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

Study Overview
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Brief Summary
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The study assessed the efficacy and safety of Brilacidin for the treatment of COVID-19 in hospitalized participants

Detailed Description
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This Phase 2 study was a randomized, blinded, placebo-controlled, parallel group design. The target population treated were patients with moderate to severe COVID-19, active SARS-CoV-2 infection confirmed by positive standard polymerase chain reaction (PCR) test (or equivalent/ other approved diagnostic test) within 4 days prior to starting study treatment, and were hospitalized with respiratory distress but not yet requiring high-level respiratory support (as defined in exclusion criterion #2). See inclusion/exclusion criteria. For each participant, the study was comprised of three parts: Screening/ Baseline visit (Day -1 to 1): Lasting up to 24-48 hours and comprised screening/ baseline assessments. This visit was to confirm that study inclusion and exclusion criteria were met by participants prior to randomization. Treatment period (Day 1-3 or Day 1-5): Randomized subjects received blinded study treatment once daily for 3 or 5 days by IV infusion, in addition to Standard of Care (SoC). Follow-up period (Day 4 or 6 through Day 60): Subjects were assessed daily while hospitalized. Discharged patients were asked to attend study visits at Days 15 and 29. A follow-up visit at Day 60(±10), by telephone call, was performed to confirm patient status. All participants had a series of efficacy and safety assessments performed, including laboratory assays. Additional blood samples and nasopharyngeal (NP) swabs were also obtained (oropharyngeal (OP) swabs were to be collected only in exceptional circumstances). Study participants/subjects were randomized to active or placebo, and the study started with 3 days of study drug administration. After an interim analysis safety review, by an independent Data Monitoring Committee (DMC), dosing was extended to 5 days. Hence, subjects recruited after the interim analysis received 5 days of study treatment. For study analyses, subjects randomized to placebo were pooled since duration of placebo should not impact efficacy or safety outcomes. As the different treatment durations for Brilacidin have potential to impact efficacy and/or safety outcomes, 3-dose and 5-dose active arms were analyzed separately.

Official Title
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A Phase 2, Randomized, Double-blind, Placebo-controlled, Multi-center Study to Evaluate the Efficacy and Safety of Brilacidin in Hospitalized Participants With COVID-19

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Brilacidin
* Drug: Placebo
* Drug: Standard of Care (SoC)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed and dated written Informed Consent Form (ICF) to participate in the clinical study by patient capable of giving consent, or, when the patient is not capable of giving consent, by his or her legal/authorized representative. Male or non-pregnant female adults between 18 and 80 years of age, inclusive, at time of informed consent. SARS-CoV-2 infection confirmed by positive standard polymerase chain reaction (PCR) test (or equivalent/ other approved diagnostic test) ≤ 4 days before randomization. Currently hospitalized and requiring medical care for COVID-19. Moderate OR severe COVID-19, defined by respiratory function at screening, as below: Moderate, meets at least one of the following criteria: Peripheral oxygen saturation SpO2 > 93% on room air; Respiratory rate ≥ 20 to < 30 breaths per minute. Severe, meets at least one of the following criteria: Peripheral oxygen saturation SpO2 ≤ 93% on room air OR arterial oxygen partial pressure (PaO2) / fraction of inspired oxygen (FiO2) < 300mmHg (1mmHg=0.133kPa) [corrective formulation should be used for higher altitude regions (over 1000m)]; Respiratory rate ≥ 30 breaths per minute. Body mass index (BMI) of ≥18 to <40kg/m2 at screening. Agrees to the collection of nasopharyngeal (NP) swabs and venous blood per protocol. In the opinion of the investigator, willing and able to comply with the study protocol assessments, and is committed to the study and the study follow up visits. Exclusion Criteria: Participation in any other clinical trial of an experimental agent treatment. Requiring invasive mechanical ventilation and/or extracorporeal membrane oxygenation (ECMO) at the time of randomization. Has explicitly expressed the wish not to receive intensive care support (Do not resuscitate or Do not intubate order) should this become necessary. In the opinion of the investigator, progression to death is imminent and inevitable within the next 72 hours, irrespective of the provision of treatment, such as rapidly progressive multiorgan failure. Requiring systemic anti-infective therapy for suspected or confirmed active bacterial/fungal/viral systemic infection other than COVID-19. Hypertensive urgency (e.g., SBP >220 mmHg or DBP >120 mmHg) or hypertensive emergency within the last 72 hours, as assessed by the investigator following local guidelines. If has a history of hypertension in the last 3 months, must have been receiving appropriate anti-hypertensive therapy in accordance with local guidelines. Evidence of moderate or severe hepatic impairment (Child-Pugh Class B or C). Estimated GFR (eGFR) <30 mL/min/1.73m2 (based on CKD-EPI formula). Prior to a participant's study entry, known allergies or intolerance to Brilacidin or formulation excipients. Any serious medical or psychiatric condition or test abnormality(ies) that, in the investigator's judgment, puts the participant at significant risk, could confound the study results, or may interfere significantly with the subject's safe participation in and completion of the study. Pregnancy or breast-feeding, or positive urine or serum pregnancy test in a pre-dose assessment. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception throughout the study and for up to 30 days after stopping treatment. Sexually active males with female partners of childbearing potential unwilling to use a condom when engaging in intercourse of reproductive potential throughout the study and for up to 30 days after stopping treatment.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Brilacidin + SoC<br>Brilacidin IV infusion, 3 days and up to 5 days, in addition to Standard of Care | Drug: Brilacidin<br>* Brilacidin IV infusion<br>Drug: Standard of Care (SoC)<br>* SoC therapies for COVID-19<br>|
| Placebo Comparator: Placebo + SoC<br>Placebo IV infusion, 3 days and up to 5 days, in addition to Standard of Care | Drug: Placebo<br>* Placebo IV infusion<br>Drug: Standard of Care (SoC)<br>* SoC therapies for COVID-19<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Sustained Recovery Through 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 | Day 1 through Day 29 | 
| Percentage of Participants With Sustained Recovery Through 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 | Day 5, Day 8, Day 11, Day 15, Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and Percentage of Participants Achieving Recovery Status Scores at Day 29 | 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 | Day 29 | 
| Number and Percentage of Participants Who Die or Develop Respiratory Failure by Day 29 | Composite endpoint, defined as: Death OR Respiratory failure (requires invasive mechanical ventilation) | Day 1 through Day 29 | 
| Subject Clinical Status | Clinical status was measured with an 8-point ordinal scale: Death Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) Hospitalized, on non-invasive ventilation or high flow oxygen devices Hospitalized, requiring low-flow supplemental oxygen Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care (other than for per protocol dosing or assessments, as appropriate) Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities | Day 1, Day 8, Day 15, Day 29 | 
| Number and Percentage of Participants Achieving at Least One Category Improvement in Clinical Status | Clinical status was measured with an 8-point ordinal scale: Death Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) Hospitalized, on non-invasive ventilation or high flow oxygen devices Hospitalized, requiring low-flow supplemental oxygen Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care (other than for per protocol dosing or assessments, as appropriate) Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities | Day 8, Day 15, Day 29 | 
| Number and Percentage of Participants Achieving at Least Two Category Improvement in Clinical Status | Clinical status was measured with an 8-point ordinal scale: Death Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) Hospitalized, on non-invasive ventilation or high flow oxygen devices Hospitalized, requiring low-flow supplemental oxygen Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care (other than for per protocol dosing or assessments, as appropriate) Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities | Day 8, Day 15, Day 29 | 
| Time to at Least One Category Improvement in Clinical Status | Day to achieving improvement of one or more category on 8-point clinical status ordinal scale. Clinical status scale: Death Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) Hospitalized, on non-invasive ventilation or high flow oxygen devices Hospitalized, requiring low-flow supplemental oxygen Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care (other than for per protocol dosing or assessments, as appropriate) Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities | Day 1 through Day 29 | 
| Time to at Least Two Category Improvement in Clinical Status | Day to achieving improvement of two or more categories on 8-point clinical status ordinal scale. Clinical status scale: Death Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) Hospitalized, on non-invasive ventilation or high flow oxygen devices Hospitalized, requiring low-flow supplemental oxygen Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care (other than for per protocol dosing or assessments, as appropriate) Not hospitalized, limitation on activities and/or requiring home oxygen Not hospitalized, no limitations on activities | Day 1 through Day 29 | 
| Time to a National Early Warning Score 2 (NEWS2) of <= 2 Maintained for 24 Hours | 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 | Day 1 through Day 29 | 
| Percentage of Participants Achieving a National Early Warning Score 2 (NEWS2) of <= 2 Maintained for 24 Hours | 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). | Day 5, Day 8, Day 11, Day 15 | 
| Change From Baseline in National Early Warning Score 2 (NEWS2) | 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). | Day 1 through Day 29 | 
| Number and Percentage of Participants With Treatment-Emergent Adverse Events | Treatment-Emergent Adverse Events (TEAEs) have onset dates on or after the study treatment start date | Day 1 through Day 60 | 
| Number and Percentage of Participants With Treatment-Emergent Adverse Events of Special Interest | 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. | Day 1 through Day 60 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SARS-CoV-2, coronavirus, Brilacidin, COVID-19