A Study to Evaluate the Efficacy and Safety of Brilacidin in Hospitalized Participants With COVID-19

Day of recovery is defined as the first day on which the subject satisfies one of the following three categories from the clinical status ordinal scale with response sustained through Day 29: 6\. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care (other than for per protocol dosing or assessments, as appropriate); 7. Not hospitalized, limitation on activities and/or requiring home oxygen; 8. Not hospitalized, no limitations on activities

Time frame: Day 5, Day 8, Day 11, Day 15, Day 29

Population: ITT population. For analyses, placebo subjects were pooled whereas the 3-dose and 5-dose active arms were analyzed separately.~Censoring: Subjects not achieving recovery, lost to follow-up (for this endpoint) prior to achieving recovery, or who died prior to Day 29, were censored at Day 29.

Day of recovery is defined as the first day on which the subject satisfies one of the following three categories from the clinical status ordinal scale with response sustained through Day 29: 6\. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care (other than for per protocol dosing or assessments, as appropriate); 7. Not hospitalized, limitation on activities and/or requiring home oxygen; 8. Not hospitalized, no limitations on activities

Time frame: Day 1 through Day 29

Population: Intent-to-Treat (ITT) population, which includes all subjects who were randomized and receive at least one dose of study drug; subjects analyzed according to the treatment group to which they were randomized.~For analyses, placebo subjects were pooled whereas the 3-dose and 5-dose active arms were analyzed separately.~Censoring: Subjects not achieving recovery, lost to follow-up (for this endpoint) prior to achieving recovery, or who died prior to Day 29, were censored at Day 29.

The National Early Warning Score 2 (NEWS2) assesses a participant's degree of illness as assessed by clinical risk prediction categories based on a set of seven (7) clinical parameters: respiration rate, oxygen saturation, supplemental oxygen, systolic blood pressure, pulse rate, level of consciousness, and temperature. A score of 0 to 3 was allocated to each parameter except supplemental oxygen use (score of 0 \[no\] or 2 \[yes\]) and level of consciousness (score of 0 \[alert, normal health condition\] or 3 \[altered mental state/confusion, worst health condition\]). All parameter scores were summed to get an aggregate NEWS2 assessment. Scoring for NEWS2 ranges from 0 to 20, with higher scores meaning more severity/higher clinical risk: low risk (score 1 to 4); low to medium risk (score of 3 in any individual parameter); medium risk (score 5 to 6); high risk (score 7 to 20).

Time frame: Day 1 through Day 29

Population: ITT population. For analyses, placebo subjects were pooled whereas the 3-dose and 5-dose active arms were analyzed separately.~NEWS2 Censoring: Subjects with baseline score of 3 or higher, who did not reach NEWS2 of \<=2 by Day 29, were censored at last available assessment. Subjects who died were censored on date of death. For those subjects with a baseline score of \<=2, subjects were censored at baseline.

Clinical status was measured with an 8-point ordinal scale: 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 low-flow 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 (other than for per protocol dosing or assessments, as appropriate) 7. Not hospitalized, limitation on activities and/or requiring home oxygen 8. Not hospitalized, no limitations on activities

Time frame: Day 8, Day 15, Day 29

Population: ITT population. For analyses, placebo subjects were pooled whereas the 3-dose and 5-dose active arms were analyzed separately.

Clinical status was measured with an 8-point ordinal scale: 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 low-flow 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 (other than for per protocol dosing or assessments, as appropriate) 7. Not hospitalized, limitation on activities and/or requiring home oxygen 8. Not hospitalized, no limitations on activities

Time frame: Day 8, Day 15, Day 29

Population: ITT population. For analyses, placebo subjects were pooled whereas the 3-dose and 5-dose active arms were analyzed separately.

Recovery status scores are the following three categories from the clinical status ordinal scale: 6\. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care (other than for per protocol dosing or assessments, as appropriate); 7. Not hospitalized, limitation on activities and/or requiring home oxygen; 8. Not hospitalized, no limitations on activities

Time frame: Day 29

Population: ITT population. For analyses, placebo subjects were pooled whereas the 3-dose and 5-dose active arms were analyzed separately.

Composite endpoint, defined as: Death OR Respiratory failure (requires invasive mechanical ventilation)

Time frame: Day 1 through Day 29

Population: ITT population. For analyses, placebo subjects were pooled whereas the 3-dose and 5-dose active arms were analyzed separately.

Treatment-Emergent Adverse Events (TEAEs) have onset dates on or after the study treatment start date

Time frame: Day 1 through Day 60

Population: Safety population, which includes all subjects in the ITT population; subjects in this population analyzed according to treatment received.~Subjects treated with placebo were pooled for analyses since duration of placebo should not impact outcomes. As the different treatment durations for Brilacidin have potential to impact outcomes, 3-dose and 5-dose active arms were analyzed separately.

Treatment-Emergent adverse events have onset dates on or after the study treatment start date. Adverse Events of Special Interest (AESIs) are (i) hypertension Grade 3 or greater, and (ii) paresthesias / dysesthesias Grade 2 or greater, in accordance with CTCAE (version 5.0) criteria.

Time frame: Day 1 through Day 60

Population: Safety population. Subjects treated with placebo were pooled for analyses since duration of placebo should not impact outcomes. As the different treatment durations for Brilacidin have potential to impact outcomes, 3-dose and 5-dose active arms were analyzed separately.

The National Early Warning Score 2 (NEWS2) assesses a participant's degree of illness as assessed by clinical risk prediction categories based on a set of seven (7) clinical parameters: respiration rate, oxygen saturation, supplemental oxygen, systolic blood pressure, pulse rate, level of consciousness, and temperature. A score of 0 to 3 was allocated to each parameter except supplemental oxygen use (score of 0 \[no\] or 2 \[yes\]) and level of consciousness (score of 0 \[alert, normal health condition\] or 3 \[altered mental state/confusion, worst health condition\]). All parameter scores were summed to get an aggregate NEWS2 assessment. Scoring for NEWS2 ranges from 0 to 20, with higher scores meaning more severity/higher clinical risk: low risk (score 1 to 4); low to medium risk (score of 3 in any individual parameter); medium risk (score 5 to 6); high risk (score 7 to 20).

Time frame: Day 5, Day 8, Day 11, Day 15

Population: ITT population. For analyses, placebo subjects were pooled whereas the 3-dose and 5-dose active arms were analyzed separately.~NEWS2 Censoring: Subjects with baseline score of 3 or higher, who did not reach NEWS2 of \<=2 by Day 29, were censored at last available assessment. Subjects who died were censored on date of death. For those subjects with a baseline score of \<=2, subjects were censored at baseline.

Clinical status was measured with an 8-point ordinal scale: 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 low-flow 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 (other than for per protocol dosing or assessments, as appropriate) 7. Not hospitalized, limitation on activities and/or requiring home oxygen 8. Not hospitalized, no limitations on activities

Time frame: Day 1, Day 8, Day 15, Day 29

Population: ITT population. No. of participants at each timepoint is the sum across all 8 categories of the scale.~For analyses, placebo subjects were pooled whereas the 3-dose and 5-dose active arms were analyzed separately.

Time (in days) from randomization to achieve a NEWS2 score lower or equal to 2 being maintained for at least one 24-hour period. NEWS2 was assessed twice daily while hospitalized; if one of the components of the NEWS2 was missing at a particular time point, the NEWS2 was not calculated. The National Early Warning Score 2 (NEWS2) assesses a participant's degree of illness as assessed by clinical risk prediction categories based on a set of 7 clinical parameters: respiration rate, oxygen saturation, supplemental oxygen, systolic blood pressure, pulse rate, level of consciousness, and temperature. A score of 0 to 3 was allocated to each parameter except supplemental oxygen use (score of 0 \[no\] or 2 \[yes\]) and level of consciousness (score of 0 \[alert, normal health condition\] or 3 \[altered mental state/confusion, worst health condition\]). All parameter scores were summed to get an aggregate NEWS2. NEWS2 ranges from 0 to 20, with higher scores meaning more severity/higher clinical risk

Time frame: Day 1 through Day 29

Population: ITT population. For analyses, placebo subjects were pooled whereas the 3-dose and 5-dose active arms were analyzed separately.~NEWS2 Censoring: Subjects with baseline score of 3 or higher, who did not reach NEWS2 of \<=2 by Day 29, were censored at last available assessment. Subjects who died were censored on date of death. For those subjects with a baseline score of \<=2, subjects were censored at baseline.

Day to achieving improvement of one or more category on 8-point clinical status ordinal scale. Clinical status scale: 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 low-flow 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 (other than for per protocol dosing or assessments, as appropriate) 7. Not hospitalized, limitation on activities and/or requiring home oxygen 8. Not hospitalized, no limitations on activities

Time frame: Day 1 through Day 29

Population: ITT population. For analyses, placebo subjects were pooled whereas the 3-dose and 5-dose active arms were analyzed separately.

Day to achieving improvement of two or more categories on 8-point clinical status ordinal scale. Clinical status scale: 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 low-flow 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 (other than for per protocol dosing or assessments, as appropriate) 7. Not hospitalized, limitation on activities and/or requiring home oxygen 8. Not hospitalized, no limitations on activities

Time frame: Day 1 through Day 29

Population: ITT population. For analyses, placebo subjects were pooled whereas the 3-dose and 5-dose active arms were analyzed separately.

Incidence of death during the 28 days after start of study treatment

Time frame: Day 1 through Day 29

Population: ITT population. For analyses, placebo subjects were pooled whereas the 3-dose and 5-dose active arms were analyzed separately.

Day of recovery is defined as the first day on which the subject satisfies one of the following three categories from the clinical status ordinal scale with response sustained through Day 29: 6\. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care (other than for per protocol dosing or assessments, as appropriate); 7. Not hospitalized, limitation on activities and/or requiring home oxygen; 8. Not hospitalized, no limitations on activities

Time frame: Day 1 through Day 29

Population: Pooled Placebo vs Brilacidin 5-dose arm analyzed, for Post-hoc Per Protocol (PP) CRP sub-group.~Post-hoc PP population is a subset of ITT population with the following differences:~* Excludes subjects with viral load \<10 copies/mL (i.e., below lower limit of quantitation) at baseline~* Excludes subjects with \<3 days of study drug exposure~* For 2 subjects who received the alternate treatment from which they were randomized, are switched to be analyzed according to actual treatment received

Day of recovery is defined as the first day on which the subject satisfies one of the following three categories from the clinical status ordinal scale with response sustained through Day 29: 6\. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care (other than for per protocol dosing or assessments, as appropriate); 7. Not hospitalized, limitation on activities and/or requiring home oxygen; 8. Not hospitalized, no limitations on activities

Time frame: Day 1 through Day 29

Population: Pooled Placebo vs Brilacidin 5-dose arm analyzed, for Post-hoc Per Protocol (PP) IL-6 sub-group.~Post-hoc PP population is a subset of ITT population with the following differences:~* Excludes subjects with viral load \<10 copies/mL (i.e., below lower limit of quantitation) at baseline~* Excludes subjects with \<3 days of study drug exposure~* For 2 subjects who received the alternate treatment from which they were randomized, are switched to be analyzed according to actual treatment received

Day of recovery is defined as the first day on which the subject satisfies one of the following three categories from the clinical status ordinal scale with response sustained through Day 29: 6\. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care (other than for per protocol dosing or assessments, as appropriate); 7. Not hospitalized, limitation on activities and/or requiring home oxygen; 8. Not hospitalized, no limitations on activities

Time frame: Day 1 through Day 29

Population: Pooled Placebo vs Brilacidin 5-dose arm analyzed, for Post-hoc Per Protocol (PP) SARS-CoV-2 viral load sub-group.~Post-hoc PP pop is a subset of ITT with the following differences:~* Excludes subjects with viral load \<10 copies/mL (i.e., below lower limit of quantitation) at baseline~* Excludes subjects with \<3 days of study drug exposure~* For 2 subjects who received the alternate treatment from which they were randomized, are switched to be analyzed according to actual treatment received

Day of recovery is defined as the first day on which the subject satisfies one of the following three categories from the clinical status ordinal scale with response sustained through Day 29: 6\. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care (other than for per protocol dosing or assessments, as appropriate); 7. Not hospitalized, limitation on activities and/or requiring home oxygen; 8. Not hospitalized, no limitations on activities

Time frame: Day 1 through Day 29

Population: Pooled Placebo vs Brilacidin 5-dose arm analysis shown, for the Post-hoc Per Protocol (PP) sub-group starting study treatment \<7 days from onset of COVID-19 symptoms.~Post-hoc PP pop is a subset of ITT with the following differences:~* Excludes subjects with viral load \<10 copies/mL at baseline~* Excludes subjects with \<3 days of study drug exposure~* For 2 subjects who received the alternate treatment from which they were randomized, are switched to be analyzed according to actual treatment