Reporting Each Severity Rating on an 8 Point Ordinal Scale at Day 22 | The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities. | Day 22 | 
| Percentage of Participants Reporting Each Severity Rating on an 8 Point Ordinal Scale at Day 29 | The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities. | Day 29 | 
| 14-day Participant Mortality | The mortality rate was determined as the proportion of participants who died by study Day 15. The proportions reported are Kaplan-Meier estimates | Day 1 through Day 15 | 
| 28-day Participant Mortality | The mortality rate was determined as the proportion of participants who died by study Day 29. The proportions reported are Kaplan-Meier estimates. | Day 1 through Day 29 | 
| Time to an Improvement of One Category Using an Ordinal Scale | The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities. Time to improvement by at least one category was determined for each participant. | Day 1 through Day 29 | 
| Time to an Improvement of Two Categories Using an Ordinal Scale | 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. Time to improvement by at least two categories was determined for each participant. | Day 1 through Day 29 | 
| Time to Discharge or to a National Early Warning Score (NEWS) of </= 2 and Maintained for 24 Hours, Whichever Occurs First | The NEW score has demonstrated an ability to discriminate patients at risk of poor outcomes. This score is based on 7 clinical parameters (respiration rate, oxygen saturation, any supplemental oxygen, temperature, systolic blood pressure, heart rate, level of consciousness). The NEW Score is being used as an efficacy measure. The minimum score is 0, representing the better outcome, and the maximum value is 19, representing the worse outcome. The time to discharge or a NEWS of less than or equal to 2 was determined for each participant. | Day 1 through Day 29 | 
| Time to Recovery for Patients With a Baseline Ordinal Score of 4 and 5 | Day of recovery is defined as the first day on which the subject satisfies one of the following three categories from the ordinal scale: 1) Not hospitalized, no limitations on activities; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 3) Hospitalized, not requiring supplemental oxygen and no longer requires ongoing medical care. | Day 1 through Day 29 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adaptive, COVID-19, Efficacy, Multicenter, novel coronavirus, Safety