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

Phase 2

Completed

Conditions: COVID-19

Interventions: Drug: Placebo
Drug: Brilacidin
Drug: Standard of Care (SoC)

Registration Number: NCT04784897

Lead Sponsor: Innovation Pharmaceuticals, Inc.

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

Detailed Description: 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:

1. 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.

2. 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).

3. 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 120

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Brilacidin + SoC	Standard of Care (SoC)	Brilacidin IV infusion, 3 days and up to 5 days, in addition to Standard of Care
Placebo + SoC	Placebo	Placebo IV infusion, 3 days and up to 5 days, in addition to Standard of Care
Placebo + SoC	Standard of Care (SoC)	Placebo IV infusion, 3 days and up to 5 days, in addition to Standard of Care
Brilacidin + SoC	Brilacidin	Brilacidin IV infusion, 3 days and up to 5 days, in addition to Standard of Care

Primary Outcome Measures

Name	Time	Method
Time to Sustained Recovery Through Day 29	Day 1 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
Percentage of Participants With Sustained Recovery Through Day 29	Day 5, Day 8, Day 11, Day 15, 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

Secondary Outcome Measures

Name	Time	Method
Time to at Least Two Category Improvement in Clinical Status	Day 1 through Day 29	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
Subject Clinical Status	Day 1, Day 8, Day 15, Day 29	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
Number and Percentage of Participants Achieving Recovery Status Scores at Day 29	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
Number and Percentage of Participants Who Die or Develop Respiratory Failure by Day 29	Day 1 through Day 29	Composite endpoint, defined as: Death OR Respiratory failure (requires invasive mechanical ventilation)
Number and Percentage of Participants Achieving at Least One Category Improvement in Clinical Status	Day 8, Day 15, Day 29	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
Number and Percentage of Participants Achieving at Least Two Category Improvement in Clinical Status	Day 8, Day 15, Day 29	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
Number and Percentage of Participants With Treatment-Emergent Adverse Events	Day 1 through Day 60	Treatment-Emergent Adverse Events (TEAEs) have onset dates on or after the study treatment start date
Number and Percentage of Participants With Treatment-Emergent Adverse Events of Special Interest	Day 1 through Day 60	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 to at Least One Category Improvement in Clinical Status	Day 1 through Day 29	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 to a National Early Warning Score 2 (NEWS2) of <= 2 Maintained for 24 Hours	Day 1 through Day 29	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
Percentage of Participants Achieving a National Early Warning Score 2 (NEWS2) of <= 2 Maintained for 24 Hours	Day 5, Day 8, Day 11, Day 15	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).
Change From Baseline in National Early Warning Score 2 (NEWS2)	Day 1 through 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).